Congenital and acquired immunodeficiency and their manifestations in the maxillofacial area. Immunopathology and regeneration of organs and tissues MFR. Opportunities and prospects for immunotherapy in dentistry.
The precise symptoms of a primary immunodeficiency depend on the type of defect. Generally, the symptoms and signs that lead to the diagnosis of an immunodeficiency include recurrent or persistent infections or developmental delay as a result of infection. Particular organ problems (e.g. diseases involving the skin, heart, facial development and skeletal system) may be present in certain conditions. Others predispose to autoimmune disease, where the immune system attacks the body’s own tissues, or tumours (sometimes specific forms of cancer, such as lymphoma). The nature of the infections, as well as the additional features, may provide clues as to the exact nature of the immune defect.
Immunodeficiency is disturbance of the structure and function of any component of the integral immune system, loss of the ability to resist any infections by the organism and to restore the disturbances of its organs. Besides, in immunodeficiency the process of renovation of the organism is slowed down or generally stops.
Immunodeficiency is a congenital or acquired defect of the immune system, which is manifested by sharp reduction in the quantity of separate populations of immunocompetent cells or by disturbance of the synthesis of immunoglobulins (agamaglobulinemia).
All immunodeficient states are divided into two large groups:
– congenital (hereditary caused) immunodeficiency and
– acquired immunodeficiency
The hereditary caused immunodeficient state (primary immunological deficiency) is based on the genetically determined defects of the cells of the immune system.
Classification of the forms of primary specific immunological deficiency (WHO, 1980):
1. Severe combined immunodeficiencies:
a. Reticular disgenesia.
b. “Swiss type”
c. deficiency of adenaseinedeaminase (
d. severe combined immunodeficiencies with the B-lymphocytes.
2. Hypoplasias of the thymus (Di George syndrome).
3. Deficiency of purinenucleotidephosphorylase (PNP).
4. Immunodeficiency with ataxia -teleangioectasia (syndrome of Louis- Bar).
5. Immunodeficiency with thymoma.
6. X – linked agammaglobulinaemia (Bruton disease).
7. Deficiency of transcobalamine II.
8. Selective deficiency of IgA.
9. Isolated deficiency of other classes of Ig.
10. Deficiency of the secretory component of molecule IgA.
11. Deficiency of Ig with increased level of IgM.
12. Deficiency of Ig with production of IgM and without B-gama and B-alpha cells.
13. Transitory hypogammaglobulinaemia of infancy.
14. Deficiency of antibodies with the normal or increased level of immunoglobulines in blood.
15. Deficiency of kappa – chains.
16. Syndrome of Wiskott- Aldrich.
17. Variable forms of immunological deficiency (general and nonclassified):
a. Predominant deficiency of Ig.
b. predominant deficiency of T-cells.
Figure. Sites of developmental dysfunction in humoral and cell-mediated immunity immunodeficiencies (Klaus D. Elgert, Immunology, 1996).
Primary immunodeficient states in the countries of the CIS are divided into 5 groups:
1. Deficiency of the humoral B- cellular component of immunity;
2. Deficiency of T- cellular component;
3. Deficiency of the phagocyte functions: polinuclears and monocyte- macrophages;
4. Deficiency of the complement factors;
5. Combined immunodeficient states, which include deficiency of several components of the immunological reactivity and stem cells.
There is noted dependence of the nature of infectious complications on the peculiarities of the affection of the immune system. Thus, local suppurative microbial- inflammatory processes in the respiratory tract, the skin, bones, joints, caused by the pyogenic flora (staphylococcus, streptococcus, pneumococcus), are more frequently encountered in the hereditary defects of the humoral system of immunity, and predisposition to the viral, parasitic and fungal diseases and affections by mycobacteria of tuberculosis – in deficiency of the cellular immunity (D. V. Stephanie, Yu. E. Veltischev, 1988). The decreased resistance regarding Neisseriae is frequently recorded in the defects of the complement system.
There are many immunodeficiencies caused by different causes. At present more than 70 congenital (primary) immunnodeficiencies are identified. Usually these are severe diseases in children, caused by defects of any component of the immune system. Defects may affect different immunocompetent cells, including T- and B-lymphocytes and macrophages. The syndrome of Di George, which is accompanied by the underdevelopment of the thymus, may be an example of the predominant affection of the T- cellular component of immunity. The defects of T-cells increase sensitivity of the organism to various microorganisms (from yeast(s) to the viruses), which are harmless in the normal conditions.
Impairments in the macrophages also lead to severe pathologies, for example, to chronic granulematosis. There are pathologies associated with the production of antibodies by B-lymphocytes. In this case the organism susceptibility to the repeated infections, caused by pyogenic bacteria, grows. The congenital immunodeficiencies are encountered sufficiently rarely (on the average 1 case per 25,000-100,000 people).
The basic kinds of B – cellular deficiency include X-linked agammaglobulinaemia, deficiency of IgA, deficiency of the sub-classes of IgG, immunodeficiency with the hyperproduction of IgM, common variable immunodeficiency, transitory hypogammaglobulinaemia of childhood.
The basic kinds of T- cellular deficiency include severe combined immunodeficiency, deficiency of adenosinedeaminase, deficiency of purinenucleoside phosphorylase, deficiency of the MHC- antigens of class II, the syndrome of Di George, hereditary ataxia-teleangiectasia, Wiskott- Aldrich syndrome. Since functioning of the B-lymphocytes in man in general is T- dependant, T- cellular deficiency is also accompanied by humoral immunodeficiency; in other words, T- cellular deficiency leads to the combined deficiency of both humoral and cellular immunity.
Deficiency of the complement system is expressed in the defects of the controlling proteins and it leads, for example, to night hemoglobinuria, angioneurotic edemas, extraordinarily high rate of the syndromes of lupus erythematosis. The complement deficiency makes not more than 2% of all primary immunodeficiencies, and is manifested by the disturbance of opsonization, phagocytosis and destruction of microorganisms and is accompanied by severe infections, up to sepsis. Deficiency of complement is frequently observed in the autoimmune diseases, for example, SLE.
Deficiency of the components of the classic way of the complement activation – C1q, C1r and C1s, C4 or C2 causes predisposition to the diseases, caused by disturbances in formation and clearance of the immune complexes, for example, to the development of systemic lupus erythematosis. Deficiency of C3, B factor or I factor leads to increased sensitivity of the organism to purulent infections. Deficiency of the terminal components C5 , C6, C7 and C8, and components of the alternative way – factor D and properdin creates special predisposition to the infections, caused by two forms of Neisseria – N.gonorrhoeae and N.meningitidis. In general the forms of deficiency of the complement components are inherited as autosomal- recessive signs.
Deficiency of phagocytes makes 10-15% of all primary immunodeficiencies. Insufficiency of phagocytes is caused by the disturbance of proliferation, differentiation, chemotaxis of neutrophils and macrophages and by the disturbance of the process of phagocytosis. The expressed insufficiency of polymorphonuclear leukocytes (neutropenia) may lead to the development of the generalized bacterial infection. Of special importance are two genetic defects, disturbing the phagocyte function, associated with development of severe diseases, frequently with the lethal outcome – chronic granulematosis (the cause of which consists in the disturbance of the mechanism of the oxygen restoration) and the insufficiency of the leukocyte adhesion (caused by defects in the genes of integrins).
Recurrent infections of the respiratory tract (e.g., lungs, sinuses, ears, nose and throat) are common clinical presentations of patients that are often referred to an allergist/immunologist for evaluation. Many patients who have received multiple courses of antibiotics for frequent sinus infections, colds, chest infections, ear infections and sore throats are evaluated yearly for defects of the immune system. In most cases, these infections turn out to be due to respiratory allergy or simply frequent infections. However, in a few cases, a specific immunodeficiency will be diagnosed and the resulting treatment may be lifesaving.
Immunologically deficient individuals can be categorized into two major groups. One group suffers from a specific defect that originates in the immune system, defined as a primary immunodeficiency (e.g., x-linked agammaglobulinemia). In contrast, immunodeficiency that is a consequence of a disease process not directly related to the immune system (e.g., kidney disease associated with nephotic syndrome and loss of immunoglobulin) is defined as a secondary immunodeficiency.
Primary immunodeficiency
Primary immunodeficiency may result from defects in the production of circulating antibodies (humoral immunological defense system) or from a cellular defect in the immune system, which would include defects in T-cells, phagocytes and/or macrophages. Combined immunodeficiency indicates the existence of defects in both the humoral and cellular arms of the immune system.
Once considered rare diseases involving severely ill individuals, primary immunodeficiencies now appear to be more common than previously thought. In fact, the estimated frequency of the most common immunodeficiency—selective IgA immunodeficiency (SIgAID)—is present in 1 out of 500 people (See Table 1).
Initially, an immunodeficiency disorder associated with mild clinical symptoms might go undiagnosed (See Table 2 for 10 warning signs of immunodeficiency). However, over time, immunodeficiency can lead to recurrent and/or severe infections that respond poorly to conventional therapy. Therefore, early diagnosis of immunodeficiency can limit severe damage due to poorly controlled infection and might be lifesaving. Genetic counseling of family members may be invaluable in decision-making once the potential risks are understood.
Immune defects
The immune system defends the body from infection through a series of complex interactions involving antibodies, plasma cells, sensitized T- and B-cells, circulating complement proteins, soluble mediators (cytokines), neutrophils, macrophages and dozens of other mediators and cellular components involved in immunoregulation.
Deficiency or defects in any part of an immune response can impair the body’s ability to protect itself against invading viruses, bacteria, fungi, or parasites resulting in an increased chance of severe infection (See Figure 1).
Primary immunodeficiencies (Table 1) result from genetic, developmental, or acquired defects, whereas secondary immunodeficiencies (Table 3) are due to other medical diseases that damage the immune system. For example, chronic disease of the gastrointestinal tract can lead to a protein losing enteropathy, resulting in decreased circulating antibodies. Another example would be the AIDS virus, which damages cellular components of the immune system, leading to recurrent infections.
The immune system can be defined (a) in terms of its components (e.g., antibodies, T-cells, etc.) or (b) by its type of response to foreign antigens, referred to as either innate or adaptive.
The innate immune response is based on the presence of preformed antibodies and sensitized cells that can immediately attack foreign antigens or invading organisms early in the process of infection. In contrast, the adaptive immune responsedevelops slowly, as antigen exposure induces immunological changes that take days to weeks to achieve optimum results. Fortunately, the innate response fights infection early, giving the adaptive system time to develop a stronger response.
The adaptive immune response is much more specific and potent than the innate immune response, thus resulting in far morespecific and potent antibodies and sensitized cells that can more effectively attack antigens present in invading viruses and bacteria. Following exposure to an antigen, the immune system adapts its response by developing increasingly specific and effective antibodies and sensitized cells. In time, clones of these cells begin to develop, thus enhancing the immune response.
The secondary adaptive immune response will occur more quickly if there has been prior exposure and the immune system is primed to produce the necessary cells and specific antibodies. This quickened response is known as the amnestic response, indicating the presence of immunologic memory and its role in rapidly activating the adaptive response.
This specific—or adaptive—immune system is mediated by T- and B-lymphocytes and their cytokines, adaptive antibodies (IgG), and specifically sensitized cells. At this time, more than 120 genetic defects in the immune system have been identified and there are still more to be defined.
Clinically, immunodeficiency diseases are broadly characterized by defects of B-lymphocytes (50% of cases), defects of combined T- and B- lymphocytes (20-30% of cases), unique T-cell defects, phagocyte defects (18% of cases) and complement deficiencies (2% of cases). The type and site of infection often indicates the probable type of immunodeficiency (Tables 4 and 5). For example, B-cell or humoral (antibody) defects mostly result in susceptibility to bacteria (sino-pulmonary infections, enteroviruses and parasites). In contrast, T-cell-mediated defects often result in increased susceptibility to opportunistic organisms (e.g., P.carinii), viruses and fungi. Additionally, phagocytic defects frequently result in pyogenic (bacterial) infections involving the sinuses, lungs, skin and lymph nodes. Complement deficiencies are associated with pyogenic infections, sepsis and recurrent meningitis, caused by encapsulated bacteria.
Recognizing immunodeficiency
A detailed history, physical examination and laboratory studies will help differentiate frequent infections due to common risk factors (e.g., daycare attendance; frequent exposure to school-age children; exposure to cold temperatures; allergies or passive smoke exposure) from a primary immunodeficiency due to a specific immune defect.
Early in the course of immunodeficiency, the pattern of symptoms of recurrent infection may be mild or intermittent, often attributed to other causes such as allergies. However, persistence of these symptoms should raise suspicion of the presence of immunodeficiency (See Table 2).
Immunodeficiency and its co-morbidities
1. Gastrointestinal symptoms. Although many patients with primary immune deficiencies present with recurrent and chronic respiratory infections, gastrointestinal disorders are also commonly diagnosed in immunodeficient patients. The combination of recurrent respiratory infections along with gastrointestinal symptoms may also prompt immunologic screening. It should be noted that infection with Giardia lamblia and bacterial overgrowth in the small intestine are frequently observed in patients with antibody deficiencies.
2. Autoimmune disease may be limited to a single tissue or organ, or may be more global iature (e.g., autoimmune hemolytic anemia and systemic lupus erythematosis or rheumatoid arthritis). Gastrointestinal symptoms in immunodeficient patients may be secondary to autoimmune disease (e.g., inflammatory bowel disease, lymphoid hyperplasia, Celiac disease, atrophic gastritis with pernicious anemia) or infections (Giardia lamblia, rotavirus, cryptosporidiosis).
3. Proliferative disorders and/or solid malignancies like gastric carcinoma may also be a feature of some primary immunodeficiencies, especially the B-cell disorders (common variable hypogammaglobulinemia, CVH, SIgAID).
4. Family history of immunodeficiency, autoimmune disease and/or infantile death may help predict immunodeficiency. Primary immunodeficiencies—especially B-cell defects are familial and often arise in the setting where other family members have autoimmune diseases, especially rheumatoid arthritis, SLE or autoimmune hematologic disorders.
5. Adverse reactions to vaccines or transfusions may also be indicative of an underlying immunodeficiency. For example, anaphylactic reactions to blood or blood products can occur in patients with selective IgA immunodeficiency due to IgE antibodies directed against IgA present on unwashed, transfused red cells. Patients with B-cell deficiencies or severe combined immunodeficiencies may experience infections or adverse reactions to live attenuated vaccines—including live oral polio vaccine or even exposure to individuals vaccinated with live viruses, which could lead to the development of paralytic polio.
Patient evaluation
1. The patient history
A patient’s history of past infections helps determine the appropriate laboratory tests required to identify and explain the patient’s symptoms. The pattern of infection might be helpful in identifying the probable immune defect. For example, infections with encapsulated extracellular bacterial pathogens—particularly of the respiratory tract—are suggestive of defects in antibody production. Non-invasive mucosal infections may particularly suggest isolated IgA deficiency. While infections with opportunistic pathogens, (protozoa and fungi) and severe or recurrent infections due to chicken pox or herpes may suggest defects in cell-mediated immunity . Deficiencies in the complement system may lead to failure to clear bacteria promptly from the blood stream, resulting in bacteremia/sepsis, or hematogenously disseminated infections such as osteomyelitis.
The seriousness of the immunodeficiency can be supported by the frequency of absence from school or work, hospitalizations, emergency room visits and disability resulting from infection-related illness. The family history should include questions about infection among siblings and preceding generations. In particular, families with a history of premature deaths of male infants should raise suspicion of x-linked immune deficiencies.
2. The physical exam
The physical exam in patients with primary immunodeficiencies is ofteormal, but cases of identifiable physical abnormalities may offer clues to defects in host defenses. The initial exam should include assessment of general appearance. Children with underlying immunodeficiencies may fail to thrive in early childhood, or older children may look chronically ill and/or appear underweight or have dysmorphic features. Repeated pyogenic infections may lead to permanent scars of the eardrums or the skin. Digital clubbing may imply serious pulmonary damage from repeated infections. The presence or absence of tonsils, lymph nodes or splenic tissue may be helpful in identifying B-cell disorders.
Conversely, the presence of palpable lymph nodes and easily visible tonsils essentially excludes x-linked agammaglobulinemia. In contrast, the presence of cervical or peripheral adenopathy, splenomegaly, or hepatomegaly may suggest common variable immunodeficiency (CVID), human immunodeficiency virus (HIV), chronic granulomatous disease (CGD), or other abnormalities. Abnormalities involving the skin may point to an immunodeficiency. For example, certain skin rashes like eczema, thrush, vitiligo, persistent warts, and molluscum contagiosum may also be indicative of an underlying primary immunodeficiency.
3. Common sense laboratory testing for immunodeficiency
Generally, patients with T-cell disorders have opportunistic infections, whereas patients with antibody, phagocytic cell or complement deficiencies usually have recurrent infections due to encapsulated bacteria.
Screening for primary immunodeficiency is not currently performed at birth. Fortunately, many immunologic defects can be easily assessed with a simple blood count. For example, a complete blood cell count with differential with a normal absolute neutrophil count will rule out congenital or acquired neutropenia.
If the patient’s absolute lymphocyte count is normal, a severe T-cell defect is unlikely.
General blood chemistry panels often reveal low total protein but normal albumin in agammaglobulinemia due to very low gammaglobulin levels. A low uric acid level may be indicative of Adenosine deaminase (
Normal quantitative immunoglobulins will rule out most B-cell immunoglobulin deficiencies.
It is also possible that clinically significant antibody deficiency may be present even with normal levels of all classes of immunoglobulins. Therefore, specific antibody production should be assessed in patients with a history of recurrent bacterial infections, particularly of the respiratory tract.
Antibody response to vaccination is required for functional antibody deficiencies (e.g., selective anti-polysaccharide antibody deficiency). Measurements of antibodies against tetanus and diphtheria toxins and several pneumococcal polysaccharides as well as H. influenzae type-B polysaccharide are quite helpful in this area. Lack of a significant rise in specific antibody titers after immunization and/or failure to achieve protective levels indicates that the patient is unable to mount specific antibody responses and therefore has an immunodeficiency.
A total hemolytic complement assay (the CH-
A cost-efficient test for T-cell function is the anergy panel (skin testing) for assessing T-cell function. An anergy panel consists of intradermal skin testing to common recall antigens (candida, trichophyton and tetanus). If the test is positive significant induration and erythema), then virtually all primary T-cell defects are excluded, thus limiting the need for more expensive in-vitro tests such as lymphocyte phenotyping (T-cell enumeration by flow cytometry) and lymphocyte proliferation responses to mitogen and/or antigen challenge.
If a phagocytic defect is suspected, especially in an individual with staphylococcal gram-positive infections, screening with a neutrophil oxidative burst by flow cytometry should be performed. Detailed laboratory analysis in patients suspected of phagocyte disorders should include assessment of neutrophil chemotaxis and the oxidative respiratory burst that accompanies phagocytosis.
Genetic testing may ultimately be required for definitive diagnosis in some cases and for genetic family counseling.
Specific examples of immunodeficiency disorders and B-cell disorders
a. X-linked immunodeficiency (also called XLA, Bruton’s agammaglobulinemia, sex-linked agammaglobulinemia) XLA was the first defined primary immunodeficiency. A rare x-linked genetic disorder, XLA is more common in males. XLA patients do not generate mature B-cells resulting in antibody immunodeficiency. Patients with untreated XLA are prone to develop serious and even fatal infections. A genetic mutation has occurred at the Bruton’s tyrosine kinase gene which leads to a severe block in B-cell development resulting in a marked reduction of immunoglobulin (antibody) production in the serum. Patients typically present in early childhood with recurrent bacterial infections, particularly with extracellular, encapsulated bacteria such as pneumococcus. XLA is treated by infusion of human IgG antibody. Treatment with pooled gamma globulin can usually reduce the severity and number of infections through passive immunity offered by IVIG administered every 3 or 4 weeks.
b. Common variable hypogammaglobulinemia
CVH is characterized immunologically by IgG, IgA and IgM levels at least two standard deviations below age-adjusted means. In adults, IgG levels must be less than 400 mg/dl (normal range 600-1600 mg/dl). T- and B-cell numbers in the peripheral blood are normal and T cell function is normal. There is a reduced antibody response to antigen challenge.
Clinically, the disease begins between ages 15 and 40 and equally affects males and females. Recurrent sino-pulmonary infections, bacterial conjunctivitis, bronchiectasis, pulmonary granulomas and malabsorption (secondary to G.lambdia) are the common presentations of this immunodeficiency. Leukemia, lymphoma, gastric cancer, autoimmune disease (rheumatoid arthritis, SLE, vitiligo, hemolytic or pernicious anemia), and upper and lower respiratory allergies are often associated with this defect. Treatment includes replacement gamma globulin therapy with rotating antibiotics in those with relapsing respiratory infections.
c. Selective IgA Immunodeficiencies (SIgAID)
This is the most common immunodeficiency. SIgAID refers to the absence of IgA antibodies in serum, typically less than 5 mg/dl (normal range 80-500 mg/dl) with normal IgG and IgM levels. Over time, SIgAID may evolve into a pan-hypogammaglobulinemic state consistent with common variable hypogammaglobulinemia. The T- and B-cell numbers in the peripheral blood are normal and T-cell function is usually normal.
Clinically, many individuals are asymptomatic, but some have symptoms similar to common variable hypogammaglobulinemia, allergies, autoimmune disease (rheumatoid arthritis, SLE/Celiac disease), recurrent sino-pulmonary disease and bronchiectasis. Antibodies (IgE and IgG) against IgA may develop in some patients with SIgAID which in turn leads to an increased incidence of anaphylactic reactions to the IgA present in transfused blood or blood products. Anaphylaxis from blood products can be diminished by screening IgA-deficient patients for the presence of anti-IgA antibodies. Blood transfusion from IgA-deficient donors will be tolerated in IgA-deficient patients with circulating anti-IgA antibodies. Patients with SIgAID do not require gammaglobulin replacement, since they don’t lack IgG and immunoglobulin infusions don’t contain replacement IgA.
d. Selective IgM immunodeficiencies (SIgMID)
SIgM immunodeficiency appears to be increasingly recognized and its prevalence appears to be increasing to the point that it may be among the most common of immunodeficiencies. SIgMID patients typically have IgM levels at least two standard deviations below age-adjusted norms (usually less than 50 mg/dl in adults with a normal range of 52-71 mg/dl). Serum IgA and IgG levels are normal. T- and B-cell numbers are normal and T-cell function is normal.
In a retrospective analysis and literature review (Goldstein, M.; Dunsky, E.; Annals of Allergy, Asthma and Immunology. 2006;97:717–730.) from our practice, the clinical features of SIgMID in adults and children were characterized. Clinical features are similar to SIgAID with a range of presentations from an asymptomatic state to recurrent sino-pulmonary infections, bronchiectasis, allergies, asthma, autoimmune disease and surprisingly idiopathic anaphylaxis, chronic urticaria and angioedema. These latter three disorders have not been reported with increased frequency in any other B-cell immunodeficiencies. Some patients may require gamma globulin replacement, but most will not benefit.
e. Selective polysaccharide antibody deficiencies (SPAD)
These individuals have normal quantitative immunoglobulin levels, however, they demonstrate a selective defect in their antibody response to polysaccharide vaccination (e.g., strep pneumonae, H. influenza and N. meningitis). Functionally, SPAD patients have an increased incidence of infections (e.g., pneumonia, meningitis, otitis media and sepsis). This disease can be demonstrated by a lack of response to unconjugated polysaccharide vaccine in patients with normal quantitative immunoglobulin levels. Patients with SPAD rarely require gamma globulin replacement.
f. T-cell disorders
Severe combined immunodeficiency (SCID). This disorder is extremely rare, with only about 30-50 new cases per year. Immunologically, it is characterized by failure of stem cells to differentiate into T-cells and B-cells. Infants with SCID have very few lymphocytes in their peripheral blood and have no or few lymphocytes in their lymphoid tissue. In some cases, lymphocytes are present but fail to express major histocompatability complex molecules. Genetically, this is more common in male infants because over 50% of cases are caused by a genetic defect on the x-chromosome. The remaining cases are due to autosomal recessive genes on other chromosomes. More than half of these cases have a gene deficiency of adenosine deaminase (
Clinically, patients who have SCID are susceptible to all microbial infections, but most notably rotavirus, Candida albicans and P. carinii. They have chronic diarrhea, pneumonia, failure to thrive and may have progressive infections if immunized with live organisms. The symptoms occur in early childhood and prove fatal within the first year of life if untreated with bone marrowtransplantation or gene therapy (
• Congential thymic aplasia (DiGeorge Syndrome)
Patients with DiGeorge syndrome have a failed development of the thymus and parathyroid glands. Newborns often suffer from hypocalcemic tetany during the first 24 hours of life. They also suffer from a number of other congenital defects involving the heart, kidneys and other organs. Children have distinct facial features with wide-set eyes and low-set notched ears. There are few or no T-cells, B-cells, or plasma cells. Total immunoglobulin levels may be normal but immunization does not result
• Ataxia-telangiectasia
This disorder is inherited as an autosomal recessive trait and presents in early childhood. Patients typically display a wobbly gait, have telangectasia appearing on their eyes and skin by age 6 and suffer from severe sino-pulmonary infections. They may also have other neurologic, endocrine, hepatic and cutaneous symptoms.
• Wiskott-Aldrich Syndrome
This is an x-linked disorder affecting males who have thrombocytopenia and progressive T-cell dysfunction. Their serum contains increased levels of IgA and IgE, with normal levels of IgG, and reduced levels of IgM. Clinically, these patients usually suffer from eczema, pyogenic and opportunistic infections.
g. Phagocytic cell deficiencies
Most of the defects of phagocytic cells present with recurrent bacterial infections. There are several stages along the process of phagocytosis which may be impaired, including: cell motility, adherence and inability to phagocytize and kill micro-organisms. These phagocytic disorders include chronic granulomatous disease, leukocyte adhesion deficiency and Chediak-Higashi syndrome.
· Chronic granulomatous disease (CGD) Chronic granulomatous disease (CGD) is defined by the inability of neutrophils to kill ingested micro-organisms stemming from defective nicotinamide adenine dinucleotide phosphate oxidase enzyme. These enzymes allow for the generation of super oxide ions and hydrogen peroxide, which are necessary for the intracellular survival of the bacteria and leads to granuloma formation. Children who have chronic granulomatous disease are susceptible to pneumonia, lymphadenitis and abscesses in the skin, liver and other viscera. The patients suffer from infections often due to organisms of low virulence such as staphylococcus epidermitis, serratia marcescens and aspergillus. Diagnosis of this disease may be made by a neutrophil respiratory burst assay done by flow cytometry.
· Leukocyte adhesion deficiency As a result of a genetic defect, phagocytes cannot adhere to vascular epithelium expressing intracellular adhesion molecule-1 and thus cannot migrate out of blood vessels into areas of infection. The process results in an elevated blood neutrophil count and an inability to form pus effectively. In patients who have leukocyte adhesion deficiency severe bacterial infections can spread rapidly from within the mouth and the GI tract. Patients with this disorder have been successfully treated with bone marrow transplantation.
· Chediak-Higashi Syndrome Patients with this illness have partial albinism and recurrent pyogenic infections with staphylococcus and streptococcus. The prognosis is poor, with most children dying early. Defective neutrophil chemotaxis, phagocytosis and intracellular killing results from defects in micro-tubules and an inability of enzymes to release their granules.
h. Complement deficiencies
The complement system consists of over 20 glycoproteins and is a major effector component of the humoral branch of the immune system. Mechanisms dependent on complement activation include: opsinization, which promotes phagocytosis of particular antigens, recruitment and activation of immunologically active cells at sites of inflammation, processing and clearance of immune complexes as well as direct lysis of target cells including viruses.
Complement deficiencies—although uncommon—have been described for each complement component. Complement deficiencies are usually associated with bacterial infections, predominantly sino-pulmonary infections and immune complex disease and angioedema.
Patients lacking any of the complement components may suffer recurrent episodes of meningococcemia, meningococcal meningitis and disseminated gonococcal infections.
The total hemolytic complement test (CH-50) may be useful as a screen for complement deficiency. There is no specific treatment for complement component abnormalities. Acute infections are treated with antibiotics and long-term management may include the use of prophylactic antibiotics. Complement proteins cannot be replaced currently except for C-1 esterase deficiency where a blood concentrate has recently been approved for acute episodes of hereditary angioedema due to C-1 esterase deficiency.
Treatment
The principal treatments for primary immunodeficiency include:
1. Protective isolation—prevention of infections
2. Antibiotic prophylaxis and acute treatment of infections
3. Replacement therapy for missing humoral or, rarely, cellular immunologic functions
Although the molecular etiology of many of the primary immunodeficiencies has been reported, gene therapy is not available for except for a few select cases of severe combined immunodeficiency.
1. Prevention by controlling infection: Limit the immunodeficient patient’s exposure to infectious disease. Remove immunodeficient children from day care or pre-school, avoid others with colds, as well as crowds. In addition, avoid high-risk situations and ensure the patient has received all appropriate vaccines (e.g., conjugated polysaccharide vaccines and annual immunization against influenza). Checking specific antibody titers post immunization can provide assurance of protection.
Vaccines used to treat immunodeficient patients and their families and close contacts should be killed vaccines, since live vaccines pose a serious risk.
Prompt and rigorous treatment of apparent bacterial infections associated with sinusitis and bronchitis. Treat adequately with antibiotics until you are certain that the infection has been completely resolved.
Frequent follow-up visits are needed to assure treatment is truly effective as well to identify infection in its early stage.
When infection is resistant, prolonged courses of oral antibiotics and/or parenteral treatment may be required.
2. Prophylactic antibiotic treatment in immunodeficiency
Prophylactic antibiotic treatment can be carried out with a once-daily dose of trimethoprim-sulfamethoxazole (e.g., half of the total daily dose that would be used for otitis media). Other oral antibiotics, such as ampicillin or a cephalosporin, may also be used, especially in patients who are allergic to sulfonamides, but these may be associated with a higher risk for resistant bacteria. Patients who develop diarrhea or other gastrointestinal side effects, oral thrush, or vaginal candidiasis may be poor candidates for this approach.
3. Immunoglobulin treatment in immunodeficiency
Half or more of all primary immune deficiencies involve defects in antibody production. Patients with X-linked agammaglobulinemia, common variable hypogammaglobulinemia, hyper-IgM syndromes, and other severe immunoglobulin deficiencies often require immunoglobulin replacement. In patients with severe antibody deficiency, lack of efficacy of antibiotics, or when prophylaxis has not been effective, immunoglobulin replacement may be the treatment of choice.
Immunoglobulin therapy is administered mostly by the intravenous route (IVIG), but subcutaneous administration has recently been made available. Since the half-life of IgG is about 21 days, IV infusions are typically administered every three to four weeks, versus subcutaneous infusions which may be given at home at weekly intervals or even more often. The dose and interval of IVIG needs to be optimized to control infections and other symptoms, but it usually ranges from 300 mg/kg/month to 800 mg/kg/month. Higher doses are reserved for patients with chronic lung and/or sinus infections. Serum IgG concentrations are measured just prior to an infusion to determine their trough or low level to ensure adequacy of dosing.
Patients with active acute or chronic infection may experience severe systemic symptoms (e.g., shaking chills, fevers, and/or inflammatory reactions at the site of infection) when initially receiving infusions of IVIG. Therefore, it may be wise to treat the patient with an adequate course of antibiotics prior to initial IVIG infusions. When initiating treatment with IVIG, we recommend beginning with a slow infusion rate (0.5 mg/kg/min to 1 mg/kg/min)—which would be 0.01 mL/kg/min to 0.02 mL/kg/min of 5% solution—and slowly increase the rate at 30-minute intervals, as tolerated, until a maximum rate of 4 mg/kg/min to 6 mg/kg/min is achieved. The rate should be slowed at the first sign of a reaction. Most non-reactive patients can complete their infusions within a few hours. Some patients may experience adverse reactions during IV infusions. Common symptoms may include: headache, backache, flushing, chills, and nausea. Severe symptoms might include: dyspnea, wheezing, anxiety, chest pain, and anaphylactoid symptoms.
Severe symptoms are not usually a result of a true anaphylactic reaction, since they are not usually mediated by IgE and are frequently associated with increased rather than decreased blood pressure. Such reactions can be treated by decreasing the rate of infusion and/or by administration of diphenhydramine, corticosteroids, acetaminophen, or aspirin prior to treatment. Patients with consistent patterns of reactions can be kept at slower rates during future treatment and/or pretreated with the previously mentioned medications. In rare cases, pretreatment with corticosteroids (e.g., 0.5 mg/kg to 1 mg/kg of prednisone or intravenous methylprednisolone) may be necessary.
True anaphylaxis is extremely uncommon and has been reported in IgA- deficient patients in which IgE antibodies are present against IgA.
Rare complications of IVIG therapy include aseptic meningitis, thrombotic events, and acute renal failure. These complications are usually associated with high doses of IVIG (>1,000 mg/kg) which are used for their anti-inflammatory or immunomodulatory effects. Such adverse reactions are rare in patients receiving conventional doses as replacement therapy for immune deficiencies.
Finally, late adverse reactions may include headache, which may have migraine-like features and may be associated with nausea and fever. These reactions may occur up to 48 hours after the infusion and they generally respond to acetaminophen, aspirin, or other non-steroidal anti-inflammatory drugs.
Management of patients with phagocytic dysfunction and complement disorders is best accomplished by treatment of the specific infections, as no replacement therapies have been identified except in the case of hereditary angioedema.
Management of t-cell deficiencies is more difficult, as there is no readily available cure. Bone marrow transplantation and gene therapy have been tried in certain disorders. These aggressive forms of therapy have been associated with various adverse effects. Members of the patient’s household should receive regular immunizations with killed vaccinations.
In the future, further definition of gene abnormalities may lead to more effective interventions in immunodeficiency treatment.
The acquired (second) immunodeficiency
The acquired (second) immunodeficiency arises in the course of the patients’ life and they are the result of influence of a number of chemical, radioactive, drug and other substances on the organism as well as influence of viral infections, chronic inflammatory processes, difficult surgery, injuries, stress.
The acquired immunodeficiencies are a group of the diseases, the basis of which are the disturbances either of separate components of immunity or the complex damage of this system under the effect of the factors of environment or pathologic processes, not associated in their etiology with the immune system, but exerting a suppressing effect on it.
The immunodeficient state may be caused by irradiation, glucocorticoid therapy, application of pharmacological medicines but according to the data of world statistics, the emaciation as a result of underfeeding –is the most frequent cause of the immunodeficient states. Furthermore, immunodeficiency appears as associated phenomenon in such pathologies as the diseases of the gastrointestinal tract, nephotic disturbances, multiple myelomas and others.
Viral infections frequently exerts an immunodepressive influence. Lymphoproliferative diseases (chronic lymphoid leucosis, myeloma and macroglobulinemia of Waldenstrem) are responsible for the general suppression of the cellular immunity. Many effects, such as X-ray irradiation, introduction of the cytotoxic agents and corticosteroids can also suppress immunoreactivity. Second immunodeficiencies are observed in the malignant neoplasms, including hemoblastoses, viral infections, for example, HIV- infection or the infection, caused by Epstein-Barr virus, [immunosuppressive therapy , aging, emaciation, loss of immunoglobulins, for example, in the nephotic syndrome or exudative enteropathy. HIV- infection is the leading cause for second immunodeficiency today. It is manifested by chronic infections including those caused by conditionally pathogenic microorganisms, and by malignant neoplasms, first of all, lymphomas and Kaposi’s sarcoma.
Many factors can decrease immunoreactivity nonspecifically. In particular, the reactions of the cellular immunity are impaired in malnutrition, deficiency of iron is especially important in this respect.
Clinical manifestations in the immunodeficient states
Suppositional dysfunction of the T- cellular system:
1. Systemic disease after the immunization by any living virus or vaccine BCG; the uncommon, life threatening complications after the infections caused by the common, not dangerous viruses (gigantocellular pneumonia in rubella, pneumonia in chickenpox).
2. Chronic candidiasis of the oral cavity persisting after the child has reached the age of 6 months and not yielded to the action of adequate chemotherapeutic drugs.
3. Chronic candidiasis of the skin and mucous membranes.
4. Characteristic signs (soft thin hair, dwarfism due to shortening of the extremities, typical roentgenological changes) of the syndrome of hypoplasia of the hair and cartilage.
5. Intrauterine reaction of the transplant against the master – erythroderma and total baldness (absence of eyebrows).
6. Reaction of the transplant against the master after blood transfusion.
7. Hypocalciemia of newborns (syndrome of Di George, especially in combination with the characteristic anomalies of the face, pinnae, and heart).
8. Small size of (the diameter less than 10 mcm) lymphocytes, their number constantly comprises less than
Suppositional dysfunction of the B- cellular system:
1. relapsing bacterial pneumonia, sepsis, meningitis.
2. main lymphoid hyperplasia.
Suppositional dysfunction of the B- and T- cellular systems: (combined immunodeficiency):
1. All enumerated manifestations except chronic candidiasis of the skin and mucous membranes as well as main lymphoid hyperplasia.
2. Signs of the syndrome of Wiskott- Aldrich (purulent otitis, thrombocytopenia and eczema).
3. Signs of ataxia and teleangioectasia (syndrome of
Signs, which are evidence of the immunodeficient state but without clear indications of T- or B-cellular defect:
1. Pneumonia caused by Pneumocystis carinii.
2. Eczema, which is not yielded to action by medicines.
3. Ulcerous colitis in children at the age under 1 year old.
4. Diarrhea, which is not yielded to correction.
5. Inexplicable hematologic deficiency (deficiency of erythrocytes, leukocytes, thrombocytes).
6. Severe generalized seborrheic dermatitis (Laner disease) can be evidence of the C5 insufficiency; seborrhea frequently accompanies the combined immunodeficiency.
7. Relapsing purulent infections are observed in the C3 insufficiency.
Presumptive biochemical defect:
1. Signs of the combined immunodeficiency with the characteristic damages of the bone system (insufficiency of adenosine deaminase).
2. Signs of the aplastic anemia of Diamond – Blackfan (insufficiency of nucleoside phosphorylase).
Supposed disturbance of the function of the polymorphonuclear leukocytes.
1. Skin infections (if they are combined with bronchial asthma, eczema, rough features of the face, it is possible to think about Buckley’s syndrome)
2. Chronic osteomyelitis, caused by Klebsiella or Serratia purulent lymphadenitis (chronic granulomatous disease).
The some of diseasses
Selective deficiency of IgA Selective deficiency of IgA is the most common immune deficiency disorder. Persons with this disorder have low or absent levels of a blood protein called immunoglobulin A. IgA deficiency is usually inherited, which means it is passed down through families. It may be inherited as an autosomal dominant or autosomal recessive trait. It is found in approximately
Transient hypogammaglobulinaemia of infancy In healthy babies, antibody levels in the blood reach a natural low point when they are between three and four months of age. In children who have Transient hypogammaglobulinemia of infancy, the levels of IgG and IgA levels remain low after six months of age because not enough immunoglobulin is produced. The disorder is temporary. It usually resolves between the ages of two and four years old. In rare cases, the disorder can persist until the children reaches six year old. Causes: The reason for B-cell developmental abnormalities is unknown. There may be a hereditary component to Transient hypogammaglobulinemia of infancy, which causes problems with the conversion of B-cells to plasma cells. Common symptoms of Transient hypogammaglobulinemia of infancy include, recurrent ear infections or non-infectious inflammation of the middle ear, recurrent bronchitis, frequent sinusitis (infection or inflammation of the sinuses), bacterial infection (like pneumonia) and infections of the skin or meningitis (infection of the membranes that cover the spinal cord and brain). Diagnosis: Transient hypogammaglobulinemia of infancy is usually suspected if a child experiences recurrent infections past the age of six months. A blood test can indicate low levels of antibodies in the bloodstream. If the antibody levels are less than what is considered normal for children of the same age, the child may have this disease. However, low levels of antibodies are nonspecific because it can be the result of any other immunodeficiency disorder. Treatment: Transient hypogammaglobulinemia of infancy will resolve on its own, without treatment. Antibiotics. Intravenous immunoglobulin therapy is debate A conjugated heptavalent pneumococcal vaccine is recommended for routine immunization in children who are two months old. Probiotics. Hydrotherapy. Propolis.
Wiskott-Aldrich syndrome is a rare inherited disorder marked by a low level of blood platelets, eczema, recurrent infections, and a high risk of leukemia or lymph node tumors. The gene responsible for WAS is located on on the short arm of the X chromosome (Xp11.22-p11.23). The syndrome is caused by a defect (mutation) in a specific gene called the WAS gene that normally codes for the proteiamed Wiskott-Aldrich Syndrome Protein (WASP). This vital protein is a component of cells that are important in the body’s defense against infection (lymphocytes). The same protein also functions in the cells that help prevent bleeding (platelets). WAS is inherited as an X-linked genetic disorder and will therefore only affect males. Symptoms: Increased susceptibility to infections, eczema, and excessive bleeding are the hallmarks of WAS, although the symptoms can vary significantly from one patient to another. Ear infections, meningitis, and pneumonia are common in boys with WAS. WAS patients also have thrombocytopenia, a decreased number of platelets. Anemia and an enlarged spleen (splenomegaly) are seen in some patients. About 10% of patients develop malignancies, usually leukemia or tumors in the lymph nodes (non-Hodgkin’s lymphoma). The diagnosis of WAS is usually suspected in male infants who have excessive bleeding, eczema, and frequent bacterial or viral infections. Special blood tests can then be ordered to confirm WAS. The blood of patients with Wiskott-Aldrich will show a low platelet count and a weak immune (antibody) response. Standard treatments for individuals with WAS include antibiotics for infections and platelet transfusions to limit bleeding. Immune globulin is given to strengthen the individual’s immune system. The spleen is sometimes removed to reduce the risk of bleeding. Treatment with transfer factor. Bone marrow transplantation has been successful in a number of cases.
Di George,s syndrome is an inherited condition that lies at the more severe end of a spectrum of syndromes (also known as CATCH22 or 22q11.2 deletion syndrome) that occur when a part of the DNA on chromosome 22 is missing. The parathyroid glands in the neck may have failed to develop, leading to low levels of calcium in the blood. This can result in muscle spasms (tetany) and seizures. The thymus gland may also be underdeveloped or absent, resulting in a deficiency of an important type of immune cell known as the T lymphocyte. Infections (seldom life-threatening) and autoimmune disease (such as haemolytic anaemia, inflammatory bowel disease and juvenile rheumatoid arthritis) are common. There are often heart defects, particularly affecting the large vessels that lead out of the heart. There may be a typical facial appearance withfeatures such as a small jaw, small, low-set ears with abnormal folds, unusual eyes, small mouth, a rather bulbous nose and square nasal tip, and hypernasal speech with a cleft palate. Short stature and learning difficulties which may range from mild to moderate are also common. Sometimes the syndrome isn’t detected until later in infancy, especially when problems are mild. The symptoms most frequently observed are: abnormality of the palate and the ears, arousing difficulties of language and understanding, or deficit of the hearing (audition); cardiac deformation; disturbs immune systems; hypotony; risks mattering of schizophrenia which begins in the childhood or the adolescence.
Antenatal diagnosis, usually using CVS or amniocentesis, is possible especially when there’s a family history or abnormalities on ultrasound scanning. Di George,s syndrome can’t be cured, but treatment of problems such as low calcium, surgery for heart problems and thymus cell transplants to restore the immune system can reduce complications. The treatment of Di George’s syndrome aims at correcting the abnormalities of organs or affected tissues. The treatment thus depends on the nature and on the gravity of the abnormality. The treatment of the hypocalcémie and the hypoparathyroïdie can require a treatment by the calcium and the administration of hormone parathyroïdienne of replacement. An abnormality of the heart can require the administration of medicines to improve the cardiac function or the surgical correction. The type of surgical operation depends on the nature of the cardiac defect. New techniques of transplant of thymus also improved the long-term results. The future of a child with Di George’s syndrome depends on the level of gravity of the present abnormalities. The gravity of the cardiac infringement is generally the most determining factor. In case of grave and persevering deficit, a corrective treatment is necessary.
Louis-Bar syndrome The main features are progressive cerebellar ataxia with onset in infancy; progressive telangiectasia of the bulbar conjunctivae, simulating conjunctivitis, and of the butterfly area of the face; frequent sinopulmonary infection, including bronchiectasis; and peculiarity of eye movements, simulating ophthalmoplegia. The essential components of this familial syndrome are the ataxia and the telangiectasia, the most striking identifying feature being the characteristic telangiectases of the bulbar conjunctivae. Symptomatic and supportive treatments: the use of exercises and physical activities; occupational therapy; speech therapy; gamma-globulin injections; high-dose vitamin regimes.
Disease of Bruton Mutations in the gene for BTK (located at Xq21.3-22) are responsible for the disease. X-linked agammaglobulinemia (XLA) is a genetic disorder in which the development of B cells arrests during differentiation. It has been shown to be caused by a variety of mutations in the gene encoding Bruton tyrosine kinase (BTK, also known as BPK or ATK) – enzyme needed for maturation of B-cells. XLA is often characterized by recurrent bacterial infections due to a decrease in the number of B-cells and a subsequent reduction in the level of serum immunoglobulin. Bruton agammaglobulinemia is an X-linked genetic condition caused by an abnormality in a key enzyme needed for proper function of the immune system. People who have this disorder have low levels of protective antibodies and are vulnerable to repeated and potentially fatal infections. Bruton agammaglobulinemia is inherited in an X-linked recessive manner; thus, almost all persons with the disorder are male. Females have two X chromosomes, which means they have two copies of the BTK gene, whereas males only have one X chromosome and one copy of the BTK gene. If a male has an altered BTK gene, he will have Bruton agammaglobulinemia. If a female has one altered BTK gene, she will be a carrier and will be at risk to pass the altered gene on to her children. Symptoms: children with Bruton agammaglobulinemia are born healthy and usually begin to show signs of infection in the first three to nine months of life, when antibodies that come from the mother during pregnancy and early breast-feeding disappear. Patients with Bruton agammaglobulinemia can have infections that involve the skin, bone, brain, gastrointestinal tract, sinuses, eyes, ears, nose, airways to the lung, or lung itself. Besides signs of recurrent infections, other physical findings in patients with Bruton agammaglobulinemia include slow growth, wheezing, small tonsils, and abnormal levels of tooth decay. Children may also develop unusual symptoms such as joint disease, destruction of red blood cells, kidney damage, and skin and muscle inflammation. Diagnosis: recurrent infections or infections that fail to respond completely or quickly to antibiotics; the presence of unusually small lymph nodes and tonsils; patients do not have periods of well-being between bouts of illness. Detect level of immunoglobulins. Genetic testing of the BTK gene. Treatment: replacing immunoglobulin; antibiotics; bone marrow transplantation.
Causes
Many primary immunodeficiency disorders are inherited — passed down from one or both parents. Problems in the DNA — the genetic code that acts as a blueprint for producing the cells that make up the human body — cause many of the immune system defects in primary immunodeficiency.
There are numerous types of primary immunodeficiency disorders. They can be broadly classified into six groups based on the part of the immune system that’s affected:
B cell (antibody) deficiencies
T cell deficiencies
Combination B and T cell deficiencies
Defective phagocytes
Unknown (idiopathic)
B cell deficiencies are the most common type of primary immunodeficiency disorder.
Protein and gene defects in B-cell development and function.
Haematopoietic stem cells (HSCs) give rise to progenitor (pro)-B cells, which then rearrange their immunoglobulin heavy-chain gene segments to generate precursor (pre)-B cells. Pre-B cells subsequently rearrange their immunoglobulin light-chain gene segments to produce a functional cell-surface receptor (IgM). This protein is composed of heavy and light chains that are derived from these gene rearrangements, and it functions as a receptor for responding to stimulation with antigen, resulting in the induction of proliferation and differentiation of the B cell. In the periphery, after stimulation with antigen, mature B cells further develop following class-switch recombination and somatic hypermutation and, ultimately, differentiate into memory B cells or plasma cells. Developmental blocks throughout B-cell maturation and differentiation occur as a result of defects in genes encoding the molecules listed in the yellow boxes. Blocks in the function of mature B cells can also occur. Primary immunodeficiency syndromes that cause these blocks are also listed. AID, activation-induced cytidine deaminase; BAFFR, B-cell-activating-factor receptor; BCR, B-cell receptor; BLNK, B-cell linker; BTK, Bruton’s tyrosine kinase; c, common cytokine-receptor -chain; CVID, common variable immunodeficiency; HIGM4, hyper-IgM syndrome 4; ICOS, inducible T-cell co-stimulator; IgAD, selective IgA deficiency; Ig, immunoglobulin heavy chain; IKK-, inhibitor-of-nuclear-factor-B kinase-; IL-7R, interleukin-7 receptor -chain; JAK3, Janus kinase 3; NK cell, natural killer cell; RAG, recombination-activating gene; TACI, transmembrane activator and calcium-modulating cyclophilin-ligand interactor; UNG, uracil-DNA glycosylase.
Tests and diagnosis
To help decide whether recurrent infections could be due to primary immunodeficiency, your doctor will begin by asking a number of questions, such as what health problems you have, how long infections last, how severe they are and whether they respond to treatment. Your doctor will also want to know whether any close relatives have an inherited immune system disorder. Your doctor will perform a physical examination to look for clues that may indicate the cause of your illness. Primary immune disorders are rare, so your doctor will want to be sure your signs and symptoms aren’t caused by a more common health problem.
There are several tests used to diagnose an immune disorder. They include:
Blood tests. In most cases, blood tests can reveal abnormalities in the immune system that indicate an immune deficiency disorder. Tests can determine if you have normal levels of infection fighting proteins (immunoglobulin) in your blood. Tests can measure the levels of different blood cells and immune system cells. Abnormal numbers of certain cells can indicate an immune system defect. Other blood tests can determine if your immune system is responding properly and producing antibodies — proteins that identify and kill foreign invaders such as bacteria or viruses.
Identifying infections. If you have an infection that’s not responding to standard treatment, your doctor may do tests to try to identify exactly what germs are causing it.
Prenatal testing. Parents who’ve already had a child with a primary immunodeficiency disorder may want to have testing done for certain immunodeficiency disorders during future pregnancies. Samples of the amniotic fluid, blood or cells from the tissue that will become the placenta (chorion) are tested for abnormalities. In some cases, DNA testing is done to test for a genetic defect. Test results make it possible to prepare for treatment soon after birth, if necessary.
Diagnosis he basic tests performed when an immunodeficiency is suspected should include a full blood count (including accurate lymphocyte and granulocyte counts) and immunoglobulin levels (the three most important types of antibodies: IgG, IgA and IgM).
Other tests are performed depending on the suspected disorder:
· Quantification of the different types of mononuclear cells in the blood (i.e. lymphocytes and monocytes): different groups of T lymphocytes (dependent on their cell surface markers, e.g. CD4+, CD8+, CD3+, TCRαβ and TCRγδ), groups of B lymphocytes (CD19, CD20, CD21 and Immunoglobulin), natural killer cells and monocytes (CD15+), as well as activation markers (HLA-DR, CD25, CD80 (B cells).
· Tests for T cell function: skin tests for delayed-type hypersensitivity, cell responses to mitogens and allogeneic cells, cytokine production by cells
· Tests for B cell function: antibodies to routine immunisations and commonly acquired infections, quantification of IgG subclasses
· Tests for phagocyte function: reduction of nitro blue tetrazolium chloride, assays of chemotaxis, bactericidal activity.
Due to the rarity of many primary immunodeficiencies, many of the above tests are highly specialised and tend to be performed in research laboratories. Criteria for diagnosis were agreed in 1999. For instance, an antibody deficiency can be diagnosed in the presence of low immunoglobulins, recurrent infections and failure of the development of antibodies on exposure to antigens. The 1999 criteria also distinguish between “definitive”, “probable” and “possible” in the diagnosis of primary immunodeficiency. “Definitive” diagnosis is made when it is likely that in 20 years, the patient has a >98% chance of the same diagnosis being made; this level of diagnosis is achievable with the detection of a genetic mutation or very specific circumstantial abnormalities. “Probable” diagnosis is made wheo genetic diagnosis can be made, but the patient has all other characteristics of a particular disease; the chance of the same diagnosis being made 20 years later is estimated to be 85-97%. Finally, a “possible” diagnosis is made when the patient has only some of the characteristics of a disease are present, but not all.
Conditions
The International Union of Immunological Societies recognises eight classes of primary immunodeficiencies, totaling over 120 conditions. Their most recent update retained the classification into eight groups, while adding several new conditions into these groups (such as coronin-1A deficiency, immunodeficiency with centromeric instability and facial anomalies, and defects of Ficolin 3).
Genetic immunodeficiencies. (In general, those on the left are in Table I, while those on the right are in Table II, but there are exceptions.)
In these disorders both T lymphocytes and often B lymphocytes, regulators of adaptive immunity, are dysfunctional or decreased iumber. The main members are various types of severe combined immunodeficiency (SCID).
1. T-/B+ SCID (T cells predominantly absent): γc deficiency, JAK3 deficiency, interleukin 7 receptor chain α deficiency, CD45 deficiency, CD3δ/CD3ε deficiency.
2. T-/B- SCID (both T and B cells absent): RAG 1/2 deficiency, DCLRE1C deficiency, adenosine deaminase (
3. Omenn syndrome
4. DNA ligase type IV deficiency
5. Cernunnos deficiency
6. CD40 ligand deficiency
7. CD40 deficiency
8. Purine nucleoside phosphorylase (PNP) deficiency
9. CD3γ deficiency
10. CD8 deficiency
11. ZAP-70 deficiency
12. Ca++ channel deficiency
13. MHC class I deficiency
14. MHC class II deficiency
15. Winged helix deficiency
16. CD25 deficiency
17. STAT5b deficiency
18. Itk deficiency
19. DOCK8 deficiency
II: Predominantly antibody deficiencies
In primary antibody deficiencies, one or more isotypes of immunoglobulin are decreased or don’t function properly. These proteins, generated by plasma cells, normally bind to pathogens, targeting them for destruction.
1. Absent B cells with a resultant severe reduction of all types of antibody: X-linked agammaglobulinemia (btk deficiency, or Bruton’s agammaglobulinemia), μ-Heavy chain deficiency, l 5 deficiency, Igα deficiency, BLNK deficiency, thymoma with immunodeficiency
2. B cells low but present or normal, but with reduction in 2 or more isotypes (usually IgG & IgA, sometimes IgM): common variable immunodeficiency (CVID), ICOS deficiency, CD19 deficiency, TACI (TNFRSF13B) deficiency, BAFF receptor deficiency.
3. Normal numbers of B cells with decreased IgG and IgA and increased IgM: Hyper-IgM syndromes
4. Normal numbers of B cells with isotype or light chain deficiencies: heavy chain deletions, kappa chain deficiency, isolated IgG subclass deficiency, IgA with IgG subsclass deficiency, selective immunoglobulin A deficiency
5. Specific antibody deficiency to specific antigens with normal B cell and normal Ig concentrations
6. Transient hypogammaglobulinemia of infancy (THI)
III: Other well defined immunodeficiency syndrome
A number of syndromes escape formal classification but are otherwise recognisable by particular clinical or immunological features.
1. Wiskott-Aldrich syndrome
2. DNA repair defects not causing isolated SCID: ataxia telangiectasia, ataxia-like syndrome,
3. DiGeorge syndrome (when associated with thymic defects)
4. Various immuno-osseous dysplasias (abnormal development of the skeleton with immune problems): cartilage-hair hypoplasia, Schimke syndrome
5. Hermansky-Pudlak syndrome type 2
6. Hyper-IgE syndrome
7. Chronic mucocutaneous candidiasis
8. Hepatic venoocclusive disease with immunodeficiency (VODI)
9. XL-dyskeratosis congenita (Hoyeraal-Hreidarsson syndrome)
IV: Diseases of immune dysregulation
In certain conditions, the regulation rather than the intrinsic activity of parts of the immune system is the predominant problem. Immunodeficiency with hypopigmentation or albinism: Chediak-Higashi syndrome, Griscelli syndrome type 2
1. Familial hemophagocytic lymphohistiocytosis: perforin deficiency, MUNC13D deficiency, syntaxin 11 deficiency
2. X-linked lymphoproliferative syndrome
3. Syndromes with autoimmunity:
1. (a) Autoimmune lymphoproliferative syndrome: type 1a (CD95 defects), type 1b (Fas ligand defects), type 2a (CASP10 defects), type 2b (CASP8 defects)
2. (b) APECED (autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy)
3. (c) IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome)
4. (d) CD25 deficiency
V: Congenital defects of phagocyte number, function, or both
Phagocytes are the cells that engulf and ingest pathogens (phagocytosis), and destroy them with chemicals. Monocytes/macrophages as well as granulocytes are capable of this process. In certain conditions, either the number of phagocytes is reduced or their functional capacity is impaired.[4]
1. Severe congenital neutropenia: due to ELA2 deficiency (with myelodysplasia)
2. Severe congenital neutropenia: due to GFI1 deficiency (with T/B lymphopenia)
3. Kostmann syndrome
4. Neutropenia with cardiac and urogenital malformations
5. Glycogen storage disease type 1b
6. Cyclic neutropenia
7. X-linked neutropenia/myelodysplasia
8. P14 deficiency
9. Leukocyte adhesion deficiency type 1
10. Leukocyte adhesion deficiency type 2
11. Leukocyte adhesion deficiency type 3
12. RAC2 deficiency (Neutrophil immunodeficiency syndrome)
13. Beta-actin deficiency
14. Localized juvenile periodontitis
15. Papillon-Lefèvre syndrome
16. Specific granule deficiency
17. Shwachman-Diamond syndrome
18. Chronic granulomatous disease: X-linked
19. Chronic granulomatous disease: autosomal (CYBA)
20. Chronic granulomatous disease: autosomal (NCF1)
21. Chronic granulomatous disease: autosomal (NCF2)
22. IL-12 and IL-23 β1 chain deficiency
23. IL-12p40 deficiency
24. Interferon γ receptor 1 deficiency
25. Interferon γ receptor 2 deficiency
26. STAT1 deficiency (2 forms)
27. AD hyper-IgE
28. AR hyper-IgE
29. Pulmonary alveolar proteinosis
VI: Defects in innate immunity
Several rare conditions are due to defects in the innate immune system, which is a basic line of defence that is independent of the more advanced lymphocyte-related systems. Many of these conditions are associated with skin problems.[4]
1. Hypohidrotic ectodermal dysplasia
2. IKBA deficiency
2. EDA-ID
3. IRAK-4 deficiency
4. MyD88 deficiency
5. WHIM syndrome (warts, hypogammaglobulinaemia, infections, myleokathexis)
6. Epidermodysplasia verruciformis
7. Herpes simplex encephalitis
8. Chronic mucocutaneous candidiasis
9. Trypanosomiasis
VII: Autoinflammatory disorder
Rather than predisposing for infections, most of the autoinflammatory disorders lead to excessive inflammation. Many manifest themselves as periodic fever syndromes. They may involve various organs directly, as well as predisposing for long-term damage (e.g. by leading to amyloid deposition).[4]
1. Familial Mediterranean fever
2. TNF receptor associated periodic syndrome (TRAPS)
3. Hyper-IgD syndrome (HIDS)
4. CIAS1-related diseases:
Muckle-Wells syndrome
Familial cold autoinflammatory syndrome
Neonatal onset multisystem inflammatory disease
5. PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, acne)
6. Blau syndrome
8. Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)
9. DIRA (deficiency of the IL-1 receptor antagonist)
VIII. Complement deficiencies
The complement system is part of the innate as well as the adaptive immune system; it is a group of circulating proteins that can bind pathogens and form a membrane attack complex. Complement deficiencies are the result of a lack of any of these proteins. They may predispose to infections but also to autoimmune conditions.
1. C1q deficiency (lupus-like syndrome, rheumatoid disease, infections)
2. C1r deficiency (idem)
3. C1s deficiency
4. C4 deficiency (idem)
5. C2 deficiency (lupus-like syndrome, vasculitis, polymyositis, pyogenic infections)
6. C3 deficiency (recurrent pyogenic infections)
7. C5 deficiency (Neisserial infections, SLE)
8. C6 deficiency (idem)
9. C7 deficiency (idem, vasculitis)
10. C8a deficiency
11. C8b deficiency
12. C9 deficiency (Neisserial infections)
13. C1-inhibitor deficiency (hereditary angioedema)
14. Factor I deficiency (pyogenic infections)
15. Factor H deficiency (haemolytic-uraemic syndrome, membranoproliferative glomerulonephritis)
16. Factor D deficiency (Neisserial infections)
17. Properdin deficiency (Neisserial infections)
18. MBP deficiency (pyogenic infections)
19. MASP2 deficiency
20. Complement receptor 3 (CR3) deficiency
21. Membrane cofactor protein (CD46) deficiency
22. Membrane attack complex inhibitor (CD59) deficiency
23. Paroxysmal nocturnal hemoglobinuria
24. Immunodeficiency associated with ficolin 3 deficiency
Treatment
The treatment of primary immunodeficiencies depends foremost on the nature of the abnormality. This may range from immunoglobulin replacement therapy in antibody deficiencies—in the form of intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG)—to hematopoietic stem cell transplantation for SCID and other severe immunodeficiences. Reduction of exposure to pathogens may be recommended, and in many situations prophylactic antibiotics may be advised.
The primary immunodeficiency disorders reflect abnormalities in the development and maturation of cells of the immune system.
These defects result in an increased susceptibility to infection; recurrent pyogenic infections occur with defects of humoral immunity, and opportunistic infections with defects of cell-mediated immunity. These two broad categories of illness correspond
roughly to defects in the two principal types of immunocompetent cells, B lymphocytes and T lymphocytes. Defective development of B cells results in abnormalities in humoral immunity, whereas defects in the development of T cells cause problems with cellular immunity.
When pathogens are taken up by macrophages or dendritic cells, their antigens are degraded and presented on the cell surface to T cells, which subsequently induce the maturation of B cells through the release of cytokines. T cells also recruit other cells (macrophages, eosinophils, basophils, and mast cells) to induce an inflammatory response. The specific immune responses of T cells and antibodies (along with components of serum complement) result in resistance to infection. These responses are assisted by natural killer cells, which nonspecifically kill tumor cells and virus-infected cells.
We describe recent advances in the understanding of six of the primary immunodeficiencies: X-linked agammaglobulinemia, the hyper-IgM syndrome, common variable immunodeficiency, severe combined immunodeficiency, defects in the expression of the major histocompatibility complex (MHC), and the Wiskott–Aldrich syndrome. The underlying defects in each can be better understood by reference to Figure, which shows the development and maturation of T and B lymphocytes from the multipotent hematopoietic stem cell.
X-Linked Agammaglobulinemia
X-linked agammaglobulinemia was first described 43 years ago and remains the prototypic syndrome of a pure B-cell deficiency. The disorder has a relatively homogeneous clinical presentation — a characteristic that suggested a monogenic defect, inherited as an X- linked recessive trait. Recently, the genetic defect has been shown to result from mutations in a hitherto unknown cytoplasmic signal-transducing molecule. This discovery has broadened the description of the phenotype and led to the realization that X-linked agammaglobulinemia is more common than was previously thought. Affected boys are usually well for the first 9 to 12 months of life because they are passively protected by transplacentally acquired IgG from their mothers. Subsequently, they have recurrent pyogenic infections such as otitis media, sinusitis, conjunctivitis, pneumonia, and pyoderma. These infections are mainly due to Haemophilus influenzae and Streptococcus pneumoniae and less frequently to Staphylococcus aureus and Streptococcus pyogenes. Although readily controlled by antibiotics, these recurrent infections lead to anatomical destruction, particularly of the lungs; chronic obstructive lung disease and bronchiectasis invariably result when proper prophylactic treatment is not undertaken. Boys with X-linked agammaglobulinemia may have persistent viremia and are at risk of acquiring paralytic poliomyelitis from live-virus vaccines. They are also susceptible to an unusual and potentially fatal form of persistent enterovirus (usually echovirus) infection that is associated with chronic meningoencephalitis and a syndrome resembling dermatomyositis. Giardia lamblia infestation leads to chronic diarrhea, weight loss, protein-losing enteropathy, and steatorrhea. About 35 percent of affected boys present with arthritis of the large joints; this symptom is usually controlled by immune globulin therapy. In many cases it is probably due to mycoplasma (Ureaplasma urealyticum).
During the past decade prophylaxis with intravenous immune globulin has become the standard therapy for X-linked agammaglobulinemia. With the use of this route it has been possible to administer large doses of immune globulin so that patients can lead relatively normal lives. The optimal dose and frequency of administration must be determined for each patient. Usually, a dose of 350 to 500 mg per kilogram of body weight is given each month, but it may be preferable to divide this dose for administration every other week. Some patients require as much as 600 mg of immune globulin per kilogram to maintain adequate prophylaxis. Immune globulin is a safe biologic product. Nevertheless, the risk of transmitting hepatitis C virus is ever present, and a few unfortunate outbreaks have occurred. This problem may soon be overcome with detergent treatment of immune globulin preparations. Attempts are also being made to pump immune globulin into subcutaneous tissue.
Typically, the serum of patients with X-linked agammaglobulinemia contains less than 100 mg of IgG per deciliter and no detectable IgM or IgA. The patients are incapable of making antibodies in response to standard antigenic provocations. B cells are virtually absent from the blood. Cell-mediated immunity is relatively normal in affected male patients; they have normal numbers of circulating T cells, which can respond appropriately to specific and nonspecific mitogens. It has recently been recognized, since the identification of the genetic defect, that these laboratory findings define X-linked agammaglobulinemia too narrowly; this diagnosis should be suspected in all young boys with recurrent pyogenic infections, decreased immunoglobulin levels, or low numbers of B cells.
Standard linkage analysis was used to map the gene for X-linked agammaglobulinemia to the long arm of the X chromosome at position Xq21.2–22, and X-linked agammaglobulinemia exhibited no crossovers with a polymorphic DNA marker. A candidate signal-transducing molecule encoded by a tyrosine kinase gene called btk was identified and cloned. Missense and nonsense mutations in btk, as well as splice-site mutations, have been identified. The gene is called btk for Bruton’s, or B-cell, tyrosine kinase and is expressed early in B-cell development, but not in T cells or plasma cells. It is expressed in myeloid cells, where its role is obviously less crucial than in B cells, because granulocyte defects are rarely seen in X-linked agammaglobulinemia. Early B cells are generated in the bone marrow of affected male patients. However, these early B cells mature at an extremely low rate. The btk gene must therefore have a vital but as yet undetermined role in the maturation of B-lineage cells.
In X-linked agammaglobulinemia, mutations have been found in all parts of the btk gene.,
There is no apparent correlation between the phenotype and the different mutations, although there can be marked phenotypic differences among affected male patients in a single kindred. A point mutation has been found in btk in male CBA/N mice with a mild humoral immunodeficiency (called Xid for X-linked immunodeficiency). Recently, it has been possible to disrupt btk in mice. The severity of the phenotype in these mice depends on their genetic background. This may provide an excellent model for experimental gene therapy.
Female carriers of X-linked agammaglobulinemia, who are immunologically normal, have two populations of B-cell precursors. The
Hyper-IgM Syndrome
In 1961 two boys with a syndrome that resembled X-linked agammaglobulinemia clinically were found to have elevated serum concentrations of IgM but no IgA and very low concentrations of IgG. This new defect was presumed to be inherited as an X-linked recessive trait. Then, two female patients with the same clinical phenotype were identified.
Many patients with this syndrome have since been described, approximately 70 percent of whom have the X-linked form of the hyper-IgM syndrome. The mode of inheritance in the remaining patients is not clear-cut. The genetic defect in the X-linked form has recently been discovered and reveals new facets of collaboration between T and B lymphocytes.
Male patients with X-linked hyper-IgM syndrome have a clinical history of pyogenic infections that resembles that encountered in male patients with X-linked agammaglobulinemia. In addition, they are susceptible to opportunistic infections, particularly those due to Pneumocystis carinii. They also are prone to autoimmune diseases involving the formed elements of the blood — autoimmune hemolytic anemia, thrombocytopenic purpura, and most important of all, recurrent, often severe, and prolonged neutropenia. The neutropenia responds well to immune globulin and granulocyte–macrophage colony-stimulating factor. In these patients administration of intravenous immune globulin in the same doses as are used in X-linked agammaglobulinemia is recommended. This therapy usually results in a decrease in the serum IgM concentration. In the second decade of life there may be uncontrollable proliferation of IgM-producing plasma cells, which extensively invade the gastrointestinal tract, liver, and gallbladder. Although the proliferating cells always exhibit polyclonality, the cellular infiltrates may be so extensive as to prove fatal. Patients with X-linked hyper-IgM syndrome also have an increased risk of abdominal cancers.
The serum of patients with X-linked hyper-IgM syndrome usually contains undetectable amounts of IgA and IgE and very low concentrations of IgG (<150 mg per deciliter). However, IgM concentrations may be in the high normal range, and may even be 1000 mg per deciliter or more; IgD concentrations are also elevated. The blood contains a normal number of B lymphocytes, but they have only surface IgM and IgD. As in X-linked agammaglobulinemia, there is no germinal-center development in the lymph nodes and spleen despite the presence of normal numbers of B cells and T cells.
In an immune response IgM and IgD antibodies are produced first. As the immune response progresses, IgG antibodies appear, followed by IgA antibodies and finally by IgE antibodies. The sequential appearance of different classes of immunoglobulins is called class switching. It was possible to induce class switching to IgG and IgA in B cells from patients with X-linked hyper-IgM syndrome by incubating B cells with activated CD4+ T cells from a woman with the Sézary syndrome. Studies of class switching iormal B cells show that two signals are required for the B cell to switch from synthesizing and secreting IgM to synthesizing and secreting IgE: the binding of interleukin-4 secreted by T cells to the interleukin-4 receptor on B cells and the interaction of CD40 on the B-cell surface with the CD40 ligand, which is expressed on activated T cells. This observation led to the discovery that T cells of patients with X-linked hyper-IgM syndrome could not synthesize the CD40 ligand. The gene for X-linked hyper-IgM syndrome was mapped to Xq26 on the long arm of the X chromosome. The gene encoding the CD40 ligand was cloned and mapped to the same location. Several groups simultaneously discovered that the defect in X-linked hyper-IgM syndrome resides in mutations in the gene for the CD40 ligand. Missense as well as nonsense mutations and deletions have been found in the CD40 ligand gene in patients with X-linked hyper-IgM syndrome.
This syndrome illustrates the importance of physical contact between B cells and T cells through CD40 and its ligand in the activation of B cells and in germinal-center formation and immunoglobulin class switching. Further work is required to explain the high frequency of autoimmune disease and neutropenia, susceptibility to opportunistic infections, and the lymphoproliferative complications in X-linked hyper-IgM syndrome. Because the CD40 ligand molecule is not required for the normal development of T lymphocytes, female obligate heterozygous carriers of X-linked hyper-IgM syndrome, unlike carriers of X-linked agammaglobulinemia, have random inactivation of the X chromosome in lymphocytes. A polymorphic region at the 3′ end of the CD40 ligand gene makes prenatal diagnosis of X-linked hyper-IgM syndrome possible.
Common Variable Immunodeficiency
The term “common variable immunodeficiency” is used to designate a group of as yet undifferentiated syndromes. All are characterized by defective antibody formation. The diagnosis is based on the exclusion of other known causes of humoral immune defects. As would be expected in a heterogeneous group of undifferentiated diseases, several patterns of inheritance (autosomal recessive, autosomal dominant, and X-linked) have beeoted. Sporadic cases are, however, most common.
Among populations of European origin, common variable immunodeficiency is the most frequent of the primary specific immunodeficiency diseases.51 It affects men and women equally. The usual age at presentation is the second or third decade of life. The terms “late-onset hypogammaglobulinemia,” “adult-onset hypogammaglobulinemia,” and “acquired immunodeficiency,” which were used in the past, are no longer appropriate.
The clinical presentation of common variable immunodeficiency disease is generally that of recurrent pyogenic sinopulmonary infections. Appropriate early investigation and diagnosis are important; many cases are only identified after serious chronic obstructive lung disease and bronchiectasis have developed. A few patients with common variable immunodeficiency present with infections involving unusual organisms such as P. carinii, mycobacteria, or various fungi. Recurrent attacks of herpes simplex are common, and herpes zoster develops in about one fifth of patients. As in patients with X-linked agammaglobulinemia, some patients with common variable immunodeficiency have unusual enteroviral infections with a chronic meningoencephalitis and a syndrome resembling dermatomyositis. The patients are also highly prone to infection with enteric pathogens, such as chronic G. lamblia infection.
There is an unusually high incidence of malignant lymphoreticular and gastrointestinal conditions in common variable immunodeficiency. A 50-fold increase in gastric carcinoma has been observed. Lymphoma is about 300 times more frequent in women with common variable immunodeficiency than in affected men. In contrast to patients with X-linked agammaglobulinemia, many patients with common variable immunodeficiency have diffuse lymphadenopathy and often splenomegaly. The lymph nodes and spleen show a striking reactive follicular hyperplasia. The gastrointestinal tract is also commonly involved in the process, with nodular lymphoid hyperplasia. As in celiac disease, malabsorption with weight loss, diarrhea, and associated findings such as hypoalbuminemia and vitamin deficiencies is seen. Inflammatory bowel diseases are more frequent. Patients with common variable immunodeficiency are also prone to a variety of other autoimmune disorders (e.g., pernicious anemia, hemolytic anemia, thrombocytopenia, and neutropenia). Noncaseating (sarcoid-like) granulomas occur in the skin, the gut, and other viscera.
Defective antibody formation is accompanied by decreased serum IgG concentrations and usually by decreased serum IgA and IgM concentrations. There is no convincing evidence of any intrinsic B-cell defects. Although the number of B cells may be reduced, with appropriate stimulation they can produce and secrete immunoglobulins. However, the B cells are immature. The findings in common variable immunodeficiency are consistent with insufficient in vivo stimulus for B-cell activation rather than an intrinsic failure of B cells to differentiate.
Relatives of patients with common variable immunodeficiency have an unusually high incidence of IgA deficiency and an increased incidence of autoimmune disorders, autoantibodies (including antilymphocyte antibodies), and malignant conditions. Families whose members include persons with common variable immunodeficiency and IgA deficiency often have certain fixed haplotypes in the MHC. One or more genes in the MHC may be involved in the pathogenesis of common variable immunodeficiency and IgA deficiency.
Since immature B cells in common variable immunodeficiency appear to be functionally intact, the defect might logically reside in the T-cell component of the interaction between B cells and T cells requisite for B-cell maturation. However, it is often difficult to interpret studies of T cells in common variable immunodeficiency, because of the activation of T cells that is probably a result of recurrent or chronic infections or infusions of intravenous immune globulin.
In most patients with common variable immunodeficiency, stimulation of T-cell receptors produces diminished responses and there is decreased gene transcription of cytokines such as interleukin-2, interleukin-4, interleukin-5, and interferon-. Decreased production of interleukin-2 after direct stimulation of T-cell receptorsis correlated with diminished expression of CD40 ligand and may reflect an abnormality in CD4+ T cells in common variable immunodeficiency. This abnormality of T-cell triggering can be bypassed by direct activation of signal transduction.
Thus, many patients with common variable immunodeficiency appear to have defective interactions between T cells and B cells. Defective T-cell signal transduction could contribute to the diminished humoral immunity found in these disorders in the presence of immature but otherwise potentially normal B cells. In the absence of appropriate T-cell signaling, B cells would fail not only to produce antibody, but also to proliferate and differentiate, which would result in both the decreased numbers and the arrested maturation of B cells seen frequently in common variable immunodeficiency.
Severe Combined Immunodeficiency
In contrast to X-linked agammaglobulinemia and X-linked hyper-IgM syndrome, severe combined immunodeficiency has many genetic causes even though the phenotype is fairly uniform. Usually, affected infants are ill by three months of age with persistent thrush or an extensive rash in the diaper area due to monilia. They may have intractable diarrhea or a persistent pertussis-like cough due to interstitial pneumonia caused by P. carinii.
Although growth and development may have proceeded normally for the first three months of life, growth and weight gain subsequently fall off, and failure to thrive becomes a striking feature. Sometimes these infants have a morbilliform rash shortly after birth, due to transplacental passage of maternal lymphocytes, which mount a graft-versus-host reaction. The rash becomes hyperpigmented. Death from varicella, herpes, adenovirus, or cytomegalovirus may occur very rapidly after infection. Giant-cell pneumonia has resulted from measles infection and live-measles vaccine, and progressive vaccinia has occurred after smallpox vaccination; both were uniformly fatal. A diagnosis of severe combined immunodeficiency represents a medical emergency; this immunodeficiency can be rapidly fatal if affected infants are not rendered immunocompetent by bone marrow transplantation in a timely fashion.
Infants with severe combined immunodeficiency almost invariably have profound lymphopenia (<1000 lymphocytes per cubic millimeter). The number of natural killer cells may be normal or high. In the X-linked form of severe combined immunodeficiency the number of B cells is normal or elevated, but these B cells fail to mature and function normally. CD3+ T cells, when present, may be of maternal origin. These infants are not capable of cell-mediated immunity. Lymphocytes do not respond in vitro to nonspecific mitogens such as phytohemagglutinin and concanavalin A. They also do not respond to an allogeneic stimulus or to specific antigens such as tetanus toxoid, which may have been used as an immunogen. The failure of the thymus to become a lymphoid organ is a common feature. The thymic shadow cannot be seen on a chest film. The serum immunoglobulin concentrations are all low. Rarely, an M component may be present in the serum, and in an infant this is virtually diagnostic of severe combined immunodeficiency.
Severe combined immunodeficiency is three times as common in boys as in girls, because the most common form — accounting for 50 to 60 percent of the cases — is X-linked. It has been mapped to Xq13. The genetic defect in X-linked severe combined immunodeficiency has recently been identified as a mutation of the gamma chain of the interleukin-2 receptor, which had been cloned earlier. Mutations were found in the gamma chain of the interleukin-2 receptor in a number of patients with X-linked severe combined immunodeficiency. The disorder has also been found in basset hounds, and these dogs also have a mutation in the gamma chain of the interleukin-2 receptor.
At first this finding was very surprising because it did not seem likely that such a profound immunodeficiency could result from mutations in the gamma chain of the interleukin-2 receptor. It was soon discovered that the gamma chain is a component of several interleukin receptors — namely, receptors for interleukin-4, interleukin-7, interleukin-11, and interleukin-15. Thus, the early lymphoid progenitor cells in X-linked severe combined immunodeficiency, lacking intact interleukin receptors, fail to be stimulated by all these growth factors that are vital to the normal development and differentiation of T cells and the late phases of B-cell development. The T cells, natural killer cells, and late-stage B cells of obligate female heterozygous carriers of X-linked severe combined immunodeficiency exhibit nonrandom X-chromosome inactivation; only cells with the normal X chromosome survive.
The remainder of the cases of severe combined immunodeficiency result from autosomal recessive inheritance. The most common causes of the autosomal recessive form are inherited deficiencies of the purine-degradation enzymes adenosine deaminase and nucleoside phosphorylase. Deficiencies of both these enzymes have been extensively reviewed. Many patients with adenosine deaminase deficiency have benefited from regular injections of adenosine deaminase conjugated to polyethylene glycol. Adenosine deaminase deficiency was also the underlying problem treated in the first successful gene therapy.
In 1968 the first successful bone marrow transplantation in an infant with X-linked severe combined immunodeficiency was performed. Subsequently, scores of these infants have been treated successfully with bone marrow transplantation from histoidentical related donors as well as from unrelated donors and from donors with one or more HLA mismatches whose bone marrow was depleted of T cells. These bone marrow transplantations should be performed as quickly as possible, since X-linked severe combined immunodeficiency is invariably fatal. In families with a previously affected infant, prenatal diagnosis is now possible so that preparations for transplantation can be made in advance of the birth.
In a few rare instances, cases of severe combined immunodeficiency have been reported as a result of defective interleukin-1 receptors, mutated interleukin-2 genes, failure of signal transduction in T cells, or defective T-cell–specific promoters. In these cases, the lymphocyte counts may be normal but the T cells are not functional.
Defects in the Expression of the MHC
Defects in the expression of the MHC were originally called the “bare lymphocyte syndrome.” Use of this unfortunate term should be dropped since it fails to differentiate the several distinct types of MHC class I and class II defects that have been described. The MHC class II molecules are constitutively expressed on antigen-presenting cells such as B lymphocytes, dendritic cells, and cells of monocyte or macrophage lineage and on thymic epithelial cells, where they have an important role in the maturation of CD4+ T cells. The MHC class II molecules are also expressed on activated T cells. The chief function of these molecules is to bind and present antigenic fragments to the T-cell receptor on CD4+ T cells and thereby activate them. This interaction is vital to both cell-mediated immunity and humoral immunity. In contrast, MHC class I molecules are expressed on virtually all cells. They bind and present antigenic peptides to the T-cell receptor of CD8+ T cells and activate their cytotoxic function. Class I molecules also have a vital role in the intrathymic maturation of CD8+ T cells.
A number of children, largely of North African origin, with a moderately severe immunodeficiency, were found to be unable to express MHC class II molecules. These children had severe, protracted diarrhea, frequently associated with candidiasis and cryptosporidiosis, and failure to thrive. Sclerosing cholangitis supervened in a number of them after prolonged gastrointestinal symptoms. Pneumonia, in addition to severe upper respiratory tract infections, was frequent. When given bacille Calmette–Guérin (BCG) in infancy, they survived, in contrast to infants with severe combined immunodeficiency, who invariably die of progressive bacille Calmette–Guérin infection. Graft-versus-host disease does not develop after transfusion with whole blood, whereas it is the inevitable outcome of transfusion in infants with severe combined immunodeficiency.
MHC class II deficiency is inherited as an autosomal recessive trait, but the defect does not segregate with the MHC genes, which are encoded on chromosome 6.
As expected, children with MHC class II deficiency have insufficient numbers of CD4+ T cells but not of CD8+ T cells and cannot mount delayed hypersensitivity reactions. Although the number of B cells is normal, affected children have hypogammaglobulinemia. The in vitro responses to phytohemagglutinin and other nonspecific mitogens are normal, but T cells fail to respond to specific antigens.
There are three major MHC class II molecules: HLA-DP, DQ, and DR. The coordinate expression of these molecules on the surface of B cells and macrophages is regulated in a complex way. At least three unique promoter boxes, called the Y, X, and S boxes, upstream of the MHC genes are involved in the regulation of transcription of MHC class II molecules. The regulation of this transcription is defective in MHC class II deficiency.
Complementation analysis has shown that there are several different types of MHC class II defects. B lymphocytes from patients with MHC class II deficiency were transformed with Epstein–Barr virus and maintained in culture. When transformed B cells from certain patients were fused, they corrected one another’s defect to allow the expression of MHC class II molecules. This led to the identification of so-called complementation groups of MHC class II deficiency. Only cells within one complementation group do not cross-correct; cells from any two complementation groups cross-correct.
It is well known that interferon- induces the expression of MHC class II molecules after a considerable lag period. However, interferon- fails to induce the expression of MHC class II molecules in patients with MHC class II deficiency. During the lag period that follows exposure to interferon- the cells synthesize a new protein called class II transactivator, which does not itself bind to the Y, X, or S boxes but appears to coordinate the binding of the promoters that do. This intracellular protein is defective in one of the complementation groups. The gene encoding the class II transactivator maps to chromosome
Although MHC class II deficiency is less clinically severe than the profound immunodeficiency of severe combined immunodeficiency, it is uniformly fatal in the first or second decade of life. Bone marrow transplantation has resulted in long-term survival.
Because the expression of MHC class I molecules may be decreased in MHC class II deficiency, the identification of isolated MHC class I defects has been elusive. The molecular basis of MHC class I deficiency has recently been defined in a Moroccan family, in which two affected siblings had recurrent, severe bacterial pulmonary infections starting in late childhood. In this large kindred the MHC class I deficiency segregated with the MHC genes, unlike MHC class II deficiency. From this observation it was possible to define the defect. The assembly of MHC class I molecules in the Golgi apparatus proceeds successfully when the chain of these molecules associates with beta2-microglobulin and the complex is joined by antigenic peptides transported across the Golgi membrane by a transporter protein, called TAP. The unit then moves to the cell membrane. If the assembly of the components cannot be completed, usually because no antigenic peptide is loaded onto the chain, the MHC class I complex is destroyed in the cytoplasm of the cell. TAP is encoded by two genes in the MHC, TAP1 and TAP2. The defect in the family studied results from a nonsense mutation in the TAP2 gene.113 As expected, the affected children have a deficiency of CD8+ T cells.
The Wiskott–Aldrich Syndrome
The Wiskott–Aldrich syndrome is inherited as an X-linked recessive disease. Wiskott was the first to report, in 1937, that affected male patients had recurrent bloody diarrhea and thrombocytopenia. The early onset of profound thrombocytopenia with small platelets is diagnostic. In addition, affected male patients have moderate-to-severe eczema and are susceptible to pyogenic and opportunistic infections. Serum IgM concentrations are low, but IgA and IgE concentrations are elevated and total IgG concentrations are normal. Affected patients do not make antibodies to polysaccharide antigens and have a poor response to protein antigens. The number of T cells progressively decreases, whereas the number of B cells progressively expands. In vitro tests of T-cell function yield extremely variable results, but the T cells consistently respond poorly or not at all to the mitogenic effects of antibodies to CD3. In the past, patients with the Wiskott–Aldrich syndrome generally died within the first decade of life of infection, bleeding, or malignant conditions, but improved management with splenectomy, intravenous immune globulin therapy, and other measures has improved their life expectancy. In 1978 the first successful bone marrow transplantation for the Wiskott–Aldrich syndrome was reported, and subsequently, transplantation has resulted in complete bone marrow chimerism in many patients with the syndrome.
The Wiskott–Aldrich syndrome maps to Xp11.23 on the short arm of the X chromosome (and Kwan S-P, et al.: unpublished data). In several kindreds isolated X-linked thrombocytopenia maps to the same locus and is probably a variant of the syndrome. Obligate female heterozygous carriers of the Wiskott–Aldrich syndrome, who are clinically normal, have nonrandom inactivation of their X chromosomes. Only the normal X chromosome survives in T and B lymphocytes, monocytes, and granulocytes. Precursor cells of these lineages exhibit nonrandom inactivation of X chromosomes early in the process of differentiation. A polymorphism in the DNA very close to the gene for the Wiskott–Aldrich syndrome facilitates prenatal diagnosis.
The blood elements that are most severely affected in the Wiskott–Aldrich syndrome are the platelets and T cells. The T cells in particular exhibit disorganization of the cytoskeleton and loss of microvilli. Scanning electron microscopy of fetal lymphocytes from the umbilical vein establishes the prenatal diagnosis. In addition, the cell-surface sialoglycoproteins, most notably CD43, are unstable, and their expression is decreased in the cell membranes of lymphocytes. The gene that is defective in the Wiskott–Aldrich syndrome has recently been identified and encodes the Wiskott–Aldrich syndrome protein. It has no relation to any known protein, and its function is unknown. Several nonsense and missense mutations, as well as deletions and insertions, have been found in this gene. It is extremely rich in proline residues and has long stretches of prolines. This suggests that it binds to the SH3 domains of tyrosine protein kinases, but the enigmatic role of this protein in the pathogenesis of the defect in the Wiskott–Aldrich syndrome remains to be determined.
Treatments and drugs
Treatments for primary immunodeficiency involve preventing and treating infections, boosting the immune system and treating the underlying cause of the immune problem. In some cases, primary immune disorders are linked to a serious illness, such as an autoimmune disorder or cancer, which also needs to be treated.
Managing infections
Antibiotics. Infections are typically treated with antibiotics. In cases where infections don’t respond to standard medications, hospitalization and treatment with intravenous (IV) antibiotics may be necessary. Some people need to take antibiotics long term to prevent infections from occurring and to prevent permanent damage to the lungs and ears.
Treating symptoms. You may need medications to relieve symptoms caused by infections, such as ibuprofen for pain and fever, decongestants for sinus congestion, and expectorants to help clear your airways.
Treatment to boost the immune system
Immunoglobulin therapy. Also called gamma globulin therapy, this treatment can be a lifesaver for people who have an antibody deficiency. Immunoglobulin consists of antibody proteins needed for the immune system to fight infections. It can be either injected into a vein through an IV line, or inserted underneath the skin (subcutaneous infusion). Treatment with intravenous gamma globulin is needed every few weeks to maintain sufficient levels of immunoglobulins. Subcutaneous infusion is needed once or twice a week.
Gamma interferon therapy. Interferons are naturally occurring substances that fight viruses and stimulate immune system cells. Gamma interferon is a man-made (synthetic) substance given as an injection in the thigh or arm three times a week. It’s used to treat chronic granulomatous disease, one form of primary immunodeficiency.
Growth factors. When immune deficiency is caused by a lack of certain white blood cells, growth factor therapy — such as granulocyte-macrophage colony-stimulating factor (Leukine) and granulocyte colony-stimulating factor (Neupogen, Neulasta) — can help increase the levels of immune-strengthening white blood cells.
Treatment to cure primary immunodeficiency
Stem cell transplantation. Stem cell transplantation offers a permanent cure for several forms of life-threatening immunodeficiency. With this treatment, normal stem cells are transferred to the person with immunodeficiency, giving them a normally functioning immune system. Stem cells can be harvested through bone marrow, or they can be obtained from the placenta at birth (cord blood banking). For stem cell transplantation to work, the donor — usually a parent or other close relative — must have body tissues that are a close biological match to those of the person with primary immunodeficiency. Stem cells that aren’t a good match may be rejected by the immune system. But even with a good match, stem cell transplants don’t always work. Additionally, the treatment often requires that any functioning immune cells be destroyed using chemotherapy or radiation prior to the transplants, leaving the transplant recipient even more vulnerable to infection temporarily.
Future treatments
Gene therapy. Researchers hope this treatment will one day be a cure for primary immune disorders and many other conditions. Gene therapy actually replaces defective genes with genes that work correctly. A harmless virus is used to carry the genes into the body’s cells. In turn, the newly introduced genes trigger the production of healthy immune system enzymes and proteins. Experts have identified many of the genes that cause primary immune deficiencies — but they still need to work out many problems. For example, some of the missing or defective genes are only activated during the early development of the immune system, so even if scientists can figure out how to get that gene where it needs to be, it would also have to trigger the development of the missing functions. Although the technique has shown promise in some initial trials, gene therapy is still experimental.
Prevention
Because primary immune disorders are caused by genetic defects, there’s no way to prevent them. But when you or your child has a weakened immune system, you can take steps to prevent infections:
Use proper hygiene. Wash your hands and skin with mild soap whenever using the toilet and before eating.
Take care of your teeth. Brush your teeth at least two times a day.
Eat right. A healthy, balanced diet can help prevent infections.
Avoid exposure. Stay away from people with colds or other infections and avoid crowds of people.
Take your medications. You may need to take regular medications to prevent infection.
Check with your doctor about which vaccinations you should have.
Secondary immune deficiency
The acquired (second) immunodeficiencyarises in the course of the patients’ life and they are the result of influence of a number of chemical, radioactive, drug and other substances on the organism as well as influence of viral infections, chronic inflammatory processes, difficult surgery, injuries, stress.
The acquired immunodeficienciesare a group of the diseases, the basis of which are the disturbances either of separate components of immunity or the complex damage of this system under the effect of the factors of environment or pathologic processes, not associated in their etiology with the immune system, but exerting a suppressing effect on it.
The immunodeficient state may be caused by irradiation, glucocorticoid therapy, application of pharmacological medicines but according to the data of world statistics, the emaciation as a result of underfeeding –is the most frequent cause of the immunodeficient states. Furthermore, immunodeficiency appears as associated phenomenon in such pathologies as the diseases of the gastrointestinal tract, nephotic disturbances, multiple myelomas and others.
Viral infectionsfrequently exertsan immunodepressive influence. Lymphoproliferative diseases(chronic lymphoid leucosis, myelomaand macroglobulinemia of Waldenstrem) are responsible for the general suppression of the cellular immunity. Many effects, such as X-ray irradiation, introduction of the cytotoxic agents and corticosteroidscan also suppress immunoreactivity. Second immunodeficiencies are observed in the malignant neoplasms, including hemoblastoses, viral infections, for example, HIV- infection or the infection, caused by Epstein-Barr virus, [immunosuppressive therapy , aging, emaciation, loss of immunoglobulins, for example, in the nephotic syndromeor exudative enteropathy. HIV- infection is the leading cause for second immunodeficiency today. It is manifested by chronic infections including those caused by conditionally pathogenic microorganisms, and by malignant neoplasms, first of all, lymphomasand Kaposi’s sarcoma.
There are many possible causes and so it is difficult to obtain exact epidemiological data. It is known that the current epidemics of AIDsand tuberculosishave caused global increases in the condition.
Secondary immunodeficiency is common in people who are hospitalised for:
Lymphoreticular malignancy.
Drugs – particularly cytotoxic drugs and immunosuppressants.
Malnutrition – the most common cause worldwide.
Metabolic disorders, eg renal disease requiring peritoneal dialysis.
Trauma or major surgery.
Protein loss – for example, due to nephrotic syndrome.
Presentation
The most common presenting feature is frequent infections. Recurrent respiratory infections are common, but this is by no means pathognomonic, as every GP will be aware of the ‘sickly child’ who seems to acquire infections from his or her siblings frequently.
The development of severe, persistent recurrent bacterial infection is a better indicator. A common scenario is repeated episodes of sore throat or upper respiratory tract infection which lead to sinusitis, chronic otitis and bronchitis. Another feature is the ease with which complications develop. For example, bronchitis progresses to pneumonia, bronchiectasis and respiratory failure.
Opportunistic infections are common, such as Pneumocystis jirovecii or cytomegalovirus, especially in patients with T-cell deficiencies. Infection of the skin and mucous membranes occurs frequently, including resistant thrush, oral ulcers and periodontitis. Conjunctivitis, pyoderma, severe warts, alopecia, eczemaand telangiectasia are also prominent features.
Common gastrointestinal symptoms include diarrhoea, malabsorption and failure to thriveor losing weight. The diarrhoea is usually non-infectious, although a range of organisms, including rotavirus, Giardia lamblia, Cryptosporidium spp. and cytomegalovirus may be involved.
Less commonly, haematological abnormalities such as autoimmune haemolytic anaemia, leukopenia, or thrombocytopenia can occur.
Neurological problems, such as seizures and encephalitis, and autoimmune conditions, such as vasculitis and arthritis, are also sometimes seen. There is also a higher incidence of gastric carcinomaand liver disease.
Paradoxically, autoimmune diseases can be associated with primary immunodeficiencies]
History
Check family history. There may be a familial tendency to early death, similar disease, autoimmunity, allergy, early malignancy or intermarriage.
Check for risk factors – diabetes, medications, illicit drug use and sexual history.
A history of adverse reactions to immunisations or complications of viral infections may be signficant.
Enquiry should be made about the frequency of previous antibiotic prescriptions and any history of relevant surgery, eg splenectomy, tonsillectomy, adenoidectomy.
A history of radiation therapy to the thymus or nasopharynx may also be a pointer to the diagnosis.
Examination
Patients with immunodeficiency often look ill on presentation, with pale skin, general malaise, cachexia and a distended abdomen. Various skin manifestations may be apparent, such as rashes, vesicles, pyoderma, eczema and telangectasia.
The eyes may be inflamed and infected.
Signs of chronic ENT disease, such as scarred eardrums, encrusted nostrils and postnasal drip may be evident.
There may be a chronic cough with crepitations in both lungs.
Hepatomegaly and splenomegaly may be detected in the abdomen.
In infants, crusting around the anus may be a sign of chronic diarrhoea. Delayed developmental milestones or ataxia may be evident.
Investigation
Specialist tests are often required to elucidate the exact diagnosis, but screening tests can be done in primary care. These should include:
FBC, IgG, IgM and IgA levels and tests to confirm the presence and type of any infection. A systematic review called for screening in patients with recurrent
infections, irrespective of age]
An elevated ESR may indicate chronic infection and CXR and sinus X-ray may confirm the source.
Appropriate microbiological swabs should be taken, as dictated by the clinical picture.
More advanced investigations include assays of lymphocyte response, antibody response to immunization of diphtheria, tetanus and pneumococcal polysaccharides, phagocytosis assay and quantitation of individual complement components
Management
General measures include making sure that patients have a healthy lifestyle and are protected as far as possible from infection. This includes having regular dental checks and their own accommodation. There may be an element of social isolation and psychological issues may need to be addressed.
If there is any evidence of antibody response, the standard regime of killed vaccines should be given. Live vaccines are contra-indicated in T-cell deficiency.
Bacterial and fungal infection should be recognised and treated early. Swabs should be taken before treatment so that empirical treatment failures can be rectified rapidly. Continuous prophylactic antibiotics may be appropriate in some circumstances. Chest infections may require physiotherapy and lung exercises.
Antiviral therapies such as amantidine and ramantadine may be life-saving in the management of viral infections.
Intravenous or subcutaneous immunoglobulin replacement is the first-line treatment for most immunoglobulin deficiency states. Subcutaneous therapy is preferred by many patients because it is more convenient and they can be more independent. Immunoglobulin replacement is contra-indicated in selective IgAD, as serious anaphylactic reactions can be caused. Fortunately, selective IgAD is a relatively mild disease and usually responds to general support measures and appropriate treatment of infections.
The best treatment for T-cell deficiency conditions is bone marrow transplant, if a donor can be found.
Other treatment options, some of which are still in the experimental phase, include cytokines), thymic transplants, gene therapy, and stem-cell transplantation.
Prognosis (primary)
Most primary immunodeficiencies are genetic and lifelong. Some conditions such as selective IgAD have a good prognosis. Many patients have a normal lifespan, especially if the condition is diagnosed early and infections are treated regularly.
The prognosis in other conditions such as severe combined immunodeficiency is less optimistic. Many patients suffer from chronic illness and require intensive treatment.
Prognosis (secondary)
This depends on the underlying cause. Many conditions secondary to acute disease resolve when the underlying pathology is treated.
Prevention (primary)
Prevention of primary immunodeficiency depends on the identification and genetic counsellingof likely carriers in families with a positive history. X-linked disorders may be excluded by sex determination.
Few large randomised controlled trials exist and international pooling of information is required to identify areas for future research
Many human pathogens have evolved sophisticated means for surviving attack by the immune systems of their hosts. In most cases, these mechanisms selectively affect host response to the invader and are not generally immunosuppressive. A clear exception is the profound immune suppression resulting from HIV infection.
Instances in which microbial infection leads to less profound generalized immune suppression will be discussed here. Laboratory studies of immune function are not routinely conducted in patients with these infections.
Viral infections — Other than HIV, measles (morbillivirus) is the only viral agent implicated in significant global immune suppression, leading to severe, and sometimes fatal, superinfection . In contrast, herpesvirus infections are associated with transient depressions in cell-mediated immunity.
Measles — In one retrospective study of measles fatalities in
Immune alterations induced by measles include T cell lymphopenia with depletion of T-dependent areas of lymph nodes and spleen, cutaneous anergy, diminished in vitro T cell proliferation with mitogens or alloantigens, and diminished antibody production. These effects are caused by direct infection of T cells by measles virus and by infection of dendritic cells, impairing their important antigen presenting/accessory function in T cell activation. A diminished number of circulating T cells indicates the potential for significant immune compromise and is associated with doubling of the fatality rate. Malnutrition is an important independent risk factor for severe immune compromise, superinfection, and death from measles infection.
References:
1. Stephen Holgate, Martin Church, David Broide, Fernando Martinez. Allergy // Hardbound, Published: November 2011.- 432 p.
2. Mark Peakman, Diego Vergani. Basic and Clinical Immunology with STUDENT // Imprint: Churchill Livingstone Published: – April 2009.
3. Roderick Nairn, Matthew Helbert. Immunology for medical students / / Hardboun. – 2012. –326 p.
4. Linda Cox. Allergen Immunotherapy, An Issue of Immunology and Allergy Clinics // Published: May 2011.- Hardbound, – 312p.
5. Dédée Murrell. Autoimmune Diseases of the Skin, An Issue of Immunology and Allergy Clinics.- Imprint: Saunders.- Published: May 2012
