Lipoproteins and Apoproteins





Plasma is the straw-colored liquid in which the blood cells are suspended.

Composition of blood plasma











Glucose (blood sugar)


Plasma transports materials needed by cells and materials that must be removed from cells:

                    various ions (Na+, Ca2+, HCO3−, etc.

                    glucose and traces of other sugars

                    amino acids

                    other organic acids

                    cholesterol and other lipids


                    urea and other wastes

Most of these materials are in transit from a place where they are added to the blood (a "source")

                    exchange organs like the intestine

                    depots of materials like the liver

to places ("sinks") where they will be removed from the blood.

                    every cell

                    exchange organs like the kidney, and skin.

Serum Proteins

Proteins make up 6–8% of the blood. They are about equally divided between serum albumin and a great variety of serum globulins.

After blood is withdrawn from a vein and allowed to clot, the clot slowly shrinks. As it does so, a clear fluid called serum is squeezed out. Thus:

Serum is blood plasma without fibrinogen and other clotting factors.

The serum proteins can be separated by electrophoresis.


·   A drop of serum is applied in a band to a thin sheet of supporting material, like paper, that has been soaked in a slightly-alkaline salt solution.

·   At pH 8.6, which is commonly used, all the proteins are negatively charged, but some more strongly than others.

·   A direct current can flow through the paper because of the conductivity of the buffer with which it is moistened.

·   As the current flows, the serum proteins move toward the positive electrode.

·   The stronger the negative charge on a protein, the faster it migrates.

·   After a time (typically 20 min), the current is turned off and the proteins stained to make them visible (most are otherwise colorless).

·   The separated proteins appear as distinct bands.

·   The most prominent of these and the one that moves closest to the positive electrode is serum albumin.

·   Serum albumin

o      is made in the liver

o      binds many small molecules for transport through the blood

o      helps maintain the osmotic pressure of the blood

·   The other proteins are the various serum globulins.

·   They migrate in the order

o      alpha globulins (e.g., the proteins that transport thyroxine and retinol [vitamin A])

o      beta globulins (e.g., the iron-transporting protein transferrin)

o      gamma globulins.

§                Gamma globulins are the least negatively-charged serum proteins. (They are so weakly charged, in fact, that some are swept in the flow of buffer back toward the negative electrode.)

§                Most antibodies are gamma globulins.

§                Therefore gamma globulins become more abundant following infections or immunizations.

Albumins – multidispersed fraction of blood plasma which are characterized by the high electrophoretic mobility and mild dissolubility in water and saline solutions. Molecular weight of albumins is about 60000. Due to high hydrophilic properties albumins bind a significant amount of water, and the volume of their molecule under hydratation is doubled. Hydrative layer formed around the serum albumins provides to 70-80 % of oncotic pressure of blood plasma proteins, that can be applied in clinical practice at albumins transfusion to patients with tissue edemas. The decreasing of albumins concentration in blood plasma, for example under disturbance of their synthesis in hepatocytes at liverfailure, can cause the water transition from a vessels into the tissues and development of oncotic edemas.

Albumins execute also important physiological function as transporters of a lot of metabolites and diverse low molecular weight structures. The molecules of albumins have several sites with centers of linkage for molecules of organic ligands, which are affixed by the electrostatic and hydrophobic bonds. Serum albumins can affix and convey fatty acids, cholesterol, cholic pigments (bilirubin and that similar), vitamins, hormones, some amino acids,  toxins and medicines.

Albumins also execute the buffer function. Due to the availability in their structure amino and carboxylic groups albumins can react both as acids and as alkaline.

Albumins can bound different toxins in blood plasma (bilirubin, foreign substances et c.). This is the desintoxicative  function of albumins.

Albumins also play role of amino acids depot in the organism. They can supply amino acids for the building of another proteins, for example enzymes.

Globulins - heterogeneous fraction of blood proteins which execute transport (a1-globulins – transport of lipids, thyroxin, corticosteroid hormones; a2-globulins - transport of lipids, copper ions; b-globulins - transport of lipids, iron) and protective (participation of b-globulins in immune reactions as antitoxins; g-globulins as immunoglobulins) functions. They also support the blood oncotic pressure and acid-alkaline balance, provide amino acids for the organism requirements. The molecular weight of globulins is approximately 150000-300000.

The globulin level in blood plasma is 20-40 g/l. A ratio between concentrations of albumins and globulins (so called “protein coefficient”) in blood plasma is often determined in clinical practice. In healthy people this coefficient is 1,5-2,0.

Fibrinogen – important protein of blood plasma, precursor of fibrin, the structural element of blood clots. Fibrinogen participates in blood clotting and thus prevents the loss of blood from the vascular system of vertebrates. The approximate molecular weight of fibrinogen is 340000. It is the complex protein, it contains the carbohydrate as prosthetic group. The content of firinogen in blood is 3-4 g/l.


Subfractions of a1a2b and g globulins, their structure and functions.

Immunoglobulins  (Ig A, Ig G, Ig E, Ig M) - proteins of g-globulin fraction of blood plasma executing the functions of antibodies which are the main effectors of humoral immunity. They appear in the blood serum and certain cells of a vertebrate in response to the introduction of a protein or some other macromolecule foreign to that species.

Immunoglobulin molecules have bindind sites that are specific for and complementary to the structural features of the antigen that induced their formation. Antibodies are highly specific for the foreign proteins that evoke their formation.

Molecules of immunoglobulins  are glycoproteins. The protein part of immunoglobulins  contain four polipeptide chains: two heavy H-chains and two light L-chains.

The acute phase response develops in a wide range of acute and chronic inflammatory conditions like bacterial, viral, or fungal infections; rheumatic and other inflammatory diseases; malignancy; and tissue injury or necrosis. These conditions cause release of interleukin-6 and other cytokines that trigger the synthesis of CRP and fibrinogen by the liver. During the acute phase response, levels of CRP rapidly increase within 2 hours of acute insult, reaching a peak at 48 hours. With resolution of the acute phase response, CRP declines with a relatively short half-life of 18 hours. Measuring CRP level is a screen for infectious and inflammatory diseases. Rapid, marked increases in CRP occur with inflammation, infection, trauma and tissue necrosis, malignancies, and autoimmune disorders. Because there are a large number of disparate conditions that can increase CRP production, an elevated CRP level does not diagnose a specific disease. An elevated CRP level can provide support for the presence of an inflammatory disease, such as rheumatoid arthritis, polymyalgia rheumatica or giant-cell arteritis.

The physiological role of CRP is to bind to phosphocholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system. CRP binds to phosphocholine on microbes and damaged cells and enhances phagocytosis by macrophages. Thus, CRP participates in the clearance of necrotic and apoptotic cells.

CRP is a member of the class of acute-phase reactants, as its levels rise dramatically during inflammatory processes occurring in the body. This increment is due to a rise in the plasma concentration of IL-6, which is produced predominantly by macrophages as well asadipocytes. CRP binds to phosphocholine on microbes. It is thought to assist in complement binding to foreign and damaged cells and enhances phagocytosis by macrophages (opsonin mediated phagocytosis), which express a receptor for CRP. It is also believed to play another important role in innate immunity, as an early defense system against infections.

CRP rises up to 50,000-fold in acute inflammation, such as infection. It rises above normal limits within 6 hours, and peaks at 48 hours. Its half-life is constant, and therefore its level is mainly determined by the rate of production (and hence the severity of the precipitating cause).

Serum amyloid A is a related acute-phase marker that responds rapidly in similar circumstances.

C-reactive protein (g-fraction). This protein received the title owing to its capacity to react with C-polysaccharide of a pneumococcus forming precipitates. According to its chemical nature C-reactive protein is glycoprotein.

C-reactive protein, pentraxin-related

In blood plasma of healthy people the C-reactive protein is absent but it occurs at pathological states accompanied by an inflammation and necrosis of tissues. The availability of C-reactive protein is characteristic for the acute period of diseases – “protein of an acute phase”. The determination of C-reactive protein has diagnostic value in an acute phase of rheumatic disease, at a myocardial infarction, pneumococcal, streptococcal, staphylococcal infections.

Diagnostic use

CRP is used mainly as a marker of inflammation. Apart from liver failure, there are few known factors that interfere with CRP production.[2]

Measuring and charting CRP values can prove useful in determining disease progress or the effectiveness of treatments. Blood, usually collected in a serum-separating tube, is analysed in amedical laboratory or at the point of care. Various analytical methods are available for CRP determination, such as ELISA, immunoturbidimetry, rapid immunodiffusion, and visual agglutination.

Reference ranges for blood tests, showing C-reactive protein in brown-yellow in center.

A high-sensitivity CRP (hs-CRP) test measures low levels of CRP using laser nephelometry. The test gives results in 25 minutes with a sensitivity down to 0.04 mg/L.

Normal concentration in healthy human serum is usually lower than 10 mg/L, slightly increasing with aging. Higher levels are found in late pregnant women, mild inflammation and viral infections (10–40 mg/L), active inflammation, bacterial infection (40–200 mg/L), severe bacterial infections and burns (>200 mg/L).

CRP is a more sensitive and accurate reflection of the acute phase response than the ESR (Erythrocyte Sedimentation Rate). The half-life of CRP is constant. Therefore, CRP level is mainly determined by the rate of production (and hence the severity of the precipitating cause). In the first 24 h, ESR may be normal and CRP elevated. CRP returns to normal more quickly than ESR in response to therapy.

Cardiology diagnostic test

Arterial damage results from white blood cell invasion and inflammation within the wall. CRP is a general marker for inflammation and infection, so it can be used as a very rough proxy for heart disease risk. Since many things can cause elevated CRP, this is not a very specific prognostic indicator.[27] Nevertheless, a level above 2.4 mg/L has been associated with a doubled risk of a coronary event compared to levels below 1 mg/L;[2] however, the study group in this case consisted of patients who had been diagnosed with unstable angina pectoris; whether elevated CRP has any predictive value of acute coronary events in the general population of all age ranges remains unclear.

Crioglobulin - the protein of the g-globulin fraction. Like to the C-reactive protein crioglobulin absent in blood plasma of the healthy people and occurs at leukoses, rheumatic disease, liver cirrhosis, nephroses. The characteristic physico-chemical feature of crioglobulin is its dissolubility at standard body temperature (37 oC) and capacity to form the sediment at cooling of a blood plasma up to 4 oC.

a2-macroglobulin - protein of a2-globulin fraction, universal serum proteinase inhibitor. Its contents (2,5 g/l) in blood plasma is highest comparing to another proteinase inhibitors.

The biological role of a2-macroglobulin consists in regulation of the tissue proteolysis systems which are very important in such physiological and pathological processes as blood clotting, fibrinolysis, processes of immunodefence, functionality of a complement system, inflammation, regulation of vascular tone (kinine and renin-angiothensine system).

a1-antitrypsin (a1-globulin) – glycoprotein with a molecular weight 55 kDa. Its concentration in blood plasma is 2-3 g\l. The main biological property of this inhibitor is its capacity to form complexes with proteinases oppressing proteolitic activity of such enzymes as trypsinchemotrypsin, plasmin, trombin. The content of a1-antitrypsin is markedly increased in inflammatory processes. The inhibitory activity of a1-antitrypsin is very important in pancreas necrosis and acute pancreatitis because in these conditions the proteinase level in blood and tissues is sharply increased. The congenital deficiency of a1-antitrypsin results in the lung emphysema.

Fibronectin – glycoprotein of blood plasma that is synthesized and secreted in intercellular space by different cells. Fibronectin present on a surface of cells, on the basalmembranes, in connective tissue and in blood. Fibronectin has properties of a «sticking» protein and contacts with the carbohydrate groups of gangliosides on a surface of plasma membranes executing the integrative function in intercellular interplay. Fibronectin also plays important role in the formation of the pericellular matrix.

Haptoglobin - protein of a2-globulin fraction of  blood plasma. Haptoglobin has capacity to bind a free haemoglobin forming a complex that refer to b-globulins electrophoretic fraction. Normal concentration in blood plasma - 0,10-0,35 g/l.

Haptoglobin-hemoglobin complexes are absorbed by the cells of reticulo-endothelial system, in particular in a liver, and oxidized to cholic pigments. Such haptoglobinfunction promotes the preservation of iron ions in an organism under conditions of a physiological and pathological erythrocytolysis.

Transferrin - glycoprotein belonging to the b-globulin fraction. It binds in a blood plasma iron ions (Fe3+). The protein has on the surface two centers of linkage of iron.Transferrin is a transport form of iron delivering its to places of  accumulation and usage.

Ceruloplasmin - glycoprotein of the a2-globulin fraction. It can bind the copper ions in blood plasma. Up to 3 % of all copper contents in an organism and more than 90 % copper contents in plasma is included in ceruloplasminCeruloplasmin has properties of ferroxidase oxidizing the iron  ions. The decrease of ceruloplasmin in organism (Wilson disease) results in exit of copper ions from vessels and its accumulation in the connective tissue that shows by pathological changes in a liver, main brain, cornea.

The place of synthesis of each fraction and subfruction of blood plasma proteins.

Albumins, a1-globulins, fibrinogen are fully synthesized in hepatocytes. Immunoglobulins are produced by plasmocytes (immune cells). In liver cryoglobulins and some other  g-globulins are produced too.  a2-globulins and b-globulins are partly synthesized in liver and partly in reticuloendothelial cells.

Causes and consequences of protein content changes in blood plasma.

Hypoproteinemia  - decrease of the total contents of proteins in blood plasma. This state occurs in old people as well as in pathological states accompanying with the oppressing of protein synthesis (liver diseases) and activation of decomposition of tissue proteins (starvation, hard infectious diseases, state after hard trauma and operations, cancer). Hypoproteinemia (hypoalbuminemia) also occurs in kidney diseases, when the increased excretion of proteins via the urine takes place.

Hyperproteinemia  - increase of the total contents of proteins in blood plasma. There are two types of  hyperproteinemia - absolute and relative.

Absolute hyperproteinemia – accumulation of the proteins in blood. It occurs in infection and inflammatory diseases (hyperproduction of immunoglobulins),  rheumatic diseases (hyperproduction of C-reactive protein), some malignant tumors (myeloma) and others.

Relative hyperproteinemia – the increase of the protein concentration but not the absolute amount of proteins. It occurs when organism loses water (diarrhea, vomiting, fever, intensive physical activity etc.).

The principle of the measurement of protein fractions by electrophoresis method.    

Electrophoresis is the separation of proteins on the basis of their electric charge. It depends ultimately on their base-acid properties, which are largely determined by the number and types of ionizable R groups in their polipeptide chains. Since proteins differ in amino acid composition and sequence, each protein has distinctive acid-base properties. There are a number of different forms of electroforesis useful for analyzing and separating mixtures of proteins



Residual nitrogen, its components, ways of their formation, blood content


The state of protein nutrition can be determined by measuring the dietary intake and output of nitrogenous compounds from the body. Although nucleic acids also contain nitrogen, protein is the major dietary source of nitrogen and measurement of total nitrogen intake gives a good estimate of protein intake (mg N Ч 6.25 = mg protein, as nitrogen is 16% of most proteins). The output of nitrogen from the body is mainly in urea and smaller quantities of other compounds in urine and undigested protein in feces, and significant amounts may also be lost in sweat and shed skin.

The difference between intake and output of nitrogenous compounds is known as nitrogen balance. Three states can be defined: In a healthy adult, nitrogen balance is in equilibrium when intake equals output, and there is no change in the total body content of protein. In a growing child, a pregnant woman, or in recovery from protein loss, the excretion of nitrogenous compounds is less than the dietary intake and there is net retention of nitrogen in the body as protein, ie, positive nitrogen balance. In response to trauma or infection or if the intake of protein is inadequate to meet requirements there is net loss of protein nitrogen from the body, ie, negative nitrogen balance. The continual catabolism of tissue proteins creates the requirement for dietary protein even in an adult who is not growing, though some of the amino acids released can be reutilized.

Nitrogen balance studies show that the average daily requirement is 0.6 g of protein per kilogram of body weight (the factor 0.75 should be used to allow for individual variation), or approximately 50 g/d. Average intakes of protein in developed countries are about 80–100 g/d, ie, 14–15% of energy intake. Because growing children are increasing the protein in the body, they have a proportionately greater requirement than adults and should be in positive nitrogen balance. Even so, the need is relatively small compared with the requirement for protein turnover. In some countries, protein intake may be inadequate to meet these requirements, resulting in stunting of growth.

Residual nitrogennonprotein nitrogen, that is nitrogen of organic and inorganic compounds that remain in blood after protein sedimentation.

Organic and inorganic compounds of residual nitrogen are as follows: urea (50 % of the residual nitrogen), amino acids (25 %), creatine and creatinine (7,5 %), salts of ammonia and indicane (0,5 %), other compounds (about 13 %).

Urea is formed in liver during the degradation of amino acids, pyrimidine nucleotides and other nitrogen containing compounds. Amino acids are formed as result of protein decomposition or owing to the conversion of fatty acids or carbohydrates to amino acids. The pool of amino acids in blood is also supported by the process of their absorption in intestine. Creatine is produced in kidneys and liver from amino acids glycine and arginine, creatinine is formed in muscles as result of creatine phosphate splitting. In result of ammonia neutralization the ammonia salts can be formed. Indicane is the product of indol neutralization in the liver.;_ylu=X3oDMTA4NDgyNWN0BHNlYwNwcm9m/SIG=12h1aoilr/EXP=1176732914/**http%3A/;_ylu=X3oDMTA4NDgyNWN0BHNlYwNwcm9m/SIG=12b3o76ni/EXP=1176733010/**http%3A/

Creatinine Urine Test

Creatinine Urine

The content of residual nitrogen in blood is 0,2 – 0,4 g/l.

 The pathways of convertion of amino acid nonnitrogen residues.

The removal of the amino group of an amino acid by transamination or oxidative deamination produces an α-keto acid that contains the carbon skeleton from the amino acid (nonnitrogen residues). These α-keto acids can be used for the biosynthesis of non-essential amino acids or undergoes a different degradation process. For alanine and serine, the degradation requires a single step. For most carbon arrangements, however, multistep reaction sequences are required.  There are only seven degradation sequences for 20 amino acids. The seven degradation products are pyruvate, acetyl CoA, acetoacetyl CoA, α-ketoglutarate, succinyl CoA, fumarate, and oxaloacetate. The last four products are intermediates in the citric acid cycle. Some amino acids have more than one pathway for degradation.

The major point of entry into the tricarboxylate cycle is via acetyl-CoA; 10 amino acids enter by this route. Of these, six (alanine, glycine, serine, threonine, tryptophan and cysteine) are degraded to acetyl-CoA via pyruvate, five (phenylalanine, tyrosine, leucine, lysine, and tryptophan) are degraded via acetoacetyl-CoA, and three (isoleucine, leucine and tryptophan) yield acetyl-CoA directly.  Leucine and tryptophan yield both acetoacetyl-CoA and acetyl-CoA as end products.

The carbon skeletons of five amino acids (arginine, histidine, glutamate, glutamine and proline) enter the tricarboxylic acid cycle via a-ketoglutarate.

The carbon skeletons of methionine, isoleucine, and valine are ultimately degraded via propionyl-CoA and methyl-malonyl-CoA to succinyl-CoA; these amino acids are thus glycogenic.

Fumarate is formed in catabolism of phenylalanine, aspartate and tyrosine.

Oxaloacetate is formed in catabolism of aspartate and asparagine. Aspartate is converted to the oxaloacetate by transamination.

Amino acids that are degraded to citric acid cycle intermediates can serve as glucose precursors and are called glucogenic. A glucogenic amino acid is an amino acid whose carbon-containing degradation product(s) can be used to produce glucose via gluconeogenesis.

Amino acids that are degraded to acetyl CoA or acetoacetyl CoA can contribute to the formation of fatty acids or ketone bodies and are called ketogenic. A ketogenic amino acid is an amino acid whose carbon-containing degradation product(s) can be used to produce ketone bodies.

Amino acids that are degraded to pyruvate can be either glucogenic or ketogenic. Pyruvate can be metabolized to either oxaloacetate (glucogenic) or acetyl CoA (ketogenic).

Only two amino acids are purely ketogenic: leucine and lysine. Nine amino acids are both glucogenic and ketogenic: those degraded to pyruvate (alanine, glycine, cysteine, serine, threonine, tryptophan), as well as tyrosine, phenylalanine, and isoleucine (which have two degradation products). The remaining nine amino acids are purely glucogenic (arginine, asparagine, aspartate, glutamine, glutamate, valine,  histidine, methionine, proline)


Clinical significance of residual nitrogen measurement in blood. The kinds of azotemia.

Azotemia  - increase of the residual nitrogen content in blood. There are two kinds of azotemia: absolute and relative.

Absolute azotemiaaccumulation of the components of residual nitrogen in blood. Relative azotemia occurs in dehydration of the organism (diarrhea, vomiting).

Absolute azotemia can be divided on the productive azotemia and retention azotemia. Retention azotemia is caused by the poor excretion of the nitrogen containing compounds via the kidneys; in this case the entry of nitrogen containing compounds into the blood is normal.

Retention azotemia can be divided on the renal and extrarenal. Renal retention azotemia occurs in kidney diseases (glomerulonephritis, pyelonephritis, kidney tuberculosis et c.). Extrarenal retention azotemia is caused by the violations of kidney hemodynamic and decrease of glomerulus filtration processes (heart failure, local disorders of kidney hemodynamic).

Productive azotemia is conditioned by the enhanced entry of nitrogen containing compounds into the blood. The function of kidneys in this case doesn’t suffer. Productive azotemia can be observed in cachexia, leukoses, malignant tumors, treatment by glucocorticoids.

Prerenal Azotemia

Alternate Names : Azotemia - Prerenal, Renal Underperfusion, Uremia

Kidney Anatomy

Kidney Anatomy


Azotemia is a medical condition characterized by abnormal levels of urea, creatinine, various body waste compounds, and other nitrogen-rich compounds in the blood as a result of insufficient filtering of the blood by the kidneys.

Uremia can be used as a synonym, or can be used to indicate severe azotemia, in which symptoms are produced.

Azotemia can be classified according to its cause. In prerenal azotemia the blood supply to the kidneys is inadequate. In postrenal azotemia the urinary outflow tract is obstructed. Other forms of azotemia are caused by diseases of the kidneys themselves.

Other causes of azotemia include congestive heart failure, shock, severe burns, prolonged vomiting or diarrhea, some antiviral medications, liver failure, or trauma to the kidney(s).

Signs and symptoms (prerenal azotemia)

  • Decreased or absent urine output

  • Fatigue

  • Decreased alertness

  • Confusion

  • Pale skin color

  • Rapid pulse

  • Dry mouth

·              Thirst, swelling (edema, anasarca)

·              Orthostatic blood pressure (rises or falls, significantly depending on position)

A urinalysis will typically show a decreased urine sodium level, a high urine creatinine-to- serum creatinine ratio, a high urine urea-to-serum urea ratio, and concentrated urine (determined by osmolality and specific gravity). None of these is particularly useful in diagnosis.

Prompt treatment of some causes of azotemia can result in restoration of kidney function; delayed treatment may result in permanent loss of renal function. Treatment may include hemodialysis or peritoneal dialysis, medications to increase cardiac output and increase blood pressure, and the treatment of the condition that caused the azotemia to begin with. NOTE: Azotemia is not diagnosed with abnormally high levels of Creatinine. Azotemia simply refers to an elevated level of urea in the blood.

Added Note: Uremia is not azotemia. Azotemia is one of many clinical characteristics of uremia, which is a syndome characteristic of renal disease. Uremia includes Azotemia, as well as acidosis, hyperkalemia, hypertension, anemia and hypocalcemia along with other findings.


Lipoproteins and Apoproteins

Lipids are a group of fatty substances that includes triglycerides (fat), phospholipids and sterols (e.g. cholesterol).  They constitute an important source of energy, serve as precursors for a number of essential compounds, and are key components of cells and tissues.  Cholesterol, for example, is an indispensable constituent of cellular membranes (1), as well as the precursor for both steroid hormones and bile acids.  On average, the body utilizes approximately 1000 milligrams of cholesterol per day, 30% of which comes directly from foods of animal origin, and the rest is synthesized in the liver. Due to the insolubility of cholesterol and other fatty compounds in the blood, their redistribution in the body requires specialized carriers capable of solubilzing, ferrying, and unloading them at specific target sites. Miscarriage of lipids while in circulation may lead to atherosclerosis; a clinical condition marked by fatty deposits in the inner walls of arteries, and the leading cause of death and disability in Western countries.

Most lipids are transported in the blood as part of soluble complexes called lipoproteins (LPs). Plasma LPs are spherical particles composed of a hydrophobic lipid core surrounded by a hydrophilic layer, which renders the particles soluble. The lipid core contains primarily triglycerides (TG) and cholesteryl esters (CE), as well as small amounts of other fatty compounds, such as sphingolipids and fat-soluble vitamins (e.g. vitamins A, D, E, and K). The external layer is made of phospholipids, unesterified cholesterol, and specialized proteins, called apolipoproteins or apoproteins. These proteins facilitate lipid solubilization and help to maintain the structural integrity of LPs. They also serve as ligands for LP receptors and regulate the activity of LP metabolic enzymes. As depicted in (Figure 1), the amphipathic molecules that compose the outer layer of LPs are arranged so that their hydrophobic parts face the central core, and their hydrophilic regions face the surrounding aqueous environment.

Figure 1: Schematic Illustration of a Lipoprotein Particle

Cholesteryl esters, which do not contain a free hydroxyl group (-OH) are more hydrophobic than cholesterol, and better accommodated in the core of LPs. The conversion of cholesterol to CE is catalyzed by a LP-associated enzyme called lecithin-cholesterol acyltransferase (LCAT). This enzyme, which promotes packaging of cholesteryl molecules in LPs, is critical for normal cholesterol metabolism. Deficiency of LCAT activity leads to accumulation of unesterified cholesterol in tissues, and is associated with a number of clinical conditions including corneal opacity, hemolytic anemia, and premature atherosclerosis.

During ordinary metabolism, plasma LPs lose, acquire, and exchange their lipid and protein constituents. Normally, fat-rich LPs lose most of their fat within a few hours of food ingestion, and become smaller and denser particles with higher relative cholesterol content. The depletion of fat from LPs is catalyzed by lipoprotein lipase (LPL). This lipolytic enzyme is located on the surface of endothelial capillaries, and degrades triglycerides to free fatty acids (FFAs) and glycerol. The released FFAs may stay in circulation bound to albumin, or be taken-up by muscle and fat cells for usage and storage, respectively.

Lipids of dietary origin are processed by intestinal epithelial cells, and then secreted into the bloodstream as part of large, fat-rich LPs called chylomicrons (chylo = milky, micron= indicates particle size).  En route to the liver, chylomicrons (CM) pass through endothelial capillaries, lose some fat, and their remnants are taken-up by liver cells. In the liver, the lipids obtained from CM remnants are re-processed and then secreted back into the bloodstream as part of very low-density LPs (VLDL). Depletion of fat from VLDL transforms the particle into an intermediate density lipoprotein (IDL), which upon further degradation of its fat is converted into a relatively stable particle, called low density lipoprotein (LDL). Because of its high cholesterol content, LDL is also called LDL-cholesterol. Of the total blood cholesterol, 60-75% is found in LDL and the rest primarily in high-density lipoprotein (HDL) particles. The main characteristics of plasma LPs and their associated apoproteins are summarized in (Tables I and II), respectively.

All peripheral cells express the LDL-receptor (LDLR), and recycle it to the cell surface upon need for cholesterol. Cholesterol is delivered to these cells through binding of LDL to LDLR, which triggers endocytosis (internalization) of both species. When the need for cholesterol is satisfied, the recycling of LDLR is discontinued.  Normally, an LDL particle stays in circulation for no more than a few days before being consumed by a cholesterol needing cell. However, under conditions of sustained cholesterol excess, the particle stays in circulation for longer periods of time, and becomes more vulnerable to undesired modifications (e.g. oxidation). As high levels of oxidized LDL are commonly found in atherosclerotic plaques, they are thought to be the major inducer of atherosclerotic lesions. Hence, LDL became known as bad cholesterol. However, today we know that not all LDL particles are bad, and that some LDL particles, especially very large ones (with diameter >21.3nm), may even provide protection against atherosclerosis (2).  LDL and HDL particle sizes are largely determined by a LP-associated protein, called CETP (cholesteryl ester transfer protein). This protein enhances exchange of non-polar lipids, primarily CE and TG, and facilitates tight packaging of CE within the core of the particles. The end result of prolonged and/or efficient CETP action is smaller LDL and HDL particles. [The LP-anchored CETP can be envisioned as having a hand that rotates between the interior and exterior of the particle and  capable of holding only one lipid molecule at a time. Grasping of one molecule releases another and vise versa.]

Genetic variation at the human CETP gene generates proteins with varying degrees of activity.  For example, a single codon variation, from isoleucine to valine at position 405, generates a mutant protein, designated I405V, which manifests significantly reduced CETP activity (3, 4). In a new observational study, Barzilai, N. et al. (2) found that people with homozygosity for the I405V allele have larger HDL and LDL particles, and that this genotype is associated with exceptional longevity and a markedly reduced risk of coronary artery disease (CAD). Of the 213 centenarians enrolled in the study, 80% had a high proportion of large LDL particles, compared to just 8% of the subjects in the control group (256 people in their 60’s and 70’s) (2). Interestingly, HDL and LDL particle sizes are significantly larger in women than in men, which may account, at least in part, for the longer life expectancies of women.

Unlike LDL, HDL is not recognized by LDLR, and cannot deliver cholesterol to tissue cells. Instead, it has the ability to remove excess peripheral cholesterol and return it to the liver for recycling and excretion. This process, called reverse cholesterol transport, is thought to protect against atherosclerosis. Observational studies over the last 2 decades have consistently shown strong correlation between elevated HDL levels and low incidents of coronary heart disease (CHD). Hence HDL has been dubbed “good” cholesterol.

HDL is synthesized in the liver and intestine as a nascent, discoid-shaped particle that contains predominantly apoA-I, and some phospholipids. Upon maturation, HDL assumes a spherical shape, and the composition of its core lipids becomes very similar to that of LDL. However, the relative higher protein content in HDL renders the particle denser and more resistant to undesired modifications. Unlike the case of LDL, the clearance of HDL from circulation is not negatively affected by excess cholesterol, which may be another reason why HDL, despite being much smaller particle than LDL (10nm versus 20nm), is not found in atherosclerotic plaques. It’s worth noting, that the potential of LPs to become harmful is also influenced by the character of their lipid constituents. For example, vitamin E and lipids containing omega-3 fatty acid moieties appear to protect the particles from harmful oxidation and from getting stuck on the walls of blood vessels.

The functional difference between LDL and HDL results primarily from the different character of their major apoproteins, apoB-100 and apoA-I, respectively.  ApoB-100, which is found in VLDL, IDL, and LDL, but not in HDL, serves as a ligand for LDLR, and provides LDL with the means to deliver cholesterol to tissue cells. On the other hand, apoA-I, which is found exclusively in HDL, has a unique ability to capture and solubilze free cholesterol. This apoA-I ability enables HDL to act as a cholesterol scavenger.

A mutant apoA-I protein, called apoA-I Milano (apoA-Im), has been identified in a group of people that live in a small village in northern Italy (5). Carriers of this protein, all heterozygous for the mutation, had very low levels of HDL (7-14 mg/dl) but showed no clinical signs of atherosclerosis (5-7). HDL particles in these subjects were markedly larger than control (12nm versus 9.4nm), which may account for their immunity against premature atherosclerosis.  ApoA-Im differs from natural apoA-I by having a cysteine residue at position 173 instead of arginine. This cysteine residue forms disulfide bridges with other apoA-I molecules or with apoA-II (6, 7), which apparently lead to larger HDL particles. It also renders apoA-I more susceptible to catabolism (8), accounting for the low HDL levels in apoA-Im carriers.

The therapeutic potential of apoA-I has been recently assessed in patients with acute coronary syndromes (9). Of the 47 patients that participated in a randomized controlled trial, 36 received 5 weekly infusions of recombinant apoA-Im/phospholipid complexes, and 11 received only saline infusions. The results showed significant regression in coronary atherosclerotic volume in the apoA-Im treated group, and virtually no change in the control group (9). These results, if reproduced in larger clinical trials, may constitute a revolutionary breakthrough in the non-invasive treatment of cardiovascular disease. They should also encourage further exploration into the therapeutic usefulness of apoA-Im and normal apoA-I in managing atherosclerotic vascular diseases.



The lilipoproteins - Any of the series of soluble lipid-protein complexes which are transported in the blood; each aggregate particle consists of a spherical hydrophobic core containing triglycerides and cholesterol esters surrounded by an amphipathic monolayer of phopholipids, cholesterol and apolipoproteins; classes of lipoproteins include chylomicrons, very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL).

chylomicrons - The class of largest diameter soluble lipid-protein complexes which the lowest in density (mass to volume ratio); their composition is ~2% apolipoproteins, ~5% cholesterol, and ~93% triglycerides and phospholipids; their normal role is to be synthesized by the intestinal mucosal cells to transport dietary (exogenous) triglycerides and other lipids from the intestines via the lacteals and lymphatic system to the systemic circulation to the adipose tissue and liver for storage and use; they are only present in the blood in significant quantities after the digestion of a meal.

low-density lipoproteins (LDL) - The class of large diameter soluble lipid-protein complexes which the fourth lowest in density (mass to volume ratio); their composition is ~25% apolipoproteins, ~45% cholesterol, and ~30% triglycerides and phospholipids; their normal role is to transport cholesterol and other lipids from the liver and intestines to the tissues for use; elevated levels of LDL are associated with increased risk of cardiovascular disease.  nickname - bad cholesterol

high-density lipoproteins (HDL) - The class of small diameter soluble lipid-protein complexes which the highest in density (mass to volume ratio); their composition is ~45% apolipoproteins, ~25% cholesterol, and ~30% triglycerides and phospholipids; their normal role is to transport cholesterol and other lipids from the tissues to the liver for disposal; elevated levels of HDL are associated with decreased risk of cardiovascular disease.

very low-density lipoproteins (VLDL) - The class of very large diameter soluble lipid-protein complexes which the second lowest in density (mass to volume ratio); their composition is ~10% apolipoproteins, ~40% cholesterol, and ~50% triglycerides and phospholipids; their normal role is to transport triglycerides and other lipids from the liver and intestines to the tissues for use; elevated levels of VLDL are associated with some increased risk of cardiovascular disease.

formation of lipoproteins

Cholesterol diagram showing HDL  (good) lipoproteins help to eliminate LDL (bad) lipoproteins from the blood.


What is Cholesterol?

Cholesterol is a waxy fat found in the body and, despite what you may have been told, is a necessary nutrient for the body. Cholesterol is used in the formation of cell membranes and plays an important role in hormone, bile and vitamin D production. Cholesterol comes from two sources: the foods that we eat, such as meat, dairy products and eggs, and our own liver, which produces about eighty percent of all the cholesterol in the body. That means that only about twenty percent of our total cholesterol is obtained from food. Since cholesterol is not water-soluble, the liver packages the cholesterol into tiny spheres called lipoproteins so that the cholesterol can be transported through the blood. The lipoproteins can be divided into two different categories: low density and high density lipoproteins.


Low density lipoprotein (LDL): LDL, often dubbed the "bad" cholesterol, carries most of the cholesterol in the blood and seems to play a role in the deposition of fat in arteries. These deposits result in blockages called plaque. In addition to narrowing the arteries and increasing blood pressure, plaque contributes to the hardening of artery walls, a condition known as atherosclerosis.

LDL lipoproteins

High density lipoprotein (HDL): HDL is known as the "good" cholesterol. HDL carries cholesterol from the blood back to the liver for elimination. It is also responsible for removing the plaque buildup along the artery walls. Elevated levels of HDL are very desirable because it helps to clear blockages in the arteries, reduces LDL and decreases blood pressure.

HDL lipoproteins

What are Triglycerides?

Triglycerides are lipids normally found in increased levels in the blood following the digestion of fats in the intestine. Consumed calories that are not immediately used are stored in fat cells in the form of triglycerides and are later released from fatty tissues when the body needs energy between meals. The major transporter of triglycerides is a forerunner of LDL, a simpler molecule known as VLDL (very low density lipoprotein). As the VLDL loses triglycerides, the VLDL particle is converted into intermediate and then low density lipoprotein. Over time, elevated triglyceride levels may result in pancreatitis—a condition that can cause malabsorption of nutrients and lead to diabetes. As pancreatitis progresses, damage can spread to other organs, including the heart, lungs and kidneys. High triglyceride levels also promote the deposition of cholesterol in the arteries and are associated with known risk factors for heart disease. The exact role that triglycerides play as an independent risk factor is not yet clear because people with high LDL and low HDL levels also have high triglyceride levels.

Coronary artery cross-section showing plaque build up and blockage.

Although These Researchers Beg to Differ…

One study by Koren-Morag, Graff and Goldbourt, published in the American Heart Association journal Circulation, found that individuals with elevated triglyceride levels have a nearly thirty percent increased probability of suffering a stroke, even after taking into account other risk factors such as cholesterol levels. One of the most important aspects of the study is that it clarifies the independent link of triglyceride levels to stroke, meaning that a causal relationship is likely.

What is Plaque?

Excess LDL cholesterol clings to arterial walls as it is transported through the system. Macrophages eat the LDL and become "foam cells." The cells eventually rupture and begin to form a lipid layer called plaque. Connective fibers form in and around the fatty layer, causing it to harden. Over time, the fibrous layer thickens, narrowing the arterial pathway. When calcium deposits form a crust, the plaque becomes brittle and is more likely to rupture.

The Problem With Plaque

High blood cholesterol levels increase the likelihood that the fat will be deposited as plaque on the inner surface of arterial walls. As these deposits increase, the channel of the artery narrows, contributing to an increase in blood pressure. To compensate, the heart must work harder to pump the same volume of blood through the narrower arteries. When the coronary arteries themselves are affected by plaque, the harder working heart receives less oxygen, thus increasing the risk of heart attack. Plaque also contributes to hardening of the arteries, or atherosclerosis. This loss of flexibility in arterial walls elevates blood pressure, putting the heart at additional risk. When the plaque deposits become unstable, they burst, releasing their cholesterol into the bloodstream all at once. This can trigger clotting in small coronary arteries. When the artery is completely obstructed, blood flow stops and a heart attack occurs.


What is a Lipoprotein?

Lipids, such as triacylglycerols and cholesterol esters, are virtually insoluble in aqueous solution. Therefore, lipids must be transported by the circulation in COMPLEX WITH water-soluble PROTEINS.

This complex LIPOPROTEIN is a globular micelle-like particle that consists of a nonpolar core of triacylglycerols and cholesterol esters surrounded by an amphiphilic coating of protein, phospholipid, and cholesterol.

Here is a diagram of Low-Density Lipoprotein (LDL) which is approximately 25nm in diameter:


You need "Quick Time" Player and Plug-In to view this LDL particle in motion:



Characteristics of Lipoproteins in Human Plasma







Density (g/cm)






Particle Diameter (nm)






Particle Mass (kD)


















%Free Cholesterol












%Cholesteryl Esters






Major Apolipoproteins






Surface Components

Core Lipids  

VLDLy Found in Egg Yolk

"VLDLy" was coined to signify specific lipoproteins that selectively deposit triacylglycerol to yolk follicles.

The average size of a VLDLy particle is 30nm, whereas a generic VLDL particle is approximately 70 nm.


VLDLy Metabolism

Watch us Assemble


Theoretically, a 17g egg yolk that contains 2.8g of protein would contain 1.4g of apoB (49% total yolk protein, MW = 5.5 x 105). Because VLDLy contains only one apoB protein per particle, this single egg yolk would contain 1.5 x 1018 VLDLy particles. The hen would be producing VLDLy particles at a rate of 1.5 x 1014 particles per minute for seven days!


Biochemistry of immune processes.

Viruses, bacteria, fungi, and parasites that enter the body of vertebrates of are recognized and attacked by the immune system. Endogenous cells that have undergone alterations— e. g., tumor cells—are also usually recognized as foreign and destroyed. The immune system is supported by physiological changes in infected tissue, known as inflammation. This reaction makes it easier for the immune cells to reach the site of infection. Two different systems are involved in the immune response. The innate immune system is based on receptors that can distinguish between bacterial and viral surface structures or foreign proteins (known as antigens) and those that are endogenous. With the help of these receptors, phagocytes bind to the pathogens, absorb them by endocytosis, and break them down. The complement system (see p. 298) is also part of the innate system. The acquired (adaptive) immune system is based on the ability of the lymphocytes to form highly specific antigen receptors “on suspicion,” without ever having met the corresponding antigen. In humans, there are several billion different lymphocytes, each of which carries a different antigen receptor. If this type of receptor recognizes “its” cognate antigen, the lymphocyte carrying it is activated and then plays its special role in the immune response. In addition, a distinction is made between cellular and humoral immune responses.

The T lymphocytes (T cells) are responsible for cellular immunity. They are named after the thymus, in which the decisive steps in their differentiation take place. Depending on their function, another distinction is made between cytotoxic T cells (green) and helper T cells (blue).

Humoral immunity is based on the activity of the B lymphocytes (B cells, light brown), which mature in the bone marrow. After activation by T cells, B cells are able to release soluble forms of their specific antigen receptors, known as antibodies (see p. 300), into the blood plasma. The immune system’s “memory” is represented by memory cells. These are particularly long–lived cells that can arise from any of the lymphocyte types described. Simplified diagram of the immune response.

Pathogens that have entered the body—e. g., viruses (top)—are taken up by antigen-presenting cells (APCs) and proteolytically degraded (1). The viral fragments produced in this way are then presented on the surfaces of these cells with the help of special membrane proteins (MHC proteins; see p. 296) (2). The APCs include B lymphocytes, macrophages, and dendritic cells such as the skin’s Langerhans cells. The complexes of MHC proteins and viral fragments displayed on the APCs are recognized by T cells that carry a receptor that matches the antigen (“T-cell receptors”) (3). Binding leads to activation of the T cell concerned and selective replication of it (4, clonal selection”).

The proliferation of immune cells is stimulated by interleukins (IL). These are a group of more than 20 signaling substances belonging to the cytokine family (see p. 392), with the help of which immune cells communicate with each other. For example, activated macrophages release IL-1 (5), while T cells stimulate their own replication and that of other immune cells by releasing IL-2 (6). Depending on their type, activated T cells have different functions. Cytotoxic T cells (green) are able to recognize and bind virusinfected body cells or tumor cells (7). They then drive the infected cells into apoptosis (see p. 396) or kill them with perforin, a protein that perforates the target cell’s plasma membrane (8). B lymphocytes, which as APCs present viral fragments on their surfaces, are recognized by helper T cells (blue) or their T cell receptors (9). Stimulated by interleukins, selective clonal replication then takes place of B cells that carry antigen receptors matching those of the pathogen (10). Thesemature into plasma cells (11) and finally secrete large amounts of soluble antibodies (12).

         Antigen receptors

Many antigen receptors belong to the immunoglobulin superfamily. The common characteristic of these proteins is that they aremade up from “immunoglobulin domains.” These are characteristically folded substructures consisting of 70–110 amino acids, which are also found in soluble immunoglobulins (Ig; see p. 300). The illustration shows schematically a few of the important proteins in the Ig superfamily. They consist of constant regions (brown or green) and variable regions (orange). Homologous domains are shown in the same colors in each case. All of the receptors have transmembrane helices at the C terminus, which anchor them to the membranes. Intramolecular and intermolecular disulfide bonds are also usually found in proteins belonging to the Ig family. Immunoglobulin M (IgM), a membrane protein on the surface of B lymphocytes, serves to bind free antigens to the B cells. By contrast, T cell receptors only bind antigens when they are presented by another cell as a complex with an MHC protein (see below). Interaction between MHC-bound antigens and T cell receptors is supported by co-receptors. This group includes CD8, a membrane protein that is typical in cytotoxic T cells. T helper cells use CD4 as a co-receptor instead (not shown). The abbreviation “CD” stands for “cluster of differentiation.” It is the term for a large group of proteins that are all located on the cell surface and can therefore be identified by antibodies. In addition to CD4 and CD8, there are many other co-receptors on immune cells

The MHC proteins are named after the “major histocompatibility complex”—the DNA segment that codes for them. Human MHC proteins are also known as HLA antigens (“human leukocyte-associated” antigens). Their polymorphism is so large that it is unlikely that any two individuals carry the same set of MHC proteins—except formonozygotic twins. Class I MHC proteins occur in almost all nucleated cells. They mainly interact with cytotoxic T cells and are the reason for the rejection of transplanted organs. Class I MHC proteins are heterodimers (áâ). The â subunit is also known as â2-microglobulin. Class II MHC proteins also consist of two peptide chains, which are related to each other. MHC II molecules are found on all antigen- presenting cells in the immune system. They serve for interaction

T-cell activation The illustration shows an interaction between a virus-infected body cell (bottom) and a CD8- carrying cytotoxic T lymphocyte (top). The infected cell breaks down viral proteins in its cytoplasm  and transports the peptide fragments into the endoplasmic reticulum with the help of a special transporter (TAP) . Newly synthesized class I MHC proteins on the endoplasmic reticulum are loaded with one of the peptides  and then transferred to the cell surface by vesicular transport . The viral peptides are bound on the surface of the á2 domain of the MHC protein in a depression formed by an insertion as a “floor” and two helices as “walls” (see smaller illustration). Supported by CD8 and other co-receptors, a T cell with a matching T cell receptor binds to the MHC peptide complex (5). This binding activates protein kinases in the interior of the T cell, which trigger a chain of additional reactions (signal transduction). Finally, destruction of the virus-infected cell by the cytotoxic T lymphocytes takes place.

Complement system

The complement system is part of the innate immune system. It supports nonspecific defense against microorganisms. The system consists of some 30 different proteins, the “complement factors,” which are found in the blood and represent about 4% of all plasma proteins there. When inflammatory reactions occur, the complement factors enter the infected tissue and take effect there. The complement system works in three different ways: Chemotaxis. Various complement factors attract immune cells that can attack and phagocytose pathogens. Opsonization. Certain complement factors (“opsonins”) bind to the pathogens and thereby mark them as targets for phagocytosing cells (e. g., macrophages). Membrane attack. Other complement factors are deposited in the bacterial membrane, where they create pores that lyse the pathogen (see below).

   The reactions that take place in the complement system can be initiated in several ways. During the early phase of infection, lipopolysaccharides and other structures on the surface of the pathogens trigger the alternative pathway (right). If antibodies against the pathogens become available later, the antigen– antibody complexes formed activate the classic pathway (left). Acute-phase proteins are also able to start the complement cascade (lectin pathway). Factors C1 to C4 (for “complement”) belong to the classic pathway, while factors B and D form the reactive components of the alternative pathway. Factors C5 to C9 are responsible for membrane attack. Other components not shown here regulate the system. As in blood coagulation (see p. 290), the early components in the complement system are serine proteinases, which mutually activate each other through limited proteolysis. They create a self-reinforcing enzyme cascade.


Factor C3, the products of which are involved in several functions, is central to the complement system. The classic pathway is triggered by the formation of factor C1 at IgG or IgM on the surface of microorganisms (left). C1 is an 18-part molecular complex with three different components (C1q, C1r, and C1s). C1q is shaped like a bunch of tulips, the “flowers” of which bind to the Fc region of antibodies (left). This activates C1r, a serine proteinase that initiates the cascade of the classic pathway. First, C4 is proteolytically activated into C4b, which in turn cleaves C2 into C2a and C2b. C4B and C2a together form C3 convertase [1], which finally catalyzes the cleavage of C3 into C3a and C3b. Small amounts of C3b also arise from non-enzymatic hydrolysis of C3.

The classic pathway is triggered by the formation of factor C1 at IgG or IgM on the surface of microorganisms (left). C1 is an 18-part molecular complex with three different components (C1q, C1r, and C1s). C1q is shaped like a bunch of tulips, the “flowers” of which bind to the Fc region of antibodies (left). This activates C1r, a serine proteinase that initiates the cascade of the classic pathway. First, C4 is proteolytically activated into C4b, which in turn cleaves C2 into C2a and C2b. C4B and C2a together form C3 convertase [1], which finally catalyzes the cleavage of C3 into C3a and C3b. Small amounts of C3b also arise from non-enzymatic hydrolysis of C3. The alternative pathway starts with the binding of factors C3b and B to bacterial lipopolysaccharides (endotoxins). The formation of this complex allows cleavage of B by factor D, giving rise to a second form of C3 convertase (C3bBb). Proteolytic cleavage of factor C3 provides two components with different effects. The reaction exposes a highly reactive thioester group in C3b, which reacts with hydroxyl or amino groups. This allows C3b to bind covalently to molecules on the bacterial surface (opsonization, right). In addition, C3b initiates a chain of reactions leading to the formation of the membrane attack complex Together with C4a and C5a (see below), the smaller product C3a promotes the inflammatory reaction and has chemotactic effects. The “late” factors C5 to C9 are responsible for the development of the membrane attack complex (bottom). They create an ion-permeable pore in the bacterial membrane, which leads to lysis of the pathogen. This reaction is triggered by C5 convertase [2]. Depending on the type of complement activation, this enzyme has the structure C4b2a3b or C3bBb3b, and it cleaves C5 into C5a and C5b. The complex of C5b and C6 allows deposition of C7 in the bacterial membrane. C8 and numerous C9 molecules—which form the actual pore—then bind to this core. Antibodies


   Soluble antigen receptors, which are formed by activated B cells (plasma cells; see p. 294) and released into the blood, are known as antibodies. They are also members of the immunoglobulin family (Ig; see p. 296). Antibodies are an important part of the humoral immune defense system. They have no antimicrobial properties themselves, but support the cellular immune system in various ways: 1. They bind to antigens on the surface of pathogens and thereby prevent them from interacting with body cells (neutralization; see p. 404, for example). 2. They link single-celled pathogens into aggregates (immune complexes), which are more easily taken up by phagocytes (agglutination). 3. They activate the complement system (see p. 298) and thereby promote the innate immune defense system (opsonization). In addition, antibodies have become indispensable aids in medical and biological diagnosis.

Domain structure of immunoglobulin G

Type G immunoglobulins (IgG) are quantitatively the most important antibodies in the blood,where they form the fraction of ã-globulins (see p. 276). IgGs (mass 150 kDa) are tetramers with two heavy chains (H chains; red or orange) and two light chains (L chains; yellow). Both H chains are glycosylated (violet; see also p. 43). The proteinase papain cleaves IgG into two Fab fragments and one Fc fragment. The Fab (“antigen-binding”) fragments, which each consist of one L chain and the N-terminal part of an H chain, are able to bind antigens. The Fc (“crystallizable”) fragment is made up of the C-terminal halves of the two H chains. This segment serves to bind IgG to cell surfaces, for interaction with the complement system and antibody transport. Immunoglobulins are constructed in a modular fashion from several immunoglobulin domains (shown in the diagram on the right in Ω form).

Classes of immunoglobulins

Human immunoglobulins are divided into five classes. IgA (with two subgroups), IgD, IgE, IgG (with four subgroups), and IgM are defined by their H chains, which are designated by the Greek letters á, ä, å, ã, and µ. By contrast, there are only two types of L chain (ê and ë). IgD and IgE (like IgG) are tetramers with the structure H2L2. By contrast, soluble IgA and IgM are multimers that are held together by disulfide bonds and additional J peptides (joining peptides). The antibodies have different tasks. IgMs are the first immunoglobulins formed after contact with a foreign antigen. Their early forms are located on the surface of B cells (see p. 296), while the later forms are secreted from plasma cells as pentamers. Their action targets microorganisms in particular. Quantitatively, IgGs are the most important immunoglobulins (see the table showing serum concentrations). They occur in the blood and interstitial fluid. As they can pass the placenta with the help of receptors, they can be transferred from mother to fetus. IgAs mainly occur in the intestinal tract and in body secretions. IgEs are found in low concentrations in the blood. As they can trigger degranulation of mast cells (see p. 380), they play an important role in allergic reactions. The function of IgDs is still unexplained. Their plasma concentration is also very low.



Causes of antibody variety

There are three reasons for the extremely wide variability of antibodies: 1. Multiple genes. Various genes are available to code for the variable protein domains. Only one gene from among these is selected and expressed. 2. Somatic recombination. The genes are divided into several segments, of which there are various versions. Various (“untidy”) combinations of the segments during lymphocyte maturation give rise to randomly combined new genes (“mosaic genes”). 3. Somaticmutation. During differentiation of B cells into plasma cells, the coding genes mutate. In this way, the “primordial” germline genes can become different somatic genes in the individual B cell clones.


Biosynthesis of a light chain

We can look at the basic features of the genetic organization and synthesis of immunoglobulins using the biosynthesis of a mouse ê chain as an example. The gene segments for this light chain are designated L, V, J, and C. They are located on chromosome 6 in the germ-line DNA (on chromosome 2 in humans) and are separated from one another by introns (see p. 242) of different lengths. Some 150 identical L segments code for the signal peptide (“leader sequence,” 17–20 amino acids) for secretion of the product

The V segments, of which there are 150 different variants, code formost of the variable domains (95 of the 108 amino acids). L and V segments always occur in pairs—in tandem, so to speak. By contrast, there are only five variants of the J segments (joining segments) at most. These code for a peptide with 13 amino acids that links the variable part of the ê chains to the constant part. A single C segment codes for the constant part of the light chain (84 amino acids). During the differentiation of B lymphocytes, individual V/J combinations arise in each B cell. One of the 150 L/V tandem segments is selected and linked to one of the five J segments.

The immune system is a complex, dynamic, and beautifully orchestrated mechanism with enormous responsibility. It defends against foreign invasion by microorganisms, screens out cancer cells, adapts as we grow, and modifies how we interact with our environment. When it malfunctions, disease, cancer or death can occur. Although it is not necessary to understand all the intimate details of the immune system, it is wise to have a basic grasp of its functions. More precisely, we should understand how to stay healthy.

Training the immune system -- the "J" curve

It appears that the immune system has a training effect, similar to other areas of physiology (e.g., cardiovascular, muscular). In other words, a balanced training program of exercise and rest leads to better performance. Studies in the laboratory and epidemiological observations have shown improved immune function and fewer URIs in athletes as compared to their couch-potato counterparts. This is especially true in older athletes and it appears that regular exercise can help attenuate the age related decline in immune function.

On the other hand, too much exercise can lead to a dramatically increased risk of URIs. The stress of strenuous exercise transiently suppresses immune function. This interruption of otherwise vigorous surveillance can provide an "open window" for a variety of infectious diseases -- notably viral illnesses -- to take hold. This is especially true following single bouts of excessive exercise. For example, it has been observed that two-thirds of participants developed URIs shortly after completing an ultramarathon. Similarly, cumulative overtraining weakens the athlete's immune system, leading to frequent illness and injury.

The best model that accommodates clinical observations and laboratory experiments is described by the "J"-curve ( Fig. 1). It is important to note that this curve is individualized. What is moderate training for some is overtraining for others.

Stress is cumulative

In addition to strenuous exercise, other forms of stress may also transiently suppress immune function. Since exercise is not the only stress factor, an athlete must consider a host of other variables. There are job responsibilities, family obligations, social interactions, financial concerns and other components that shape our lives. The sum of all of these affects a central axis in the body which ultimately influences immune function. Some of these (e.g., exercise) are under our direct control, and others only partially or not at all. Recognizing when excess stress occurs is easier if it just comes from one source. However, all too often it is the sum of many small, difficult to recognize changes that tips the scales and sends the athlete into the whirlpool of overtraining and immunosuppression. Alone and in isolation these small changes would be manageable, but combined they can overwhelm. (Fig. 2.)


Currently, the best way to stay healthy is to listen to your body. Recognizing the early warning signs and adapting the training schedule accordingly can help keep you healthy. In that light, here are some points to ponder and a few recommendations,

·                    Keep a training log. In addition to recording workouts, keep a fatigue score (scale 0-5). It is expected that a hard workout will make you tired, so it is more important to note the cumulative "feel" during the day. Granted, the scale is individualized and subjective, but this simple tool is very useful. If you notice that your fatigue is progressively increasing over days or weeks, then it is time to add more rest.

·                    A properly constructed training program that allows for rest and recovery will help head off problems before they start. Periodization is a way to achieve that goal.

·                    Record your resting morning heart rate. A progressive increase may tip you off that you are exceeding your ability to recover.

·                    Anticipate added stress in advance (e.g. new job) and adjust the workout schedule correspondingly. A small amount of rest early will prevent a bigger problem later.

·                    To make sure your anti-oxidant defense system is tuned up, eat five servings of fruit or vegetables per day. Note: vitamin supplements do not appear to have the same benefits as fruits and vegetables.

·                    Heed your body's early warning signs,

o        Disordered sleep (too much or insomnia)

o        Loss of interest in pleasurable activities

o        Moodiness or depression

o        Excessive muscle soreness

o        Poor concentration. Lack of mental energy.

o        Altered appetite.

o        Frequent injury or illness

o        Lack of physical energy

·                    Get an annual influenza vaccine (usually available each year starting in October)

·                    Because frequent URIs or unrelenting fatigue may be a sign of an underlying illness, it is recommended that you consult your physician.

The Anatomy of the Immune System

The organs of the immune system are stationed throughout the body. They are generally referred to as lymphoid organs because they are concerned with the growth, development, and deployment of lymphocytes, the white cells that are the key operatives of the immune system. Lymphoid organs include the bone marrow and the thymus, as well as lymph nodes, spleen, tonsils and adenoids, the appendix, and clumps of lymphoid tissue in the small intestine known as Peyer's patches. The blood and lymphatic vessels that carry lymphocytes to and from the other structures can also be considered lymphoid organs.

Cells destined to become immune cells, like all other blood cells, are produced in the bone marrow, the soft tissue in the hollow shafts of long bones. The descendants of some so-called stem cells become lymphocytes, while others develop into a second major group of immune cells typified by the large, cell-and particle-devouring white cells known as phagocytes.

The two major classes of lymphocytes are B cells and T cells. B cells complete their maturation in the bone marrow. T cells, on the other hand, migrate to the thymus, a multilobed organ that lies high behind the breastbone. There they multiply and mature into cells capable of producing immune response-that is, they become immunocompetent. In a process referred to as T cell "education," T cells in the thymus learn to distinguish self cells from nonself cells; T cells that would react against self antigens are eliminated.

anatomy of the immune system

Upon exiting the bone marrow and thymus, some lymphocytes congregate in immune organs or lymph nodes. Others-both B and T cells-travel widely and continuously throughout the body. They use the blood circulation as well as a bodywide network of lymphatic vessels similar to blood vessels.

Laced along the lymphatic routes-with clusters in the neck, armpits, abdomen, and groin-are small, bean-shaped lymph nodes. Each lymph node contains specialized compartments that house platoons of B lymphocytes, T lymphocytes, and other cells capable of enmeshing antigen and presenting it to T cells. Thus, the lymph node brings together the several components needed to spark an immune response.

The spleen, too, provides a meeting ground for immune defenses. A fist-sized organ at the upper left of the abdomen, the spleen contains two main types of tissue: the red pulp that disposes of worn-out blood cells and the white pulp that contains lymphoid tissue. Like the lymph nodes, the spleen's lymphoid tissue is subdivided into compartments that specialize in different kinds of immune cells. Microorganisms carried by the blood into the red pulp become trapped by the immune cells known as macrophages. (Although people can live without a spleen, persons whose spleens have been damaged by trauma or by disease such as sickle cell anemia, are highly susceptible to infection; surgical removal of the spleen is especially dangerous for young children and the immunosuppressed.)

Nonencapsulated clusters of lymphoid tissue are found in many parts of the body. They are common around the mucous membranes lining the respiratory and digestive tracts-areas that serve as gateways to the body. They include the tonsils and adenoids, the appendix, and Peyer's patches.

The lymphatic vessels carry lymph, a clear fluid that bathes the body's tissues. Lymph, along with the many cells and particles it carries-notably lymphocytes, macrophages, and foreign antigens, drains out of tissues and seeps across the thin walls of tiny lymphatic vessels. The vessels transport the mix to lymph nodes, where antigens can be filtered out and presented to immune cells.

Additional lymphocytes reach the lymph nodes (and other immune tissues) through the bloodstream. Each node is supplied by an artery and a vein; lymphocytes enter the node by traversing the walls of the very small specialized veins.

lymph node


All lymphocytes exit lymph nodes in lymph via outgoing lymphatic vessels. Much as small creeks and streams empty into larger rivers, the lymphatics feed into larger and larger channels. At the base of the neck, large lymphatic vessels merge into the thoracic duct, which empties its contents into the bloodstream.

Once in the bloodstream, the lymphocytes and other assorted immune cells are transported to tissues throughout the body. They patrol everywhere for foreign antigens, then gradually drift back into the lymphatic vessels, to begin the cycle all over again

Disorders of the Immune System: Allergy


The most common types of allergic reactions-hay fever, some kinds of asthma, and hives-are produced when the immune system response to a false alarm. In a susceptible person, a normally harmless substance-grass pollen or house dust, for example-is perceived as a threat and is attacked.

Such allergic reactions are related to the antibody known as immunoglobulin E. Like other antibodies, each IgE antibody is specific; one reacts against oak pollen, another against ragweed. The role of IgE in the natural order is not known, although some scientists suspect that it developed as a defense against infection by parasitic worms.

The first time an allergy-prone person is exposed to an allergen, he or she makes large amounts of the corresponding IgE antibody. These IgE molecules attach to the surfaces of mast cells (in tissue) or basophils (in the circulation). Mast cells are plentiful in the lungs, skin, tongue, and linings of the nose and intestinal tract.

When an IgE antibody siting on a mast cell or basophil encounters its specific allergen, the IgE antibody signals the mast cell or basophil to release the powerful chemicals stored within its granules. These chemicals include histamine, heparin, and substances that activate blood platelets and attract secondary cells such as eosinophils and neutrophils. The activated mast cell or basophil also synthesizes new mediators, including prostaglandins and leukotrienes, on the spot.

It is such chemical mediators that cause the symptoms of allergy, including wheezing, sneezing, runny eyes and itching. They can also produce anaphylactic shock, a life-threatening allergic reaction characterized by swelling of body tissues, including the throat, and a sudden fall in blood pressure.



Autoimmune Diseases

Sometimes the immune system's recognition apparatus breaks down, and the body begins to manufacture antibodies and T cells directed against the body's own constituents-cells, cell components, or specific organs. Such antibodies are known as autoantibodies, and the diseases they produce are called autoimmune diseases. (Not all autoantibodies are harmful; some types appear to be integral to the immune system's regulatory scheme.)

Autoimmune reactions contribute to many enigmatic diseases. For instance, autoantibodies to red blood cells can cause anemia, autoantibodies to pancreas cells contribute to juvenile diabetes, and autoantibodies to nerve and muscle cells are found in patients with the chronic muscle weakness known as myasthenia gravis. Autoantibody known as rheumatoid factor is common in persons with rheumatoid arthritis.

Persons with systemic lupus erythematosus (SLE), whose symptoms encompass many systems, have antibodies to many types of cells and cellular components. These include antibodies directed against substances found in the cell's nucleus-DNA, RNA, or proteins-which are known as antinuclear antibodies, or ANAs. These antibodies can cause serious damage when they link up with self antigens to form circulating immune complexes, which become lodged in body tissue and set off inflammatory reactions (Immune Complex Diseases).

Autoimmune diseases affect the immune system at several levels. In patients with SLE, for instance, B cells are hyperactive while suppressor cells are underactive; it is not clear which defect comes first. Moreover, production of IL-2 is low, while levels of gamma interferon are high. Patients with rheumatoid arthritis, who have a defective suppressor T cell system, continue to make antibodies to a common virus, whereas the response normally shuts down after about a dozen days.

No one knows just what causes an autoimmune disease, but several factors are likely to be involved. These may include viruses and environmental factors such as exposure to sunlight, certain chemicals, and some drugs, all of which may damage or alter body cells so that they are no longer recognizable as self. Sex hormones may be important, too, since most autoimmune diseases are far more common in women than in men.

Heredity also appears to play a role. Autoimmune reactions, like many other immune responses, are influenced by the genes of the MHC. A high proportion of human patients with autoimmune disease have particular histocompatibility types. For example, many persons with rheumatoid arthritis display the self marker known as HLA-DR4.

Many types of therapies are being used to combat autoimmune diseases. These include corticosteroids, immunosuppressive drugs developed as anticancer agents, radiation of the lymph nodes, and plasmapheresis, a sort of "blood washing" that removes diseased cells and harmful molecules from the circulation.


Immune Complex Diseases


Immune complexes are clusters of interlocking antigens and antibodies. Under normal conditions immune complexes are rapidly removed from the bloodstream by macrophages in the spleen and Kupffer cells in the liver. In some circumstances, however, immune complexes continue to circulate. Eventually they become trapped in the tissues of the kidneys, lung, skin, joints, or blood vessels. Just where they end up probably depends on the nature of the antigen, the class of antibody-IgG, for instance, instead of IgM-and the size of the complex. There they set off reactions that lead to inflammation and tissue damage.

Immune complexes work their damage in many diseases. Sometimes, as is the case with malaria and viral hepatitis, they reflect persistent low-grade infections. Sometimes they arise in response to environmental antigens such as the moldy hay that causes the disease known as farmer's lung. Frequently, immune complexes develop in autoimmune disease, where the continuous production of autoantibodies overloads the immune complex removal system.

Immunodeficiency Diseases

Lack of one or more components of the immune system results in immunodeficiency disorders. These can be inherited, acquired through infection or other illness, or produced as an inadvertent side effect of certain drug treatments.

People with advanced cancer may experience immune deficiencies as a result of the disease process or from extensive anticancer therapy. Transient immune deficiencies can develop in the wake of common viral infections, including influenza, infectious mononucleosis, and measles. Immune responsiveness can also be depressed by blood transfusions, surgery malnutrition, and stress.

Some children are born with defects in their immune systems. Those with flaws in the B cell components are unable to produce antibodies (immunoglobulins). These conditions, known as agammaglobulinemias or hypogammaglobulinemias, leave the children vulnerable to infectious organisms; such disorders can be combated with injections of immunoglobulins.

Other children, whose thymus is either missing or small and abnormal, lack T cells. The resultant disorders have been treated with thymic transplants.

Very rarely, infants are born lacking all the major immune defenses; this is known as severe combined immunodeficiency disease (SCID). Some children with SCID have lived for years in germ-free rooms and "bubbles." A few SCID patients have been successfully treated with transplants of bone marrow (Bone Marrow Transplants).

The devastating immunodeficiency disorder known as the acquired immunodeficiency syndrome (AIDS) was first recognized in 1981. Caused by a virus (the human immunodeficiency virus, or HIV) that destroys T4 cells and that is harbored in macrophages as well as T4 cells, AIDS is characterized by a variety of unusual infections and otherwise rare cancers. The AIDS virus also damages tissue of the brain and spinal cord, producing progressive dementia.


AIDS infections are known as "opportunistic" because they are produced by commonplace organisms that do not trouble people whose immune systems are healthy, but which take advantage of the "opportunity" provided by an immune defense in disarray. The most common infection is an unusual and life-threatening form of pneumonia caused by a one-celled organism (a Protozoa) called Pneumocystis carinii. AIDS patients are also susceptible to unusual lymphomas and Kaposi's sarcoma, a rare cancer that results from the abnormal proliferation of endothelial cells in the blood vessels.

Some persons infected with the AIDS virus develop a condition known as AIDS-related complex, or ARC, characterized by fatigue, fever, weight loss, diarrhea, and swollen lymph glands. Yet other persons who are infected with the AIDS virus apparently remain well; however, even though they develop no symptoms, they can transmit the virus to others.

AIDS is a contagious disease, spread by intimate sexual contact, by direct inoculation of the virus into the bloodstream, or from mother to child during pregnancy. Most of the AIDS cases in the United States have been found among homosexual and bisexual men with multiple sex partners, and among intravenous drug abusers. Others have involved men who received untreated blood products for hemophilia; persons who received transfusions of inadvertently contaminated blood-primarily before the AIDS virus was discovered and virtually eliminated from the nation's blood supply with a screening test; the heterosexual partners of persons with AIDS; and children born to infected mothers.

There is presently no cure for AIDS, although the antiviral agent zidovuzine (AZT) appears to hold the virus in check, at least for a time. Many other antiretroviral drugs are being tested, as are agents to bolster the immune system and agents to prevent or treat opportunistic infections. Research on vaccines to prevent the spread of AIDS is also under way.


Cancers of the Immune System

Cells of the immune system, like those of other body systems, can proliferate uncontrollably; the result is cancer. Leukemias are caused by the proliferation of white blood cells, or leukocytes. The uncontrolled growth of antibody-producing (plasma) cells can lead to multiple myeloma. Cancers of the lymphoid organs, known as lymphomas, include Hodgkin's disease. These disorders can be treated-some of them very successfully-by drugs and/or irradiation.;_ylu=X3oDMTA4NDgyNWN0BHNlYwNwcm9m/SIG=12ootr1bo/EXP=1176731483/**http%3A/

The Human Immune Response System

An overview of the system

Overview of how our immune response system guards against infection

An overview of the system

T cells and antigens

The human immune response system recognizes pathogens and acts to remove, immobilize, or neutralize them. The immune system is antigen-specific (responding to specific molecules on a pathogen) and has memory (its defense to a pathogen is encoded for future activation). The immune system relies on several components to fight an infecting pathogen. T cells are lymphocytes that circulate between the blood, lymph, and lymphoid organs to trigger a systemic immune response with antigen-receptors on the T cell membrane. B cells are lymphocytes that activate the primary immune response when antigens bind to their receptors, causing the B cells to proliferate. Daughter cells of B cells later differentiate into antibody-releasing plasma cells. B cells also comprise the immune system's memory (see diagram).

Antibodies, also called immunoglobulins, are divided into five classes by structure and function, enabling them to recognize a wide spectrum of antigens. Antibody functions include complement fixation that can lead to antigen-cell lysis (rupture) and can cause inflammation. Antibodies also generate a neutralization response where viruses and bacteria are destroyed by phagocytes. Agglutination, or clumping together, of foreign cells are caused by B cells' promotion of complex cross-linking of antibodies binding to antigens. These agglutinated cells are phagocytized. B cells are cloned in massive quantities for a single specific antigen.

Immune response to T. cruzi

The human immune response to T. cruzi infection is inadequate; it provides only a partial defense at best. The immune system's response at its worst causes the defense mechanisms to turn on the body it is intended to protect, thus often causing more harm to the person than does T. cruzi.

T cells and T. cruzi

As T. cruzi immunizes humans to their own antigens, human antibodies attack myocardial and neural cells.

Complement in humans does not become activated solely by T. cruzi invasion; antibodies must be present for complement to bind to a specific T. cruzi antigen. This allows T. cruzi to have time to infect human tissue. Parasite strain and an individual's immune competence are prime factors in determining the T. cruzi's pathology of an individual.

Once infected with T. cruzi, humans acquire partial immunity or resistance to the severe pathologies of Chagas' disease's acute phase through subsequent infections of T. cruzi. This guards many individuals who live in highly endemic areas from the acute symptoms of chagas. Complete removable of the parasite from these individuals would risk the onset of acute chagas through future infection, which is deadly - especially for children.

T. cruzi incorporates certain host cell membrane proteins onto its surface thereby masking its antigenic signal to the immune system's lymphocytes. T. cruzi can also cleave antibody molecules on its surface thereby escaping the immune response's detection. T. cruzi frequently invade monocytes, a circulating phagocyte. Intracellular phagocytosis bring amastigotic T. cruzi into tissue cells where they can proliferate. Once inside tissue cells, T. cruzi are undetected by immune response. Trypomastigotes remain in the blood stream for a short period of time so that the T. cruzi-specific immunoglobulins don't have sufficient time to be activated. T. cruzi employs successful strategies to escape the remarkably potent immune response system. By masking themselves or by eluding the response mechanisms, the parasite is able to adapt to survive and continue the life of the species.

Immune response that damages the human body

Unintentional damage is done to the body's otherwise healthy tissue as the response system attacks what it recognizes as a trigger for a defensive response but does not recognize that it is attacking itself. This is what's known as an autoimmune reaction.

T. cruzi and our autoimmune response


Autoimmune responses are responsible in large part for the destructive symptoms of Chagas disease. This pathology is referred to as immunopathology. Severe inflammation occurs around tissue that embody amastigotes as the amastigotes release themselves from the tissue's dead cells. Among the tissue most often encysted is myocardial neural plexes. Plexes are networks of nerves that serve a variety of organs and functions. Digestive system neural plexes are targets as well, namely in the colon and esophagus. During the acute phase of chagas, B and T cells are incited to produce antibodies. Since T. cruzi is able to mask its presence in the blood, these antibodies do not attack T. cruzi but instead go after cell membrane antigenic components called epitopes, that the body's healthy cells and T. cruzi share. Research is being done to isolate the epitope and how T. cruzi uses it to elude recognition by the immune system.

Scientists work to find a cure to T. cruzi's infecting the human species. As research continues into how T. cruzi uses the human body as a host, the disciplines of parasitology and immunology learn much about how these organisms adapt and thrive in changing environments. T. cruzi proves to be a formidable opponent in the fight.

Mediated by Macrophages

Mediated by Lymphocytes and mast cells



Phagocytosis (engulfment)


Activation of Antibodies









Oddsei - What are the odds of anything.