Plasma Proteins & Immunoglobulins

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CHAPTER 52 Plasma Proteins & Immunoglobulins Peter J. Kennelly, PhD, Robert K. Murray, MD, PhD, Molly Jacob, MBBS, MD, PhD & Joe Varghese, MBBS, MD 1529

Transcript of Plasma Proteins & Immunoglobulins

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C H A P T E R

52Plasma Proteins &ImmunoglobulinsPeter J. Kennelly, PhD, Robert K. Murray, MD, PhD, MollyJacob, MBBS, MD, PhD & Joe Varghese, MBBS, MD

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BIOMEDICAL IMPORTANCEThe proteins that circulate in blood plasma play important roles in humanphysiology. Albumins facilitate the transit of fatty acids, steroidhormones, and other ligands between tissues, while transferrin aids theuptake and distribution of iron. Circulating fibrinogen serves as a readilymobilized building block of the fibrin mesh that provides the foundation ofthe clots used to seal injured vessels. Formation of these clots is triggeredby a cascade of latent proteases, or zymogens, called blood coagulationfactors. Plasma also contains several proteins that function as inhibitors ofproteolytic enzymes. Antithrombin helps confine the formation of clots tothe vicinity of a wound, while α1-antiproteinase and α2-macroglobulinshield healthy tissues from the proteases that destroy invading pathogensand remove dead or defective cells. Circulating immunoglobulins calledantibodies form the front line of the body’s immune system.

Perturbances in the production of plasma proteins can have serioushealth consequences. Deficiencies in key components of the blood clottingcascade can result in excessive bruising and bleeding (hemophilia).Persons lacking plasma ceruloplasmin, the body’s primary carrier ofcopper, are subject to hepatolenticular degeneration (Wilson disease),while emphysema is associated with a genetic deficiency in the productionof circulating α1-antiproteinase. More than one in every 30 residents ofNorth America suffer from an autoimmune disorder, such as type 1diabetes, asthma, and rheumatoid arthritis, resulting from the production ofaberrant immunoglobulins (Table 52–1). Insufficiencies in the productionof protective antibodies, such as occur in many persons infected by thehuman immunodeficiency virus (HIV) or patients administeredimmunosuppressant drugs, render them immunocompromised, extremely

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susceptible to infection by microbial and viral pathogens. While the rootcauses of plasma protein–related diseases such as hemophilia are relativelystraightforward, others—in particular many autoimmune disorders—arisedue to the complex and cryptic interplay of genetic, dietary, nutritional,environmental, and medical factors.

THE BLOOD HAS MANY FUNCTIONSAs the primary avenue by which tissues are connected to each other andthe surrounding environment, the blood that circulates throughout ourbody performs a variety of functions. These include delivering nutrients

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and oxygen, removing waste products, conveying hormones, anddefending against infectious microorganisms (Table 52–2). These myriadfunctions are carried out by a diverse set of components that includecellular entities such as red blood cells, platelets, and leukocytes (seeChapters 53 and 54), and the water, electrolytes, metabolites, nutrients,proteins, and hormones that comprise the plasma.

TABLE 52–2 Major Functions of Blood

PLASMA CONTAINS A COMPLEX MIXTURE OFPROTEINSPlasma contains a complex mixture of proteins. Early scientists classifiedthese proteins into three groups, fibrinogen, albumin, and globulins, onthe basis of their relative solubility in the presence of added organicsolvents such as ethanol or salting out agents such as as ammoniumsulfate. Subsequently, clinical scientists employed electrophoresis within acellulose acetate matrix to analyze the protein composition of plasma.Using this technique, salt-soluble serum protein fraction separated into fivemajor components designated albumin and the α1-, α2-, β-, and γ-globulins, respectively (Figure 52–1). Plasma proteins tend to be rich indisulfide bonds and frequently contain bound carbohydrate

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(glycoproteins) or lipid (lipoproteins). The relative dimensions andmolecular masses of several plasma proteins are shown in Figure 52–2.

FIGURE 52–1 Technique of cellulose acetate zone electrophoresis. (A)A small amount of serum or other fluid is applied to a cellulose acetatestrip. (B) Electrophoresis in electrolyte buffer is performed. (C) Stainingenables separated bands of protein to be visualized. (D) Densitometerscanning reveals the relative mobilities of albumin, α1-globulin, β2-globulin, β-globulin, and γ-globulin. (Reproduced, with permission, fromParslow TG et al (editors): Medical Immunology, 10th ed. McGraw-Hill,2001.)

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FIGURE 52–2 Relative dimensions and approximate molecularmasses of protein molecules in the blood.

Plasma Proteins Help Determine the Distribution ofFluid Between Blood & TissuesThe aggregate concentration of the proteins present in human plasmatypically falls in the range of 7 to 7.5 g/dL. The resulting osmoticpressure (oncotic pressure) is approximately 25 mm Hg. Since thehydrostatic pressure in the arterioles is approximately 37 mm Hg, withan interstitial (tissue) pressure of 1 mm Hg opposing it, a net outward forceof about 11 mm Hg drives fluid from the plasma into the interstitial spaces.By contrast, the hydrostatic pressure in venules is about 17 mm Hg; thus, anet force of about 9 mm Hg drives water from tissues back into thecirculation. The above pressures are often referred to as the Starlingforces. If the concentration of plasma proteins is markedly diminished (eg,

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due to severe protein malnutrition), fluid will cease flowing back into theintravascular compartment and begin to accumulate in the extravasculartissue spaces, resulting in a condition known as edema.

Most Plasma Proteins Are Synthesized in the LiverRoughly 70 to 80% of all plasma proteins are synthesized in the liver.These include albumin, fibrinogen, transferrin, and most components ofthe complement and blood coagulation cascades. Two prominentexceptions are von Willebrand factor, which is synthesized in the vascularendothelium, and the γ-globulins, which are synthesized in thelymphocytes. Most plasma proteins are covalently modified by theaddition of either N- or O-linked oligosaccharide chains, or both (seeChapter 46). Albumin is the major exception. These oligosaccharidechains fulfill a variety of functions (see Table 46–2). Loss of terminalsialic acid residues accelerates clearance of plasma glycoproteins from thecirculation.

As is the case for other proteins destined for secretion from a cell, thegenes for plasma proteins code for an amino-terminal signal sequence thattargets them to the endoplasmic reticulum. As this leader sequenceemerges from the ribosome, it binds to a transmembrane protein complexin the endoplasmic reticulum called the signal recognition particle. Theemerging polypeptide chain is pulled through the signal recognitionparticle into the lumen of the endoplasmic reticulum, during which processthe leader sequence is cleaved off by an associated signal peptidase (seeChapter 49). The newly synthesized proteins then traverse the majorsecretory route in the cell (rough endoplasmic membrane → smoothendoplasmic membrane → Golgi apparatus → secretory vesicles) prior toentering the plasma, during which process they are subject to variousposttranslational modifications (proteolysis, glycosylation,phosphorylation, etc). Transit times from the site of synthesis in thehepatocyte from to the plasma vary from 30 minutes to several hours forindividual proteins.

Many Plasma Proteins Exhibit PolymorphismA polymorphism is a mendelian or monogenic trait that exists in thepopulation in at least two phenotypes, neither of which is rare (ie, it occurswith frequency of at least 1-2%). Most polymorphisms are innocuous. TheABO blood group substances (see Chapter 53) are perhaps the best known

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example of a human polymorphism. Other human plasma proteins thatexhibit polymorphism include α1-antitrypsin, haptoglobin, transferrin,ceruloplasmin, and immunoglobulins.

Each Plasma Protein Has a Characteristic Half-Lifein the CirculationThe half-life of a plasma protein is the time required for 50% of themolecules present at any given moment to be degraded or otherwisecleared from the blood. For example, the half-lives of albumin andhaptoglobin in healthy adults are approximately 20 and 5 days,respectively. Under normal circumstances, as older protein molecules arecleared they are replaced by newly synthesized ones, a process calledturnover. During normal turnover, the total concentration of theseproteins will remain constant as the countervailing processes of synthesisand clearance reach a steady state.

In certain diseases, the half-life of a protein may be markedly altered.For instance, in some gastrointestinal diseases such as regional ileitis(Crohn disease), considerable amounts of plasma proteins, includingalbumin, may be lost into the bowel through the inflamed intestinalmucosa. The half-life of albumin in these subjects may be reduced to aslittle as 1 day, a condition referred to as a protein-losinggastroenteropathy.

ALBUMIN IS THE MOST ABUNDANT PROTEININ HUMAN PLASMAThe liver synthesizes approximately 12 g of albumin per day, representingabout 25% of total hepatic protein synthesis and half its secreted protein.About 40% of the body’s albumin circulates in the plasma, where itaccounts for roughly three-fifths of total plasma protein by weight (3.4-4.7g/dL). The remainder resides in the extracellular space. Because of itsrelatively low molecular mass (about 69 kDa) and high concentration,albumin is thought to contribute 75 to 80% of the osmotic pressure ofhuman plasma. Like most other secreted proteins, albumin is initiallysynthesized as a preproprotein. Its signal peptide is removed as it passesinto the cisternae of the rough endoplasmic reticulum. A secondhexapeptide is cleaved from the new N-terminus farther along thesecretory pathway.

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Mature human albumin consists of a single polypeptide chain, 585amino acids in length, that is organized into three functional domains. Itsellipsoidal conformation is stabilized by a total of 17 intrachain disulfidebonds. A major role of albumin is to bind to and transport numerousligands. These include free fatty acids (FFA), calcium, certain steroidhormones, bilirubin, copper, and tryptophan. A variety of drugs, includingsulfonamides, penicillin G, dicumarol, and aspirin, also bind to albumin; afinding with important pharmacologic implications. Preparations of humanalbumin have been widely used in the treatment of burns and ofhemorrhagic shock.

Some humans suffer from genetic mutations that impair their ability tosynthesize albumin. Individuals whose plasma is completely devoid ofalbumin are said to exhibit analbuminemia. Surprisingly, personssuffering from analbuminemia display only moderate edema. Depressedsynthesis of albumin also occurs in a variety of diseases, particularly thoseof the liver. The plasma of patients with liver disease often shows adecrease in the ratio of albumin to globulins (decreased albumin-globulinratio). The synthesis of albumin decreases relatively early in conditions ofprotein malnutrition, such as kwashiorkor.

THE LEVELS OF CERTAIN PLASMA PROTEINSINCREASE DURING INFLAMMATION ORFOLLOWING TISSUE DAMAGETable 52–3 summarizes the functions of many of the plasma proteins. C-reactive protein (CRP, so named because it reacts with the Cpolysaccharide of pneumococci), α1-antiproteinase, haptoglobin, α1-acidglycoprotein, and fibrinogen are classified as acute-phase proteins.Acute-phase proteins are believed to play a role in the body’s response toinflammation. C-reactive protein stimulates the complement pathway (seebelow), while α1-antitrypsin neutralizes certain proteases released duringacute inflammation.

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The levels of acute-phase proteins may increase by 50% to as much as1000-fold (in the case of CRP) during chronic inflammatory states and in

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TABLE 52–3 Some Functions of Plasma Proteins

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patients with cancer. Interleukin 1 (IL-1), a polypeptide released frommononuclear phagocytic cells, is the principal—but not the sole—stimulator of acute-phase reactant synthesis by hepatocytes. Additionalmolecules such as IL-6 also participate. Because its concentration can riseso dramatically, CRP is used as a biomarker of tissue injury, infection, andinflammation.

The small proteins such as interferons, ILs, and tumor necrosis factorsthat facilitate cell–cell communication between the components of theimmune system are called cytokines. Cytokines can be both autocrine andparacrine in nature. One of the primary targets of IL-1 and IL-6 is nuclearfactor kappa-B (NFκB), a transcription factor that regulates theexpression of the genes encoding many cytokines, chemokines, growthfactors, and cell adhesion molecules. NFκB, a heterodimer comprised of a50- and a 65-kDa polypeptide, normally resides in the cytosol as aninactive complex with a second protein, NFκB inhibitor-α, also known asIκBα. When stimulation by inflammation, injury, or radiation, IκBαbecomes phosphorylated, which targets it for ubiquitination anddegradation. Once freed from its inhibitory partner, active NFκBtranslocates to the nucleus where it stimulates transcription of its targetgenes.

HAPTOGLOBIN PROTECTS THE KIDNEYSIron in Senescent Erythrocytes Is Recycled byMacrophagesErythrocytes normally have a lifespan of approximately 120 days.Senescent or damaged erythrocytes are phagocytosed by macrophages ofthe reticuloendothelial system (RES) present in the spleen and liver.Around 200 billion erythrocytes are catabolized every day. Within themacrophage, heme derived from hemoglobin is converted by the enzymheme oxygenase to biliverdin (see Figure 31–13), releasing carbonmonoxide and iron as by-products. Iron released from heme is exportedfrom phagocytic vesicles in the macrophage by NRAMP 1 (naturalresistance–associated macrophage protein 1), a transporter homologous toDMT1. Iron is subsequently secreted into the circulation by thetransmembrane protein ferroportin (Figure 52–3). Thus, ferroportin playsa central role in both iron absorption by the intestine and iron secretionfrom macrophages.

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FIGURE 52–3 Recycling of iron in macrophages. Senescenterythrocytes are phagocytosed by macrophages. Hemoglobin is degradedand iron is released from heme by the action of the enzyme hemeoxygenase. Ferrous iron is then transported out of the macrophage viaferroportin (Fp). In the plasma, it is oxidized to the ferric form byceruloplasmin before binding to transferrin (Tf). Iron circulates in bloodtightly bound to Tf.

In the blood, Fe2+ is oxidized to Fe3+ in a reaction catalyzed by theferrioxidase ceruloplasmin (see below), a copper-containing plasmaenzyme synthesized by liver. Once oxidized, Fe3+ is then bound totransferrin in blood. The iron released from macrophages in this way(about 25 mg/d) is recycled, thereby reducing the need for intestinal ironabsorption, which averages only 1 to 2 mg/d.

Haptoglobin Scavenges Hemoglobin That HasEscaped RecyclingDuring the course of red blood cell turnover, approximately 10% of anerythrocyte’s hemoglobin escapes into the circulation. This free,extracorpuscular hemoglobin is sufficiently small at ≈65 kDa to passthrough the glomerulus of the kidney into the tubules, where it tends toform damaging precipitates. Haptoglobin (Hp) is a plasma glycoprotein

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that binds extracorpuscular hemoglobin (Hb), forming a tight noncovalentcomplex (Hb-Hp). Human haptoglobin exists in three polymorphicforms, known as Hp 1-1, Hp 2-1, and Hp 2-2 that reflect the patterns ofinheritance of two genes, designated Hp1 and Hp2. Homozygotessynthesize Hp 1-1 or Hp 1-2, respectively, while Hp 2-1 is synthesized byheterozygotes.

Normally, the level of haptoglobin in a deciliter of human plasma issufficient to bind 40 to 180 mg of hemoglobin. Since the resulting Hb-Hpcomplex is too large (≥ 155 kDa) to pass through the glomerulus, thekidney is protected from the formation of harmful precipitates while theloss of the iron associated with extracorpuscular hemoglobin is reduced.

Certain other plasma proteins bind heme, but not hemoglobin. Theyinclude a β1-globulin hemopexin, which binds free heme, and albumin,which binds metheme (ferric heme) to form methemalbumin.Methemalbumin subsequently transfers this metheme to hemopexin.

Haptoglobin Can Serve as a Diagnostic IndicatorIn situations where hemoglobin is constantly being released from redblood cells, such as occurs in hemolytic anemias, the level of haptoglobincan fall dramatically. This decrease reflects the marked difference in thehalf-lives of free haptoglobin, approximately 5 days, and the Hb-Hpcomplex, approximately 90 minutes. The level of haptoglobin-relatedprotein, a homologue of haptoglobin also present in plasma, is elevated insome patients with cancers, although the significance of this is notunderstood.

IRON IS STRICTLY CONSERVEDIron is a key constituent of many human proteins, including hemoglobin,myoglobin, the cytochrome P450 group of enzymes, numerouscomponents of the electron transport chain, and ribonucleotide reductase,which catalyzes the conversion of ribonucleotides intodeoxyribonucleotides. Body iron, which is distributed as shown in Table52–4, is highly conserved. A healthy adult loses only about 1 to 1.5 mg (<0.05%) of their 3 to 4 g of body iron each day. However, an adultpremenopausal female can experience iron deficiency due to blood lossduring menstruation.

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TABLE 52–4Distribution of Iron in a 70-kg Adult Malea

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Oxidation by Ceruloplasmin Is a Key Feature of theIron CycleMacrophages play a key role in the turnover of red blood cells. Followingphagocytosis and digestion via lysosomal hydrolases, the iron is expelledlargely in the ferrous, Fe2+, state. In order to be recovered via thetransferrin cycle, this iron must be oxidized to the ferric, Fe3+, state by theferroxidase ceruloplasmin, a 160-kDa α2-globulin synthesized by theliver. With six, catalytically essential, copper atoms, ceruloplasmin is themajor copper-containing protein in plasma.

Deficiencies in Ceruloplasmin Perturb IronHomeostasisCeruloplasmin deficiency can arise from genetic causes as well as a lack ofcopper, an essential micronutrient, in the diet. When adequate quantities ofcatalytically functional ceruloplasmin are lacking, the body’s ability torecycle Fe2+ becomes impaired, leading to iron accumulation in tissues.While persons suffering from hypoceruloplasmenia, a geneticallyheritable condition in which ceruloplasmin levels are roughly 50% ofnormal, generally display no clinical abnormalities, genetic mutations thatabolish the ferroxidase activity of ceruloplasmin, aceruloplasminemia,can have severe physiologic consequences. If left untreated, theprogressive accumulation of iron in pancreatic islet cells and basal gangliaeventually leads to the development of insulin-dependent diabetes andneurologic degeneration that may manifest as dementia, dysarthria, anddystonia.

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In Wilson disease, a mutation in the gene for a copper-binding P-typeATPase (ATP7B protein) blocks the excretion of excess copper in the bile.As a consequence, copper accumulates in the liver, brain, kidney, and redblood cells. Paradoxically, rising levels of copper within the liverapparently interferes with the incorporation of this metal into newlysynthesized ceruloplasmin polypeptides (apoceruloplasm) leading to a fallin plasma ceruloplasmin levels. If left untreated, patients suffering fromthis form of copper toxicosis may develop a hemolytic anemia or chronicliver disease (cirrhosis and hepatitis). Accumulation of copper in the basalganglia and other centers can lead to neurologic symptoms. Wilson diseasecan be treated by limiting the dietary intake of copper while depleting anyexcess copper by the regular administration of penicillamine, whichchelates copper and is subsequently excreted in the urine.

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Ceruloplasmin Levels Decrease in Wilson Disease

SERUM INHIBITORS PREVENTINDISCRIMINATE PROTEOLYSISProteases are essential participants in tissue remodeling, blood clotting,elimination of old or diseased cells, destruction of invading pathogens, andother physiologic functions. Left unchecked, however, proteolyticenzymes that are secreted or escape into the blood can damage healthy

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tissue. Protection from indiscriminate proteolysis involves a battery ofserum proteins that inhibit, and thereby limit the scope of, protease action.

Deficiency of α1-Antiproteinase Is Associated WithEmphysema & Liver Diseaseα1-Antiproteinase, a 394-residue glycoprotein that makes up >90% of theα1-albumin fraction, is the principal serine protease inhibitor (serpin) inhuman plasma. Formerly called α1-antitrypsin, α1-antiproteinase inhibitstrypsin, elastase, and other serine proteases by forming an inactivecovalent complex with them. α1-Antiproteinase is synthesized byhepatocytes and macrophages. At least 75 polymorphic forms of thisserpin, or Pi, exist. The major genotype is MM, whose phenotypic productis PiM. A deficiency in α1-antiproteinase plays a role in some cases (~ 5%)of emphysema, particularly in subjects with the ZZ genotype (whosynthesize PiZ) and in PiSZ heterozygotes, both of whom secrete lowerlevels of serpins than PiMM individuals.

Oxidation of Met358 Inactivates α1-AntiproteinaseIn the lungs, components of the smoke produced by burning tobaccoproducts and industrial activities can oxidize a key methionine residue,Met358, located in the protease-binding domain of α1-antiproteinase.Oxidation renders α1-antiproteinase unable to covalently bind andneutralize serine proteases. The subsequent damage produced byunchecked proteolytic activity in the lungs can contribute to thedevelopment of emphysema. Smoking can be particularly devastating forpatients who already have low levels of α1-antiproteinase (eg, PiZZphenotype). Intravenous administration of serpins (augmentation therapy)has been used as an adjunct in the treatment of patients with emphysemathat exhibit α1-antiproteinase deficiency.

Individuals deficient in α1-antiproteinase are also at greater risk of lungdamage from pneumonia or other conditions that induce the accumulationof polymorphonuclear white blood cells in the lung. Deficiency of α1-antiproteinase is also implicated in α1-antitrypsin deficiency liverdisease, a form of cirrhosis that afflicts persons possessing the ZZphenotype. In these individuals, substitution of Glu342 by lysine promotes

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the formation of polymeric aggregates of α1-antiproteinase in the cisternaeof the endoplasmic reticulum in hepatic cells.

α2-Macroglobulin Neutralizes Proteases & TargetsCytokines to Tissuesα2-Macroglobulin, a member of the thioester plasma protein family,comprises 8 to 10% of the total plasma protein in humans. Thishomotetrameric glycoprotein is the most abundant member of a group ofhomologous plasma proteins that include complement proteins C3 and C4.α2-Macroglobulin is synthesized by monocytes, hepatocytes, andastrocytes. It mediates the inhibition and clearance of a broad spectrum oftruant proteases by a “Venus flytrap” mechanism. The key components ofthe trap include a 35-residue “bait domain” located near the center of itspolypeptide sequence and an internal cyclic thioester linking a cysteineand a glutamine residue (Figure 52–10). Cleavage of the bait domainproduces a massive conformational change, triggering the envelopment ofthe attacking protease. The reactive thioester then reacts with the proteaseto covalently link the two proteins. This conformational change alsoexposes a sequence in α2-macroglobulin that is recognized by cell surfacereceptors that subsequently bind and remove the complex from the plasma.

FIGURE 52–10 An internal cyclic thiol ester bond, as present in α2-macroglobulin. AAx and AAy are neighboring amino acids to cysteineand glutamine.

In addition to serving as the plasma’s predominant broad-spectrum, orpanproteinase, inhibitor, α2-macroglobulin also binds to and transports

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approximately 10% of the zinc in plasma (the remainder being transportedby albumin) as well as cytokines such as platelet-derived growth factorand transforming growth factor β. As a cytokine transporter, α2-macroglobulin appears to be involved in targeting these effectors towardparticular tissues or cells. Once taken up by cells, the cytokines dissociate,freeing them to modulate their growth and function.

DEPOSITION OF PLASMA PROTEINS INTISSUES LEADS TO AMYLOIDOSISAmyloidosis refers to an impairment of tissue function that results fromthe accumulation of insoluble aggregates of proteins in the interstitialspaces between cells. The term is a misnomer, as it was originally thoughtthat the fibrils were starch-like in nature. The fibrils generally are made upof proteolytic fragments of plasma proteins whose conformation is rich inβ-pleated sheet. They generally also contain a P component derived froma plasma protein closely related to C-reactive protein called serumamyloid P component.

Structural abnormalities or overproduction of more than 20 differentproteins have been implicated in various types of amyloidosis. Primaryamyloidosis (Table 52–7) typically is caused by a monoclonal plasma celldisorder that leads to the accumulation of protein fragments derived fromimmunoglobulin light chains (see below). Secondary amyloidosis resultsfrom an accumulation of fragments of serum amyloid A (SAA)consequent to chronic infections or cancer. In these instances, elevatedlevels of inflammatory cytokines stimulate the liver to synthesize SAA,which leads to a concomitant rise in its proteolytic degradation products.Familial amyloidosis results from accumulation of mutated forms ofcertain plasma proteins such as transthyretin (Table 52–3). Over 80mutationally altered forms of this protein have been identified. Patientsundergoing regular, long-term dialysis are at risk from β2-microglobulin,a plasma protein that is retained by dialysis membranes.

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PLASMA IMMUNOGLOBULINS DEFENDAGAINST INVADERSThe three major components of the body’s immune system are Blymphocytes (B cells), T lymphocytes (T cells), and the innate immunesystem. B lymphocytes are mainly derived from bone marrow cells, whileT lymphocytes originate from the thymus. B cells are responsible for thesynthesis of circulating, humoral antibodies, also known asimmunoglobulins. The T cells are involved in a variety of important cell-mediated immunologic processes such as graft rejection, hypersensitivityreactions, and defense against malignant cells and many viruses. B and Tcells respond in an adaptive manner, developing a targeted response foreach invader encountered. The innate immune system defends againstinfection in a nonspecific manner. It contains a variety of cells such asphagocytes, neutrophils, natural killer cells, and others that will bediscussed in Chapter 54.

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TABLE 52–7 A Classification of Amyloidosis