Harper's Illustrated Biochemistry Chapter 52: Plasma Proteins & Immunoglobulins PDF

52 C H A P T E R Plasma Proteins & Immunoglobulins Peter J. Kennelly, PhD, Robert K. Murray, MD, PhD, Molly Jacob, MBBS, MD, PhD & Joe Varghese, MBBS, MD OBJEC TIVES...

52 C H A P T E R Plasma Proteins & Immunoglobulins Peter J. Kennelly, PhD, Robert K. Murray, MD, PhD, Molly Jacob, MBBS, MD, PhD & Joe Varghese, MBBS, MD OBJEC TIVES List the major functions of blood. Describe the principal functions of serum albumin. After studying this chapter, Explain how haptoglobin protects the kidney against formation of damaging you should be able to: iron precipitates. Describe the roles of ferritin, transferrin, and ceruloplasmin in iron homeostasis. Describe the mechanism by which transferrin, transferrin receptors, and HFE protein interact to regulate synthesis of hepcidin, a key regulator of iron homeostasis. Explain how iron homeostasis can be perturbed by dietary deficiencies or certain disorders. Describe the general structures and functions of the five classes of immunoglobulins and the uses of monoclonal antibodies. Explain how our bodies are able to synthesize up to a million different immunoglobulins utilizing fewer than 150 genes. Describe the how the complement system becomes activated and subsequently lyses invading microorganisms. Explain how the body’s adaptive immune system differs from its innate immune system. Define the term lectin. Outline the key differences between polyclonal and monoclonal antibodies. Explain the salient features of autoimmune and immunodeficiency disorders. BIOMEDICAL IMPORTANCE and α2-macroglobulin prevent the proteases used to destroy invading pathogens and dead or defective cells from damaging The proteins that circulate in blood plasma play important healthy tissue. Circulating immunoglobulins called antibod- roles in human physiology. Albumins facilitate the transit of ies form the front line of the body’s immune system. fatty acids, steroid hormones, and other ligands between tis- Perturbances in the production of plasma proteins can sues. Transferrin aids the uptake and distribution of iron, a have serious health consequences. Deficiencies in key com- component of many critically important metalloproteins. ponents of the blood clotting cascade can result in excessive Circulating fibrinogen serves as a readily mobilized building bruising and bleeding (hemophilia). Persons lacking plasma block of the fibrin mesh that provides the foundation of the ceruloplasmin, the body’s primary carrier of copper, are sub- clots used to seal injured vessels. Clot formation is triggered ject to hepatolenticular degeneration (Wilson disease), while by a cascade of blood coagulation factors, latent proteases that emphysema is associated with a genetic deficiency in the normally circulate as inactive proproteins, or zymogens. Plasma production of circulating α1-antiproteinase. Aberrant pro- also contains several proteins that function as inhibitors of duction of immunoglobulins characterizes the numerous proteolytic enzymes. Antithrombin helps confine the forma- autoimmune disorders, such as type-1 diabetes, asthma, and tion of clots to the vicinity of a wound, while α1-antiproteinase rheumatoid arthritis, that affect more than one in every thirty 668  CHAPTER 52 Plasma Proteins & Immunoglobulins 669 TABLE 521 Prevalence of Selected Autoimmune Diseases TABLE 522 Major Functions of Blood Among U.S. Population 1. Respiration—transport of oxygen from the lungs to the tissues Autoimmune Mean Prevalence Percentage and of CO2 from the tissues to the lungs Disease Rate (per 100,000) Female 2. Nutrition—transport of absorbed food materials 3. Excretion—transport of metabolic waste to the kidneys, lungs, Graves disease/ 1152 88 skin, and intestines for removal hyperthyroidism 4. Maintenance of the normal acid–base balance in the body Rheumatoid arthritis 860 75 5. Regulation of water balance through the effects of blood on the Thyroiditis/ 792 95 exchange of water between the circulating fluid and the tissue fluid hypothyroidism 6. Regulation of body temperature by the distribution of body heat Vitiligo 400 52 7. Defense against infection by the white blood cells and circulating Type 1 diabetes 192 48 antibodies Pernicious anemia 151 67 8. Transport of hormones and regulation of metabolism 9. Transport of metabolites Multiple sclerosis 58 64 10. Coagulation Primary 40 32 glomerulonephritis Systemic lupus 24 88 erythematosus IgA 23 67 PLASMA CONTAINS A COMPLEX glomerulonephritis Sjogren syndrome 14 94 MIXTURE OF PROTEINS Plasma contains a complex mixture of proteins, many of Myasthenia gravis 5 73 which contain high numbers of disulfide bonds as well as Addison’s disease 5 93 covalently bound carbohydrate (glycoproteins) or lipid (lipo- Schleroderma 4 92 proteins). Based upon their relative solubility in the presence of an organic solvent such as ethanol, or salting out agents Source: Data from Jacobson DL, Gange SJ, Rose NR, Graham NMH: Epidemiology and estimated population burden of selected autoimmune diseases in the United such as ammonium sulfate, early researchers separated plasma States. J Clin Immunol Immunopathol 1997;84:223. proteins into three groups: fibrinogen, albumin, and globu- lins. Subsequently, clinical scientists employed electrophore- sis within a cellulose acetate matrix to analyze the protein residents of North America (Table 52–1). Insufficiencies in the production of protective antibodies, such as occur in many composition of plasma. Following electrophoretic separation, persons infected by the human immunodeficiency virus staining reagents revealed five major bands that were designated (HIV) or patients administered immunosuppressant drugs, albumin, α1, α2, β, and γ fractions, respectively (Figure 52–1). renders them immunocompromised, extremely susceptible to The relative dimensions and molecular masses of several infection by microbial and viral pathogens, and vulnerable to plasma proteins are shown in Figure 52–2. their spread. While the root causes of plasma protein-related diseases such as hemophilia are relatively straightforward, Plasma Proteins Help Determine the others—in particular many autoimmune disorders—arise due Distribution of Fluid Between Blood & Tissues to the complex and cryptic interplay of genetic, dietary, nutri- The aggregate concentration of the proteins present in plasma tional, environmental, and medical factors. typically falls in the range of 7.0 to 7.5 g/dL for humans. The osmotic pressure (oncotic pressure) exerted by the plasma THE BLOOD HAS MANY proteins is approximately 25 mm Hg. Since the hydrostatic pressure in the arterioles is approximately 37 mm Hg, with FUNCTIONS an interstitial (tissue) pressure of 1 mm Hg opposing it, a As the primary avenue by which tissues are connected to each net outward force of about 11 mm Hg drives fluid out into other and the surrounding environment, the blood that cir- the interstitial spaces. In venules, the hydrostatic pressure is culates throughout our body performs a variety of functions. about 17 mm Hg, with the oncotic and interstitial pressures as These include delivering nutrients and oxygen, removing described above; thus, a net force of about 9 mm Hg attracts waste products, conveying hormones, and defending against water back into the circulation. The above pressures are infectious microorganisms (Table 52–2). These myriad func- often referred to as the Starling forces. If the concentration tions are carried out by a diverse set of components that of plasma proteins is markedly diminished (eg, due to severe include cellular entities such as red blood cells, platelets, and protein malnutrition), fluid will no longer flow back into the leukocytes (see Chapters 53 and 54), and the water, electrolytes, intravascular compartment. The resulting accumulation of metabolites, nutrients, proteins, and hormones that comprise fluid in the extravascular tissue spaces results in a condition the plasma. known as edema. ↓ Plasma proteins - exerts pressure will back accumulation ↓ If plasma proteins - > Fluid no longer flow > - of Fluid > - educa 670 SECTION X Special Topics (B) + – A C Albumin α1 α2 β γ + – Albumin α1 α2 β γ B D FIGURE 521 Technique of cellulose acetate zone electrophoresis. (A) A small amount of serum or other fluid is applied to a cellulose acetate strip. (B) Electrophoresis in electrolyte buffer is performed. (C) Staining enables separated bands of protein to be visualized. (D) Densitometer scanning reveals the relative mobilities of albumin, α1-globulin, β2-globulin, β-globulin, and γ-globulin. (Reproduced, with permission, from Parslow TG et al (editors): Medical Immunology, 10th ed. McGraw-Hill, 2001.) Most Plasma Proteins is synthesized in the vascular endothelium. One prominent exception is the γ-globulins, which are synthesized in the lym- Are Synthesized in the Liver phocytes. Most plasma proteins are covalently modified by the Roughly 70% to 80% of all plasma proteins are synthesized in addition of either N- or O-linked oligosaccharide chains, or the liver. These include albumin, fibrinogen, transferrin, and both (see Chapter 46). Albumin is the major exception. These most components of the complement and blood coagulation oligosaccharide chains have perform various functions (see cascade with the exception of von Willebrand factor, which Table 46–2). Loss of terminal sialic acid residues accelerates clearance of plasma glycoproteins from the circulation. As is the case for other proteins destined for secretion Scale from a cell, the genes for plasma proteins code for an amino- terminal signal sequence that targets them to the endoplas- 10 nm Na+ CI– Glucose mic reticulum. As this leader sequence emerges from the ribosome, it binds to a transmembrane protein complex in the endoplasmic reticulum called the signal recognition particle. The emerging polypeptide chain is pulled through the signal Albumin Hemoglobin 69,000 64,500 recognition particle into the lumen of the endoplasmic reticu- lum, during which process the leader sequence is cleaved off by an associated signal peptidase (see Chapter 49). The newly synthesized proteins then traverse the major secretory route in β1-Globulin γ-Globulin the cell (rough endoplasmic membrane → smooth endoplasmic 90,000 156,000 membrane → Golgi apparatus → secretory vesicles) prior to entering the plasma, during which process they are subject to various posttranslational modifications (proteolysis, gly- cosylation, phosphorylation, etc). Transit times through the α1-Lipoprotein hepatocyte from the site of synthesis to the plasma vary from 200,000 30 minutes to several hours for individual proteins. β1-Lipoprotein 1,300,000 Many Plasma Proteins Exhibit Polymorphism Fibrinogen A polymorphism is a Mendelian or monogenic trait that 340,000 exists in the population in at least two phenotypes, neither of FIGURE 522 Relative dimensions and approximate molec- which is rare (ie, neither of which occurs with frequency of ular masses of protein molecules in the blood.