PLASMA PROTEINS AND IMMUNOGLOBULINS

Blood functions as a transport and distribution system for the body, delivering essential nutrients to tissues and at the same time removing waste products. It is composed of an aqueous solution containing molecules of varying sizes and a number of cellular elements. Some of the components of blood perform important roles in the body's defense against external insult and in the repair of damaged tissues. Importantly for a clinician, plasma is also a 'window' on metabolism. Because it is easy to obtain, many diagnostic laboratory tests in biochemistry, hematology and immunology are performed on plasma samples. The most commonly used tests are listed in the Appendix together with their reference values.

PLASMA AND SERUM

Plasma is the natural environment of blood cells but most chemical measurements are done in serum. The formed elements of blood are suspended in an aqueous solution that is termed plasma. Plasma is the supernatant obtained by centrifuging a blood sample that has been treated with an anticoagulant to prevent clotting of red cells. Serum is the supernatant obtained if a blood sample is allowed to clot (usually requires 30-45 minutes) and then centrifuged.

In laboratory practice, the most common anticoagulants are lithium heparinate and ethylenediamine tetraacetic acid (EDTA). Heparinate prevents clotting by binding to thrombin. EDTA and citrate bind Ca2+ and Mg2+, thus interfering with the action of calcium/magnesium-dependent enzymes (prothrombin-converting complex, thromboplastin and thrombin) involved in the clotting cascade. When blood is collected for transfusion, citrate is used as an anticoagulant. During clotting, fibrinogen is converted to fibrin as a result of proteolytic cleavage by thrombin, and so a major difference between plasma and serum is the absence of fibrinogen in serum.

ERYTHROCYTES :
Erythrocytes are not complete cells, as they do not possess nuclei and intracellular organelles. They are cellular remnants, containing specific proteins and ions, which can be present in high concentrations. Erythrocytes are the end-product of erythropoiesis in the bone marrow, which is under the control of erythropoietin produced by the kidney.

Hemoglobin is synthesized in the erythrocyte precursor cells (erythroblasts and reticulocytes) under a tight control dictated by the concentration of heme, the synthesis of which involves the chelation of reduced ferrous iron (Fe2+) by four nitrogen atoms in the center of a porphyrin ring. The main functions of erythrocytes are the transport of oxygen and the removal of carbon dioxide and hydrogen ion; as they lack cellular organelles, they are not capable of protein synthesis and repair. As a result, erythrocytes have a finite life span of 60-120 days before being trapped and broken down in the spleen.

LEUKOCYTES
Leukocytes are cells, the main function of which is to protect the body from infection. Most leukocytes are produced in the bone marrow, some are produced in the thymus, and others mature within several tissues. Leukocytes can control their own synthesis by secreting into the blood signal peptides that subsequently act on the bone marrow stem cells. In order to function correctly, leukocytes have the ability to migrate out of the bloodstream into surrounding tissues.

THROMBOCYTES (PLATELETS)
Thrombocytes (platelets) are not true cells, but are membrane-bound fragments derived from megakaryocytes residing in the bone marrow. They have a key role in the process of blood clotting.

The Blood Has Many Functions

The functions of blood except for specific cellular ones such as oxygen transport and cell-mediated immunologic defense- are carried out by plasma and its constituents.

Major Functions of Blood........

Plasma consists of water, metabolites, electrolytes, nutrients, proteins, and hormones The water and electrolyte composition of plasma is practically the same as that of all exstracellular fluids. Laboratory determinations of levels of Na+, K+, Ca+2, Mg+2, Cl-, HCO3-, PaCO2 and of blood pH are important in the management of many patients.

Plasma contains a Complex Mixture of Proteins

The concentration of total protein in human plasma is approximately 7.0-7.5 g/dL and comprises the major part of the solids of the plasma. The proteins of plasma are actually a complex mixture that includes not only simple proteins but also conjugated proteins such as glycoproteins and various types of lipoproteins. Thousands of antibodies are present in human plasma.

Relative dimension and approximate molecular masses of protein molecules in the blood

The plasma proteins are found into three major groups :

fibrinogen albumin globulins

Proteins Cation binding Albumin Ceruloplasmin Transferrin Hormone binding

Transport proteins and their ligands Ligands Divalent and trivalent cations, e.g. Cu2+, Fe3+ Cu2+ Fe3+ Thyroxine (T4), tri-iodothyronine (T3) Cortisol Androgens (testosterone), estrogens (estradiol) Heme, bilirubin, biliverdin Hemoglobin dimers Nonesterified fatty acids, steroids

Thyroid-binding globulin (TBG) Cortisol-binding globulin (CBG) Sex hormone-binding globulin (SHBG) Hemoglobin/protoporphyrin binding Albumin Haptoglobin Fatty acid binding Albumin

Almost all plasma proteins bind ligands, and this is a major function of many proteins. Albumin can bind many molecules weakly and nonspecifically, but other proteins bind tightly to specific molecules - for example, transferrin is specific for ferric iron (Fe3+).

Methods of Analyzing Plasma Proteins

Electrophoresis By

(cellulose acetate)

solubility characteristics (salting out methods)

Proteomics

The Concentration of Protein in Plasma is Important in Determinig the Distribution of Fluid Between Blood & Tissues In arterioles, the hydrostatic pressure is about 37 mm Hg, with an interstitial (tissue) pressure of 1 mm Hg opposing it. The osmotic pressure (oncotic pressure) exerted by the plasma proteins is approximately 25 mm Hg. In venules, the hydrostatic pressure is about 17 mm Hg. A net force of about 9 mm Hg attracts water back into the circulation. These pressures are often referred to as the Starling forces.

EDEMA If the concentration of plasma proteins is markedly diminished (eg, due to severe protein malnutrition), fluid is not attracted back into the intravascular compartement and accumulates in the exstravascular tissue spaces, a condition known as EDEMA.

Most plasma proteins are synthesized in the liver and glycosylated (further sorted in the trans-Golgi). Globulins are synthesized in the plasma cells and certain plasma proteins are synthesized in other sites such as endothelial cells. Plasma proteins are generally synthesized on membrane bound polyribosomes proceed to the Golgi apparatus and the plasma membrane in transport vesicles. Major secretory route in the cell : Rough endoplasmic membrane smooth endoplasmic membrane Golgi apparatus secretory vesicles entering the plasma. Plasma proteins are synthesized as preproteins and initially contain amino terminal single peptides. In some cases a second peptide is also removed, and in that event the original protein is known as preprotein (eg preproalbumin). They are usually subjected to various posttranslational modifications (proteolysis, glycosylation, phosphorilation, etc)

Plasma Proteins are glycoproteins

They generally contain either oligosaccharide chains or both. Nor O-linked

Albumin is the major exception; it does not contain sugar residues. The oligosaccaride chains have various functions : 1. removal of terminal sialic acid residues from certain plasma proteins (eg, ceruloplasmin), 2. affect proteolytic processing of precurser proteins to smaller products, 3. affect embriyonic development and differentiation, 4. protect against proteolysis, from inside and outside of cell.

Many Plasma Proteins Exhibit Polymorphism

Human plasma proteins that exhibit polymorphism include

1- antitrypsin, haptoglobin, transferrin, ceruloplasmin, and immunoglobulins

The polymorphic forms of these proteins can be distinguished by different procedures (eg, various types of electrophoresis or isoelectric focusing), in which each form may show a characteristic migration. Analysis of these human polymorphisms have proved to be of genetic, anthropologic, and clinical interest.

Each plasma protein has a characteristic Half-Life in the Circulation The half-lives obtained for albumin and haptoglobulin in normal healty adults are approximately 20 and 5 days respectively. 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, including albumin, may be lost into the bowel through the inflamed intestinal mucosa. Patients with this condition have a proteinlosing gastroenteropathy, and the half-life of injected iodinated albumin in these subjects may be reduced to as little as 1 day.

The levels of Acute-Phase Proteins (including C-reactive protein (CRP), 1- antitrypsin, haptoglobulin, 1- acid glycoprotein and fibrinogen) in plasma increase during acute inflammatory states and in patients with cancer or secondary to certain types of tissue damage. C-reactive protein (CRP, so named because it reacts with the C polysaccharide of pneumococci). CRP is used as a marker of tissue injury, infections, inflammations, and certain cardiovascular conditions (secondary to atherosclerosis). 1- antitrypsin can neutralize certain proteases during the acute inflammatory state. Nuclear factor kappa-B (NFkB) is an transcription factor that has been involved in the stimulation of synthesis of certain of the acute phase proteins. This important factor is also involved in the expression of many cytokines, chemokines, growth factors, and cell adhesion molecules implicated in immunologic phenomona. NFkB exists in an inactive form in the cytosol but is activated and translocated to the nucleus via the action of a number of molecules(eg. nterleukin-1) produced in processes such as inflammation, infection, and radiation injury.

Some Functions of Plasma Proteins

ALBUMIN
Albumin (69 kDa) is the major protein of human plasma (3.4-4.7 g/dL) and makes up approximately 60% of the total plasma protein. About 40% of albumin is present in the plasma, and the other 60% is present in the exstracellular space. The liver produces about 12g of albumin per day.

Albumin is synthesized by hepatocytes as preproalbumin. Its signal peptide is removed, converting it to proalbumin. In turn, proalbumin, while inside transport vesicles, is converted to albumin by action of furin.
Signal Peptide Furin Preproalbumin Signal Peptide + Proalbumin

Hexapeptide + ALBUMIN

Furin is a enzyme that cleaves a hexapeptide from proalbumin immediately C-terminal to a dibasic amino acid site (ArgArg). The resulting mature albumin is secreted into the plasma. The synthesis of albumin decreases relatively early in conditions of protein malnutrition, such as kwashiorkor. In liver diseases the synthesis of albumin is depressed (decrease in albumin/globulin ratio).

Structure and Functions of Albumin I

Mature human albumin consists of one polypeptide chain of 585 amino acids and contains 17 disulfide bonds. Albumin has an ellipsoidal shape, which means that it does not increase the viscocity of the plasma. Because of its relatively low molecular mass (about 69 kDa) and high concentration albumin is thought to be responsible for 70-80% of the osmotic pressure of human plasma. By the use of proteases, albumin can be subdivided into three domains, ehich have different functions. Electrophoretic studies have shown that the plasma of certain humans lacks albumin. These subjects are said to exhibit analbuminemia. Subjects with analbuminemia show only moderate EDEMA.

Structure and Functions of Albumin II

Another important function of albumin is its ability to bind various ligands (free fatty acids, calcium, certain steroid hormones, bilirubin, and some of the plasma tryptophan. In addition, albumin appears to play an important role in transport of copper in the human body. A variety of drugs, including sulfonamides, penicillin G, dicumarol, and aspirin, are bound to albumin. Preparations of human albumin have been widely used in the treatment of hemorrhagic shock and of burns.

HAPTOGLOBIN (Hp)
Haptoglobin (Hp) is a plasma glycoprotein that binds exstracorpuscular hemoglobin (Hb) in a tight noncovalent complex (Hb-Hp). Haptoglobin binds to exstracorpuscular hemoglobin, preventing free hemoglobin from entering the kidney. Hb-Hp complex is too large to pass through the glomerulus. The function of Hp thus appears to be to prevent loss of free Hb into the kidney.
Different fates of free hemoglobin and of the Hb-Hg complex

Functions of Haptoglobin I
Free Hb passes through the glomerulus of the kidney, enters the tubules, and tends to precipitate therein. However the Hb-Hp complex is too large to pass through the glomerulus. The function of Hp thus appears to be to prevent loss of free free Hb into the kidney. This conserves the valuable iron present in hemoglobin, which would otherwise be lost to the body.

Polymorphic forms of Haptoglobulin

Human haptoglobulin exists in three polymorphic forms, known as Hp 1-1, Hp 2-1, and Hp 2-2. Hp 1-1 ,is the simplest polymorphic form in human. Hp 1-1 migrates in starch gel electrophoresis as a single band, whereas Hp 2-1 and Hp 2-2 exhibit much more complex patterns. It has been suggested that the haptoglobuin polymorphism may be associated with the prevalence of many inflammatory diseases.

Functions of Haptoglobin II
Low levels of haptoglobulin are found in patients with hemolytic anemias. Half-life of haptoglobulin is approximately 5 days. The half of the Hb-Hp complex is about 90 minutes, the complex being rapidly removed from plasma by hepatocytes. Haptoglobin-related protein is another protein found in the plasma. Its level is elevated in some patients with cancers. Certain other plasma proteins bind heme but not hemoglobin. Hemopexin is a 1-globulin that binds free heme. Metheme (ferric heme) forms methemalbumin; which transfers the metheme to hemopexin.

IRON METABOLISM
Iron is important in the human body. It occurs in many hemoproteins such as hemoglobin, myoglobin and the cytochromes. Absorbtion of iron :

DMT1 : Divalent Metal Transporter

Fe3+ is converted to Fe2+ by ferric reductaseand vitamin C. Fe2+ is transported into the enterocyte by apical membrane iron transporter (DMT1) Heme is transported into the enterocyte by a seperate heme transporter (HT). Heme oxidase (HO) releases Fe2+ from the heme.

Some of the intracellular Fe2+ is converted to Fe3+ and bound to ferritin. The reminder binds to the basolateral transporter (FP: ferroportin) and is transported into the bloodstream, aided by hephaestin (HP). Hephaestin is copper containing protein. It has a ferroxidase activity, which is important in the release of iron from cells. Thus Fe2+ is converted back to Fe3+,the form in which it is transported in the plasma by transferrin.

Regulation of Iron Metabolism

Hepcidin is a peptide (25 A.A.) synthesized by liver cells. Hepcidin release of iron from macrophages possibly by interaction with ferroportin. When plasma levels of iron are high, synthesis of hepcidin increases: the opposite occurs when plasma level of iron is low. Hepcidin is play an important role in hereditary hemochromotosis and also in the iron deficiency anemia seen in chronic inflammatory conditions. Hemojuvelin is a protein, may also act by modulating the expression of hepcidin.

TRANSFERRIN
Transferrin (Tf) is a 1-globulin with a molecular mass of approximately 76 kDa. It is a glycoprotein and is synthesized in the liver. About 20 polymorphic forms of transferrin have been found. Transferrin plays a central role in the bodys metabolism of iron because it transports iron (2 mol of Fe3+ per mole of Tf) in the circulation to sites where iron is required, eg, from the gut to the bone marrow and other organs. Approximately 200 billion red blood cells (about 20 mL) are catabolized per day, releasing about 25 mg of iron into the body.

Transferrin Receptors There are receptors (TfR1 and TfR2) on the surfaces of many cells for transferrin. It binds to these receptors and is internalized by receptormediated endocytosis. The acid pH inside the lysosome causes the iron to dissociate from the protein. The dissociated iron leaves the endosome via DMT1 to enter the cytoplasm. Abnormalities of the glycosylation of transferrin occur in the congenital disorders of glycosylation and in chronic alcohol abuse.

Iron Defficiency
Iron deficiency anemia is extremely prevalent. Iron metabolism is particularly important in women (pregnancy, growing fetus), and in addition older people and poor dietary habits (tea and toasters) may develop iron deficiency. The concentration of transferrin in plasma is approximately 300 mg/dL. This amount of transferrin can bind 300 g of iron per deciliter, so that this represents the total ironbinding capacity of plasma. In iron deficiency anemia, the protein is even less saturated with iron, whereas in conditions of storage of excess iron in the body (eg, hemochromatosis: excess of iron).

FERRITIN

Ferritin is another protein important in the metabolism of iron. Apoferritin (the protein moiety free of iron) has a molecular mass of approximately 440 kDa. Ferritin is composed of 24 subunits of 18.5 kD, which surround in a micellar form some 3000 to 4500 ferric atoms. Normally, there is a little ferritin in human plasma. In patients with excess iron, the amount of ferritin in plasma markedly elevated. Synthesis of transferrin receptor (TfR) and that of ferritin are reciprocally linked to cellular iron content. When iron levels are high, ferritin is synthesized to store iron and TfR is not synthesized. Conversely, when iron levels is low, ferritin is not synthesized and TfR is synthesized in order to promote uptake of iron from transferrin. Hemosiderin appears to be a partly degraded form of ferritin, but still it contains iron.

Laboratory Tests For Assesing Patients with Disorders of Iron Metabolism

Red

blood cell count and estimation of hemoglobin

Determination

of plasma iron, total iron binding capacity (TIBC), and % transferrin saturation of radioimmunoassay ferritin in plasma by

Determination

Prussian

blue stain of tisuue sections of amount of iron (g/g) in a tissue

Determination

biopsy

CERULOPLASMIN
Ceroloplasmin (about 160 kDa) is an 2-globulin. Each molecule of ceruloplasmin binds 6 atoms of copper tightly. Albumin carries the other 10% of the plasma copper, but binds the metal less tightly than does ceruloplasmin. The amount of ceruloplasmin decreased in liver disease. in plasma is

Low levels of ceruloplasmin are found in Wilson Disease.

Abnormal Metabolism of Copper

Ceruloplasmin binds copper, and low levels of this plasma proteins are associated with Wilson Disease. Wilson disease is a genetic disease in which copper fails to be excreted in the bile and accumulates in liver, brain, kidney and red blood cells. Treatment of Wilson Disease consists of a diet low in copper and administration of penicillamine, which chelates copper, is excreted in the urine.

If the amount of copper accumulates, patients may develop

Hemolytic anemia, Chronic liver disease (cirrhosis, hepatitis) Neurologic syndrome (copper accumulates in the basal ganglia) Kayser-Fleischer ring: This is a green golden pigment ring around the cornea due to deposition of copper in Descements membrane. Menkes Disease is due to mutation in the gene encoding a copper-binding P type ATPase (ATP7B protein). This ATPase is thought to be responsible for directing the eflux of copper from cells. When altered by mutation copper is not mobilized normally from the intestine, in which it accumulates. Despite the accumulation of copper, the activities of many copperdependent enzymes are decreased.

Some important enzymes that contain Copper

Amine oxidase Copper-dependent superoxide dismutase Cytochrome oxidase Tyrosinase

Major Laboratory Tests Used in the Investigation of Diseases of Copper Mechanism

METALLOTHIONEINS
Matallothioneins are a group of proteins (about 6.5 kDa), found in the cytosol of cells, particularly of liver, kidney, and intestine. They have a high content of cysteine and can bind copper, zinc, cadmium, and mercury. The SH groups of cysteine are involved in binding the metals. These proteins may function to store the above metals ( Zn,Cd, Hg)in a nontoxic form.

ALFA(I) ANTITRYPSIN (1-ANTIPROTEINASE)

1-Antitrypsin (about 52 kDa) is a single chain protein of 394 amino acids, contains three olygosaccharide chains. It is synthesized by hepatocytes and macrophages and is the principal serine-protease inhibitor (Serpin or Pi) of human plasma. Inhibits trypsin and elastase.

Deficiency of Antitrypsin-I
At least 75 olymorphic forms occur, many of which can be seperated by electrophoresis. The major genotype is MM and its phenotypic product is PiM. A deficiency of this protein has a emphysema. This occurs in subjects with the ZZ genotype syntyhesize PiZ and also in PiSZ heterozygotes. who

When the amount of 1-antitrypsin is deficient and polymorphonuclear white blood cells increases in the lung (eg, during pneumonia), the affected individual lacks a countercheck to a proteolytic damage of lung by proteases such as elastase.

Deficiency of Antitrypsin-II
Methionine of 1-antitrypsin is involved in its binding to proteases. Smoking oxidizes this methionine to methionine sulfoxide and this results in proteolytic destruction of lung tissue (eg, PiZZ; already have a low levels of 1-antitrypsin). Deficiency of 1-antitrypsin is also implicated in one type of liver of liver disease (in ZZ type). Conformational diseases: Most appear to be due to the formation of -sheets by conformationally unstable proteins, which in turn leads to formation of aggregates. At present, severe 1-antitrypsin deficiency liver disease can be successfully treated by liver transplantation.

ALFA-II MACROGLOBULIN
2-Macroglobulin is a large plasma glycoprotein (720 kDa) made up of 4 identical subunits of 180kDa. Approximately 10% of the zinc in plasma is transported by 2-macroglobulin , the remainder being transported by albumin.

The protein is synthesized by a variety of cell types, including monocytes, hepatocytes and astrocytes. It is the major member of a group of plasma proteins that include complement proteins C3 and C4. These proteins contain a unique internal cyclic thiol ester bond (formed between cysteine and glutamine residue) and for this reason have been designated as the thiol ester plasma protein family.

2-macroglobulin binds many proteinases and is thus an important panproteinase inhibitor. The 2-macroglobulin proteinase complexes are rapidly cleared from the plasma by a receptor located on many cell types. 2-macroglobulinbinds many cytokines (platelet derived growth factor, transforming growth factor , etc..) and appears to be involved in targeting them toward particular tissues or cells. Once taken up by cells, the cytokines can dissociate from 2-macroglobulin and subsequently exert a variety of effects on cell growth and function.

AMYLOIDOSIS
Amyloidosis is the accumulation of various insoluble fibrillar proteins between the cells of tissues to an extent that affects function. The accumulation is generally due to either increased production of certain proteins or accumulation of mutated forms of other proteins.
Classification of amyloidosis...........

Treatment of Amyloidosis
Preventing Stabilizing

production of precursor protein

the structure of precursoe protein so that they do not convert plated sheet structure. amyloid fibrils so that they re-convert to their normal conformations.

Destabilizing

PLASMA IMMUNOGLOBULINS Plasma immunoglobulins play a major role in the bodys defense mechanisms. The immune system of the body consists of three major components: B-lymphocytes T-lymphocytes The innate immune system

The B-lymphocytes are mainly derived from bone marrow cells in higher animals and from the bursa of Fabricius in birds. The B-cells are responsible for the synthesis of circulating, humoral antibodies, also known as immunoglobulins. T cells are involved in a variety of important cell-mediated immunologic processes such as graft rejection, hypersensitivity reactions, and defense against malignant cells and many viruses. The innate immune system defends against infection in a non-spesific manner and unlike B and T cells is not adaptive.

All immunoglobulins contain a minimum of two light (L) chains (23 kDa) and two heavy (H) chains(53-75 kDa), held together as a tetramer (L2H2) by disulfide bonds. The half of the light (L) chain toward the carboxyl terminal is referred to as the constant region (CL), while the amino terminal half is the variable region of the light chain (VL). Approximately one quarted of the heavy (H) chain at the amino terminals is referred to as its variable region (VH), and the other three quarters of the heavy chain are referred to as the constant regions (CH1, CH2, CH3) of that H chain.

The portion of the immunoglobulin molecule that binds the specific antigen is formed by the amino terminal portions (variable regions) of both the H and L chains ie, the VH and VL domains. Digestion of an immunoglobulin by the enzyme papain produces two antigen binding fragments fab and one crystallizable fragment (Fc) which is responsible for functions of immunoglobulins. For example for Fab regions, IgG molecules bind two molecules of antigen and are termed divalent. All light chains are either kappa () and lambda () type. The five types of heavy chain determine immunoglobulin class (,,,, and ).

Both light and heavy chains are products of multiple genes: Light chain is product of at least three seperate structural genes : a variable (VL) gene, a joining region (J) gene, and a constant region (CL) gene. Heavy chain is the product of at least four different genes : a variable region (VH) gene, a diversity region (D) gene, a joining region (J) gene, and a constant region (CH) gene.

Major Functions of Immunoglobulins

Diseases of Immunoglobulins
Both over anf under production of immunoglobulins may result in disease state. Disorders of immunoglobulins include increased production of specific classes of immunoglobulins or even specific immunoglobulin molecules, the later clonal tumors of plasma cell called myeloma. Multiple myeloma is a neoplastic condition. Electrophoresis of serum or urine will usually reveal a large increase of one particular immunoglobulin or one particular light chain (the latter termed a Bence Jones Protein).

INNATE IMMUNITY

Innate immunity (also called natural or native immunity) consists of cellular and biochemical defense mechanisms. These mechanisms react only to microbes and not to noninfectious substances, and they respond in essentially the same way to repeated infections.

Innate immunity consists of: Barriers

(physical:skin,hair,mucous) (chemical:sweat,tears,saliva, stomach acid, urine)

Cellular response phagocytosis inflammatory reaction NK (natural killer) and mast cells Soluble factors

Innate and Adaptive Immunity

The principal components of innate immunity are;
(1) physical and chemical barriers, such as epithelia and antimicrobial substances produced at epithelial surfaces; (2) phagocytic cells (neutrophils, macrophages) and NK (natural killer) cells; (3) blood proteins, including members of the complement system and other mediators of inflammation; (4) proteins called cytokines that regulate and coordinate many of the activities of the cells of innate immunity.

Adaptive Immunity

In contrast to innate immunity, there are other immune responses that are stimulated by exposure to infectious agents and increase in magnitude and defensive capabilities with each successive exposure to a particular microbe. Because this form of immunity develops as a response to infection and adapts to the infection, it is called adaptive immunity. The defining characteristics of adaptive immunity are exquisite specificity for distinct molecules and an ability to "remember" and respond more vigorously to repeated exposures to the same microbe. The adaptive immune system is able to recognize and react to a large number of microbial and nonmicrobial substances

Innate and adaptive immune responses are components of an integrated system of host defense in which numerous cells and molecules function cooperatively. The mechanisms of innate immunity provide effective defense against infections.

. . . against whatever doesnt belong

Other s use microbe Vir s

e pat Other issu s hog T ens ant it irrC he Ca m nc ica Damage/ er injury ls

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Innate and adaptive immune responses

x To s in

Innate and Adaptive Immune Responses

However, many pathogenic microbes have evolved to resist innate immunity, and their elimination requires the powerful mechanisms of adaptive immunity.

There

are two important links between innate immunity and adaptive immunity.
First,

the innate immune response to microbes stimulates adaptive immune responses and influences the nature of the adaptive responses. Second, adaptive immune responses use many of the effector mechanisms of innate immunity to eliminate microbes, and they often function by enhancing the antimicrobial activities of the defense mechanisms of innate immunity.

Types of Adaptive Immune Responses

There are two types of adaptive immune responses, called humoral immunity and cell-mediated immunity, that are mediated by different components of the immune system and function to eliminate different types of microbes Humoral immunity is mediated by molecules in the blood and mucosal secretions, called antibodies, that are produced by cells called B lymphocytes (also called B cells). Antibodies themselves are specialized, and different types of antibodies may activate different effector mechanisms. For example, some types of antibodies promote phagocytosis, and others trigger the release of inflammatory mediators from leukocytes such as mast cells.

Specific Immunity
In addition, it has an extraordinary capacity to distinguish among different, even closely related, microbes and molecules, and for this reason it is also called specific immunity. The components of adaptive immunity are;

Lymphocytes, and their products.

Adhesion Molecules
Adhesion molecules mediate adhesion between cells. The direct cellular interactions during an immune response are dependent on the expression of the molecules and ligands that mediate adhesion between cells and between cells and extracellular matrix. These are termed adhesion molecules. Adhesion molecules found on a wide variety of cell types, not only cells of the immune system (eg, vascular endothelium).

Adhesion molecules are transmembrane glycoproteins. Adhesion molecules deliver intracellular signals and during immune responses are primaraly involved in promoting cell-cell interactions and cell migration. The latter includes the movement of innatecells from blood to tissue during infection as well as aiding lymphocytes to enter and leave lymph nodes as they circulete the body looking for activation signals as a result of antigen presentation in these peripheral organs.

Adhesion molecules involved in immunity are grouped into three major families :
Integrins

(eg, lymphocyte function associated antigen-I [LFA-I], Adhesion molecule-I [MAC-I]), super gene family adhesion molecules (ICAM-1, CD54, PLATELET/Cell Adhesion Molecule [PECAM-I, CD31]), (L-selectin, P-selectin).

Immunoglobulin

Selectin

COMPLEMENTARY SYSTEM
Another important component of innate system is complement, a collection of constitutive serum proteins synthesized mainly in liver, which complement, or enhance, the effect of antibodies. The main function of the complementary system is to enable the distruction of pathogens by phagocytes (macrophages and neutrophils) by a mechanism known as opsonization. There are about 20 complement that can bind directly to microbial or fungal surfaces. Several componets of this system are proenzymes converted to active enzymes. Complementary system proteins are : (C1, C1q, C1r, C1s, C2, C2a, C2b, C3, C3a, C3b, C4, C4a, C4b, C5, C5a, C5b, C6, C7, C8, C9).

Three pathways of complementary activation.