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Plasma Proteins Plasma Proteins

Plasma proteins

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Page 1: Plasma proteins

Plasma Proteins Plasma Proteins

Page 2: Plasma proteins

Plasma Proteins (Cont.)Plasma Proteins (Cont.)

The plasma is the liquid medium of the The plasma is the liquid medium of the blood(55-60%),in which the cell components blood(55-60%),in which the cell components namely erythrocytes,leukocytes,platelets namely erythrocytes,leukocytes,platelets and many proteins are suspended.and many proteins are suspended.

Plasma – clotting factors=SerumPlasma – clotting factors=SerumTotal concentration of plasma protein in Total concentration of plasma protein in

blood is 7g/dl, which in total makes 7% of blood is 7g/dl, which in total makes 7% of total blood volume. total blood volume.

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General characteristics of General characteristics of plasma proteinsplasma proteins

All the plasma proteins are synthesized in All the plasma proteins are synthesized in liver except gamma globulins which is liver except gamma globulins which is synthesized by Plasma cells.synthesized by Plasma cells.

Almost all the plasma proteins are Almost all the plasma proteins are glycoproteins.glycoproteins.

Some of the plasma proteins exhibit Some of the plasma proteins exhibit polymorphismpolymorphism(exist in different phenotypes) (exist in different phenotypes) e.g e.g αα1 antitrypsin,transferrin and 1 antitrypsin,transferrin and hepatoglobin.hepatoglobin.

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The concentration of certain plasma The concentration of certain plasma proteins (proteins (acute phase proteins) acute phase proteins) increases in disease states such as increases in disease states such as inflamation and tissue damage.These inflamation and tissue damage.These include C-reactive proteins,hepatoglobin, include C-reactive proteins,hepatoglobin, fibrinogen andfibrinogen and α α1 antitrypsin. 1 antitrypsin.

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Electrophoresis is the most commonly Electrophoresis is the most commonly employed technique for the separation employed technique for the separation plasma proteins.plasma proteins.

Electrophoresis is used for the diagnosis Electrophoresis is used for the diagnosis of certain diseases e.g multiple of certain diseases e.g multiple myeloma,acute infections,Neprotic myeloma,acute infections,Neprotic syndrome etc.syndrome etc.

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Plasma Proteins (Cont.)Plasma Proteins (Cont.)

TypesTypes

AlbuminsAlbumins GlobulinsGlobulins αα1-Globulins1-Globulins αα1-antitrypsin1-antitrypsin LipoproteinLipoprotein OrosomucoidOrosomucoid Retinol binding proteinRetinol binding protein Thyroxin binding proteinThyroxin binding protein

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αα2 Globulins2 Globulins α α 2-Macroglobulin2-Macroglobulin HepatoglobinsHepatoglobins ProthrombinProthrombin CeruloplasminCeruloplasmin

ββ Globulins Globulins LipoproteinsLipoproteins TransferrinTransferrin HemopexinHemopexin PlasminogenPlasminogen

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γγ Globulins Globulins Immunoglobulins.Immunoglobulins.

FibrinogenFibrinogen

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Plasma Proteins (Cont.)Plasma Proteins (Cont.)

Albumins Albumins most abundant blood plasma protein. most abundant blood plasma protein. Concentration is 3.5-5.0g/dlConcentration is 3.5-5.0g/dl Produced in the liver Produced in the liver Normally constitutes about 60-80% of human Normally constitutes about 60-80% of human

plasma protein.plasma protein. Half life is of 20 daysHalf life is of 20 days ExamplesExamples In animals Serum albumin, ovalbumin,lactalbumin.In animals Serum albumin, ovalbumin,lactalbumin. In plants legumelin. In plants legumelin.

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Plasma Proteins (Cont.)Plasma Proteins (Cont.)

FunctionsFunctionsCarriers for molecules of low water Carriers for molecules of low water

solubility including lipid soluble solubility including lipid soluble hormones, bile salts, un-conjugated hormones, bile salts, un-conjugated bilirubin, free fatty acids (apo-protein), bilirubin, free fatty acids (apo-protein), calcium ions, and some drugs like calcium ions, and some drugs like warfarin. warfarin.

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Plasma Proteins (Cont.)Plasma Proteins (Cont.)

Metal Binding: Metal Binding: A large proportion of zinc in serum is bound to A large proportion of zinc in serum is bound to

albumin. Albumin binds other divalent cations, albumin. Albumin binds other divalent cations, such as Ca, Mg, Mn, Cd, Co, and Ni.such as Ca, Mg, Mn, Cd, Co, and Ni.

Fatty Acid Binding:Fatty Acid Binding: Fatty acids, such as linoleic, linolenic and oleic Fatty acids, such as linoleic, linolenic and oleic

acid are insoluble in aqueous solutions and acid are insoluble in aqueous solutions and must be delivered to cells by a carrier must be delivered to cells by a carrier molecule.molecule.

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Osmotic functionOsmotic function Albumin contributes to 75-80% OF TOTAL Albumin contributes to 75-80% OF TOTAL

PLASMA OSMOTIC PRESSURE(25 mm PLASMA OSMOTIC PRESSURE(25 mm Hg).Thus albumin plays a predominant role in Hg).Thus albumin plays a predominant role in maintaing the blood volume and body fluid maintaing the blood volume and body fluid distribution.distribution.

Decrease in plasma albumin levels results in fall Decrease in plasma albumin levels results in fall in plasma osmotic pressure,leading to enhanced in plasma osmotic pressure,leading to enhanced fluid retention in tissue spaces causing fluid retention in tissue spaces causing EDEMA.EDEMA.

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Regulation of colloidal pressureRegulation of colloidal pressure

Gaw: Clinical Biochemistry; Churchill Livingstone (1999), p. 44.

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Plasma Proteins (Cont.)Plasma Proteins (Cont.)

Mixed Disulfides or Albumin: Mixed Disulfides or Albumin: Human and bovine albumins contain an Human and bovine albumins contain an

unpaired sulfhydryl at position 34 in their unpaired sulfhydryl at position 34 in their primary sequences. This sulfhydryl group primary sequences. This sulfhydryl group often forms a covalent link with other often forms a covalent link with other sulfhydryl molecules such as cysteine or sulfhydryl molecules such as cysteine or glutathione. Protect these molecules from glutathione. Protect these molecules from oxidation and improve their availability for oxidation and improve their availability for cells.cells.

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Plasma Proteins (Cont.)Plasma Proteins (Cont.)

Albumins (Albumins (Cont.)Cont.) Low albumin (Low albumin (hypoalbuminemia) hypoalbuminemia) may be may be

caused by liver disease, nephrotic syndrome, caused by liver disease, nephrotic syndrome, burns, protein-losing enteropathy, burns, protein-losing enteropathy, malabsorption, malnutrition, pregnancy, malabsorption, malnutrition, pregnancy, genetic variations and malignancy. genetic variations and malignancy.

High albumin (hyperalbuminemia) is almost High albumin (hyperalbuminemia) is almost always caused by dehydration. always caused by dehydration.

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Plasma Proteins (Cont.)Plasma Proteins (Cont.)

GlobulinGlobulin Some globulins are produced in the liver, while Some globulins are produced in the liver, while

others are made by the immune system. others are made by the immune system. High molecular weight High molecular weight Solubility and electrophoretic migration rates Solubility and electrophoretic migration rates

lower than for albumin lower than for albumin Normal concentration in blood is 2 to 3.5 g/dl.Normal concentration in blood is 2 to 3.5 g/dl.

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Plasma Proteins (Cont.)Plasma Proteins (Cont.)

Globular protein. Globular protein. Protein electrophoresis is used to Protein electrophoresis is used to

categorize globulins into the following categorize globulins into the following four categories:four categories:

Alpha 1 globulins Alpha 1 globulins Alpha 2 globulins Alpha 2 globulins Beta globulins Beta globulins Gamma globulins Gamma globulins

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Plasma Proteins (Cont.)Plasma Proteins (Cont.)

Transferrin(Transferrin(ββ globulin) globulin) A glycoproteinA glycoprotein polypeptide chain containing 679 amino acids polypeptide chain containing 679 amino acids Binds iron reversibly Binds iron reversibly molecular weight of around 80 KDa molecular weight of around 80 KDa transferrin protein loaded with iron binds to transferrin protein loaded with iron binds to

transferrin receptortransferrin receptor transported into the cell transported into the cell

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Plasma Proteins (Cont.)Plasma Proteins (Cont.)

Each transferrin molecule has the ability to Each transferrin molecule has the ability to carry two iron ions in the ferric form (Fe3+). carry two iron ions in the ferric form (Fe3+).

Protects the body against the toxic Protects the body against the toxic effects of free iron.effects of free iron.

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Plasma Proteins (Cont.)Plasma Proteins (Cont.)

Increased serum transferrin level occurs Increased serum transferrin level occurs in iron deficiency anemia. in iron deficiency anemia.

An absence of transferrin in the body An absence of transferrin in the body occurs in a rare genetic disorder known occurs in a rare genetic disorder known as atransferrinemia. as atransferrinemia.

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Plasma Proteins (Cont.)Plasma Proteins (Cont.)

Ceruloplasmin (Ceruloplasmin (Alpha 2 globulins) Alpha 2 globulins) Copper-carrying protein Copper-carrying protein Synthesized in the liver Synthesized in the liver Carries 90% of the copper in our plasma Carries 90% of the copper in our plasma Molecular weight 151KDa . Molecular weight 151KDa . Low Ceruloplasmin levels: hepatic disease, Low Ceruloplasmin levels: hepatic disease,

Wilson's disease.Wilson's disease. Elevated levels: pregnancy, acute and chronic Elevated levels: pregnancy, acute and chronic

inflammation inflammation

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Plasma Proteins (Cont.)Plasma Proteins (Cont.)

Fibrinogen Fibrinogen Fibrous protein Fibrous protein Involved in the clotting of blood Involved in the clotting of blood Fibrin is made from Fibrin is made from fibrinogenfibrinogen Soluble plasma glycoprotein Soluble plasma glycoprotein Synthesized by the liver Synthesized by the liver 340 KDa glycoprotein 340 KDa glycoprotein

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Plasma Proteins (Cont.)Plasma Proteins (Cont.)

blood plasma is 1.5-4.0 g/L blood plasma is 1.5-4.0 g/L Hexamer containing two sets of three different Hexamer containing two sets of three different

chains (α, β, and γ), linked to each other by chains (α, β, and γ), linked to each other by disulfide bonds. The N-terminal sections of disulfide bonds. The N-terminal sections of these three chains contain the cysteines that these three chains contain the cysteines that participate in the cross-linking of the chains. participate in the cross-linking of the chains. The C-terminal parts of the α, β and γ chains The C-terminal parts of the α, β and γ chains contain a domain of about 225 amino-acid contain a domain of about 225 amino-acid residues, which can function as a molecular residues, which can function as a molecular recognition unit. recognition unit.

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Plasma Proteins (Cont.)Plasma Proteins (Cont.)

Congenital deficiency (afibrinognenemia) Congenital deficiency (afibrinognenemia) Acquired deficiency: after hemodilution.Acquired deficiency: after hemodilution.

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Haptoglobin(Alpha 2 Haptoglobin(Alpha 2 globulin)globulin)

Acute phase protein.Acute phase protein. It binds with free hemoglobin(extracorpuscular It binds with free hemoglobin(extracorpuscular

hemoglobin) that spills into the plasma due to hemoglobin) that spills into the plasma due to hemolysis.hemolysis.

The Hp-Hb complex (155,000) cannot pass The Hp-Hb complex (155,000) cannot pass through glomeruli of kidney while free Hb through glomeruli of kidney while free Hb (65,000) can.(65,000) can.

Hepatoglobin therefore prevents the loss of Hepatoglobin therefore prevents the loss of free hemoglobin into free hemoglobin into the kidney.the kidney.

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C-REACTIVE PROTEIN (CRP)

Major component of the acute phase response and a marker of bacterial infection.

Mediates the binding of foreign polysaccharides, phospholipids and complex polyanions, as well as the activation of complement

<1 mg/mL in normal plasma

Slightly elevated levels of CRP are indicative of chronic, low-grade inflammation and have been correlated with an increased risk of cardiovascular disease .

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Alpha 1 Alpha 1 antitrypsin(Alpha1 antitrypsin(Alpha1 globulin).globulin).

ASSIGNMENT.ASSIGNMENT.

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IMMUNOGLOBULINIMMUNOGLOBULIN

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Higher vertebrates including man,have Higher vertebrates including man,have evolved a defense system to protect evolved a defense system to protect themselves against the invasion of themselves against the invasion of foreign substances a virus,a bacterium or foreign substances a virus,a bacterium or a protein.The defense strategies of the a protein.The defense strategies of the body are collectively known as body are collectively known as immunityimmunity..

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CELLULAR IMMUNITY.Mediated by T CELLULAR IMMUNITY.Mediated by T cells.cells.

HUMORAL IMMUNITY.Mediated by HUMORAL IMMUNITY.Mediated by immunoglobulins or antibodioes immunoglobulins or antibodioes produced by the B cells.produced by the B cells.

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Plasma Proteins (Cont.)Plasma Proteins (Cont.)

AntibodiesAntibodies Also known as Also known as immunoglobulinsimmunoglobulins Abbreviated as Abbreviated as IgIg Gamma globulin proteins Gamma globulin proteins General structure of all antibodies is very General structure of all antibodies is very

similar similar

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AntibodiesAntibodies Proteins that recognize and bind to a particular antigen Proteins that recognize and bind to a particular antigen

with very high with very high specificityspecificity.. Made in response to exposure to the antigen.Made in response to exposure to the antigen. One virus or microbe may have several One virus or microbe may have several antigenic antigenic

determinant sites(epitopes)determinant sites(epitopes), to which different , to which different antibodies may bind.antibodies may bind.

Each antibody has at least two identical sites that bind Each antibody has at least two identical sites that bind antigen: antigen: Antigen binding sitesAntigen binding sites..

Valence of an antibody: Number of antigen binding Valence of an antibody: Number of antigen binding sites. Most are bivalent.sites. Most are bivalent.

Belong to a group of serum proteins called Belong to a group of serum proteins called immunoglobulins (Ig’s).immunoglobulins (Ig’s).

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Antibody structureAntibody structure

Variable & Constant Variable & Constant RegionsRegions VL & CLVL & CL VH & CHVH & CH

Hinge RegionHinge Region

CH1

VL

CL

VH

CH2 CH3

Hinge Region

Carbohydrate

Disulfide bond

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Human Immunoglobulin Human Immunoglobulin ClassesClasses

IgG - Gamma heavy chainsIgG - Gamma heavy chains IgM - Mu heavy chainsIgM - Mu heavy chains IgA - Alpha heavy chainsIgA - Alpha heavy chains IgD - Delta heavy chainsIgD - Delta heavy chains IgE - Epsilon heavy chainsIgE - Epsilon heavy chains

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• L chains are one of two types

•Designated κ and λ and only

•one type is found in Ig.

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• L and H chains are subdivided into

variable and constant regions.The regions

are composed of three-dimensionally folded,

repeating segments called domains. An L

chain consists of one variable (VL) and one

constant (CL) domain.Most H chains consist

of one variable (VH) and three constant(CH)

domains.(IgG and IgA have three CH

domains,whereas IgM and IgE have four.)

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The variable regions are responsible for antigenbinding ,whereas the constant regions are responsible for various biologic functions eg, complement activation and binding to cell surface receptors.

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Immunoglobulin ClassesImmunoglobulin Classes

I. IgGI. IgG Structure: MonomerStructure: Monomer Most abundant (75-80%).Most abundant (75-80%). Can traverse blood vessels.Can traverse blood vessels. Transfers mother’s immunity to fetus.Transfers mother’s immunity to fetus. Mediates foreign cell destruction by Mediates foreign cell destruction by

complement system.complement system.

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Immunoglobulin ClassesImmunoglobulin Classes

II. IgMII. IgM Structure: Pentamer Structure: Pentamer Percentage serum antibodies: 5-10%Percentage serum antibodies: 5-10% Location: Blood, lymph, B cell surface (monomer)Location: Blood, lymph, B cell surface (monomer) Half-life in serum: 5 daysHalf-life in serum: 5 days Complement Fixation: YesComplement Fixation: Yes Placental Transfer: NoPlacental Transfer: No Known Functions: First antibodies produced during Known Functions: First antibodies produced during

an infection. Effective against microbes and an infection. Effective against microbes and agglutinating antigens. agglutinating antigens.

C4

J Chain

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Immunoglobulin ClassesImmunoglobulin Classes

III. IgAIII. IgA Structure: DimerStructure: Dimer Percentage serum antibodies: 10-15%Percentage serum antibodies: 10-15% Location: Secretions (tears, saliva, intestine, milk), Location: Secretions (tears, saliva, intestine, milk),

blood and lymph.blood and lymph. Predominant antibody in the clostrum.Predominant antibody in the clostrum. Half-life in serum: 6 daysHalf-life in serum: 6 days Known Functions: Localized protection of Known Functions: Localized protection of mucosalmucosal

surfaces. Provides immunity to infant digestive tract.surfaces. Provides immunity to infant digestive tract.

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Immunoglobulin ClassesImmunoglobulin Classes

IV. IgDIV. IgD Structure: MonomerStructure: Monomer Percentage serum antibodies: 0.2%Percentage serum antibodies: 0.2% Location: B-cell surface, blood, and lymphLocation: B-cell surface, blood, and lymph Half-life in serum: 3 daysHalf-life in serum: 3 days Known Functions: In serum function is Known Functions: In serum function is

unknown. On B cell surface, act as B cell unknown. On B cell surface, act as B cell receptor, initiate immune response.receptor, initiate immune response.

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Immunoglobulin ClassesImmunoglobulin Classes

V. IgEV. IgE Structure: MonomerStructure: Monomer Percentage serum antibodies: 0.002%Percentage serum antibodies: 0.002% Location: Bound to mast cells and basophils Location: Bound to mast cells and basophils

throughout body. Blood.throughout body. Blood. Placental Transfer: NoPlacental Transfer: No Known Functions: Allergic reactions. The Known Functions: Allergic reactions. The

IgE molecules tightly bind with mast cells IgE molecules tightly bind with mast cells and release histamine and cause allergy.and release histamine and cause allergy.

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Multiple Myeloma(Plasma Multiple Myeloma(Plasma cell cancer).cell cancer).

Abnormal Ig productionAbnormal Ig production Malignancy of a single clone of plasma Malignancy of a single clone of plasma

cells in bone marrow.cells in bone marrow. Results in overproduction of Results in overproduction of

Ig’s,mostely(75%) IgG,and in some Ig’s,mostely(75%) IgG,and in some cases(25%) IgA or IgM.cases(25%) IgA or IgM.

Synthesis of normal immunoglobulins is Synthesis of normal immunoglobulins is diminshed causing diminshed immunity.diminshed causing diminshed immunity.

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Bence jones proteins.Bence jones proteins. These are light chains of These are light chains of

immunoglobulins that are synthesized in immunoglobulins that are synthesized in excess.excess.

In about 20% of patients of multiple In about 20% of patients of multiple myeloma,Bence jones proteins are myeloma,Bence jones proteins are excreated in the urine which often excreated in the urine which often damages the renal tubules.damages the renal tubules.