Immunoglobulins structure and function Immunoglobulins(Ig):They are a group of glycoproteins which presentin serum, tissue and all body fluids that have Antibody (Ab) activities (react specifically with the Antigen (Ag) that causes their productions .Ig are synthesized and secreted by plasma cell.

Basic structure of Ig:

1.Heavy and light chain;The backbone of Ig consist of 2 pairs of polypeptide chainseach pair are identical.One pair nearly double the molecular weight of the other pair so called heavy chain (50-70 KD) and light chain(23KD) respectively. 2. Disulphide bonds;The four polypeptide chains are hold together by inter chain disulphide bonds to give themonomeric structure.

3.Variable (V) and constant (C) region;Each chain has 2 terminals: a. Amino terminal in which the amino acid are variable called (variable region).b.Carboxyterminalin which the a.a. sequence ratherconstantand heterogeneous (constant region),the constant region of light chain is either Kappa() or Lambda( )while the constant region of heavy chain eitherGamma γ, Delta δ, Alpha α, Muμ,Epsilon ε

Both heavy and light chain could be divided into two regions based on variability in amino acid sequencesthese are: - Variablelight VL (110 a.a.) and constant light CL (110 a.a.). - VariableHeavy VH (110 a.a.) and Constant Heavy CH (330-440 a.a.).

4.Domains; The amino acid sequence in both light & heavy chains is not a linear sequence but there are domes or loops due to presence of intra chaindisulphide bonds these globular areas called domains. -In the variable region of each chain there is only one domain VL or VH. -In the constant region of light chain there is one constant domain CL. .

-In the constant region of heavy chain; There are 3 constant domains CH1,CH2,CH3with exception IgM, IgE there is an extra domain CH4 5. Oligosaccharides; carbohydrates are attached to the CH2 domain in most Ig;which support the Ig against proteolytic enzymes

6. Hinge region; at which the arms of antibody molecule form Y shape; Pepsin act to the right of hinge region leads to formation of FAB Dimmer (fragmentAg binding)and FC fragment(fragment crystallizable)which have several biological activities by binding toFC receptor onvarious cell of immune system and complement activation. -Three areas in the variable region of each chain with a high variability in the amino acid sequence to form the Ag binding site (paratope)

Paratope=Ag binding site;A cleft formed by three hot spots from the light chain and a farther three from the adjacent heavy chain ,it is complementary to the specific chemistry & shape of the epitope (Ag determinant)so it is also known as complementarity determing region(CDR).(Idiotype =paratope +hot spots).

Function of Ig: Ig is a bi-functional molecule Primary binding with Ag (recognition) by Fab region   Secondary biological activities(effector function) to get rid of invasion Ag by Fc region

1-Cytolysis (fixation of complement): Ag-Ab binding--------- activation of the complement system---------------Lysis of the cell 2- Opsonization Ab coat the Ag ---------- recognized by phagocytic cells ------------phagocytosis (phagocytic cell such as macrophage ,monocyte ,natural killer have receptor For FC fragment of Ig

Opsonins: is a substances that bind to Ag and make it more susceptible to phagocytosis such as Ab (IgG,IgA) ,complement component (C3b) and C. reactive protein. 3-Neutrilization ;Neutralize(react) toxins & viruses (inactivate them). 4-Blocking ;block the reaction of Ag (block viral binding site). 5-Agglutination: collect Ag bearing particles such as microbes for phagocytosis

Function of Ab

Immunoglobulin classes: Immunoglobulins are classified into five classes depend on the bases of constant region of their heavy chain peptide structure:(IgG, IgA, IgM, IgD , IgE).

IgG: IgG is considered the most protective Ab because: -predominant Ig in serum75% with low M.W. 15000. -can extra-vassate easily to the extra vascular space so it is first line of defense -Only Ig can pass the placenta protect the fetus in the first few month of life. -Long half time. -Best opsonizing Ab,it binds the Ag with high affinity. -Main Ig in the secondary immune- response. .

IgG have monomeric structure. The Gamma γ chain of IgG is subdivided into four subclasses: Gamma γ1 IgG1 65% Gamma γ2 IgG2 32% Gamma γ3 IgG3 8% Gamma γ4 IgG4 4%

These subclasses differ in their secondary biological activity: -complement fixation (CH2) through classical pathway IgG3> IgG1> IgG2 While IgG4 only fix complement through alternative pathway -crossing the placenta (CH3,CH2) IgG1 > IgG3> IgG2 -binding to monocyte (CH3 ,CH2) IgG1 > IgG3> IgG2 -blocking IgE binding only IgG4

IgA: -IgAconstitute 15% of total serum Ig. -Main Igin the external secretionsas saliva, tears, breast milk. -Subdivided into IgA1 & IgA2 subclasses. -It has 2 forms;1-Monomeric in the blood (serum type) 2-Dimericin the external secretions(secretary IgA(sIgA).

Dimeric IgA IgA synthesized by plasma cell as monomeric one in the submucosa which will be combine with another monomeric IgA by a polypeptide J chain to form dimeric IgA this will be protected by a secretary piece from the secretary epithelium to form the secretary IgA(sIgA).Secretory piece(SP)produced bymucosa epithelial cells which protect sIgA and make it resist proteolysis in extra secretory liquid.

Functions of secretary IgA: 1.Activation of the complement through the alternative pathway(cytolysis). 2.BlockingandNeutrilization. 3.Opsonization.

IgM -Constitute 10% of total serum Ig -Its molecular weight 900 000 (Heavy) - It has two forms: 1-Monomeric form on the surface of B lymphocytes asantigen receptor together with IgD 2-pentamericIgM;five monomeric connected by J chain. -IgM has no hinge region replaced by an additional domiainCH2,CH3,CH4. •It is the main Ig in the primary immune response. •It is the first Ig synthetized by the fetus

Pentameric IgM has 10 FAB so it is the most agglutinating & most complement fixing Ab

IgD: -Very low concentration in the blood less than 1% -Short half life 2-3 days -Present on the surface of B lymphocyte together with monomeric IgM as a surface antigen receptor of B lymphocyte (immature B cell only IgM on its surface while mature B cell IgM+IgD on its surface). - It exist only as monomeric form. - It does not bind complement.

IgE 0.002 % of serum Ig (detection by Elisa). it does not bind complement. - In atopic patient the level increase by hundreds. - IgE also called reagenic or homocytotropic Ab because of its ability of binding to FC receptors on the surface of Mast cells and basophiles.

Cross linking of IgEon the surface of mast cell by allergen-------Degranulation----------release of histamine and other inflammatory mediator--------Allergy

Functions of IgE; IgE increases in Parasitic infections and Atopic patients: 1.Triggering an acute inflammatory reaction and involve in allergic reactions. 2. Has the ability to bind to FC receptor on eosinophils so important against parasitic infections;eosinophils contain granules that realize cationic proteins which are toxic to the parasites.

Has the ability to bind to FC receptor on eosinophils so important against parasitic infections;eosinophils contain granules that realize cationic proteins which are toxic to the parasites

Variants of Ig Isotype: all classes ,Subclasses& forms of Ig which present in normal individual Allotype: single a.a. variation in the peptide chain of Ig Idiotype: each Ig has its own antigenic determinantin its variable region (Idiotype =paratope +hot spots).