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Immunoglobulins (Ig)

Immunoglobulins (Ig). ADAPTIVE IMMUNE SYSTEM. T-lymphocytes T-cytotoxic Cytoyoxic B-lymphocytes Plasma cells Antibodies Response takes 7 to 10 days. Adaptive Immune System. T and B Lymphocytes Highly specific for pathogen Response improves with repeated exposure Memory

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Immunoglobulins (Ig)

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  1. Immunoglobulins (Ig)

  2. ADAPTIVE IMMUNE SYSTEM T-lymphocytes T-cytotoxic Cytoyoxic B-lymphocytes Plasma cells Antibodies Response takes 7 to 10 days

  3. Adaptive Immune System • T and B Lymphocytes • Highly specific for pathogen • Response improves with repeated exposure • Memory • Life-long immunity

  4. T versus B cell Response

  5. B-lymphocytes - • Differentiate in bone marrow • Birds bursa of Fabricius • 5-10% of lymphoid pool • Majority express Class II MHC, C= receptors, Fc receptors • CD19, CD20, CD22 currently used to identify B cells. • CD5 bearing B cells are predisposed to autoantibody production

  6. Antibody Functions

  7. Antigen Recognition: B Cells and Antibodies • Antibodies bind antigen. • This interaction is non-covalent and generally highly specific. • Antibodies are only produced by B lymphocytes and are exported through the usual constitutive exocytosis pathway in both integral plasma membrane and secretory forms.

  8. Antigen Recognition: B Cells and Antibodies • Antibodies form the B cell antigen specific receptor. • Antibodies are found in the plasma and also bound to specific receptors for the invariant (Fc) region of immunoglobulin. • They are also found in secretory fluids such as mucus, milk and sweat.

  9. Antigen Recognition: B Cells and Antibodies • All antibodies have a similar overall structure with two light (L) and two heavy (H) chains. • These are linked by both covalent (disulphide bridges) and non-covalent forces. • They are made up of a series of domains of related amino acid sequence which possess a common secondary and tertiary structure.

  10. Antigen Recognition: B Cells and Antibodies • Other members of the immunoglobulin supergene family are: • T-cell receptor; • Adhesion molecules ICAM-1, -2, -3, and VCAM; • Co-receptors CD4 and CD8; • Costimulatory pairs CD28, CTLA4, B7.1 and B7.2

  11. Antibody Structure • Antibodies are made up of V (for variable) and C (for constant) regions. • The antigen binding activity is found in the V region whereas the complement fixing and Ig receptor binding activity is found in the C region.

  12. Antibody Structure

  13. Antibody Structure – V Region • Variation is mostly restricted to three regions within the N-terminal domain of both the heavy (H) and light (L) chains. • When the amino acid sequences of many antibodies are aligned then these regions display the greatest variability.

  14. Combination Diversity in Human Ig Genes

  15. Antibody Structure – V Region • In the 3-dimensional structure these regions form loops at the surface of the antibody molecule and these provide the binding surface between antibody and antigen. • The V regions determine the 'fit' between antibody and antigen they are referred to as the complementarity determining regionsor CDRs. CDR3 shows more variation that either CDR1 or 2.

  16. Hypervariable Regions in Ig

  17. Antibody Structure – C Region • The C region is made up of a series of Ig-like domains and their number varies between classes. • In humans, for example, IgM and IgE have 4 Ig-like domains (CH1 -> CH4) whereas IgG, IgA and IgD have only 3 (CH1 -> CH3). • In IgG, IgA and IgD there is an important sequence of 10-60 amino acids between CH1 and CH2 which confers flexibility on the molecule and is known as the hinge region.

  18. Antibody Domain Structure

  19. Immunoglobulin Functions-Soluble- 1.     Activate both the classical and alternative complement cascades, 2.     Transcytose across epithelial cell layers to provide a barrier to pathogens at mucosal surfaces, 3.     Travel transplacentally to confer maternal humoral immunity to the fetus and neonate, 4.     Induce phagocytosis by macrophages and granulocytes via the process of opsonization,

  20. Immunoglobulin Functions-Soluble- 5.     Foster antibody-dependent cellular cytotoxicity by lymphocytes and NK cells, 6.     Encourage anti-parasite immune responses by eosinophils, 7.     Promote degranulation by mast cells and basophils, 8.     Bind and inactivate foreign antigenic entities directly.

  21. Immunoglobulin Functions –Bound- 1.     The induction of activation and differentiation, 2.     Anergy, 3.     Apoptosis of B lymphocytes, 4.     To act as a high-affinity receptor for the recognition, 5.    Internalization, degradation, and eventual presentation of specific antigens to T cells.

  22. Antibody Isotypes • IgM • IgG • IgA • IgD • IgE

  23. Antibody Structure – Classes • In mice and humans the different types of antibody are known as IgM, IgG , IgA, IgD, and IgE. • Subtypes (subclasses) of certain classes exist both in humans (G1, G2, G3, G4, and A1, A2) and in mice (G1, G2a, G2b and G3).

  24. IgM • IgM is the most versatile antibody and almost certainly the first type of immunoglobulin to have developed evolutionarily. • Heavy chains of the m class are the first type expressed during B cell development, and IgM is the isotype produced in primary immune responses.

  25. IgM • The two most common forms of IgM are the membrane-bound monomeric form and the secreted pentamer.

  26. The high avidity of IgM for both antigen and complement is crucial in the context of its role as a front-line defense mechanism. • IgM not only is the humoral agent of primary immune responses, but also—like IgA—is transported by the pIgR across epithelia such that it serves a role as a secretory immunoglobulin at mucosal surfaces. IgM

  27. IgM • Since secretory immunoglobulins are present in breast milk as well, IgM also participates significantly in protecting the newborn from intestinal pathogens until such time as the neonatal immune system is fully functioning. • A role for IgM in mucosal immunity must have developed early in evolution, as it is the sole immunoglobulin in some animals.

  28. IgG • IgG is the predominant immunoglobulin in blood, lymph, peritoneal fluid, and cerebrospinal fluid. • Collectively, it makes up more than 75% of serum immunoglobulin and is synthesized at a high rate (over 30 mg/kg/d, second only to IgA). • The presence of high-affinity IgG is the hallmark of secondary humoral immune responses.

  29. IgG • The selection of IgG subclass by a particular immune response does not appear to be random: in murine systems, anti-carbohydrate specificities tend to be IgG3, anti-protein IgG1, and anti-viral IgG2a. • In man, reactivities against polysaccharide immunogens are skewed toward IgG1 and IgG2, while anti-protein and anti-viral g antibodies are biased in the direction of IgG1, IgG3, and IgG4.

  30. IgG • Perhaps the most studied feature of the IgG isotypes is their ability to activate the classical complement pathway. • Although all four are capable of initiating the classical cascade, they do so to varying degrees (G3>G1>G2>G4).

  31. Another means by which IgG antibodies communicate with the effector arms of the immune system is via the Fcg receptors (FcgRs). • Binders of IgG are macrophages, polymononuclear cells, and lymphocytes (including B cells). • Interactions with these receptors cause many functional effects, including phagocytosis and ADCC , both of which ultimately lead to the destruction of the bound antigen. • Specifically, the hierarchy for ADCC by mononuclear cells is IgG1, IgG3 > IgG2, IgG4. IgG

  32. IgG • IgG FcR also permit transplacental movement of maternal antibodies during gestation. • This provides the developing fetus with a source of high-affinity serum immunoglobulin that is able to interact with complement to mediate biologic effects at a time at which it has no other form of specific humoral immunity.

  33. IgG • It should not be overlooked that IgG molecules are the most stable isotype in serum (with a half-life of over 3 weeks), further maximizing their utility in this endeavor—even into the post-natal period.

  34. IgA • IgA is the major immunoglobulin in external secretions such as saliva, mucus, sweat, gastric fluid, and tears. • Moreover, it is also the major immunoglobulin of colostrum and breast milk, where it provides the neonate with a readily available source of intestinal protection against pathogens.

  35. IgA • The secretory forms of IgA are exclusively polymeric, including J chain. In addition, IgA—present predominantly in its monomeric form—is also an important component of serum Ig, where it makes up 10% to 15% of the total.

  36. IgA • The majority of IgA synthesized is in the secretory form, with the largest fraction of IgA plasma cells residing in the subepithelial mucosa of the small intestine. • Because secretory IgA coats all external surfaces except skin, it is rightly considered a first line of defense against organisms that would invade via mucosal routes.

  37. IgD • Mature, naive B cells migrate from the bone marrow as IgM+/IgD+ cells and make up about 90% of peripheral B cells in both the murine and human systems. • Similarly, B cells in the primary follicles of secondary lymphoid organs coexpress IgM and IgD, but as they mature to memory cells, IgD expression is typically lost.

  38. IgE is present in serum in the lowest concentration of all the immunoglobulins. • Its rate of synthesis is between 25- and 2,000-fold less than each of the other isotypes, it has the shortest serum half-life, is unable to activate either the classical or alternative complement cascades, and lacks the ability to opsonize antigens. IgE

  39. IgE • The principle function of IgE is to arm basophils and mast cells with specific antigen receptors. • These cells in turn act as potent dispensers of inflammatory reactions.

  40. Multivalent antigen can then cross-link the bound IgE, indirectly cross-linking the FceRI molecules as well. Ultimately, this causes mast cells and basophils to release granules containing inflammation-mediating substances and chemoattractants for a variety of cell types. • The granule contents of mast cells and basophils are powerful, able to induce rapid responses—including mucous secretion, coughing and sneezing, vomiting, diarrhea, and inflammation. IgE

  41. This IgE type of response can be vital in the clearance of parasites, it has the unfortunate consequences of also causing allergy and anaphylaxis in predisposed individuals. • In such atopicindividuals, it has been seen that increased amounts of IgE are synthesized and found on the surfaces of mast cells and basophils, likely explaining their predilection for these inappropriate responses. IgE

  42. Ig Isotypes • How are the expression of the different isotypes regulated?

  43. Cytokine Control of Isotypes

  44. Antibody Responses • Primary response • Secondary response

  45. Kinetics of Antibody Responses

  46. Ag-Ig Interaction BCR

  47. FcR • FcR allow antibodies to interact with cells of both the specific and non-specific immune systems. • In so doing, FcR connect humoral immune responses to cellular immune responses, and more globally, acquired immunity to that of innate immunity.

  48. Receptors for the Constant (Fc) Region of IgG

  49. Humoral Response • Signal 1 -Antigen interacting with the BCR (membrane-bound Ig associated with signaling molecules, Ig-a and Ig-b .

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