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Adaptive immunity. by mateen irfansha


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Adaptive immunity. by mateen irfansha

  2. 2. Adaptive immunity :- Adaptive immunity is induced as a response against a specific antigen, after the collaboration among phagocytic cells,T and B lymphocytes and the production of immunoglobulins and lymphokines (IL). Q. Differences bitween Innate immunity & Adaptive immunity? • Present at birth • developed afterbirth
  3. 3. •Types of adaptive immunity :- 1. Humoral immunity . 2. Cell-mediated immunity.
  4. 4. • Humoral immunity :- immunity that is mediated by secreted antibodies produced in the B cells . B Cells (with co-stimulation) transform into plasma cells which secrete antibodies. Humoral immunity is so named because it involves substances found in the humours, or body fluids. •(Humoral immunity block extrtracellular microbes) Exogenous antigens
  5. 5. Cell-mediated immunity :- Cell mediated immunity is an immune response that does not involve antibodies but rather involves the activation of phagocytes , natural killer cells (NK), antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen. •Cell mediated immunity block intracellular microbes:- 1. By activate macrophages to kill phagocytosed microbes i.e by Helper T lymphocytes . & 2. By killing infected cell (e.g viruses within infected cells) i.e by cytotoxic T lymphocytes.
  6. 6. T cell activation :- Endogenous antigens Th2 :-release of Interleukin 4, which results in the activation of B-cells to make neutralizing (killing) antibodies, leading to humoral immunity. Exogenous antigens Endogenous antigens
  7. 7. Phases of adaptive immune responses •peripheral lymphoid organs contain a mixture of B and T cells in at least three stages of differentiation: •naive cells that have matured, left the bone marrow or thymus, have entered the lymphatic system, but that have yet to encounter their cognate antigen, •effector cells that have been activated by their cognate antigen, and are actively involved in eliminating a pathogen. •memory cells – the long- lived survivors of past infections
  8. 8. Passive memory :-• Active Memory &
  9. 9. Active and passive immunity Active immunity: long-lasting protection (memory), multiple effector mechanisms activated, lag time Passive immunity: rapid protection, short duration Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011
  10. 10. •Properties of adaptive immune responses :-
  11. 11. humoral immune response :- is the aspect of immunity that is mediated by secreted antibodies produced in the cells of the B lymphocyte lineage (B cell).
  12. 12. •B Cells (with co-stimulation) transform into plasma cells which secrete antibodies. •This entire process is aided by CD4+ T-helper 2 cells, which provide co-stimulation. • Secreted antibodies bind to antigens on the surfaces of invading microbes (such as viruses or bacteria), which flags them for destruction. •Humoral immunity is so named because it involves substances found in the humours, or body fluids.
  13. 13. Function… •Antibody production and the accessory processes that accompany it. • Th2 activation and cytokine production. •Germinal center formation and isotype switching, affinity maturation and memory cell generation. •Classical complement activation, and •Opsonin promotion of phagocytosis and pathogen elimination
  14. 14. •COMPLEMENT SYSTEM :- Complement System is special part of immune system which consists of a number of serum proteins (C1,C2,C3,C4,C5,C6,C7,C8 & C9) which exist in the serum in an inactive form.basically these protein are pro-enzymes. Q.WHAT ARE THE FUNCTIONS OF THESE PROTEIN ? These proteins basically complement or augment the immune system & complement inflammatory reactions . Q.WHERE THESE PROTEINS ARE PRODUCED ? Major source of protein is liver. But Complement protein C1 Mainly produced by GIT mucosa. & some complementory protein also produced by macrophages. Anyways all are present in blood.
  15. 15. Q.HOW THIS PROTEINS WORKS? These proteins can be workes/activated in a cascade-like fashion by •(1) Antigen-antibody complexes in the Classical pathway. • (2) Alternative pathway. • (3) Mannan binding lectin pathway.
  16. 16. Once activated, complement can: •(1) Destroy all cells (even host cells) in the activation area, •(2) Cause inflammation (complement is an anaphylatoxin), •(3) Opsonize microbial cells (complement is an opsonin) and •(4) Attract leukocytes to the area (complement is a chemotaxin).
  17. 17. The Classical Pathway The binding of antibody to its antigen often triggers the complement system through the so-called classical pathway. It can occur when the antibodies have bound to antigens on a cell surface. •TYPES & STRUCTURE OF IMMUNOGLOBULINS :-
  18. 18. •ANTIGEN:-
  19. 19. The proteins of the classical pathway C1 C1 exists in blood serum •6 molecules of C1q •2 molecules of C1r •2 molecules of C1s •The constant regions of mu chains (IgM) and some gamma chains (IgG) contain a binding site for C1q. (A single molecule of IgM is enough to initiate the pathway. IgG is far less efficient, requiring many molecules to do so.) Antibodies Antigens Bacterial surface
  20. 20. •Binding of C1q to antibody activates C1r which cleaves & activates the serine protease C1s. •Activated C1s cleaves two serum proteins C4 &C2 : C4 is cleaved into oC4b, which binds covalently to sugar residues on cell- surface glycoproteins, leaving behind an inactive fragment of oC4a C4aC4b C4
  21. 21. C2 is cleaved into oC2b, which binds noncovalently to a site on C4b, leaving an inactive fragment of oC2a The complex of C4b.2b is called "C3 convertase" because it catalyzes the cleavage of C3. C4bC2b/C3 convertase C2a C4bC2b
  22. 22. C3b C3a C4bC2bC3b/C5 Convertase C3b •C4b.2a cuts C3 into two major fragments: C3b, which binds covalently to glycoproteins scattered across the cell surface. Macrophages and neutrophils have receptors for C3b and can bind the C3b-coated cell or particle preparatory to phagocytosis . This effect qualifies C3b as an opsonin.
  23. 23. C3a This small fragment is released into the surrounding fluids. It can bind to receptors on basophils and mast cells triggering them to release their vasoactive contents (e.g., histamine). Because of the role of these materials in anaphylaxis, C3a is called an anaphylatoxin . •Some of the C3b binds directly to the molecules of C4b.2b producing a trimolecular complex: C4b.2b.3b, which acts on C5; that is, it is a "C5 convertase". C5 Cleavage of C5 by this C5 convertase initiates the assembly of a set of complement proteins that make up the membrane attack complex. (The membrane attack complex can also be formed by another C5 convertase produce by the "alternative pathway" .)
  24. 24. . C5b C5a The Membrane Attack Complex :- Cleavage of C5 by a C5 convertase, produces: •C5a, which is released into the fluid surroundings where it is a potent anaphylatoxin(like C3a) is a chemotactic attractant for neutrophils
  25. 25. •C5b which serves as the anchor for the assembly of a single molecule each ofC6,C7 & C8 C5b C6 C7 C8 C9 •The resulting complex C5b.6.7.8 guides the polymerization of as many as 18 molecules of C9 into a tube inserted into the lipid bilayer of the plasma membrane. C9
  26. 26. • This tube forms a channel allowing the passage of ions and small molecules. • Water enters the cell by osmosis and the cell lyses. •These MACs can be imagined as ring-shaped structures with a central pore; these structures are incorporated into the lipid bilayer of cells and result in osmotic disruption of the cell
  27. 27. Clinical significance:- Q.Do you think MAC effect will be more on Gram +ve bacteria or Gram –ve bacteria ? & why …………….? Endotoxins Double lipid membrane single lipid membrane • Gram +ve bacteria contain only 1 lipid membrane dat is inner lipid membrane only… But Gram –ve bacteria contain 2 lipid membrane (outer & inner membrane). So ,MAC effect will be more on Gram –ve bacteria
  28. 28. Q. HOW THE GRAM +VE BACTERIA HANDLE ? There are 2 ways to kill Gram +ve bacterias. •By direct opsonisation. •By indirect opsonisation. •People who hav difficiency of terminal events proteins (i.e C5b,C6,C7,C8 &C9) will hav difficiency of MAC effect so they are highly vulnerable to Gram –ve bacterial infection more specially NESIERRIAL Bateria ( Gonococci & meningococci)
  29. 29. Q.HOW ANTIBODY KILLS BACTERIAS? • By direct opsonisation :- •By indirect opsonisation:- FC receptors C3b receptors Gram +ve bacteria Antibody Gram +ve bacteria Antibody Macrophages/ neutrophilis Macrophages/ neutrophilis
  30. 30. •By activating complement system till MAC formation:- MAC Gram –ve bacteria Antibody C3 convertase C5 convertase C3a C5a
  31. 31. An incompatible blood transfusion causes a transfusion reaction, which is mediated by the humoral immune response. This type of reaction, called an acute hemolytic reaction, results in the rapid destruction (hemolysis) of the donor red blood cells by host antibodies. The cause is usually a clerical error (i.e. the wrong unit of blood being given to the wrong patient). The symptoms are fever and chills, sometimes with back pain and pink or red urine (hemoglobinuria). The major complication is that hemoglobin released by the destruction of red blood cells can cause acute renal failure. Q. What is ABO incompatible blood transfusion?
  32. 32. The Alternative Pathway:- It is a part of innate immunity i.e first line of defence there is a spontaneous conversion of C3 to C3b. Ordinarily the C3b is quickly inactivated: the C3b binds to inhibitory proteins and sialic acid present on the surface of body's own cells, and the process is aborted. However, bacteria and other foreign materials that may get into the body lack these proteins and have little or no sialic acid. So the C3b •binds a protein called Factor B forming a complex of C3b.Bb. •C3b.Bb is also a C3 convertase acting on more C3 to form: C3b.Bb.C3b, which is a C5 convertase and can start the assembly of the membrane attack complex. C3 C3b C3b B Bb C3b Bb C3b C3 C5 ConvertaseC3 Convertase
  33. 33. Clinical significans:- Aggregation of IgA can cause activation of alternate pathway. Diseases related with IgA aggregations are….. 1.IgA nephropathy/Buergers disease. 2.Dermititus Herpetiformus. 3.Henoshawlin Purpura.
  34. 34. Mannan-binding lectin pathway • is similar in structure to the classical complement pathway in that, after activation, it proceeds through the action of C4 and C2 to produce activated complement proteins further down the cascade. • it is not antibody-dependent. • mannose-binding lectin binds to mannose, glucose or other sugars with 3- and 4-OH groups placed in the equatorial plane, in terminal positions on carbohydrate or glycoprotein components of microorganisms including bacteria such as Salmonella, Listeria, and Neisseria strains. •Fungal pathogens such as Candida albicans and Cryptococcus neoformans as well as some viruses such as HIV-1 and Respiratory syncytial virus (RSV) are bound by MBL
  35. 35. . Mannan-binding lectin (MBL) is a protein belonging to the collectin family that is produced by the liver and can initiate the complement cascade by binding to pathogen surfaces. MBL is a 6- to 18-headed molecule that forms a complex with MASP-1 (Mannan-binding lectin-Associated Serine Protease), MASP-2 and MASP-3, two protease zymogens. The MASPs are very similar to C1r and C1s molecules of the classical complement pathway, respectively [ MASP-1(similar to C1r) MASP-2 (similar to C1s) MBL (6- 18headed molecule) similar to C1q
  36. 36. •When the carbohydrate-recognising heads of MBL bind to specifically arranged mannose residues on the surface of a pathogen, MASP-1 and MASP-2 are activated to cleave complement components C4 and C2 into C4a, C4b, C2a, and C2b. • In addition, two smaller MBL-associated proteins (MAps) are found in complex with MBL. MBL-associated protein of 19 kDa (MAp19) and MBL-associated protein of 44 kDa (Map44). •MASP-1, MASP-3 and MAp44 are alternative splice products of the MASP1 gene, • while MASP-2 and MAp19 are alternative splice products of the MASP-2 gene. •
  37. 37. •C3 convertase :- C4b and C2b combine on the surface of the pathogen to form C3 convertase (C4bC2b). while C4a and C2a act as chemoattractants. •C5 convertase:-. C4bC2bC3b, which is a C5 convertase and can start the assembly of the membrane attack complex Clinical significance :- has been found that people deficient in MBL experience a substantial increase in infections during the early years of childhood. •MAp44 has been suggested to act as a competitive inhibitor of lectin pathway activation, by displacing MASP-2 from MBL, hence preventing cleavage of C4 and C2
  38. 38. Regulation of Complement Activity:- The explosive potential of the complement system requires that it be kept under tight control. At least 12 proteins are known that do this. Three examples: •Factor H removes Bb from the alternative pathway . •Factor I inactivates C3b. •C1 inhibitor (C1INH) binds to sites on activated C1r and C1s shutting down their proteolytic activity. So when C1 is activated by antigen-antibody complexes, there is only a brief interval during which it can cleave C4 and C2 before it is deactivated by C1INH.
  39. 39. Effector Functions of Complement :- The complement system acts in several ways to mobilize defense mechanisms. •Opsonization by C3b targets foreign particles for phagocytosis. •Chemotaxis by C5a attracts neutrophils/phagocytic cells to the site of damage. • anaphylatoxin This is aided by the increased permeability of the capillary beds mediated by C3a and C5a. •The early complement components are also important for solubilizing antigen-antibody complexes assisting in their catabolism and elimination from the body.
  40. 40. Disorders of the Complement System :- With so many proteins involved, it is not surprising that inherited deficiencies of one or another are sometimes encountered in humans. examples: •C3. An inherited deficiency of C3 predisposes the person to frequent bouts of bacterial infections(streptococcus infection i.e Gram +ve) •C2 & C4. Curiously, immune complex disorders, with a deficiency of C2 (or of one of the other "early" components like C1q, C1r, C1s, or C4). This is frequently found in patients with the immune complex disorders (autoimmune disorder) system lupus erythematosus (SLE). •Defficency of C5b,C6,C7,C8,C9 & lectin pathway lead to Gram –ve infections (Nesierrial infection)
  41. 41. •C1INH. A deficiency of C1INH produces hereditary angioneurotic edema (HANE). Patients are at risk of occasional explosive triggering of the complement system. • The massive release of anaphylatoxins (C3a, C5a) may cause dangerous swelling (edema) of the airways, as well as of the skin and intestine.