IMMUNOLOGY

1. IMMUNOLOGY Sherko A Omer MB ChB, MSc., PhD

2. THE ADAPTIVE IMMUNE RESPONSE An adaptive immune response involves a complex sequence of events that start with introduction of an immunogen (or antigen) and a series of reactions that ultimately leads to an immune response which may eliminate the provoking material. The adaptive immune response depends on interaction of many cells such as antigen presenting cells, T cell, B cells and other cells all which interact together directly or indirectly through cytokines.

3. THE ADAPTIVE IMMUNE RESPONSE Antigen Introduction Intravenous (iv) Intradermally (id), into the skin Subcutaneously (sc) beneath the skin Intramuscular (im) Intraperitoneally (ip) into the peritoneal cavity.

4. THE ADAPTIVE IMMUNE RESPONSE The administration route strongly influences which immune organs and cell populations will be involved in the response. iv antigen…..spleen sc antigen …. local lymph nodes Differences in the lymphoid cells that populate these organs may be reflected in the subsequent immune response.

5. ANTGEN (IMMUNOGEN) PROCESSING Recognition of a foreign protein antigen to a T cell requires that peptides derived from the antigen be displayed within the cleft of an MHC molecule on the membrane of a cell. The formation of these peptide-MHC complexes requires that a protein antigen be degraded into peptides by a sequence of events called antigen processing.

6. ANTGEN PRESENTATION The degraded peptides then associate with MHC molecules within the cell interior, and the peptide-MHC complexes are transported to the membrane, where they are displayed (antigen presentation).

7. ANTGEN PROCESSING & PRESENTATION

8. ANTGEN PROCESSING & PRESENTATION

9. ANTGEN PROCESSING & PRESENTATION

10. ANTGEN PROCESSING & PRESENTATION

11. ANTGEN PROCESSING & PRESENTATION

12. ANTGEN PROCESSING & PRESENTATION Presentation of nonpeptide (lipid and glycolipid) antigens derived from bacteria involves the class I–like CD1 molecules.  TCR react with glycolipid antigens derived from bacteria such as Mycobacterium tuberculosis. These nonprotein antigens are presented by members of the CD1 family of nonclassical class I molecules.

13. ANTGEN PROCESSING & PRESENTATION The CD1 family of molecules associates with 2-microglobulin and has general structural similarity to class I MHC molecules. There are five genes encoding human CD1 molecules (CD1A-E, encoding the gene products CD1a-d, with no product yet identified for E).

14. B CELL ACTIVATION AND PROLIFERATION APCs present antigens to TH cells and at the same time naïve B cells recognize the antigens through their mIgM or mIgD. B cell activation occurs either with aid of TH cells in thymus- dependent antigens TD or without TH cells in thymus independent antigens TID. Activation leads proliferation and differentiation. Some B cells will develop in to memory B cells while other develops to form antibody producing plasma cells.

15. B CELL ACTIVATION AND PROLIFERATION

16. B CELL ACTIVATION AND PROLIFERATION

17. B CELL ACTIVATION AND PROLIFERATION

18. B CELL ACTIVATION AND PROLIFERATION B- and T-cell activation share many parallels, including compartmentalization of function within receptor subunits. Activation by membrane-associated protein tyrosine kinases; assembly of large signalling complexes with protein–tyrosine-kinase activity; and recruitment of several signal-transduction pathways. The B-cell coreceptor can intensify the activating signal resulting from crosslinkage of mIg, This may be particularly important during the primary response to low concentrations of antigen.

19. B CELL ACTIVATION AND PROLIFERATION

20. B CELL ACTIVATION AND PROLIFERATION

21. B CELL ACTIVATION AND PROLIFERATION

22. B CELL ACTIVATION AND PROLIFERATION Transmission electron micrographs of initial contact between a T cell and B cell (left) and of a T-B conjugate (right). Note the broad area of membrane contact between the cells after formation of the conjugate.

23. B CELL ACTIVATION AND PROLIFERATION

24. PHASES OF HUMORAL IMMUNE RESPONSE

25. PHASES OF HUMORAL IMMUNE RESPONSE The primary response has a long lag period, a logarithmic rise in antibody formation, a short plateau, and then a decline. IgM is the first antibody class produced, followed by a gradual switch to other classes, such as IgG. The secondary response has a shorter lag time, a more rapid logarithmic phase, a longer plateau phase, and a slower decline than the primary response.

26. PHASES OF HUMORAL IMMUNE RESPONSE Mostly IgG and other isotypes are produced in the secondary response rather than IgM, and the average affinity of antibody produced is higher. Within a week or so of exposure to a TD antigen, germinal centres forms. Germinal centres are sites of somatic hypermutation of rearranged immunoglobulin genes. Germinal centres are the sites of affinity maturation, formation of memory B cells, class switching, and plasma-cell formation.

27. PHASES OF HUMORAL IMMUNE RESPONSE

28. PHASES OF HUMORAL IMMUNE RESPONSE Class switching allows any given VH domain to associate with the constant region of any isotype. This enables antibody specificity to remain constant while the biological effector activities of the molecule vary. A number of cytokines affect the decision of what Ig class is chosen when an IgM-bearing cell undergoes the class switch.

29. PHASES OF HUMORAL IMMUNE RESPONSE The humoral response to TD antigens is marked by extensive class switching to isotypes other than IgM, whereas the antibody response to TID is dominated by IgM. In the case TD antigens, membrane interaction between CD40 on the B cell and CD40L on the TH cell is essential for the induction of class switching.

30. PHASES OF HUMORAL IMMUNE RESPONSE Class switching

31. PHASES OF HUMORAL IMMUNE RESPONSE The average affinity of the antibodies produced during the course of the humoral response increases remarkably during the process of affinity maturation. Experimentally, the affinity of the serum anti-DNP antibodies produced in response to the antigen was then measured at 2, 5, and 8 weeks after immunization. The average affinity of the anti-DNP antibodies increased about 140-fold from 2 weeks to 8 weeks. Subsequent work has shown that affinity maturation is mainly the result of somatic hypermutation.

32. T CELL RESPONSES TH cell activation is initiated by interaction of the TCR-CD3 complex with a peptide-MHC complex on an antigen-presenting cell. Activation also requires the activity of accessory molecules, including the coreceptors CD4 and CD8. Many different intracellular signal-transduction pathways are activated by the engagement of the TCR.

33. T CELL RESPONSES T cells that express CD4 recognize antigen combined with a class II MHC molecule and generally function as TH cells. T cells that express CD8 recognize antigen combined with a class I MHC molecule and generally function as TC cells. Interaction of a TH cell with antigen initiates a cascade of biochemical events that induces the resting TH cell to enter the cell cycle, proliferating and differentiating into memory cells or effector cells.

34. T CELL RESPONSES ICAM intercellular adhesion molecule; LFA lymphocyte function-associated antigen

35. T CELL RESPONSES Gene activation immediate genes, expressed within half an hour of antigen recognition, encode a number of transcription factors, including c-Fos, c-Myc, c-Jun, NFAT, and NFB. Early genes, expressed within 1–2 h of antigen recognition, encode IL-2, IL-2R (IL-2 receptor), IL-3, IL-6,IFN-, and numerous other proteins. Late genes, expressed more than 2 days after antigen recognition, encode various adhesion molecules.

36. T CELL RESPONSES These profound changes are the result of signal-transduction pathways that are activated by the encounter between the TCR and MHC-peptide complexes.

37. T CELL RESPONSES  T cells (peripheral  T cell) are not MHC restricted. Most in humans bind free antigen, and most have the same specificity. They may function as part of the innate immune system.

38. MECHANISMS OF ANTIGEN ELIMINATION The adaptive immune response, whether humoral or cell mediated lead to elimination of the provoking agents by different mechanisms: Direct killing of target cells which carry foreign antigens by activated Tc* cells through cytotoxicity via two mechanisms, the perforin granzyme pathway and the Fas/FasL pathway. Toxin neutralizing antibodies can neutralize bacterial toxin or insect venom forming immune complex.

39. MECHANISMS OF ANTIGEN ELIMINATION Virus neutralization, anti-viral antibodies can block attachment of viruses to their receptors. Opsonization, antibodies coated antigen can be removed by macrophage as macrophages have receptors for Fc portions of antibodies. Humoral immune response may lead to activation of complement which will eliminate the antigen by various methods.

40. MECHANISMS OF ANTIGEN ELIMINATION ADCC, NK cell can kill IgG coated cells through cytotoxicity. LAK (lymphokine activated killer) cells can kill after being activated CD4+ T cells can produce several cytokines resulting in delayed type reaction and inflammation.

41. SUPERANTIGENS Viral or bacterial proteins that bind simultaneously to the V domain of a TCR and to the  chain of a class II MHC molecule. Exogenous (exotoxins secreted by gram-positive bacteria, such as staphylococcal enterotoxins, toxic-shock-syndrome toxin, and exfoliative-dermatitis toxin) and endogenous (cell-membrane proteins encoded by certain viruses that infect mammalian cells) superantigens have been identified.

42. SUPERANTIGENS Crosslinkage of a TCR and class II MHC molecule by either type of superantigen produces an activating signal that induces T-cell activation and proliferation.

43. REGULATION OF IMMUNE RESPONSE Suppressor T cells (Ts) were believed to be CD8+ T cells. However, the cellular and molecular basis of the observed suppression remained obscure, and eventually great doubt was cast on the existence of CD8+ suppressor T cells. Recent research has shown that there are indeed T cells that suppress immune responses. Unexpectedly, these cells have turned out to be CD4+ rather than CD8+ T cells.

44. REGULATION OF IMMUNE RESPONSE Within the population of CD4+ CD25+ FoxP3+ T cells, there are regulatory T cells that can inhibit the proliferation of other T cell populations in vitro. The suppression by these regulatory cells is antigen specific because it depends upon activation through the TCR. Cell contact between the suppressing cells and their targets is required, if the regulatory cells are activated by antigen but separated from their targets by a permeable barrier, no suppression occurs.

45. REGULATION OF IMMUNE RESPONSE RegulatoryT cell Activation, as immune response progresses, the activity of T cells with suppressor activity, such as T regs, starts to predominate. IL-10, the major immunosuppressive cytokine released by activated CD4+ CD25+ FoxP3+ T cells, downregulates both TH1 and TH2 cells, thus reducing the delivery of costimulatory signals to B cells. T cells with suppressor activity persist after the antigen is eliminated, either as a consequence of their late activation or of a longer life span.

46. REGULATION OF IMMUNE RESPONSE Several regulatory mechanisms will operate in order to turn off antibody production after the infectious agent (or any other type of immunogen) has been eliminated. Antigen Elimination, the most obvious downregulatory mechanism is the elimination of the antigen, which was the primary stimulus of the immune response.

47. REGULATION OF IMMUNE RESPONSE Immunoregulatory effects of soluble antigen-antibody complexes and anti-idiotypic antibodies.

48. TOLERANCE State of antigen-specific immunological unresponsiveness. At the cellular level, tolerance can result from clonal deletion or clonal anergy.

49. TOLERANCE Experimental demonstration of clonal anergy versus clonal expansion. (a,b) Only signal 1 is generated when resting TH cells are incubated with glutaraldehyde-fixed antigen-presenting cells (APCs) or with normal APCs in the presence of the Fab portion of anti-CD28. (c) The resulting anergic T cells cannot respond to normal APCs. (d,e) In the presence of normal allogeneic APCs or anti-CD28, both of which produce the co-stimulatory signal 2, T cells are activated by fixed APCs.

50. TOLERANCE Acquiredtolerance can be induced in experimental animals, under the right conditions, known as tolerogenic conditions, these condition include: The host Genetic predisposition Antigen (soluble, small-sized antigen) and antigen structurally similar to self protein. Administration route (intravenous administration of antigen) Antigen dosage (high- or low-dose of antigen).