PROF. MOHAMED OSMAN GAD ELRAB. , KKUH ..

1. Human defense system. Acquired immunity PROF. MOHAMED OSMAN GAD ELRAB. , KKUH ..

2. Mediated by : • 1. T- lymphocyte : Programmed in the Thymus gland. • 2. B- lymphocyte : Programmed in the bone marrow . Central lymphoid tissues .

3. Features : • 1. RECOGNITION: Microbial antigens are recognized by specific T-cell or B- cell receptor . • 2. SPECIFICITY : Specific response to each microbe ( Humoral or Cellular ). • 3. MEMORY : Immunological memory is the most important consequence of adaptive immunity .

4. Events in central lymphoid tissues . Diverse specificity of the antigen receptor is aquired. T- cell receptor : TCR. B - cell receptor : BCR . ( LYMPHOCYTE REPERTOIRE).

5. Antigen specificity is determined by : 1. Differentiation in the central lymphoid tissues . 2. Gene rearrangement . THIS ENSURES: 1. Diversity of the lymphocyte repertoire.(range of receptors ) 2. Unique antigen receptors of individual lymphocytes . ( each lymphocyte have I different receptor .)

6. T-cell receptor diversity.

7. Recognition of self & non-self . A. Antigen receptors that react weakly with self (MHC): survive by positive selection ( 2 percent .) B. Antigen receptors that react strongly with self (MHC): deleted by negative selection. (98 percent .)

8. This establish a mechanism that prevent autoimmune disease . Central immunological tolerance. ( no immune reactions against self.)

9. Activation of acquired immunity require : 1. Breakdown of microbes into peptides. ( ANTIGENS ). 2. Delivery of microbial antigens ( in the form of peptides ) to the surface of specialized cells in association with self –MHC molecules . Antigen presenting cells.

10. MHC. MHC. Major histocompatibility complex . (Tissue antigens present in chromosome 6 ) ENCODE THE HLA SYSTEM. (human leukocyte antigens. ) A POLYGENIC & HIGHLY POLYMORPHIC SYSTEM OF GENES.

11. MHC, short arm of chromosome 6. MHC REGION . include HLA.

12. Antigen .

13. HLA system (human leukocyte antigens ). • Consist of 4 loci : HLA-A ; HLA-B ; HLA-C ; HLA-D . • Each individual has 2 antigens in each locus: One haplotype : from maternal origin . One haplotype : from paternal origin .

14. MHC haplotypes .

15. MHC CLASSES . • MHC CLASS 1 : ENCODE : HLA-A ; HLA-B ; HLA-C . ( Present in all nucleated cells ). MHC CLASS 11: ENCODE : HLA-DP ; HLA-DQ ; HLA-DR . (Present in antigen presenting cells only ).

16. Distribution of MHC 1 & MHC 11 in body cells.

17. MHC & immune responses: • MHC CLASS1: Important for : Target (infected - cell ) recognition . • MHC CLASS 11: Important for : Antigen recognition & presentation.

18. ANTIGEN PRESEANTING CELLS (APC). • 1. Dendritic cells . • 2. Macrophages . • 3. B-lymphocytes .

19. ANTIGEN PRESENTING CELLS. • ACTIVATED BY : 1. Receptors that signal presence of microbes . . 2. Cytokines.

20. DISTRIBUTION OF APC. • . 1. DENDRITIC CELLS: Take up particulate & soluble microbial antigen form site of infection. ( handles a wide variety of pathogens. )

21. 2. Macrophages : Phagocytic cells in the tissues but also process: ingested pathogens & actively ingest microbes and particulate antigens entering lymph nodesthrough afferent lymphatic vessels .

22. 3. B-lymphocytes : • Process soluble antigens (microbial toxins). recirculate through the lymphoid tissues and concentratein the lymph. follicles in lymph nodes.

23. Functions of APC : • 1. On activation, express co-stimulatory molecules . • 2. Degrade microbes into antigenic peptides . • 3. Load antigenic peptides in clefts in self-MHC molecules . • 4. Transport peptide-MHC complex on the surface of the cell.

24. Antigen processing by APC : TWO PATHWAYS : 1. ENDOGENOUS PATHWAY:PROCESS INTRACELLULARMICROBES - DEGRADATION IN CYTOSOLS. - BIND PEPTIDE TO MHC 1. - RECOGNIZED BY CYTOTOXIC CD8 T-CELLS.

26. 2 .EXOGENOUS PATHWAY • -DEGRADE MICROBES IN THE VESICULAR SYSTEM . (ENDOSOMES). • A. INTRAVESICULAR PATHOGENS. - BIND PEPTIDE TO MHC-11. - RECOGNIZED BY CD4 T-CELLS. B. EXTRACELLULAR PATHOGENS. -BIND PEPTIDE TO MHC-11. -RECOGNIZED BY CD4 T-CELLS.

28. Activated CD4 T- cells : • 2 Functional classes influenced by nature of microbial antigen : A. TH 1 CELLS : Mediate cellular immunity, Destroy intracellular pathogens . B. TH 2 CELLS: Mediate humoral immunity, Destroy extra- cellular pathogens.

29. EFFECTOR MECHANISMSOF ADAPTIVE IMMUNITY. • Activation of T-cells ( TH1): Cellular immunity , ( Cell – mediated ) • Activation of B- cells (TH2+TH1,helper,) Humoral immunity ( Antibody - mediated ). ) microbes may induce both , but one is predominant for control )

30. Primary and secondary immune responses: • FIRST ENCOUNTER WITH A MICROBIAL ANTIGEN GENERATES: A PRIMARY IMMUNE RESONSE . 4 PHASES : 1. LAG. 3-4 DAYS. 2. LOG. 4-7 DAYS. 3. PLATEU. 7-10 DAYS. 4. DECLINE. (Primary I.R. may take few days to several weeks ,)

31. Features of primary immuneresponses : 1. Takes longer ( 4 phases) 2. IgM predominate . 3. Memory cells generated .

32. Features of secondary immune responses : 1. Fast response ( memory cells ) 2. IgG predominate . 3. High concentration of antibody or cells.

34. Factors influencing immune responses : • 1. Nature of microbial antigen (Epitope) * T- dependant (TD). * T- independent (TI). * protein , CHO., Iipopolysaccarhide, lipid. 2. Dose of antigen. - high , optimum , low . *Immunological paralysis.

35. FACTORS cont. 3.Route of entry: A. Blood-borne antigens – spleen . B. Skin & tissues – draining lymph nodes. C. Mucosal surfaces - MALT. D. Intranasal & inhaled - palatine tonsils & adenoids. E. Ingested –micro fold (M-cells), Peyers patches.

36. LYMPHOCYTE TRAFFIC. Naïve T-cells enter the lymphoid tissues through the : HIGH ENDOTHELIAL VENULES. ( HEV.) Contact thousands of ( APC.), then pass out into the blood & recirculate into other lymphoid organs .

37. ANTIGEN RECOGNITION. One naïve T- cell ( in thousands ) is likely to be ( specific for a particular antigen ) and will be trapped in the the L.node . LYMPHOCYTE TRAPPING.

39. SURVIVAL SIGNAL . T- cells that do not encounter antigen: * Receive survival signal from self - MHC . * Pass through efferent lymphatic into the blood to continue recirculating through other lymphoid organs .

40. Cell-mediated immunity : 1. Naive T-cells encounter specific antigen. ( on dendritic cell (APC) in peripheral lymphoid tissue. ). 2. APC express co- stimulatory signal. *Necessary for synthesis and secretion of IL-2 by T-cells.

41. T-cell proliferation . • T- cells divide 2 - 3 times / day. one cell give rise to a clone of thousands of progeny that all bear the same receptor for antigen .

42. T-cell differentiation. • IL-2 promote proliferation & differentiation of T-cells into : EFFECTOR CELLS. (mediate cellular responses) ( cell - mediated immunity ) Some T-cells remain as : MEMORY CELLS.

43. THERAPEUTIC NOTE. The immunosuppressive drugs : * Cyclosporine –A * FK 506 (Tacrolimus ) * Rapamycin . Inhibit IL-2 production. (Prevent clonal expansion of T-cells ) Inhibit immune responses.

44. EFFECTOR T-CELLS EXERTDIFFERENT FUNCTIONS: Adhesion molecules (P- selectin & E- selectin) recruit T-cells into sites of infection . 1. Some differentiate into cytotoxic T-cells . ( CTL ) 2. Some produce cytokines that act on : A - CD8 cytotoxic T-cells . B - Macrophages . C - NK-cells .

45. THE ACTIVATED T- CELLS : • INDUCE: Cellular immunity . ( Cell – mediated immunity ) * Destroy intracellular pathogens . Memory T- cells . • INDUCE: Secondary immune responses.

46. Antibody –mediated immunity : 1. B-cells encounter specific antigen & recognize it through (BCR). 2. Processed antigen is loaded on MHC 11 and appear on the cell surface. 3. Helper T-cell recognize the same antigen.

47. HELPER T- CELLS : 1. Synthesize a membrane bound molecule (CD 40 ligand ) * Bind on CD -40 on B-cells . 2. Secrete B – cell stimulatory factors: IL-4 , IL-5 , IL-6 . * These cytokines act on receptors on the B-cell & the cell become activated .

48. ACTIVATED B-CELLS : • UNDERGO : 1. Clonal expansion. 2. Proliferation . 3. Differentiation into : ( PLASMA CELLS ) * Synthesize and secrete antibodies into the blood .

49. ANTIBODIES MEDIATE : Humoral immunity . ( Antibody –mediated immunity ) * ( Destroy extracellular pathogens .) MEMORY B-CELLS. INDUCE : Secondary immune responses .

50. CONTROL OF IMMUNERESPONSES. After control of infections and elimination of the pathogens : The immune response down regulate and return to a near basal level . several mechanisms are involved.