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Human defense system. Acquired immunity PROF. MOHAMED OSMAN GAD ELRAB. , KKUH .. Mediated by : 1. T- lymphocyte : Programmed in the Thymus gland. 2. B- lymphocyte : Programmed in the bone marrow . Central lymphoid tissues . 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 . Events in central lymphoid tissues . Diverse specificity of receptor the is antigen aquired. T- cell receptor : TCR. B - cell receptor : BCR . ( LYMPHOCYTE REPERTOIRE). 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 .) T-cell receptor diversity. MHC-binding peptides Each human usually expresses: 3 types of MHC class I (A, B, C) and 3 types of MHC class II (DR, DP,DQ) The number of different T cell antigen receptors is estimated to be 1,000,000,000,000,000 Each of which may potentially recognise a different peptide antigen How can 6 invariant molecules have the capacity to bind to 1,000,000,000,000,000 different peptides? 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 .) This establish a mechanism that prevent autoimmune disease . Central immunological tolerance. ( no immune reactions against self.) Activation of acquired immunity require : 1. Breakdown of microbes into ( ANTIGENS ). 2. Delivery peptides. of microbial antigens ( in the form of peptides ) to the surface of specialized cells in association with self –MHC molecules . Antigen presenting cells. 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. MHC, short arm of chromosome 6. MHC REGION . include HLA. Antigen . 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 . MHC haplotypes . Inheritance of MHC haplotypes Parents DP-1,2 DQ-3,4 DR-5,6 B-7,8 C-9,10 A-11,12 DP DQ DR B C A DP DQ DR B C A DP-9,8 DQ-7,6 DR-5,4 B-3,2 C-1,8 A-9,10 DP-1,8 DQ-3,6 DR-5,4 B-7,2 C-9,8 A-11,10 Children X DP DQ DR B C A DP DQ DR B C A DP-1,9 DQ-3,7 DR-5,5 B-7,3 C-9,1 A-11,9 DP-2,8 DQ-4,6 DR-6,4 B-8,2 C-10,8 A-12,10 DP-2,9 DQ-4,7 DR-6,5 B-8,3 C-10,10 A-12,9 DP DQ DR B C A DP DQ DR B C A DP DQ DR B C A DP DQ DR B C A DP DQ DR B C A DP DQ DR B C A DP DQ DR B C A DP DQ DR B C A 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 ). Distribution of MHC 1 & MHC 11 in body cells. MHC & immune responses: MHC CLASS1: Important for : Target (infected - cell ) recognition . MHC CLASS 11: Important for : Antigen recognition & presentation. ANTIGEN PRESEANTING CELLS (APC). 1. Dendritic cells . 2. Macrophages . 3. B-lymphocytes . ANTIGEN PRESENTING CELLS. ACTIVATED BY : 1. Receptors that signal presence of microbes . . 2. Cytokines. DISTRIBUTION OF APC. . 1. DENDRITIC CELLS: Take up particulate & soluble microbial antigen form site of infection. ( handles a wide variety of pathogens. ) 2. Macrophages : Phagocytic cells in the tissues but also process: ingested pathogens & actively ingest microbes and particulate antigens entering lymph nodes through afferent lymphatic vessels . 3. B-lymphocytes : Process soluble antigens (microbial toxins). recirculate through the lymphoid tissues and concentrate in the lymph. follicles in lymph nodes. 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. Antigen processing by APC : TWO PATHWAYS : 1. ENDOGENOUS PATHWAY: INTRACELLULAR MICROBES PROCESS - DEGRADATION IN CYTOSOLS. - BIND PEPTIDE TO MHC 1. - RECOGNIZED BY CYTOTOXIC CD8 T-CELLS. 2 .EXOGENOUS PATHWAY - DEGRADE MICROBES VESICULAR SYSTEM . IN THE (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. Activated CD4 T- cells : 2 Functional classes influenced by nature of microbial antigen : A. TH 1 CELLS : Mediate cellular Destroy intracellular immunity, pathogens . B. TH 2 CELLS: Mediate humoral immunity, Destroy extra- cellular pathogens. EFFECTOR MECHANISMS OF 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 ) Primary and secondary immune responses: FIRST ENCOUNTER WITH A MICROBIAL ANTIGEN GENERATES: A PRIMARY IMMUNE RESONSE . 4 PHASES : 1. 2. 3. 4. LAG. 3-4 DAYS. LOG. 4-7 DAYS. PLATEU. 7-10 DAYS. DECLINE. (Primary I.R. may take few days to several weeks ,) Features of primary responses : immune 1. Takes longer ( 4 phases) 2. IgM predominate . 3. Memory cells generated . Features of secondary immune responses : 1. Fast response ( memory cells ) 2. IgG predominate . 3. High concentration of antibody or cells. 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. 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. 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 . 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. SURVIVAL T- cells that do not antigen: * Receive survival MHC . SIGNAL . encounter signal from self - * Pass through efferent lymphatic into the blood to continue recirculating through other lymphoid organs . 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. 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 . T-cell differentiation. IL-2 promote proliferation & differentiation of T-cells into : EFFECTOR CELLS. (mediate cellular responses) ( cell - mediated immunity ) Some T-cells remain MEMORY CELLS. as : THERAPEUTIC NOTE. The immunosuppressive drugs : * Cyclosporine –A * FK 506 (Tacrolimus ) * Rapamycin . Inhibit IL-2 production. (Prevent clonal expansion of T-cells ) Inhibit immune responses. EFFECTOR T-CELLS EXERT DIFFERENT 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 . THE ACTIVATED T- CELLS : INDUCE: Cellular immunity . ( Cell – mediated immunity ) * Destroy intracellular pathogens . Memory T- cells . INDUCE: Secondary immune responses. 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. HELPER T- CELLS : 1. Synthesize a membrane bound molecule (CD 40 ligand ) * Bind on CD -40 on B-cells . 2. Secrete B – cell stimulatory IL-4 , IL-5 , IL-6 . factors: * These cytokines act on receptors on the B-cell & the cell become activated . ACTIVATED B-CELLS : UNDERGO : 1. Clonal expansion. 2. Proliferation . 3. Differentiation into : ( PLASMA CELLS ) * Synthesize and secrete antibodies into the blood . ANTIBODIES MEDIATE : Humoral immunity . ( Antibody –mediated immunity ) * ( Destroy extracellular pathogens .) MEMORY B-CELLS. INDUCE : Secondary immune responses . CONTROL OF IMMUNE RESPONSES. 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. CONTROL MEHANISMS. 1. Antigen concentration gradually decrease as the infecting microbe is eliminated . 2. Antibody exert a negative feed -back that switch off responses. ( antibody & BCR linked by immune- complexes that contain the relevant antigen .) 3. Antibodies bind and idiotypic networks. 4.Cytokine - mediated form regulation. 5. Interaction of the immune system with endocrine and nervous system . This involve cytokines , hormones and neurotransmitters.