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

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

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

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

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

T-cell receptor diversity.

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

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

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

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

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

Antigen.

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

MHC haplotypes.

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

Distribution of MHC 1 & MHC 11 in body cells.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Antibody –mediated immunity : 1. B-cells encounter specific antigen & recognize it through (BCR). & 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. * Bind on CD -40 on B-cells. 2. Secrete B – cell stimulatory factors: IL-4, IL-5, IL-6. IL-4, IL-5, IL-6. * These cytokines act on receptors on the B-cell & the cell become activated. * These cytokines act on receptors on the B-cell & the cell become activated.

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

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

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

CONTROL MEHANISMS. 1. Antigen concentration gradually decrease as the infecting microbe is 1. Antigen concentration gradually decrease as the infecting microbe is eliminated. eliminated. 2. Antibody exert a negative feed -back 2. Antibody exert a negative feed -back that switch off responses. ( antibody & that switch off responses. ( antibody & BCR linked by immune- complexes BCR linked by immune- complexes that contain the relevant antigen.) that contain the relevant antigen.)

3. Antibodies bind and form idiotypic networks. 3. Antibodies bind and form idiotypic networks. 4.Cytokine - mediated regulation. 4.Cytokine - mediated regulation. 5. Interaction of the immune system 5. Interaction of the immune system with endocrine and nervous with endocrine and nervous system. This involve cytokines, system. This involve cytokines, hormones and neurotransmitters. hormones and neurotransmitters.