PROF. MOHAMED OSMAN GAD ELRAB. PROF. MOHAMED OSMAN GAD ELRAB. , KKUH , 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:1. RECOGNITION: Microbial antigens are Microbial antigens are recognized by specific T-cell or B- cellrecognized by specific T-cell or B- cell receptor .receptor . 2. SPECIFICITY :2. SPECIFICITY : Specific response to Specific response to each microbe ( Humoral or Cellular ).each microbe ( Humoral or Cellular ).

3. MEMORY :3. MEMORY : Immunological memory is the Immunological memory is the most important consequence of adaptivemost important consequence of adaptive immunity . immunity .

Features:

Diverse specificity of the antigenDiverse specificity of the antigen

receptor is aquired. receptor is aquired.

T- cell receptor : TCR.T- cell receptor : TCR.

B - cell receptor : BCRB - 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. 1. Diversity of the lymphocyte repertoire.(Diversity of the lymphocyte repertoire.(range of receptors )range of receptors )

2. Unique 2. Unique antigen receptors of individual lymphocytes . antigen receptors of individual lymphocytes .

( each lymphocyte have I different receptor .)( each lymphocyte have I different receptor .)

Antigen specificity is determined byAntigen specificity is determined by: :

T-cell receptor diversityT-cell receptor diversity..

MHC-binding peptides

Each human usually expresses:3 types of MHC class I (A, B, C) and3 types of MHC class II (DR, DP,DQ)

The number of different T cell antigen receptors is estimated to be

1,000,000,000,000,000Each of which may potentially recognise a different peptide antigen

How can 6 invariant molecules have the capacity tobind to 1,000,000,000,000,000 different peptides?

A. Antigen receptors that A. Antigen receptors that reactreact weakly with self (MHC):weakly with self (MHC): survive by survive by positive selection positive selection ( 2 percent .) ( 2 percent .)

B. Antigen receptors that B. Antigen receptors that reactreact strongly with self (MHC):strongly with self (MHC): deleted by deleted by negative selection.negative selection. (98 percent .)(98 percent .)

Recognition of self & non-self.

This establish a mechanism that prevent autoimmune disease .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 into 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.MHC.

Major histocompatibility complex .Major histocompatibility complex .

(Tissue antigens present in chromosome 6 )(Tissue antigens present in chromosome 6 )

ENCODE THE HLA SYSTEMENCODE THE HLA SYSTEM ..

(human leukocyte antigens. )(human leukocyte antigens. )

A A POLYGENIC & HIGHLY POLYMORPHICPOLYGENIC & HIGHLY POLYMORPHIC

SYSTEM OF GENES.SYSTEM OF GENES.

MHC.

MHC, short arm of chromosome 6MHC, short arm of chromosome 6..

MHC REGION. include HLA.

Antigen .

HLA HLA system (human leukocyte antigens )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 inEach 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 haplotypesMHC haplotypes. .

Inheritance of MHC haplotypes

B C ADP DQ DR

B C ADP DQ DR

B C ADP DQ DR

B C ADP DQ DR

X

ParentsDP-1,2DQ-3,4DR-5,6B-7,8C-9,10A-11,12

DP-9,8DQ-7,6DR-5,4B-3,2C-1,8A-9,10

DP-1,8DQ-3,6DR-5,4B-7,2C-9,8A-11,10

DP-1,9DQ-3,7DR-5,5B-7,3C-9,1A-11,9

DP-2,8DQ-4,6DR-6,4B-8,2C-10,8A-12,10

DP-2,9DQ-4,7DR-6,5B-8,3C-10,10A-12,9

B C ADP DQ DR

B C ADP DQ DR

B C ADP DQ DR

B C ADP DQ DR

B C ADP DQ DR

B C ADP DQ DR

B C ADP DQ DR

B C ADP DQ DR

Children

MHC CLASSESMHC 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 responsesMHC & 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 ANTIGEN PRESEANTING CELLS (APC)(APC)..

1. Dendritic cells .1. Dendritic cells .

2. Macrophages .2. Macrophages .

3. B-lymphocytes .3. B-lymphocytes .

ANTIGEN PRESENTING CELLS.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 APCDISTRIBUTION OF APC..

. 1. DENDRITIC CELLS:. 1. DENDRITIC CELLS:

Take up particulate & soluble microbialTake up particulate & soluble microbial

antigen form site of infection. ( handlesantigen form site of infection. ( handles

a wide variety of pathogens. )a wide variety of pathogens. )

22 . .MacrophagesMacrophages: :

Phagocytic cells in the tissues but also process:Phagocytic cells in the tissues but also process:

ingested pathogens & actively ingest microbes ingested pathogens & actively ingest microbes and particulate antigens and particulate antigens

entering lymph nodesentering lymph nodes through afferent through afferent lymphatic vessels . lymphatic vessels .

3. B-lymphocytes :3. B-lymphocytes :

Process soluble antigens (microbial Process soluble antigens (microbial toxins).toxins).

recirculate through the lymphoid tissuesrecirculate through the lymphoid tissues

and concentrateand concentrate in the lymph. folliclesin the lymph. follicles

in lymph nodes. in lymph nodes.

Functions of APC :Functions of APC :

1. On activation, express co-stimulatory1. 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 in3. Load antigenic peptides in clefts in

self-MHC molecules .self-MHC molecules . 4. Transport peptide-MHC complex on4. Transport peptide-MHC complex on

the surface of the cell. the surface of the cell.

Antigen processing by APC :Antigen processing by APC :

TWO PATHWAYS :TWO PATHWAYS :

1. ENDOGENOUS PATHWAY:1. ENDOGENOUS PATHWAY: PROCESS PROCESS INTRACELLULARINTRACELLULAR MICROBESMICROBES

- 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.

Antigen processing: Endogenous pathwayAntigen processing: Endogenous pathway

All nucleated cells can process endogenous proteins and

present fragments on their class I MHC.

Endoplasmic reticulum

Nucleus

Cytoplasmicproteins

degradation

Vesicle carryingMHC I-peptide

Processing in E.R. and complexing with MHC I

Display of MHC I + peptideon cell surface

22. . EXOGENOUS PATHWAYEXOGENOUS PATHWAY

-- DEGRADE DEGRADE MICROBES IN THE MICROBES IN THE VESICULAR SYSTEM . (ENDOSOMES).VESICULAR SYSTEM . (ENDOSOMES).

A. INTRAVESICULAR PATHOGENS. A. INTRAVESICULAR PATHOGENS. - BIND PEPTIDE TO MHC-11.- BIND PEPTIDE TO MHC-11. - 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.

Antigen processing: Exogenous pathwayAntigen processing: Exogenous pathwayProfessional antigen presenting cells ingest microbes and free

particles, degrade them in lysozomes, and present fragments to CD4+ T cells on MHC II.

Endoplasmic reticulum

Nucleus

Vesicle carryingMHC II

MHC II is assembled in ER

Display of MHC II + peptideon cell surface

Ingestion of microbe

Degradtion in lysozome

Vesicle fusion, assembly of

peptide/MHC II

Activated CD4 T- cells :Activated CD4 T- cells :

2 Functional classes influenced by nature of 2 Functional classes influenced by nature of microbial antigen :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 MECHANISMSEFFECTOR MECHANISMSOF ADAPTIVE IMMUNITYOF 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 immunityHumoral 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 responsesPrimary 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. 7-10 DAYS.3. PLATEU. 7-10 DAYS.

4. DECLINE.4. DECLINE.

(Primary I.R. may take few days to several (Primary I.R. may take few days to several weeks ,) weeks ,)

Features of primary immuneFeatures of primary immuneresponsesresponses: :

1. Takes longer ( 4 phases)1. Takes longer ( 4 phases)

2. IgM predominate .2. IgM predominate .

3. Memory cells generated 3. Memory cells generated ..

Features of secondary immune Features of secondary immune responsesresponses: :

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 responsesFactors 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 contFACTORS 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 TRAFFICLYMPHOCYTE TRAFFIC..

Naïve T-cells enter the lymphoidNaïve 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 Contact thousands of ( APC.), then pass out into the blood & recirculateout into the blood & recirculate

into other lymphoid organs . into other lymphoid organs .

ANTIGEN RECOGNITIONANTIGEN RECOGNITION..

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

LYMPHOCYTE TRAPPING.LYMPHOCYTE TRAPPING.

SURVIVAL SIGNALSURVIVAL SIGNAL. .

T- cells that do not encounter T- cells that do not encounter antigen: antigen:

* Receive survival signal from self - * Receive survival signal from self - MHC . MHC .

* Pass through efferent lymphatic into * Pass through efferent lymphatic into the blood to continue recirculatingthe 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 proliferationT-cell proliferation. .

T- cells divide 2 - 3 times / day.T- cells divide 2 - 3 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 that all bear the same receptorall bear the same receptor

for antigen .for antigen .

T-cell differentiationT-cell differentiation..

IL-2 promote proliferation & differentiation IL-2 promote proliferation & differentiation of T-cells into : 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 NOTETHERAPEUTIC 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 EXERTEFFECTOR T-CELLS EXERTDIFFERENT FUNCTIONS:DIFFERENT FUNCTIONS:

Adhesion molecules (P- selectin & Adhesion molecules (P- selectin & E- selectin) recruit T-cells into E- selectin) recruit T-cells into sites of infection .sites of infection .

1. Some differentiate into cytotoxic T-cells . 1. Some differentiate into cytotoxic T-cells .

( CTL )( CTL )2. Some produce cytokines that act on : 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 :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 :Antibody –mediated immunity :

1. B-cells encounter specific antigen1. B-cells encounter specific antigen

& recognize it through (BCR).& recognize it through (BCR).

2. Processed antigen is loaded on MHC 2. Processed antigen is loaded on MHC 11 and appear on the cell surface.11 and appear on the cell surface.

3. Helper T-cell recognize the same 3. Helper T-cell recognize the same antigen.antigen.

HELPER T- CELLSHELPER T- CELLS: :

1. Synthesize a membrane bound 1. Synthesize a membrane bound molecule (CD 40 ligand )molecule (CD 40 ligand )

* Bind on CD -40 on B-cells .* Bind on CD -40 on B-cells .

2. Secrete B – cell stimulatory factors:2. Secrete B – cell stimulatory factors: IL-4 , IL-5 , IL-6 .IL-4 , IL-5 , IL-6 .

* These cytokines act on receptors * These cytokines act on receptors on the B-cell & the cell become on the B-cell & the cell become activated .activated .

ACTIVATED B-CELLS :ACTIVATED B-CELLS :

UNDERGO :UNDERGO : 1. Clonal expansion.1. Clonal expansion. 2. Proliferation .2. Proliferation . 3. Differentiation into :3. Differentiation into :

( PLASMA CELLS ) ( PLASMA CELLS ) * Synthesize and secrete antibodies* Synthesize and secrete antibodies

into the blood .into the blood .

ANTIBODIES MEDIATEANTIBODIES 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 IMMUNECONTROL OF IMMUNERESPONSES.RESPONSES.

After control of infections and eliminationAfter control of infections and elimination

of the pathogens :of the pathogens :

The immune responseThe immune response

down regulate and return to a near basal down regulate and return to a near basal level . level .

several mechanisms are involved. several mechanisms are involved.

CONTROL MEHANISMSCONTROL MEHANISMS..

1. Antigen concentration gradually 1. Antigen concentration gradually decrease as the infecting decrease as the infecting microbe ismicrobe is

eliminated .eliminated .

2. Antibody exert a negative feed -back2. Antibody exert a negative feed -back that switch off responses. ( antibody &that switch off responses. ( antibody & BCR linked by immune- complexesBCR linked by immune- complexes that contain the relevant antigen .)that contain the relevant antigen .)

3. Antibodies bind and form3. Antibodies bind and formidiotypic networks. idiotypic networks.

4.Cytokine4.Cytokine - - mediated regulation. mediated regulation.

5. Interaction of the immune system5. 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.