ACQUIRED IMMUNITY

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

• 1. T- lymphocyte
• Programmed in the Thymus gland.
• 2. B- lymphocyte
• Programmed in the bone marrow .

Central lymphoid tissues .
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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 .

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Events in central lymphoid tissues .
Diverse specificity of the
antigen receptor is aquired.

T- cell
receptor TCR. B - cell
receptor BCR .

( LYMPHOCYTE
REPERTOIRE).
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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 .)

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T-cell receptor diversity.
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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 .)

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This establish a mechanism that prevent
autoimmune disease .

• Central immunological tolerance.
• ( no immune reactions against self.)

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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.

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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.

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

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MHC haplotypes .
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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 ).

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Distribution of MHC 1 MHC 11 in body cells.
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MHC immune responses

• MHC CLASS1
• Important for
• Target (infected - cell )
  recognition .
• MHC CLASS 11
• Important for
• Antigen recognition
  presentation.

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ANTIGEN PRESEANTING CELLS (APC).

• 1. Dendritic cells .
• 2. Macrophages .
• 3. B-lymphocytes .

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ANTIGEN PRESENTING CELLS.

• ACTIVATED BY
• 1. Receptors that signal
• presence of microbes .
• .
• 2. Cytokines.

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DISTRIBUTION OF APC.

• . 1. DENDRITIC CELLS
• Take up particulate soluble
  microbial
• antigen form site of infection.
  ( handles
• a wide variety of
  pathogens. )

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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 .

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3. B-lymphocytes

• Process soluble antigens (microbial
  toxins).
• recirculate through the lymphoid tissues
• and concentrate in the lymph.
  follicles
• in lymph nodes.

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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.

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Antigen processing by APC

• TWO PATHWAYS
• 1. ENDOGENOUS PATHWAY PROCESS
  INTRACELLULAR MICROBES
• - DEGRADATION IN CYTOSOLS.
• - BIND PEPTIDE TO MHC 1.
• - RECOGNIZED BY CYTOTOXIC CD8
• T-CELLS.

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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.

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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.

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EFFECTOR MECHANISMSOF ADAPTIVE
IMMUNITY.

• Activation of T-cells ( TH1)
• Cellular immunity ,
• ( Cell mediated )
• Activation of B- cells (TH2TH1,helper,)
• Humoral immunity
• ( Antibody - mediated ).
• ) microbes may induce both , but one is
  
• predominant for control )

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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 ,)

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Features of primary immuneresponses

• 1. Takes longer ( 4 phases)
• 2. IgM predominate .
• 3. Memory cells generated .

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Features of secondary immune responses

• 1. Fast response ( memory cells )
• 2. IgG predominate .
• 3. High concentration of antibody or
• cells.

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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.

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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.

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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 .
  

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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.

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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
  .

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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.

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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 .

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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.

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THERAPEUTIC NOTE.

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

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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 .

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THE ACTIVATED T- CELLS

• INDUCE
• Cellular immunity .
• ( Cell mediated immunity )
• Destroy intracellular pathogens .
• Memory T- cells .
• INDUCE
• Secondary immune responses.

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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.

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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 .

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ACTIVATED B-CELLS

• UNDERGO
• 1. Clonal expansion.
• 2. Proliferation .
• 3. Differentiation into
• ( PLASMA CELLS )
  Synthesize and secrete antibodies
• into the blood .

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ANTIBODIES MEDIATE

• Humoral immunity .
• ( Antibody mediated immunity )
• ( Destroy extracellular pathogens .)
• MEMORY B-CELLS.
• INDUCE
• Secondary immune responses .

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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.

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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 .)

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3. Antibodies bind and formidiotypic
networks.

• 4.Cytokine - mediated
  regulation.
• 5. Interaction of the immune
  system
• with endocrine and
  nervous
• system . This involve
  cytokines ,
• hormones and
  neurotransmitters.