Download acquired immunity

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.