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 the antigen

receptor is 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 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.

 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 .

DP-1,9
DP DQ DR B C A
DQ-3,7
Inheritance of MHC haplotypes DR-5,5
B-7,3 DP DQ DR B C A
C-9,1
A-11,9
Parents DP-1,8
DP-1,2 DP DQ DR B C A
DP DQ DR B C A
DQ-3,6
DQ-3,4 DR-5,4
DR-5,6 B-7,2 DP DQ DR B C A
B-7,8 DP DQ DR B C A C-9,8
C-9,10 A-11,10
A-11,12
DP-2,8 DP DQ DR B C A
X Children DQ-4,6
DR-6,4
DP-9,8 DP DQ DR B C A DP DQ DR B C A
B-8,2
DQ-7,6
C-10,8
DR-5,4
A-12,10
B-3,2 DP DQ DR B C A
C-1,8 DP-2,9
DP DQ DR B C A
A-9,10 DQ-4,7
DR-6,5
B-8,3 DP DQ DR B C A
C-10,10
A-12,9
 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: PROCESS
INTRACELLULAR MICROBES

- DEGRADATION IN CYTOSOLS.
- BIND PEPTIDE TO MHC 1.
- RECOGNIZED BY CYTOTOXIC CD8
T-CELLS.
 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.
 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.
 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. 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 ,)
 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 )

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 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 .
 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 as :

MEMORY CELLS.
 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 factors:

IL-4 , IL-5 , IL-6 .

* 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 form
idiotypic networks.

4.Cytokine - mediated regulation.

5. Interaction of the immune system

with endocrine and nervous
system . This involve cytokines ,
hormones and neurotransmitters.