MHC 22.ppt MHC and antigen presentationntation

MHC and Ag presentation

1. Antigen presentation and
Major Histocompatibility
Complex (MHC)
Prof Dr. Naael H Ali, M.Sc., Ph.D.
Clinical Immunology
Dep. of Microbiology
College of Medicine
University of Basrah
IMMUNOLOGY

2. Introduction
Antigen presentation
Structure of MHC genes and products
Polymorphism of MHC
Interactions of MHC molecules with antigenic peptides
HLA and clinical medicine
Biological function of MHC molecules

3. ANTIGEN RECOGNITION BY T AND B LYMPHOCYTES
In order to initiate an immune response antigen
must be recognized.
Antigen recognition depends on detection of
antigen by special receptors.
Antigen recognition depends on cellular
cooperation.
Cellular cooperation is controlled by recognition of
MHC-encoded receptors.
Introduction

4. T Cell Recognition of Antigen

6. Cell surface
immunoglobulin
receptor or B-cell
receptor (IgM and IgD)
Antigen contact initiates
B-cell activation, clonal
expansion, maturation
to plasma cell
Antigen receptor is
identical to
immunoglobulin that
will ultimately be
produced
B Cell Antigen Recognition

7. Major histocompatibility complex (MHC)
MHC is a cluster of genes (complex) on
chromosome 6 in humans, encoding cell
surface molecules that are polymorphic and
that code for antigens causing rapid graft
rejection between members of a single
species that differ at these loci.
Several classes of protein such as MHC class I
and II proteins are encoded in this region.
Human: Human leukocyte antigens (HLA)
Mouse: H-2

8. 1. Histocompatibility
The ability to accept grafts between individuals.
2. Histocompatibility antigen
The Ags primarily responsible for rejection of genetically
different tissues are known as histocompatibility Ags.
3. Histocompatibility antigen system
Major histocompatibility antigen system
Minor histocompatibility antigen system

10. Products of MHC class I and class II
genes---HLA molecules
HLA class I molecules
Genes: A, B, C
Distribution: every
nucleated cell
Structure: α chain, β2m
peptide-binding cleft: α1+α2
Function: recognize and
present endogenous Ags to
CD8
+
T cells

11. HLA class II molecules
Genes: DR, DQ, DP

Distribution: APC (B, DC,
MΦ)thymic epithelial cells,
activated T cells

Structure: α chain , β chain;
peptide-binding cleft: α1+β1

Function: recognize and
present the exogenous Ags
to CD4 T cells

12. Location of MHC Class I and Class II molecules in tissues

13. Other immune function related genes
1) Antigen presenting function related genes
*LMP (low molecular weight polypeptide): LMP2/7
Function: processes endogenous Ag
*TAP (transporter associated with Ag processing):
TAP1, TAP2 . Function: transports endogenous Ag peptides
*HLA-DM: participates in the exogenous pathway
*HLA-DO: negative regulation of DM
*Tapasin (TAP associated protein): participates in the
endogenous pathways.

14. 2. Serum complement encoded genes
MHC class III
3. Non-classical class I genes (HLA Ib)
HLA-E, HLA-G: inhibit NK cell activity
4. Inflammation related genes
 TNF gene family: TNF, LTA, LTB
 Transcription factor gene family: I-κBL.
Heat shock protein gene family: HSP70.

15. Polymorphism of MHC
Highly polymorphic means;
1. There are many different alleles in the
different individuals inside a population.

2. In a mixed population there are not two
individuals with exactly the same set of MHC
genes and molecules, with the exception of
identical twins

16. 3 . The polymorphic
regions in each allele
are located in the region
for peptide contact,
which is going to be
displayed to the
lymphocyte.

17. 4. The evolution of the MHC polymorphism ensures that a
population will not succumb to a new pathogen or a mutated
one, because at least some individuals will be able to develop
an adequate immune response to win over the pathogen. The
variations in the MHC molecules (responsible for the
polymorphism) are the result of the inheritance of different
MHC molecules, and they are not induced by recombination,
as it is the case for the antigen receptors :

5. Ensures survival of the population as a whole when they
encounter any new pathogens by presenting new microbial
epitopes.
Affects the ability to make immune responses
(e.g. resistance or susceptibility to infectious diseases).

18. HLA Nomenclature

19.  Interactions of MHC molecules with antigenic peptides

20. Biological function of HLA
1.Participates in the adaptive immune response
serving as antigen presenting molecules
* T cells recognize both the antigenic peptide
and MHC molecules by TCR (double
recognition)
* MHC polymorphism is a crucial determinant
of disease susceptibility in different
individuals

21. * MHC molecules can present both
autoantigens and MHC molecules themselves.
Such that MHC molecules participate in
autoimmunity, in the response to non-self
MHC molecules as well as in the
differentiation of T cells in the thymus
* MHC contributes to the genetic
heterogeneity of the population

22. 3)Inflammation related genes initiate and
control inflammation. They also play a role in
stress responses (such as HSP).
2. Participates in the innate immunity
serving as regulatory molecules
1)Classical MHC class III genes encode
complement, hereby participating in
complement reactions and in the
pathogenesis of some immune diseases.
2)Non-classical HLA class I molecules (HLA-E,
G) regulate the activity of NK cells and
prevent fetus rejuction

23. HLA clinical application
1. HLA and transplantation
HLA typing; cross-match
2. Abnormal expression of HLA
Tumor: class I molecule
Autoimmune diseases: class II molecule
3. Adverse drug reaction:
carbamazepine : HLA-B*15:02 (SJS)
allopurinol: HLA-B*58:01
4. HLA and forensic medicine

24. 5. HLA and disease susceptibility
e.g. Ankylosing spondylitis: B27

25. 5-Paternity Testing:
Wife: A2, A11; B27, Bw44
Child 1: A2, A1; Bw44, B15, Cw3
Child 2: A2, Aw24; Bw44, Bw54; Cw3
Husband: A1, A3; B15, -; Cw3
Another man: A2, Aw24; B7, Bw54; Cw3