Immunity

Major Histocompatibility Complex (MHC) Human Leukocyte Antigen (HLA)Objectives

- Define MHC system - Draw & describe Gene map of the Human Leukocyte Antigen (HLA) region - Explain Nomenclature of HLA system - Discuss the Inheritance of HLA antigens - List Medical importance of HLA typing - Explain Structure, location,& function of MHC class-I & class-II molecules - Define MHC restriction

- Explain Assembly of endogenous peptides with MHC-I (cytosolic pathway) - Explain Assembly of exogenous peptides with MHC-II (endocytic pathway) - Discuss the HLA system & Diseases - Define Non classical MHC molecules

Definition: It is a group of tissue antigens, controlled by chromosomal region, bearing a no. of genetic loci, each with multi alleles, that have relevance to transplantation rejection reaction & other immunological phenomena.


Locus: position of gene on chromosome. Allele: one of the several alternative forms of gene at a given locus.

Nomenclature of HLA system:

Locus + no. of allele e.g. HLA-A1 HLA-DR4 HLA-CW2 (W=workshop)

Inheritance of HLA- antigens:

Inheritance of HLA- antigens:
Mother A1 B27 C8 Father A5 B19 Cw6



25% chance that 2 siblings will share both haplotypes (e.g. ac & ac) » Identical50% share one haplotype (e.g. ac & ad) » semi-identical25% share no haplotype (e.g. ac & bd) » non-identical

Medical importance of HLA - typing:

1- Paternity testing2- Disease association: -HLA - B27 ankylosing spondylitis -HLA - B8 myasthenia gravis-HLA-DR3 I.D.D.M-HLA - DR4 rheumatoid arthritis-HLA - CW6 psoriasis3- HLA typing is used primarily for determination of HLA compatibility between donor & recipient prior to transplantation.4- Anthropology to study races & nations.

MHC molecule (HLA antigens)

Function of HLA Ags:
Both class I & class II MHC molecules are important in controlling immunological responses by a process known as MHC restriction.

MHC Restriction

Cytotoxic T-cells ( CD8+ ) are only activated when they recognize both antigen and class I MHC molecules in association Helper T-cells ( CD4+ ) recognize antigens on antigen-presenting cells only when the antigens are presented on the surface of cells in association with class II MHC molecules

Assembly of endogenous peptides with MHC-I (cytosolic pathway) Assembly of exogenous peptides with MHC-II (Endocytic pathway)

(cytosolic pathway)

(Endocytic pathway)

Genetic control of immune responsiveness

1- Cell interaction (CI) genes:1 A/ Control most effective macrophage-Lymphocyte Interaction. B/ Control most effective T-T & T-B , Lymphocyte Interaction. C/ Code for molecules active in enhancing & suppressing immune response. D/ Control most effective lysis of virus-infected & neoplastic target cell by cytotoxic T-Lymphocyte. 2- Immune response (Ir) & Immune suppression (Is) genes: A/ Ir genes determine the ability of an individual to respond to a given Ag determinant. These genes occur in the HLA-D region in human. B/ Is genes control stimulation of specific suppressor T-lymphocyte

HLA system & disease:

The positive association between diseases & HLA-alleles can be divided into: 1- Those ass. with class I HLA-Ag. ex. Ankylosing spondilitis + HLA-B27 Psoriasis + HLA-CW6 Myesthenia gravis + HLA-B8 2- Those ass. with class II Ag: ex. Rheumatoid arthritis + HLA-DR4 Autoimmune thyroiditis + HLA-DR3

HLA system & disease:

Theories explaining HLA-Disease association:1- HLA-Ags could act as a receptor for certain microorganisms, toxins,… foreign substances which cause dominant susceptibility to infection2- A molecular mimicry or cross reactivity (immunologic similarity) between Ag of m.o. 3- HLA-Ag act as marker for Ir or Is genes.e.g. hyper-responsiveness to collagen ass. with HLA-DR4 & appear to be secondary to lack of collagen specific supp. T-cell, (due to state of equilibrium- disequilibrium between Ir & Is genes).

Nonclassicai MHC molecules:

Recently discovered mol. encoded in MHC system.They have relatedness to classical MHC mol. but with restricted cell type expression.Function  unknown, but may: Involved in the presentation of few peptides to the immune system.Required for Ag processing & presentation. Non-classical MHC-I mol. HLA-E , HLA-F , HLA-GNon-classical MHC-II mol. HLA-DM, HLA-DN