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Immunogenetics

Dr meshack sigeiHOD department of immunologymoi university school of medicine

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Antigens

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Major Histocompatibility Complex (MHC)

* The MHC is a closely linked complex of genes that govern production of the major histocompatibility

* In humans, MHC resides on the short arm of chromosome 6

* Three genes (HLA-A, HLA-B, HLA-C) code for the class I MHC proteins

* Several HLA-D loci determine the class II MHC proteins i.e. DP, DQ and DR

* HLA genes are very diverse (polymorphic) i.e. there are many alleles of the class I and II genes

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Major Histocompatibility Complex (MHC)

* Between the class I and class II gene loci, there is a third locus (Class III)

* This locus contains genes encoding tumor necrosis factor, lymphotoxin and two complement components (C2 and C4)

* Class III antigens do not participate in MHC restriction or graft rejection

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MHC Class I Antigens* Class I MHC antigens are : HLA-A, HLA-B and HLA-C

* These antigens are glycoproteins found on surfaces of all nucleotide human cells and on platelets

* HLA-A contains 24 different antigenic specificities, HLA-B contains 52 and HLA-C contains 11

* Class I MHC antigens are involved of MHC restriction of cell mediated cytotoxicity

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MHC Class II AntigensClass II antigens are: HLA-DP, HLA-DQ, HLA-DR

antigens

These antigens are glycoproteins found on the surface of macrophages, B-cells, Dentritic cells, langerhans cells of skin and activated T cells

HLA-DP contain 6 different antigenic specificities, HLA-DQ contains 9 and HLA-DR contains 20

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MHC Class II Antigens* Helper T-cells recognize antigens on antigen-

presenting cells only when the antigens are presented on the surface of cells in association with class II MHC

* Class II antigens react with the CD4 molecule on the helper T-cells which secrete cytokines

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Class I MHC and Class II MHC

MHC Class I MHC Class IINomenclature HLA-A, HLA-B, HLA-C HLA-DP, HLA-DQ,

HLA-DR

Found on All nucleated somatic cells

Macrophages, B-cells, Dentritic cells,

langerhans cells of skin and activated T cells

Recognized by CD8 TC cells CD4 TH cells

Functions Presentation of Ag to TC cells leading to

elimination of tumor or infected host cell

Presentation of Ag to TH cells which secrete

cytokines

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Antigen Recognition• Antigens

Processed, Unprocessed

Endogenous, exogenous

Self, Foreign

• Receptors

Ag-specific ->adaptive

PRRs ->innate

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Levels of immune response

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Antigen Processing

exogenous endogenous

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Pattern Recognition Receptors (PRR)

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TLRs

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BCR, TCR

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TCR/BCR Complexes

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BCR, TCR

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BCR genetics

D-diversity, J-joining, V-variability, C-constant

Chromosome 14

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BCR genetics

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Generation of diversity• Antigens – 1011 (100 billion)

• Mechanisms – before and after contact with antigen

V(D)J recombination

Junctional diversity

Combinations of receptor chains

Somatic hypermutation (affinity maturation)

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TCR genetics

chain chromosome V D J C

α 14 50 - 70 1

β 7 57 2 13 2

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Generation of diversity• Antigens – 1011 (100 billion)

• Mechanisms – before and after contact with antigen

V(D)J recombination

Junctional diversity

Somatic hypermutation (affinity maturation)

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V(D)J recombination

* Junctional diversity

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Somatic hypermutation

Mutations are silent (yellow bars), neutral (pink bars), deleterious (red bars), positive (blue bars).

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Receptor genetics

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MHC - Histocompatibility

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Gene structure

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Location and components

Class I MHC

Class II MHC

RBCs

Professional APCs

Nucleated cellsA, B, C DP, DQ, DR

Class III codes for other proteins eg complement components, cytokines

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MHC distribution

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Linkage disequilibrium - the distribution of haplotypes is not

random in a population

Diversity (polygenic/polymorhic) – many genes/alleles (>500

for HLA-B)

-> ability to respond to millions of antigens

Inheritance pattern – co-dominance

MHC features

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Co-dominance

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Polymorphism

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Polymorphism

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Linkage disequilibriumA1 B8B8 DR3A11 B5A29 B12

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Gene combinations occuring more frequently than

expected by random combinations

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Class I MHC

• α chain (43kDa), β2 microglobulin (12 kDa)• β2-microglobulin – genes on chromosome 15• Can accommodate 10 amino acids

b2-M

a-chain

Peptide

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Class II MHC

a-chain

b-chainPeptide

• α chain (34kDa), β chain (29 kDa)• Can accommodate ~15 amino acids

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Application of HLA in medicine Transplantation

Forensic medicine

Anthropological studies

Regulating immune responses

Disease association

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MHC restriction of immune response

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Disease association

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Transplantation andGraft Rejection

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Types of grafts1) Autografts : The transfer of an individual’s own tissues from place to place e.g. Skin grafts (regularly accepted)

2) Isografts : Transfer of tissues between genetically identical persons e.g. Identical twins ( accepted permanently)

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Types of grafts 3) Allografts (homograft): - Transfer of a graft between genetically different members of same species e.g from one human to another - Rejection occur if donor and recipient are not matched

4) Xenograft (heterograft): - Transfer of tissues between different species - Always rejected

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Mechanism Of Graft Rejection1) Both TH and TC are activated - TC cells destroy graft cells by direct contact TH cells secrete cytokines that attract and activate

macrophages, NK cells and polymorphs leading to cellular infiltration and destruction of graft (Type IV)

- B cells recognize foreign antigens on the graft and produce antibodies which bind to graft cells and

. Activate complement causing cell lysis . Enhance phagocytosis, i.e. opsonization (Type II) . Lead to ADCC by macrophages, NK,PML

- Immune complex deposition on the vessel walls induce platelets aggregation and microthrombi leading to ischemia and necrosis of graft (Type II)

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Types Of Graft Rejection!) Hyperacute rejection: - It occurs hours after transplantation - In individual with preformed antibodies either due to -

blood groups incompatibility or previous sensitization by blood transfusion, previous transplantation

2) Acute Rejection: - It occurs 10 to 30 days after transplantation - It is mainly T-cell mediated

3) Chronic or late rejection: - It occurs over a period of months or years - It may be cell mediated, antibody mediated or both

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Graft Versus Host (GVH) Reaction

* An immunologically competent graft is transplanted into an immunologically suppressed recipient (host)

* The grafted cells survive and react against the host cells i.e instead of reaction of host against the graft, the reverse occurs

* GVH reaction is characterized by fever, pancytopenia, weight loss, rash , diarrhea, hepatsplenomegaly and death

Home work• History Of Immunology• Kinetics of the Immune Response• Primary response /Secondary

response• KEPI vaccination Schedule

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Books• Stites• Janeway• Roitt• Abbas• Internet

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