MHC molecules. Antigen processing and presentation Flashcards
Recognition of Antigens by B cells
- Antigen receptors are antibodies –> immunoglobulins
- can recognize Peptides, proteins, nucleic acids, carbohydrates, Lipids, small chamicals
Recognition of Antigens by T cells
- recognition mechanism is different to B cells
- receptors recognize only short linear Peptides that are displayed on specialized Antigen presenting cells
- MHC –> specialized Peptide Display molecule that Displays Antigens to T cells
- T cell si specific for a combination of aa residues of a Peptide Antigen plus part of the MHC molecule
MHC locus contains two types of polymorphic MHC genes:
class I and class II MHC genes –> encode two structurally different but humologous proteins
Class I –> Display Peptides to CD8+ T cells
Class II –> Display Peptides to CD4+ T cells
MHC genes
- Human MHC is calles HLA
Class I MHC genes: HLA-A, HLA-B, HLA-C
Class II MHC genes: HLA-DP, HLA-DQ, HLA-DR
- located in chromosome 6
- genes are the most polymorphic genes present int Genome
- MHC genes are codominantly expressed
How are MHC composed?
Class I: Alpha chain and nonpolymorphic beta 2 microglobulin
Class II: 2 polymorphic chains: Alpha and beta
Peptide binding to MHC molecules
Each class I or Class II MHC molecule has a single Peptide-binding cleft –> binds one Peptide at a time
Class I: bind Peptides 8 to 11 aa Long
Class II: bind Peptides up to 30 aa long
APCs and MHCs
APCs caputre extracellular protein Antigens, process them and Display class II associated Peptides to CD4+ T cells
Dendritic cells
- located at the common sites of entry of microbes and foreign Antigens
- receptors enable them to caputre microbes
- migrate from epithelia and tissues preterentially to the T cell zones of lymph nodes–> searching for Antigens
- high Levels of MHC complexes, co Stimulators and cytokines –> all are needed to activate naive T cells
Antigen capture and presentation steps:
- Antigen capture in periphery
- Migration to lymph nodes
- Maturation of DCs
- Activation of T cells
Antigen processing and presentation in MHC I molecules
CYTOSOLIC/ INTRACELLULAR PROTEINS are presented
- proteins are proteolytically degraded in proteasome
- formed Peptides go from cytoplasm to ER by TAP (Transporter depended on ATP)
- new class I MHC beta 2 microglobulin dimers receive These Peptides
- class I MHC molecules with Bound Peptides move out of ER –> through Golgi –> cell Surface
- MHC I molecules are expressed in all nucleated cells
- present both foreign Antigen and self Antigens
- T cells for self Antigens are eliminated in T cell maturation
Antigen processing and presentation in MHC II molecules
EXTRAVELLULAR PROTEINS are presented
- proteins are internalized into endosomes
- proteolytic cleavage of proteins
- new MHC II molecules with the Li go from ER to endosomal vesicles
- li is proteolytically cleaved
- small Peptide CLIP is removed from the Peptide-binding cleft
- Peptides from extracelllular protein then binds to the cleft
- complec MHC II Alpha and beta chains and Peptide is displayed on cell Surface
- Peptides are recognized by CD4+ T cells
MHC II moleucles are Expressed on professional APCs
Loss of MHC I and activation of NK cells
- NK cells express inhibitory receptors that recognize MHC I molecules
- Loss of MHC I in infected or transformed cells means the activation Signal for NK cells
Transplantation and graft rejection
autologous graft: graft transplanted from one idividual to the same individual
syngeneic graft: between two genetically identical or syngeneig individuals
Allogenic graft: bewteen two genetically different individuals of the same species
Xenogenic graft: between individuals of different species
–> allografts and xenografts are always rejected
Molecules that are recognized as foreign during transplantation
on allografts: alloantigens
on xenografts: xenoantigens
lymphocytes and antibodies that react with alloantigens or xenoantigens: alloreactive, xenoreactive
Routine clinical laboratory Tests before transplantation
- ABO blood typing
- HLA typing
- detection of preformed antibodies that recognize HLA and other Antigens
- detection of preformed antibodies that bind to Antigens of an identified donor’s leukocytes (crossmatching)
Influence of HLA matching on graft survivial
- Matching HLA alleles between donor and recipient improves allograft Survival
- Most HLA determinations are performed by PCR
Types of alloraft rejection
hyperacute
acute
chronic
Hyperacute allograft rejection
- thrombotic occlusion of the graft vasculature that Begins within minutes or Hours
- mediated by preexisting antibidies in the host circulation that bind to donor endothelial Antigens
Mechanism: complement activation, changes in graft Endothelium, inflammaiton, intravascular thrombosis
Acute allograft rejection
- injury to graft Parenchyme and blood vessels mediated by alloreactive T cells and antibodies
- would often begin several days to a few weeks after Transplantation
- alloreactive T cells and antibodies take time to be generated deom naive or resting Memory T cells
Chronic allograft rejection
- Chronic inflamation, arterial occlusion, Proliferation of intimal smooth muscle cells, ischemic Damage
- activation of alloreactive T cells, secretion of cytokines, Proliferation of vascular endothelial and smooth muscle cells, repair with fibrosis
Immunosuppression for preventing allograft rejection
- drugs that inhibit or kill T lymphocytes
- Cyclosporine: inhibits T cell signaling pathways and transcription of certain genes in T cells
- -> BUT: increased Risk of Tumors and infectious diseases
- Costimulatory Blockade: induction of T cell tolerance
- Induction of graft-specific regulatory T cells
Blood transfusion
ABO Antigens: carbohydrates linked to cell Surface proteins and Lipids
- individuals who express a particular ABO Antigen are tolerant to that Antigen
- Individuals who do not express that ABO Antigen produce natural antibodies against the Antigen
Transfusion reaction: immediate hemolyses, extensive phagycytosis of RBC, kidney failure, ….
Bone marrow Transplantation
Graft vs Host disease
- allogenic hematopoietic stem cells are rejected by even a minimally immunocompetent host
- donor and recipient must be carefully matched at all MHC loci
Graft vs Host disease: caused by the reaction of grafted mature T cells in the marrow inoculum with alloantigens of the host
