Flashcards in Lecture 13 Deck (17)
What occurred with early organ transplants?
The first documented attempts of this was tried in the Crimean war where graft tissue from dead soldiers was used in an attempt to replace the tissue of wounded soldiers
However within a week to 10 days the area around the graft became inflamed and the graft would become necrotic and die
If the process was repeated using the same this occurred more rapidly showing adaptation of the host immune system
If the process was repeated with a new donor then it would take the same amount of time as initially required showing that whatever cause the immune response was unique to individuals
This factor was later determined to be the MHC molecules
What are the different forms of tissue grafting?
An autograft from the same individual but a different area of tissue
An isograft from a donor who is genetically identical (this only occurs in identical twins)
An allograft from two non-genetically identical individuals of the same species
A xenograft from another species this is less common but often more succressful as there is a lower chance of rejection
What is the role of MHC molecules in cellular immunity?
T cells are the cells which cause donor tissue rejection, they express TcR which are MHC restricted as they use this molecule to recognize foreign antigen which is presented to them
CD4 T cells will produce cytokines when they recognize MHC class II and foreign antigen while CD8 cells will kill cells when they recognize foreign antigen and MHC class I together
What is MHC?
This is genetic region is the major histocompatibility complex and it codes for cell surface antigens which were expressed on all cells but most predominately on white blood cells
It is also known as the Human Leukocyte antigens or histocompatibility 2 locus in mice
What did an experiment using two H-2 congenic mouse strains prove?
These mouse strains had been inbred to the point where they differed only in their MHC loci and then infected with LCMV (lymphocyte choriomeningitis virus) and when C8 cytotoxic lymphocytes were isolated it was founsd they could only kill infected cells if they were from the same mouse strain from which they originated
This demonstrated that CD8 cytotoxic cells recognized two key components, both the presented peptide on MHC and the MHC molecule itself
What are the features of the MHC genes?
These are polymorphic, polygenic and codominant
What is the difference between classical and non-classical MHC genes?
The non classical genes (like CD1, HLA-E, HLA-F, HLA-G, HLA-H) are far less polymorphic than the classical genes
What has occurred with the MHC gene throughout evolution?
The polygeny and polymorphisms which have arisen in MHC has resulted in their being many hundreds of different MHC genes within the human population with every person having a minimum of 6 and a maximum of 12 of these genes
Due to the co-dominance of thegenes each one contributes to the histocompatibility of the individual leading to extreme complexity which makes it difficult to recognize tissue for transplantation
What drives the need for MHC molecules to be polymorphic?
These genes have become polygenic and polymorphic to ensure the species as a whole copes with common pathogens, those MHC alleles that protect against a common pathogen will quickly become over represented if they reduce the prevalence of death or loss of fertility
This explains why rare non-migratory African tribes often have rare MHC alleles which have been naturally selected by a particular pathogen within that region
It also explains why native tribes could be decimated by the arrival of Europeans
How MHC molecules are differentially expressed?
MHC class 1 is expressed on all cells except red blood cells and are the most important for tissue rejection as they regulate CD8 cell killing
MHC class 2 are only expressed by antigen presenting cells including B cells, macrophages, dendritic cells and activated human T cells
What are the structural differences between the MHC classes?
Class 1 is made of one chain associated with a soluble serum proteins while class 2 is made of two separate chains which are non-covalentally linked
Additionally the antigen binding cleft of MHC class II is open at both ends while that of MHC class I is closed causing it to have a fixed length of peptides while class II has an unlimited peptide length
What is the structure of MHC class 1?
This molecule consists of two chains highly polymorphic heavy chain with three domains (Alpha 1,2 and 3) which is noncovalentally associated with a serum protein (Beta2 microglobulin) through the invariant alpha-3 domain
This alpha3 domain is also the binding domain for CD8
The antigen binding cleft is formed from 8 beta strands which form an antiparallel beta-pleated sheet floor upon which lies two long alpha helices
This cavity or groove can bind small peptides of 8-10 amino acids long
Every person has at least three MHC class I antigens though most are heterozygous so up to 6 different class 1 molecules are expressed
What is the structure of MHC class II?
This is made from 2 chains, alpha (30kD) and beta (28 kD) which are non-covalentally linked
Each chain has two domains (alpha 1 and 2) and a polymorphic membrane anchor
The alpha 1 domain of each chain contain alpha helices which form the antigen binding groove
What are the separate roles of MHC class I and class II?
MHC class I is involved in immunity against intracellular pathogens as it binds intracellular proteins including viral peptide produced inside the cell, these will be recognized by CD8 T cells which have CTL killer activity
MHC class II molecules regulate our ability to recognize extracellular pathogens and therefore activate T cells that produce cytokines to help B cells produce antibody or drive CTL to expand and kill infected cells
What is the role of the CD4 molecules?
This monomeric protein is expressed on 80% of resting T-lymphocytes it binds the two alpha 2 domains on the MHC class II molecule
T cells expressing CD4 are predominantly helper T cells which secrete cytokines which help activate B cells and cause antibody class switching
This protein hasa tyrosine kinase attached to its intracellular domain that triggers T cell activation through phosphorylation
What is the role of CD8?
This molecule of a heterodimer expressed on about 20% of resting T cells, it binds to the alpha 3 domain of MHC class I these cells express CD8 are cytotoxic T cells they have machinery to kill cells that express the right peptide/MHC class I combination
It also has a tyrosine kinase attached which initiates the activation and killing through phosphorylation of the TcR complex