Histocompatibility antigens

Histocompatibility antigens

Tuesday 09 November 2010 Telegraph UK Livers grown in the laboratory could eventually solve organ transplant shortage. Made-to-measure organs for transplantation are a step closer to reality after scientists grew miniature human livers in the laboratory. Associate Professor Shay Soker from the Wake Forest Institute for Regenerative Medicine in North Carolina. The researchers created "working livers" the size of a walnut which functioned normally in laboratory conditions. They believe that in around five years they will be able to upscale the process and transfer the procedure from laboratory to hospital.

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Peter Gorer and George Snell Mouse strain A bred with Mouse Strain B F1 generation F1 accepts skin graft from either parent Neither parent accepts skin graft from F1 Thus it is a inherited trait.

In humans Donor cells + Mitomycin C Recipient cells If no increase in cell Doubling of Extensive Proliferation Number Cell Number OK to transplant Possibility of Rejection Acute Rejection

Simultaneously skin grafting for burns in humans and inbred mouse strains for skin grafting studies revealed proteins of the surface of cells inherited from parents determined whether a rapid or slow rejection of the graft would occur. In mice termed histocompatibility antigens (H antigens). In humans termed human leukocyte antigens (HLA).

I region genes Region genes

Mouse H 2 Locus Class 1 Antigens at K and D regions Alleles at K and at D on each chromosome are expressed thus 4 different class 1 antigens are expressed in mouse. Thus mouse inherits four different class 1 antigens. There are multiple genes of Class 2 antigens at I region.

Human Leukocyte Antigens (HLA locus)

In the population what is the diversity possible? Number of Different Human MHC you can inherit Class 1 From A B C regions 2 2 2 each >100 >100 >100 Number of possible Alleles On all your nucleated cells. Class 2 6 different regions On 2 chromosomes Thus 12 different ones expressed on each antigen expressing cell. > 100 alleles possible per class 2 gene

H2 vs HLA Notice: class 1 mouse K and D Class 1 human ABC Class 2 mouse I region Class 2 human D

I II

Most individuals are heterozygous at each locus. Lets just look at one MHC I gene (A, or B, or C aspect of the MHC locus) Maternal recombinations can occur.

Number of Different Human MHC you inherit Class 1 From A B C regions 2 2 2 >100 >100 >100 Number of possible Alleles Class 2 6 different regions 2 chromosomes 12 different ones expressed on each Antigen expressing cell. > 100 alleles possible per class 2 gene

Linkage Disequilibrium Some MHC inherited together at a nonrandom frequency rate B27 A3

Where are MHC molecules found? MHC 1 molecules are expressed on the membranes of all nucleated and some nonnucleated cells of the body. Except sperm. MHC 2 molecules are only found on specialized cells known as antigen presenting cells. These are B lymphocytes, macrophages, dendritic cells.

What do MHC molecules do? Only CD4+ T lymphocytes bind MHC 2 molecules; these are T helper cells. Only CD8+ T lymphocytes bind MHC 1 molecules; these are cytotoxic T cells.

The pocket of a MHC 1 molecule can be empty or contain a fragment of antigen.

So how do MHC molecules work? T helper and cytotoxic cells go around the body checking the pockets of the MHC molecules their TCR recognizes. If the pocket is empty they do nothing. If a CD8+ cells finds something in the pocket of a MHC 1 molecule it recognizes, it kills the cell bearing this MHC1. If a CD4+ cells finds something in the pocket of a MHC2 molecule it recognizes, it produces cytokines that can enhance immune functions of that cell and it can trigger the class switch if the cell is a B lymphocyte.

All nucleated cells of the body Only antigen presenting cells