Immunologists attempt to achieve an understanding of how our body responds when under attack by antigens. The following is an explanation of the importance of T-cells in the immune response system. T-cells are part of our adaptive immunity to foreign pathogens.
Two children of the Islayev family were found to have a flaw in their MHC. Tatiana and Alexander often suffered from chronic respiratory infections despite immunizations as infants. Analysis of their blood found low levels of CD8 T-cells, but normal levels of IgG, B-cells, and other lymphocytes which showed normal humoral immunity. Their parents and siblings were found to have normal levels of CD8 T-cells and immunity.
The difference in CD8 T-cells expressed in Tatiana and Alexander from the rest of their family was directly related to their inability to respond to respiratory infections. CD8 T-cells recognize MHC class I molecules which present endogenous antigen. The antigen is cut into peptides by proteosome and transported into the endoplasmic reticulum (ER) by TAP where it binds to the peptide binding groove. The MHC molecule is assembled in the ER by chaperone proteins and leaves in a vesicle to present itself on the cell membrane. When a CD8 T-cell binds to it, an immune response is made. The cytotoxic T-cell recognizes the viral antigen presented and kills the infected cell.
A second class of MHC molecules is MHC class II, which present exogenous antigen. MHC class II molecule is synthesized in the ER with an invariant chain on binding groove and travels by vesicle into the cytoplasm. The invariant chain cleaves and leaves a CLIP fragment on the groove. Antigen enters the cell and antigenic peptides bind to the groove displacing CLIP fragment. MHC molecule expresses the peptide at cell surface to CD4 T-cells. CD4 TH1 cells activate macrophages. CD4 TH2 cells activate B-cells to become plasma cells and release antibodies.
In Tatiana’s and Alexander’s immune system, their MHC class II molecules were functioning properly but their MHC class I molecules weren’t. A mutation in TAP would prevent MHC class I molecules from fully maturing, therefore unable to present endogenous antigen to CD8 T-cells. Because Tatiana and Alexander inherited homozygous haplotypes from their parents, they have mutated TAP. The homozygous genes lower the number and type of peptide antigens presented because of the absence of MHC class I molecules on cell surface. With minimal MHC class I activity, they're still able to have normal humoral immunity because their bodies produced normal levels of B-cells, T-cells and lymphocytes which recognize MHC class II molecules.
2 comments:
What is the rarity of someone having a mutated TAP and does that play into larger diseases such as cancer or newer diseases such as fibromyalgia?
TAP mutations definitely have a large role in cancers. Cancer patients have abnormal or absent TAP, allowing the cancer cells to go unnoticed.
I think TAP mutations occur quite often, they're even suspected to be associated with insulin-dependent diabetes mellitus.
Fibromyaglia (FM) isn't really directly related to TAP mutations, at least not that I know of. TAP is mainly used to help express antigenic peptides. Fibromyaglia is usually pain of joints, bones, skin, when under constant stress. Exact cause is still unknown, but one of the characteristics of FM are low amounts of neurotransmitters and hormones in the blood (which is why a person with FM would feel a lot of pain, depression, anxiety because the hormones needed aren't there).
Please note that I was writing about transporter associated proteins that process antigen, not neurotransmitters or carbohydrates, etc.
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