Week one: MHC molecules aka HLA - which may have a role in ME/CFS
MHC molecules are a good example of confusing immunology jargon and acronyms. They play a critical role in detecting pathogens and keeping us healthy, but the name "Major Histocompatibility Complex", MHC, doesn't give any clues. Histocompatibility refers to tissue matching, which is critical if you need an organ transplant. If the donor's MHC genes don't match yours then your body will reject the transplant, which is crucial. Yet the main role of MHC is nothing to do with transplants.
Oh, and MHC is mostly used for mice and other animals, the same genes/proteins in humans are called HLA, short for "Human Leucocyte Antigen" (don't ask).
MHC/HLA in ME/CFS and disease
Ron Davis at Stanford believes that they type
of HLA genes you have may influence the risk of getting ME/CFS, and certainly HLA gene variants have been linked to numerous diseases. One particular version of an HLA gene increases the risk of narcolepsy by 130 times. A version of
another HLA gene conveys some protection against HIV developing into AIDS - though the same gene variant increases the risk of the autoimmune disease Ankylosing spondylitis. In fact, HLA genes are linked to a number of autoimmune diseases.
MHC molecules help activate T-cells
T cells are an important part of the immune system. Our lecturer refers to T
helper cells as 'generals' of the immune system, co-ordinating the immune system response. T helper cells play a critical role in firing up antibody-producing B-cells, for instance.
Cytotoxic T cells are more like infantry acting independently and killing off rogue cells such as those infected with virus.
But T cells need to be activated first before they get going, and they are activated in part by antigens, which are helpfully defined as anything that the immune system recognises as foreign!), but we are talking here mostly about peptides, short pieces of protein. And antigens are what MHC molecules are about: they sit on the cell surface and hold out antigen morsels to the T cells. If the T-cell 'recognises' the antigen - in much the same way as an antibody recognises a specific antigen - then that will trigger activation of the T cell. In the case of cytotoxic T cells, that's curtain for the cell doing the presenting – the cell has just signed its own death warrant, but that’s the whole idea. Since cytotoxic T cells generally only recognise foreign antigen, and if the cell is displaying this it’s because it’s been infected, usually by a virus. By taking out the infected cell the cytotoxic cells are helping to contain an infection and protect other, healthy, cells.
’Don't kill me’: MHC I and Cytotoxic T cells
Almost every cell in the body displays MHC I molecules, the imaginative name for the first of two types of MHC molecule. (Red blood cells and sperm don't display MHC I, but just about everything else does). The MHC I acts as a kind of Identity card, the way a cell proves that it is healthy and should be left in peace by marauding cytotoxic T cells that will kill any cell that doesn't pass muster. You could see cytotoxic T cells as an internal security force that's licensed to kill.
The whole system is pretty elegant and very hard to cheat as the MHC I molecules pick up bits of whatever proteins the cell is producing. So if the cell is infected eg by a virus it will be manufacturing lots of viral proteins, and bits of these foreign proteins end up displayed on the MHC I molecules. That's curtains for the infected cell: once a cytotoxic T cell recognises that viral antigen it sends a signal to the infected cell to self-destruct.
Some viruses try to evade this detection system by reducing the amount of MHC I molecules that get displayed on the cell surface. We have evolved a counter-measure to this: Natural Killer cells will kill cells that aren't showing enough MHC I molecules, just to be on the safe side.
So that's MHC I: cell-surface molecules that act as Identity cards by displaying to cytotoxic T cells bits of whatever proteins the cell is making. It's a way for healthy cells to show to lethal cytotoxic T-cells that they are 'clean', while infected cells mark themselves for destruction. Cytotoxic T cells can also detect other types of damaged cells, including those that have become cancerous.
MHC II: displaying enemy heads on pikes
MHC II also display antigens, but while MHC I is on all cells, MHC II is used by the 'professionals'. That's professional immune system 'antigen presenting cells', such as macrophages, dendritic cells and B-cells. Their role is to pick up foreign antigen and present it to T helper cells to kick start the adaptive immune response. (Adaptive immune responses are very specific eg antibodies that recognise a particular viral protein, as opposed to ‘innate’ responses that recognises classes of pathogens eg recognising viral RNA, or bacterial cells walls.
T helper cells don't act directly against an infection, but regulate other immune cells, especially the cytotoxic T cells we've just discussed and antibody-producing B-cells.
The big difference between MHC II and MHC I is that MHC II presents foreign antigen, picked up from outside the cell, whereas MHC I presents self-antigen from inside a cell.
Think of MHC II molecules as pikes used to display the heads of enemy pathogens to T helper cells. T cells can't recognise antigens on their own, but can when they are processed right and displayed on MHC molecules. Fussy, you could say.
Bonus info! T helper cells, CD4 and HIV
T helper cells carry the CD4 cell surface marker, which helps the cells lock on to MHC II molecules. You may have heard about CD4 counts as a way of measuring the status of HIV patients. Unfortunately HIV infects and kills T helper cells, reducing the ability of the body to target HIV itself. As (or if) the disease develops, the number of T helper cells falls, which is measured by the CD4 count in blood: a lower CD4 count means fewer T helper cells and is a sign the disease is progressing towards Aids.
MHC molecules and organ transplant
Having just said that T cells can’t recognise antigen on there is one unfortunate exception: some T cells will recognise foreign MHC molecules, though it’s not really clear why they do this. The result is that your body will ‘reject’ organs donated from someone else as cytotoxic T cells and T helper cells will attack the foreign tissue. However, if the donor has the same MHC molecules as you, the T cells won’t see any difference and the transplant should be accepted. There are hundreds (at least) of different types of MHC molecules so most unrelated people won’t be a match. However there is a one in four chance that your brothers and sisters will be a match, which is why searching for a donor usually starts with siblings (though even a sibling is unlikely to donate a heart….).