A new histocompatibility protein
Hidden mutations in patients' DNA prevented kidney transplantation
Up to 15% of patients of European and African origin may face this
Polina Loseva, "The Attic"
The main criterion in the selection of donors for organ transplantation (except for health, of course) is genetic compatibility. In order for the immune system not to mistake the new organ for an enemy, the donor and the recipient must have at least several proteins of the main complex of tissue compatibility in common. However, even with a perfect match of proteins, an immune response often develops, which can lead to rejection. An international group of doctors has found a new compatibility protein – LIMS1. It turned out that many donors, due to an inconspicuous mutation, practically do not have it. And if you transplant them a kidney whose cells are covered with LIMS1, rejection develops 60% more often than if this conflict did not exist.
The main problem that occurs during organ transplants is immune aggression, or the "host versus transplant" reaction. All people, except identical twins, differ in the structure of some proteins, and the patient's immune system can mistake a new organ for foreign cells, like tumor cells. In such a situation, inflammation develops in the organ, and then the recipient's body rejects it and the organ dies.
The easiest way to avoid this is to check the donor and recipient for compatibility. There are six proteins in the human body that belong to the major histocompatibility complex (MHC, major histocompatibility complex). The more of them match the donor and recipient of the organ, the less risk that rejection will occur.
Nevertheless, doctors have long noticed that the organ may not take root even with full compatibility in MHC proteins, as happens with brothers or sisters. Today, it is believed that about 56% of organ rejections occur for immunological reasons, of which 36% are not related to MNS.
Therefore, there was an idea of minor compatibility antigens – molecules that affect the survival of an organ not as much as MHC, but can play a role, for example, if the recipient's immunity is extremely sensitive. One of these antigens may be proteins encoded by the Y chromosome: when transplanting organs from men to women, the risk of rejection is higher than between people of the same sex. Doctors have found other minor antigens, but the reaction to them is quite rare.
In a recent paper, an international group of physicians reported on a new minor antigen, the LIMS1 protein. The authors of the article in the New England Journal of Medicine (Steers et al., Genomic Mismatch at LIMS1 Locus and Kidney Allograft Rejection) the genomes of 705 donor–recipient pairs were analyzed and the risk of rejection was calculated depending on the mismatch of certain genes. It turned out that if the variants of the LIMS1 gene in a couple do not match, then the risk increases by 60% – about the same as if they differed in three MHC proteins out of six.
The fact is that many people have a deletion in the LIMS1 gene, that is, part of the gene is simply missing. This leads to the fact that cells almost do not produce the LIMS1 protein, and, consequently, immune cells do not consider it "their own". When someone else's kidney enters the body, the cells of which are covered with this protein, the immune system begins to attack.
At the same time, a mutation in the LIMS1 gene does not significantly affect the life of cells, even if it affected both copies of the gene and there is actually no such protein in the human body. Therefore, many people may not be aware of their mutation until they need a donor kidney and complications arise after surgery.
According to the authors of the study, a genetic conflict – a donor without a mutation and a recipient with a mutation – can occur in 12-15% of cases of kidney transplantation between unrelated people of European and African descent, but not East Asian – this mutation does not occur there.
The LIMS1 protein can also be found on cells of other frequently transplanted organs, such as the heart and lung. Probably, even in these cases, it may be associated with the risk of transplant rejection. In addition, other genes are known in which mutations are often "hidden": DNA analysis showed that 7.7% of Icelanders have genetic defects that deprive the cell of a certain protein, although they may not appear outwardly. Therefore, the search for minor histocompatibility antigens is unlikely to stop in the near future.
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