Histocompatibility system genes and longevity
The study of genetic markers of aging and age-related diseases is one of the most relevant areas in gerontology. It is obvious that a person's life success and longevity cannot be determined by a single gene. This would be very unreliable and fatal for both the individual and the species. Systematizing the search for death and longevity genes, Schachter F. and co-author. (1994) proposed the following classification:
1 – homologous genes of humans and other animal species that determine longevity;
2 – genes necessary for maintaining the body's homeostasis - cellular balance and repair;
3 – genes responsible for the development of major diseases associated with aging.
Normal immune response and undisturbed genetic regulation of immunoreactivity are a necessary condition for resistance to diseases and aging. To date, data have been accumulated on the participation of histocompatibility system genes in the regulation of immunoreactivity and their connection with pathology. Based on the above, they can be attributed to the third group according to the above classification.
The histocompatibility gene system is designated as HLA in humans and MHC in mice. The specified genetic system performs genetic control of the interaction of immunocompetent cells of the body, recognition of its own and foreign cells (including modified own cells), the launch and implementation of the immune response. The variety of functions performed by HLA ensures the survival of humans as a species in conditions of exogenous and endogenous aggression and is due to the structural features of the main histocompatibility complex. The main of these features consists in extreme polymorphism: HLA genes are represented in many variants (alleles). This allelic polymorphism is the most important mechanism of variability and natural selection, which allows a person to resist a constantly evolving set of pathogens.
The HLA gene complex is located on the short arm of the 6th chromosome, has a length of about 3,500 kb (one thousand base pairs) and contains more than 220 genes, which are divided into three groups - classes I, II and III.
HLA-I class molecules are present on all human nuclear cells, and they play an important role in the immune response. Firstly, the effector function of cytotoxic T-lymphocytes (CTL) for the destruction of infected cells depends on them: CTL bind to target cells, recognizing the antigen only in combination with HLA-I class. In addition, HLA-I class molecules provide interaction between all nucleated cells of the body.
The HLA-I class molecules belong to glycoproteins and consist of two chains – α and β. The α chain encodes the HLA-A, B or C genes, for which extreme polymorphism has been detected. 22 alleles are known in the HLA-A locus, 42 alleles in HLA-B, and 8 alleles in HLA-C. In recent years, new non–classical types - E, F, G, H, J - have been discovered within Class I of the HLA system, but polymorphism and their biological function have not been established.
HLA-II class molecules are present on immunocompetent cells, including monocytes, macrophages, T- and B-lymphocytes. They ensure the interaction of the antigen-presenting cell with T-helper lymphocytes, contribute to the formation of populations of Th1 and Th2 and thereby direct the development of cellular or humoral links of immunity. HLA-II class molecules are membrane glycoproteins, consist of two chains - α and β, are encoded by the DP, DQ, DR, and DM, DO genes. Polymorphism is also characteristic of these genes. Class III molecules are located between the HLA-I and HLA-II genes.
The result of genetic polymorphism of the HLA system is the formation of molecules that differ in structural and functional characteristics. A strictly individual set of HLA antigens of each individual determines the functioning of many organs and systems. The most important of them are the genetic control of the immune response and the maintenance of immune homeostasis, which determines the health and longevity of a person. Their violation is the basis of many pathological conditions.
The relationship of the main histocompatibility complex with sensitivity to viral infections, tumors and autoimmune diseases was revealed. According to the degree of correlation between the antigenic structure of HLA and the risk of developing the disease, the following groups are distinguished: 1) - arthropathies associated with HLA-B27 (ankylosing spondylitis, reactive arthritis and acute anterior uveitis); 2) - immunopathies associated with HLA-B8 and DR3 (juvenile diabetes, myasthenia gravis, celiac disease, hypertiform dermatitis, addison's disease, thyrotoxicosis); 3) - diseases associated with the phenotype of HLA-B7, DR2 (multiple sclerosis, insufficiency of the C4 component of the complement). Studies have shown that in different age groups, the set of histocompatibility antigens differs mainly due to rarely occurring antigens, and such antigens that are associated with a predisposition to pyogenic infection (HLA-A9) were less common in older age groups, and antigens associated with autoimmune diseases (HLA-B8), in this age group, they were detected much more often. A number of studies have shown that antigens A9, A10, B5, B8, B16 were significantly more common in the group of centenarians.