Pathogenesis of lymphogystyocytosis

The hereditary nature of primary hemophagocytic lymphogystyocytosis was postulated already in early studies. The high frequency of related marriages in families with hemophagocytic lymphohistiocytosis, multiple bumps of waterborne disease in healthy parents, also indicated the autosomal recessive nature of inheritance, but only with the development of modern methods of genetic analysis has it been possible to partially decipher the genesis of familial hemophagocytic lymphogystyocytosis (SWHRH).

The first attempts to localize the genetic defect were undertaken in the early 90's on the basis of an analysis of the linkage of polymorphic markers associated with genes involved in the regulation of T-lymphocyte and macrophage activation. Data from these studies made it possible to exclude from the list of candidates such genes as STLA-4, interleukin (IL) -10, CD80 / 86. In 1999, as a result of the analysis of the cohesion of hundreds of polymorphic markers in more than twenty families with familial hemophagocytic lymphogystyocytosis, two significant loci were identified: 9q21.3-22 and 10qHl-22. Locus 9q21.3-22 was mapped in the analysis of four Pakistani families, however, in the study of patients of another ethnicity, the involvement of this locus was not recorded, indicating a possible "founder effect"; candidate genes located in this area have not been identified to date. By indirect estimates, the frequency of 9q21.3-22-associated hemophagocytic lymphohistiocytosis is no more than 10% of all patients, Locus 10q21-22 was identified by the analysis of 17 families of different ethnicity. At the initial analysis, none of the genes located in this region seemed to be a clear candidate for the leading role in the development of hemophagocytic lymphogeocytosis, however, a direct analysis of the sequence of the perforin gene located in the 10q21 region in patients with 10q21-22-associated familial hemophagocytic lymphogystyocytosis revealed nonsense and missense mutations in the second and third exons of the gene. The pathogenetic role of perforin mutations was confirmed by the lack of protein expression in the cytotoxic cells of patients with PRF1-HLH and a sharp decrease in their cytotoxic activity. Approximately 20 different mutations of perforin have been identified, most of which are associated with the classical phenotype of hemophagocytic lymphogystyocytosis, but there are reports of the development of PRFl-HLH at the age of 22 and 25, indicating a wide range of clinical manifestations of this genetic defect. The importance of isolating this mutation is related to the possibility of eliminating the disease in a potential related donor for allogeneic bone marrow transplantation (similar tragic cases have been described), as well as the possibility of prenatal diagnosis. According to various estimates, the frequency of perforin mutations among patients with hemophagocytic lymphogeocytosis is about 30%. In 2003, in addition to mutations in the genes of perforin 1 (PRF1), which determine the variant of hemophagocytic lymphohistiocytosis, called FHL2. Feldmann J. Et al. Mutations in the gene Munc13-4 (UNC13D), in 10 patients with perforin-lytic FHL, were described. It turned out that locus 17q25 contains the protein Muncl3-4, which is a member of the family of proteins Munc13, and its deficiency leads to a violation of exocytosis at the level of cytolytic granules. Hemophagocytic lymphohistiocytosis, which is a consequence of this mutation, was called FHL3. Finally, more recently, in addition to these mutations associated with two variants of familial hemophagocytic lymphohystiocytosis - FHL2 and FHL3, zur Stadt et al. Described another, responsible for the next variant of the disease - FHL4. The fact is that in the analysis of homozygotes in a large closely related Kurdish family, five children with hemophagocytic lymphogystyocytosis were identified. The involved locus was 6q24, which was defined as the "new FHL locus". In screening candidate genes, scientists identified a homozygous 5bp deletion in the syntaxin 11 gene (syntaxin 11) (STX11), and they were able to show that the syntaxin 11 protein was absent in the cells of the mononuclear fraction of patients with a homozygous 5bp deletion. In addition to this family, homozygous mutations of STX11 were found in five other closely related Turkish-Kurdish families. Based on the fact that in recent years, in some patients with hemophagocytic lymphogystiocytosis mutations in the genes Munc13-4 and STX11 have been revealed, the authors believe that endo- and jococytosis disorders in which the corresponding proteins are involved are key in the pathogenesis of FHL3 and FHU.

Thus, given the variety of involved genes and mutations in the pathogenesis of primary hemophagocytic lymphohistiocytosis, it should be considered as a genetically heterogeneous disease in which the defect of various genes, some of which are identified, can lead to the formation of a similar clinical phenotype. The clinical manifestations of FHL2 are most heterogeneous, since they depend on the nature of the mutations of the perforin gene. More homogeneous are FHL3, which are a consequence of the mutations of the gene hMunc13-4, and FHL4, which is a consequence of a deficiency of syntax-11. Perhaps the interpretation of the molecular mechanisms of the development of primary hemophagocytic lymphogystyocytosis will help to understand the role of hereditary factors in the development of secondary hemophagocytic syndromes. In this regard, in our opinion, the primary, in particular, family hemophagocytic lymphogystyocytosis should be considered as a prototype of lymphohistiocytic diseases.

The central element of the pathogenesis of hemophagocytic lymphogystyocytosis is a violation of the control of activation and proliferation of T-lymphocytes and tissue macrophages. Physiological development of the immune response to infection, which in most cases "triggers" the development of clinically manifested hemophagocytic lymphogystyocytosis, limits the activation of immunocompetent cells as the eradication of the infectious agent is effective. Molecular mechanisms of negative regulation of the immune response have only been partially studied and include such processes as activation-induced death of effector cells, clonal anergy, production of immunosuppressive mediators. Studies of patients with primary hemophagocytic lymphohistiocytosis indicate an important role of cellular cytotoxicity in the negative regulation of the immune response. Uncontrolled activation of T-lymphocytes leads to the hyperproduction of a number of cytokines, primarily Th1 cytokines: INF-y, IL-2, IL-12, TNF-alpha and, mediated, to the activation of macrophage monocytes and production of pro-inflammatory cytokines IL1a, IL-b , TNF-alpha. Lymphogistiocytic organ infiltration and systemic effect of hypercytokinemia lead to organ damage and characteristic clinical manifestations of hemophagocytic lymphogystyocytosis. Hypercytokinemia explains such manifestations of hemophagocytic lymphogystyocytosis as fever, hypofibrinogenemia, hypertriglyceridemia (inhibition of lipoprotein lipase), hyperfertinemia, edematous syndrome, and hemophagocytosis. The hypocellularity of the bone marrow to a certain extent is probably also related to the action of cytokines.

Inability of NK cells. The presence of cytotoxic cytotoxic functions is a universal phenomenon in primary hemophagocytic lymphohystiocytosis and is associated with a mutation in the perforin gene, the main component of cytotoxic T- and NK-cell granules, in some patients. With secondary hemophagocytic syndromes, a decrease in the function of NK cells can also be detected, but this defect is not detected in all patients, and almost never is complete.

Hyperactivation of T-lymphocytes is an obligate finding in primary hemophagocytic lymphogystyocytosis. Activation markers are an increase in the content of activated (CD25 + HLA-DR + CD69 +) T lymphocytes in peripheral blood, a high level of soluble receptor for IL-2 and a number of cytokines in serum.

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