Pathogenesis of lymphohistiocytosis

The hereditary nature of primary hemophagocytic lymphohistiocytosis was postulated already in early studies. The high frequency of consanguineous marriages in families with hemophagocytic lymphohistiocytosis, multiple cases of the disease in one generation with healthy parents, indicated an autosomal recessive nature of inheritance, but only with the development of modern methods of genetic analysis was it possible to partially decipher the genesis of familial hemophagocytic lymphohistiocytosis (FHLH).

The first attempts to localize the genetic defect were made in the early 1990s based on linkage analysis of polymorphic markers associated with genes involved in the regulation of T-lymphocyte and macrophage activation. The data from these studies allowed excluding such genes as CTLA-4, interleukin (IL)-10, and CD80/86 from the list of candidates. In 1999, linkage analysis of hundreds of polymorphic markers in more than twenty families with familial hemophagocytic lymphohistiocytosis identified two significant loci: 9q21.3-22 and 10qHl-22. Locus 9q21.3-22 was mapped in four Pakistani families, but no involvement of this locus was detected in patients of other ethnicities, indicating a possible “founder effect”; candidate genes located in this region have not been identified to date. According to indirect estimates, the frequency of 9q21.3-22-associated hemophagocytic lymphohistiocytosis is no more than 10% of all patients. Locus 10q21-22 was identified during the analysis of 17 families of different ethnicity. During the initial analysis, none of the genes located in this region seemed to be an obvious candidate for the leading role in the development of hemophagocytic lymphohistiocytosis, however, direct analysis of the perforin gene sequence, located in the 10q21 region, in patients with 10q21-22-associated familial hemophagocytic lymphohistiocytosis revealed nonsense and missense mutations in the second and third exons of this gene. The pathogenetic role of perforin mutations was confirmed by the absence of protein expression in cytotoxic cells of patients with PRF1-HLH and a sharp decrease in their cytotoxic activity. About 20 different perforin mutations have been identified, most of which are associated with the classical phenotype of hemophagocytic lymphohistiocytosis, but there are reports of the development of PRFl-HLH at the age of 22 and 25 years, which indicates a wide spectrum of clinical manifestations of this genetic defect. The importance of isolating this mutation is associated with the possibility of excluding the disease in a potential related donor for allogeneic bone marrow transplantation (such tragic cases have been described), as well as with the possibility of prenatal diagnosis. According to various estimates, the frequency of perforin mutations among patients with hemophagocytic lymphohistiocytosis is about 30%. In 2003, in addition to mutations in the perforin 1 (PRF1) genes, which cause a variant of hemophagocytic lymphohistiocytosis called FHL2. Feldmann J. et al. Mutations in the Мunc13-4 (UNC13D) gene were described in 10 patients with perforin-positive FHL. It turned out that the 17q25 locus contains the Muncl3-4 protein, a member of the Мunc13 protein family, 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, quite recently, in addition to these mutations,associated with two variants of familial hemophagocytic lymphohistiocytosis - FHL2 and FHL3, zur Stadt et al. described another one, responsible for yet another variant of the disease - FHL4. The fact is that during the analysis of homozygotes in a large closely related Kurdish family, five children with hemophagocytic lymphohistiocytosis were identified. The involved locus was 6q24, which was defined as a "new FHL locus". During the screening of candidate genes, the scientists identified a homozygous deletion of 5bp in the syntaxin 11 gene (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 deletion of 5bp. In addition to this family, homozygous STX11 mutations were found in five other closely related Turkish-Kurdish families. Based on the fact that mutations in the Мunc13-4 and STX11 genes have been identified in some patients with hemophagocytic lymphohistiocytosis in recent years, the authors suggest that disturbances in endo- and giocytosis, in which the corresponding proteins are involved, are key in the pathogenesis of FHL3 and FHU.

Thus, given the diversity of genes and mutations involved in the pathogenesis of primary hemophagocytic lymphohistiocytosis, it should be considered as a genetically heterogeneous disease in which a defect in various genes, some of which have been identified, can lead to the formation of a similar clinical phenotype. The most heterogeneous clinical manifestations of FHL2, since they depend on the nature of perforin gene mutations. More homogeneous are FHL3, which are a consequence of hМunc13-4 gene mutations, and FHL4, which is a consequence of syntaxin-11 deficiency. Perhaps, deciphering the molecular mechanisms of primary hemophagocytic lymphohistiocytosis development will help to understand the role of hereditary factors in the development of secondary hemophagocytic syndromes. In this regard, in our opinion, primary, in particular, familial hemophagocytic lymphohistiocytosis should be considered as a prototype of lymphohistiocytic diseases.

The central element of the pathogenesis of hemophagocytic lymphohistiocytosis is the disruption of the control of activation and proliferation of T-lymphocytes and tissue macrophages. The physiological development of the immune response to infection, which in most cases "triggers" the development of clinically manifest hemophagocytic lymphohistiocytosis, limits the activation of immunocompetent cells as the infectious agent is effectively eradicated. The molecular mechanisms of negative regulation of the immune response are only partially understood and include processes such as activation-induced death of effector cells, clonal anergy, and 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 hyperproduction of a number of cytokines, primarily Th1 cytokines: INF-y, IL-2, IL-12, TNF-alpha and, indirectly, to activation of macrophage monocytes and production of proinflammatory cytokines IL1a, IL-6, TNF-alpha. Lymphohistiocytic infiltration of organs and the systemic effect of hypercytokinemia lead to organ damage and characteristic clinical manifestations of hemophagocytic lymphohistiocytosis. Hypercytokinemia explains such manifestations of hemophagocytic lymphohistiocytosis as fever, hypofibrinogenemia, hypertriglyceridemia (inhibition of lipoprotein lipase), hyperferritinemia, edema syndrome, hemophagocytosis. Hypocellularity of the bone marrow to a certain extent is probably also associated with the action of cytokines.

Inability of NK cells to perform cytotoxic effector functions is a universal phenomenon in primary hemophagocytic lymphohistiocytosis and is associated in some patients with a mutation in the perforin gene, the main component of cytotoxic granules of T and NK cells. In secondary hemophagocytic syndromes, decreased NK cell function may also be detected, but this defect is not detected in all patients and is almost never complete.

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

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