Advances in understanding the pathogenesis of HLH

Abstract

Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder resulting from immune dysfunction reflecting either primary immune deficiency or acquired failure of normal immune homeostasis. Familial HLH includes autosomal recessive and X-linked disorders characterized by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines, secondary to defects in genes encoding proteins involved in granule-dependent cytolytic pathways. In older children and adults, HLH is associated more often with infections, malignancies, autoimmune diseases, and acquired immune deficiencies. HLH, macrophage activation syndrome, sepsis, and systemic inflammatory response syndrome are different clinical entities that probably represent a common immunopathological state, termed cytokine storm. These conditions may be clinically indistinguishable; all include massive inflammatory response, elevated serum cytokine levels, multi-organ involvement, haemophagocytic macrophages, and often death. Tissues of haematopoietic and lymphoid function are directly involved; other organs are secondarily damaged by circulating cytokines and chemokines. Haemophagocytic disorders are now increasingly diagnosed in the context of severe inflammatory reactions to viruses, malignancies and systemic connective tissue diseases. Many of these cases may reflect underlying genetic predispositions to HLH. The detection of gene defects has contributed considerably to our understanding of HLH, but the mechanisms leading to acquired HLH have yet to be fully determined

Down-regulation of CD5 expression on activated CD8+ T cells in familial hemophagocytic lymphohistiocytosis with perforin gene mutations

“…HLH is a heterogeneous group of diseases that are characterized by uncontrolled proliferation of activated macrophages and T cells with overproduction of proinflammatory cytokines [1,2]. Activated CD8 + T cells are frequently observed during the acute phase of HLH.…”

“…Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal disease that is characterized by marked systemic inflammation and unregulated activation of macrophages and T cells [1,2]. Patients with HLH may present with fever, cytopenia, hepatosplenomegaly, liver dysfunction, coagulation abnormalities, and hemophagocytosis [1,2].…”

“…Patients with HLH may present with fever, cytopenia, hepatosplenomegaly, liver dysfunction, coagulation abnormalities, and hemophagocytosis [1,2]. HLH is comprised of primary and secondary forms.…”

IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis

“…1,2 The principal immunologic features of this syndrome are uncontrolled expansion of CD8 1 cytotoxic T cells, activation of antigen-presenting cells/macrophages (histiocytes), natural killer cell dysfunction, and florid cytokine storm, including high amounts of IFN-g and TNF-a. Clinical manifestations are a consequence of hypercytokinemia and infiltration by activated lymphocytes and histiocytes of the bone marrow, spleen, liver, and central nervous system.…”

“…Clinical manifestations are a consequence of hypercytokinemia and infiltration by activated lymphocytes and histiocytes of the bone marrow, spleen, liver, and central nervous system. 1,2 Familial hemophagocytic lymphohistiocytosis (FHL) is caused by genetic deficiency in the cytotoxic pathways of T and natural killer cells, with mutations in the genes encoding perforin (Prf1) or the perforin secretion components Munc13-4, Munc18-2, or Syntaxin 11 accounting for most cases. 2 A secondary form of acquired HLH can also arise after a broad variety of initiators, including infections, malignancies, or autoimmune diseases, with a specific condition called macrophage activation syndrome (MAS) mainly diagnosed in patients with systemic juvenile idiopathic arthritis.…”