Hemophagocytic lymphohistiocytosis: pathogenesis and treatment

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is not an independent disease but rather a life-threatening clinical syndrome that occurs in many underlying conditions and in all age groups. HLH is the consequence of a severe, uncontrolled hyperinflammatory reaction that in most cases is triggered by an infectious agent. Persistent stimulation of lymphocytes and histiocytes results in hypercytokinemia, leading to the characteristic symptoms of HLH. Genetic defects in familial HLH and in immunodeficiency syndromes associated with albinism affect the transport, processing, and function of cytotoxic granules in natural killer cells and cytotoxic T lymphocytes. This leads to defective killing of target cells and a failure to contract the immune response. The defects are increasingly found also in adolescents and adults. Acquired HLH occurs in autoinflammatory and autoimmune diseases (macrophage activation syndrome) and in patients with iatrogenic immunosuppression or with malignancies, but also in otherwise healthy persons with infections. Treatment of HLH aims at suppressing hypercytokinemia and eliminating the activated and infected cells. In genetic HLH, hematopoietic stem cell transplantation (HSCT) is needed for the correction of the immune defect. Treatment modalities include immunosuppressive, immunomodulatory, and cytostatic drugs; T-cell antibodies; and anticytokine agents. Using immunochemotherapy, familial HLH, which had been invariably fatal, has become a curable disease with more than 50% survivors. Reduced intensity conditioning for HSCT, which is associated with less transplantation-related mortality, will further improve cure rates.

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

“…1,2 This prompted us to measure sCD25 levels in our model. Importantly, we observed extremely high sCD25 levels in Prf1 2/2 mice sera compared with wild-type mice on day 10 after infection (Fig 6, A).…”

“…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.…”

“…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. 1,2 Despite progress in our understanding of HLH pathogenesis, treatment of HLH has remained unsatisfactory. In addition to treating the trigger event, current treatments for HLH are based on highly immunosuppressive drugs and chemotherapy, whereas allogeneic hematopoietic stem cell transplantation can be considered in patients with FHL and severe forms of HLH.…”

Multicenter study of combination DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis

“…22 Allogenic hematopoietic stem cell transplantation after response induction is a key method for improving survival for primary HLH with genetic defects. However, the primary disease in patients with acquired HLH significantly affects their survival.…”