Inherited Hemophagocytic Lymphohistiocytosis (HLH)

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal immune disorder characterized by uncontrolled lymphocyte- and macrophage-activation. The resulting hypercytokinemia and cell infiltration of organs lead to the clinical and laboratory features of HLH. Viral infections and other triggers can induce both, inherited and acquired forms of HLH. Disease-causing mutations in the genes encoding perforin (PRF1, FHL2), munc13-4 (UNC13D, FHL3), syntaxin 11 (STX11, FHL4), and munc18-2 (UNC18-2/STXBP2, FHL5) have been previously identified in Familial Hemophagocyic Lymphohistiocytosis (FHL), whereas mutation in RAB27A and LYST account for Griscelli syndome type 2 and Chediak-Higashi syndrome, respectively. These genes all encode proteins which are involved in the cytotoxic activity of lymphocytes. The inability of activated cytotoxic cells to clear antigen-presenting targets results in sustained immune stimulation, likely accounting for the unremitting polyclonal CD8 T-cell activation and hyperimmune reaction which characterizes FHL. Treatment of HLH consists of elimination of the trigger and immunosuppressive treatment in order to induce remission from the uncontrolled inflammation. Allogeneic hematopoietic stem cell transplantation can be indicated in the inherited forms of HLH.

Zusammenfassung

Die hämophagozytische Lymphohistiozytose (HLH) ist eine potenziell fatale Entzündungsreaktion, die durch eine übermäßige Aktivierung und Vermehrung von Lymphozyten und Makrophagen charakterisiert ist. Virale Infekte und andere Trigger vermögen sowohl angeborene als auch erworbene Formen der HLH auszulösen. Mutationen in den Genen, welche für Perforin (PRF1, FHL2), Munc13-4 (UNC13D, FHL3), Syntaxin 11 (STX11, FHL4) und Munc18-2 (UNC18-2/STXBP2, FHL5) kodieren, werden für die familiäre hämophagozytische Lymphohistiozytose (FHL) verantwortlich gemacht, Mutationen in RAB27A für das Griscelli-Syndrom und Mutationen in LYST für das Chediak-Higashi-Syndrom. Alle diese Gene kodieren für Proteine, welche für die Zytotoxizität von Lymphozyten wichtig sind. Die Unfähigkeit der zytotoxischen Lymphozyten, antigenpräsentierende Zellen zu eliminieren, führt wahrscheinlich dazu, dass die Zytokinausschüttung länger und intensiver unterhalten wird. Die Behandlung der HLH besteht einerseits in der Beseitigung des Auslösers, anderseits in der Eindämmung der überschießenden Immunreaktion mittels immunsuppressiver Medikamente. Bei angeborenen Formen der HLH kann eine Knochenmarktransplantation indiziert sein.

Key words

hemophagocytic lymphohistiozytosis HLH - macrophage activation - immunodeficiency - hemophagocytosis - fever - genetic diseases

Schlüsselwörter

hämophagozytische Lymphohistiozytose HLH - Makrophagenaktivierung - Immundefekt - Hämophagozytose - Fieber - genetische Krankheit

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