Hemophagocytic Lymphohistiocytosis: When the Immune System Runs Amok

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome in which an exaggerated but ineffective immune response leads to severe hyperinflammation. Key players in HLH are activated lymphocytes and histiocytes which infiltrate all organs and secrete large amounts of cytokines. Cardinal symptoms are prolonged fever, hepatosplenomegaly, cytopenias, and hemophagocytosis. Biochemical markers include elevated ferritin, triglycerides, and low fibrinogen. HLH occurs on the basis of various inherited and acquired immune defects. Impaired function of natural killer cells and cytotoxic T cells is shared by all forms of HLH. Nearly all genetic defects identified in inherited cases of HLH are either mutations in the perforin gene or in genes important for the exocytosis of cytotoxic granules. Cytotoxic granules contain perforin and granzymes which induce apoptosis upon entering the target cell. Additionally perforin is important for the down-regulation of the immune response. Acquired forms of HLH are found in association with infectious agents, in patients with autoimmune diseases, in malignant diseases, and in patients receiving immune suppression or after organ transplantation. – HLH is still difficult to diagnose and may be overlooked since initially it may masquerade as a normal infection. HLH should be considered when symptoms are more pronounced than usual and in case of progression. Suppression of the severe hyperinflammation can be achieved with immunosuppressive and immunomodulatory agents and cytostatic drugs. Patients with genetic HLH have to undergo stem cell transplantation for cure.

Zusammenfassung

Die hämophagozytische Lymphohistiozytose (HLH) ist ein lebensbedrohliches Syndrom, bei dem eine enorm gesteigerte, aber ineffektive Immunantwort zu einer schweren Hyperinflammation führt. Aktivierte Histiozyten und Lymphozyten infiltrieren alle Organe und setzten große Mengen an Zytokinen frei. Kardinalsymptome sind Fieber, Hepatosplenomegalie, Zytopenien und Hämophagozytose. Laborparameter sind unter anderem erhöhtes Ferritin, Triglyzeride und erniedrigtes Fibrinogen. Die HLH entsteht auf dem Boden verschiedener angeborener oder erworbener Immundefekte. Eine verminderte Funktion der natürlichen Killer Zellen und zytotoxischen T-Zellen ist beiden Formen gemeinsam. Nahezu alle Gendefekte, die bei angeborenen Formen der HLH gefunden wurden, sind entweder Mutationen im Perforin-Gen oder in Genen, die für die Exozytose der zytotoxischen Granula wichtig sind. Diese enthalten Perforin und Granzymes, die beim Eindringen in die Zielzelle zur Apoptose führen. Zusätzlich spielt Perforin eine wichtige Rolle bei der Abschaltung der Immunantwort. Erworbene Formen der HLH werden in Zusammenhang mit infektiösen Erregern gefunden, bei Patienten mit Autoimmunerkrankungen, bei malignen Erkrankungen und bei Patienten unter Immunsuppression oder nach Organtransplantation. – Die HLH ist immer noch schwierig zu diagnostizieren. Sie kann übersehen werden, da die initialen Symptome zunächst eine normale Infektion nahe legen. Sind die Symptome ausgeprägter als üblich oder sind sie progressiv, sollte an eine HLH gedacht werden. Die Unterdrückung der schweren Hyperinflammation kann mit immunsuppressiven und immunmodulatorischen Medikamenten erreicht werden. Patienten mit genetischen Formen der HLH können nur durch eine Stammzelltransplantation geheilt werden.

Key words

histiocytosis - hemophagocytosis - immune deficiency - review

Schlüsselwörter

Histiocytose - Hämophagozytose - Immundekt - Übersicht

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