ReviewHemophagocytic lymphohistiocytosis and primary immune deficiency disorders
Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life threatening disorder characterized by uncontrolled immune activation, particularly of macrophages, as well as overproduction of cytokines such as interferon-γ, IL-6 and IL-10 [1], [2]. These cytokines contribute to the typical clinical and laboratory features commonly observed among patients including prolonged fever, hematological cytopenias, liver failure, seizures and abnormal natural killer (NK) cell function (Table 1). Additional laboratory tests, including soluble CD25, and CD168 as well as the surface expression of CD107 on NK and cytotoxic T cells (marker of granule-mediated cytotoxicity integrity) can assist in rapidly diagnosing some patients with HLH [3]. Traditionally, affected patients have been categorized as suffering from a genetic (also known as the familial/primary) form or an acquired (also known as the secondary) form [4], [5]. Patients in the genetic form have an identifiable genetic defect and often, albeit not invariably, present at young age or have additional affected family members. In contrast, among patients in the acquired form there are often precipitating factors such as infections, autoimmunity diseases, malignancies, metabolic abnormalities or immune modulating medications, but no known affected family members or inherited defects in susceptibility genes [6]. Establishing the diagnosis of HLH and assigning the patient to the correct group has significant management implications. Treating the precipitating factors and suppressing the exaggerated immune activation can help many patients with the acquired form of HLH, while urgent allogeneic hematopoietic stem cell transplantation (HSCT) is often indicated for those suffering from the genetic form [7], [8].
Since the seminal description of mutations in the PERFORIN as a cause for the familial form of HLH [9], defects in additional molecules important for cytotoxic granules and lysosomes have been identified among patients with genetic HLH. These discoveries have emphasized the role of NK cells in the development of HLH. In recent years, there have also been reports of patients suffering from HLH who had a variety of primary immune deficiency disorders (PID), particularly T cell deficiencies; however a comprehensive review of this association is lacking. We used the terms hemophagocytic, lymphohistiocytosis, HLH, macrophage activating syndrome, MAS, immune deficiency, primary, T cells, B cells, individually and in combination to probe the English medical literature (PubMed and Google Scholar) for the all descriptions of HLH among patients with PID. We found that HLH is reported infrequently among patients with PID, particularly those suffering from abnormal T cells (Table 2). This association implicates abnormal T cell function as an important factor in the development of HLH. It also suggests that the partition of HLH into genetic versus acquired forms might be misleading as patients with presumably acquired HLH might be suffering from PID and thus require a different management approach.
Section snippets
Isolated granule-mediated cytotoxic dysfunction of T cells and NK cells
Identification of mutations in the PERFORIN gene among patients with the genetic form of HLH (familial HLH type 2) significantly advanced the understanding of the pathogenesis of this condition [9]. Patients' lymphocytes demonstrate defective cytotoxic activity, thereby emphasizing the crucial role of granule mediated cytotoxicity of NK and T cells in down-regulating the immune response.
Mutations in other genes important for the priming and fusion of cytotoxic granules have subsequently been
Discussion
Uncontrolled activation of macrophages is a common feature of HLH, however HLH occurs in many inherited T cell defects that are not associated with macrophage abnormalities, suggesting that abnormal T cell function is an important factor in the development of HLH. Indeed, HLH and macrophage activation syndrome (MAS) are frequent among patients with acquired T cell deficiencies secondary to HIV or patients who receive antibodies and medications that suppress T cells [65], [66]. Moreover,
Conflict of interest statement
The author(s) declare that there are no conflicts of interest.
Acknowledgments
This work was supported in part by grants from the Jeffrey Modell Foundation and the Donald and Audrey Campbell Chair of Immunology to EG.
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