Stromal interaction molecule 1 (STIM1)4 deficiency is a rare genetic disorder of store-operated Calcium entry (SOCE), associated with a complex syndrome including immunodeficiency and immune dysregulation. The link from the molecular defect to these clinical manifestations is incompletely understood. We report 2 patients with a homozygous R429C point mutation in STIM1 completely abolishing SOCE in T cells. Immunological analysis of one patient revealed that despite the expected defect of T cell proliferation and cytokine production in vitro, significant antiviral T cell populations were generated in vivo. These T cells proliferated in response to viral antigens and showed normal antiviral cytotoxicity. However, antiviral immunity was insufficient to prevent chronic CMV and EBV infections with a possible contribution of impaired NK cell function and a lack of NKT cells. Furthermore, autoimmune cytopenia, eczema and intermittent diarrhea suggested impaired immune regulation. Forkhead box protein 3 (FOXP3) positive regulatory T cells (Treg) were present but showed an abnormal phenotype. The suppressive function of STIM1 deficient Treg cells in vitro, however, was normal. Given these partial defects in cytotoxic and regulatory T cell function, impairment of other immune cell populations probably contributes more to the pathogenesis of immunodeficiency and autoimmunity in STIM1 deficiency than previously appreciated.

Familial hemophagocytic lymphohistiocytosis (FHL) is a life-threatening disorder

No abstract

No abstract

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages secreting high amounts of inflammatory cytokines. It is a frequent manifestation in patients with predisposing genetic defects, but can occur secondary to various infectious, malignant, and autoimmune triggers in patients without a known genetic predisposition. Clinical hallmarks are prolonged fever, cytopenias, hepatosplenomegaly, and neurological symptoms, but atypical variants presenting with signs of chronic immunodeficiency are increasingly recognized. Impaired secretion of perforin is a key feature in several genetic forms of the disease, but not required for disease pathogenesis. Despite progress in diagnostics and therapy, mortality of patients with severe HLH is still above 40%. Reference treatment is an etoposide-based protocol, but new approaches are currently explored. Key for a favorable prognosis is the rapid identification of an underlying genetic cause, which has been facilitated by recent immunological and genetic advances. In patients with predisposing genetic disease, hematopoietic stem cell transplantation is performed increasingly with reduced intensity conditioning regimes. Current research aims at a better understanding of disease pathogenesis and evaluation of more targeted approaches to therapy, including anti-cytokine antibodies and gene therapy.