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The syndromic diarrhea/trichohepatoenteric syndrome (SD/THE) is a rare and multi-system genetic disorder caused by mutation in SKIV2L or in TTC37 , two genes encoding subunits of the putative human SKI complex involved in RNA degradation. The main features are intractable diarrhea of infancy, hair abnormalities, facial dysmorphism, and intrauterine growth restriction. Immunologically this syndrome is associated with a hypogammaglobulinemia leading to an immunoglobulin supplementation. Our immune evaluation of a large French cohort of SD/THE patient revealed several immunological defects. First, switched memory B lymphocytes count is very low. Second, IFN-γ production by T and NK cells is impaired and associated with a reduced degranulation of NK cells. Third, T cell proliferation was abnormal in 3/6 TTC37 -mutated patients. These three patients present with severe EBV infection and a transient hemophagocytosis which may be related to these immunological defects. Moreover, an immunological screening of patients with clinical features of SD/THE could facilitate both diagnosis and therapeutic management of these patients.

IgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder involving virtually every organ with a risk of organ dysfunction. Despite recent studies regarding B cell and T cell compartments, the disease's pathophysiology remains poorly understood. We examined and characterized subsets of circulating lymphocytes in untreated patients with active IgG4-RD. Twenty-eight consecutive patients with biopsy-proven IgG4-RD were included in a prospective, multicentric study. Lymphocytes' subsets were analyzed by flow cytometry, with analysis of T H 1/T H 2/T H 17, T FH cells, and cytokine release by peripheral blood mononuclear cells. Results were compared to healthy controls and to patients with primary Sjögren's syndrome. Patients with IgG4-RD showed an increase of circulating T regulatory, T H 2, T H 17, and CD4 + CXCR5 + PD1 + T FH cell subsets. Accordingly, increased levels of IL-10 and IL-4 were measured in IgG-RD patients. T FH increase was characterized by the specific expansion of T FH 2 (CCR6 - CXCR3 - ), and to a lesser extent of T FH 17 (CCR6 + CXCR3 - ) cells. Interestingly, CD4 + CXCR5 + PD1 + T FH cells normalized under treatment. IgG4-RD is characterized by a shift of circulating T cells toward a T H 2/T FH 2 and T H 17/T FH 17 polarization. This immunological imbalance might be implicated in the disease's pathophysiology. Treatment regimens targeting such T cells warrant further evaluation.

Innate lymphoid cells (ILCs) have potent immunological functions in experimental conditions in mice, but their contributions to immunity in natural conditions in humans have remained unclear. We investigated the presence of ILCs in a cohort of patients with severe combined immunodeficiency (SCID). All ILC subsets were absent in patients with SCID who had mutation of the gene encoding the common γ-chain cytokine receptor subunit IL-2Rγ or the gene encoding the tyrosine kinase JAK3. T cell reconstitution was observed in patients with SCID after hematopoietic stem cell transplantation (HSCT), but the patients still had considerably fewer ILCs in the absence of myeloablation than did healthy control subjects, with the exception of rare cases of reconstitution of the ILC1 subset of ILCs. Notably, the ILC deficiencies observed were not associated with any particular susceptibility to disease, with follow-up extending from 7 years to 39 years after HSCT. We thus report here selective ILC deficiency in humans and show that ILCs might be dispensable in natural conditions, if T cells are present and B cell function is preserved., Competing Interests: E.V. is the cofounder of and a shareholder in Innate Pharma. The other authors have no conflicting financial interest to declare.

Interleukin (IL)-6 transsignaling plays a pivotal role in the shift from neutrophil to monocyte recruitment at the inflammatory site. Release of neutrophil IL-6 receptor-alpha (IL-6Ralpha, CD126) in its soluble form is a key step of IL-6 transsignaling, however, its physiological inducers are poorly known. Here, we observed that the neutrophil chemoattractants IL-8, C5a complement fraction, platelet activating factor, leukotriene B4 and N-formyl-methionyl-leucyl-phenylalanine rapidly decreased IL-6Ralpha membrane expression and increased soluble IL-6Ralpha concentrations in the neutrophil supernatants, consistent with a shedding process. IL-6Ralpha shedding involved a TNF-alpha-converting enzyme-type metalloproteinase since it was partly decreased in the presence of a specific inhibitor, but not cathepsin G since PMSF or alpha1 antichymotrypsin had no effect. Neutrophil IL-6Ralpha shedding may be a common feature of neutrophilic infiltrates in various inflammatory situations, allowing IL-6 transsignaling, decreasing neutrophil infiltration and in the meantime favoring monocyte recruitment, thus the initiation of an immune response and subsequently the resolution of inflammation.