Mutations in genes encoding components of the immune system cause primary immunodeficiencies. Here, we study a patient with recurrent atypical mycobacterial infection and early-onset metastatic bladder carcinoma. Exome sequencing identified two homozygous missense germline mutations, P733L and P832S, in the JAK1 protein that mediates signalling from multiple cytokine receptors. Cells from this patient exhibit reduced JAK1 and STAT phosphorylation following cytokine stimulations, reduced induction of expression of interferon-regulated genes and dysregulated cytokine production; which are indicative of signalling defects in multiple immune response pathways including Interferon-γ production. Reconstitution experiments in the JAK1-deficient cells demonstrate that the impaired JAK1 function is mainly attributable to the effect of the P733L mutation. Further analyses of the mutant protein reveal a phosphorylation-independent role of JAK1 in signal transduction. These findings clarify JAK1 signalling mechanisms and demonstrate a critical function of JAK1 in protection against mycobacterial infection and possibly the immunological surveillance of cancer.

Autoimmune lymphoproliferative syndrome (ALPS) is a rare immunodeficiency caused by mutations in genes affecting the extrinsic apoptotic pathway (FAS, FASL, CASP10). This study evaluated the clinical manifestations, laboratory findings and molecular genetic results of 215 patients referred as possible ALPS. Double negative T-cell (DNT) percentage and in vitro apoptosis functional tests were evaluated by FACS; interleukin 10 and 18 (IL-10, -18) and soluble FAS ligand (sFASL) were measured by ELISA. Genetic analysis was performed by next generation sequencing. Clinical background data were collected from patients' records. Patients were categorised into definite, suspected and unlikely ALPS, and laboratory parameters were compared among these groups. From 215 patients, 38 met the criteria for definite ALPS and 17 for suspected ALPS. The definite and suspected ALPS patient population showed higher DNT than unlikely ALPS and had higher rates of lymphoproliferation. Definite ALPS patients had a significantly more abnormal in vitro apoptosis function with lower annexin than patients with suspected ALPS (P=0.002) and patients not meeting the ALPS criteria (P<0.001). The combination of elevated DNT and an abnormal in vitro apoptosis functional test was the most useful to identify all types of ALPS patients; the combination of abnormal in vitro apoptosis functional test and elevated sFASL was a predictive marker for ALPS-FAS group identification. Lymphoproliferation, apoptosis functional test and DNT are the most sensitive markers; elevated IL-10 and IL-18 are additional indicators for ALPS. The combination of elevated sFASL and an abnormal apoptosis function was the most valuable prognosticator for patients with FAS mutations.

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Severe combined immunodeficiency (SCID) is a heterogeneous group of inherited defects involving the development of T- and/or B-lymphocytes. We report a female with atypical severe combined immunodeficiency caused by a novel homozygous mutation at cDNA position 2290 (c.2290C > T) in exon 2 of the RAG1 gene. The patient presented with bronchopneumonia, pyoderma gangrenosum (PG), pancytopenia and splenomegaly. She presented to us with pancytopenia and splenomegaly at the age of 11. Her condition was complicated by PG on left lower ankle at the age of 12. She experienced bronchopneumonia at the age of 15. She was diagnosed with RAG1 deficiency at the age of 16. Her immunological presentation included leucopenia and diminished number of B cells.