Our study identifies a novel role for WDR1 in adaptive immunity, highlighting WDR1 as a central regulator of actin turnover during formation of the B-cell and T-cell immunologic synapses.

Background The autosomal recessive hyper IgE syndrome (AR-HIES) due to Dedicator Of Cytokinesis 8 (DOCK8) deficiency shares clinical features with the autosomal dominant HIES (AD-HIES) due to Signal Transducer and Activator of Transcription 3 (STAT3) mutations, including recurrent infections and mucocutaneous candidiasis, suggestive of Th17 cell dysfunction. The mechanisms underlying this phenotypic overlap are unclear. Objective We sought to elucidate common mechanisms operative in the different forms of HIES. Experimental Design We analyzed the differentiation of CD4+ T helper (Th) cell subsets in control and DOCK8-deficient subjects. We also examined the role of DOCK8 in regulating STAT3 activation in T cells. Methods Th cell differentiation was analyzed by ELISA, flow cytometry and real time PCR measurements of cytokines and Th cell transcription factors. The interaction of DOCK8 and STAT3 signaling pathways was examined by flow cytometry, immunofluorescence, co-immunoprecipitation and gene expression analysis. Results There was a profound block in the differentiation of DOCK8-deficient naïve CD4+ T cells into Th17 cells. A missense mutation that disrupts DOCK8 guanine exchange factor (GEF) activity while sparing protein expression also impaired Th17 cell differentiation. DOCK8 constitutively associated with STAT3 independent of GEF activity, while it regulated STAT3 phosphorylation in a GEF activity-dependent manner. DOCK8 also promoted STAT3 translocation to the nucleus and induction of STAT3-dependent gene expression. Conclusion DOCK8 interacts with STAT3, regulates its activation and the outcome of STAT3-dependent Th17 differentiation. These findings may explain the phenotypic overlap between DOCK8 deficiency and AD-HIES.

The aim of this study was to determine the relationship between clinical findings and the most common mutated alleles of MEFV gene in a childhood population and to determine the sensitivity of the 12-mutation-strip assay test in familial Mediterranean fever (FMF). Records of 452 FMF children living in western Anatolia, Turkey, (12.3 ± 4.7 years mean) were retrospectively reviewed. Of the 408 patients who met the Tel-Hashomer criteria, 364 were classified into two main groups (two-mutant/one-mutant allele) either of which had three subgroups. The two-mutant allele frequency was 51% and one-mutant allele 38%; 1% had complex-mutant alleles and 10% no mutant-alleles. The mean severity score was 8.3 ± 2.5. Most common clinical features were fever (81.9%), abdominal pain (86.3%) and myalgia (58.8%), and the least common ones: diarrhea (1.7%), protracted febrile myalgia (1.2%) and acute orchitis (1.5%). We detected 33 different genotypes of the MEFV gene: the most common mutant allele was M694V followed by symptomatic allele mutation of E148Q. Although not significantly associated with clinical findings, P369S mutation was not rare (7.5%). Phenotype-genotype correlation revealed that patients with two-allele mutations had more severe clinical presentation and high constipation rate (22.5%); 32.6% of patients with M694V/M694V had splenomegaly. Acute orchitis and protracted febrile myalgia as rare clinical findings were more common in M694V homozygotes. Comparisons of clinical findings among patients with one-mutation allele were made for the first time, but no significant association was found. Positive predictive value of strip assay screening for 12 mutations was recorded as 89%. We suggest that whole sequence analysis for supportive diagnosis of FMF should be performed for selected patients only.

Somekh and colleagues identify CD137, a member of the tumor necrosis factor superfamily, as a novel cause of immunodeficiency associated with a risk of autoimmunity and lymphoid malignancy.

Background Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis. Methods We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers. Results We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG). Conclusions This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation.