Purpose. Inborn errors of IFN-γ-mediated immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD), which is characterized by an increased susceptibility to severe and recurrent infections caused by weakly virulent mycobacteria, such as Bacillus Calmette–Guérin (BCG) vaccines and environmental, nontuberculous mycobacteria (NTM). Methods. In this study, we investigated four patients from four unrelated consanguineous families from Isfahan, Iran with disseminated BCG disease. We evaluated the patients’ whole blood cell response to IL-12 and IFN-γ, IL-12Rβ1 expression on T-cell blasts, and sequenced candidate genes. Results. We reported four patients from Isfahan, Iran, ranging from 3 months to 26 years old, who had impaired IL-12 signaling. All patients suffered from BCG infectious diseases. One of them presented mycobacterial osteomyelitis as a form of infection. By Sanger sequencing, we identified three different types of homozygous mutations in IL12RB1. Expression of IL-12Rβ1 was completely abolished in the four patients with IL12RB1 mutations. Conclusions. IL-12Rβ1 deficiency was found in the four MSMD Iranian families tested. It is the first report of an Iranian case with S321X mutant IL-12Rβ1 protein. Mycobacterial osteomyelitis is another type of location of mycobacterial infection in an IL-12Rβ1-deficient patient, notified for the first time in this study.

Candidiasis is characterized by susceptibility to recurrent or persistent infections caused by Candida spp., typically Candida albicans, of cutaneous and mucosal surfaces. In this report, function and frequency of Th17 cells as well as genetics of patients susceptible to mucocutaneous candidiasis were studied. For patients, T-cell proliferation tests in response to Candida antigen, Th17 cell proportions, and STAT1 phosphorylation were evaluated through flow cytometry. Expression of IL17A, IL17F and IL22 genes were measured by real-time quantitative PCR. At the same time, whole exome sequencing was performed for all patients. We identified two heterozygous substitutions, one: c.821G > A (p. R274Q) was found in a multiplex family with three individuals affected, the second one: c.812A > C (p. Q271P) was found in a sporadic case. Both mutations are located in the coiled-coil domain (CCD) of STAT1. The frequency of Th17 cells, IL17A, IL17F, and IL22 gene expression in patients’ peripheral blood mononuclear cells (PBMCs), and T-cell proliferation to Candida antigens were significantly reduced in the patients as compared to healthy controls. An increased STAT1 phosphorylation was observed in patients’ PBMCs upon interferon (IFN)-γ stimulation as compared to healthy controls. We report two different but neighboring heterozygous mutations, located in exon 10 of the STAT1 gene, in four Iranian patients with CMC, one of whom also had hypothyroidism. These mutations were associated with impaired T cell proliferation to Candida antigen, low Th17 cell proportions, and increased STAT1 phosphorylation upon IFN-γ. We suggest that interfering with STAT1 phosphorylation might be a promising way for potential therapeutic measurements for such patients.

Little is known about the frequency, clinical presentation and natural history of IgM-selectively deficient (IgM-sd) patients METHODS: Records of 46 patients with serum IgM between 0-52mg/dl and normal or elevated total serum IgG and total serum IgA levels from an academic/private practice over a 10 year period were reviewed. RESULTS: 22 were selected from patients presenting with recurrent sinopulmonary issues, 14 were selected from patients presenting with chronic urticaria/angioedema, and 10 were selected from patients with other presentations. 17 of the 24 patients from the latter 2 groups also have respiratory issues. There was one familial case. One patient has no detectable serum IgM but has detectable surface IgM+ CD19 B cells. Serum IgM was between 14-52 for the remaining patients. 4/25(16%) has IgG subclass abnormality. 6/18 have abnormal antigen specific response. 2 patients have acquired the IgM-sd from previous normal amounts. 24/27 patients have stable low IgM levels and 3 normalize to low normal IgM levels when followed over a period of 2-16 years. 3/27 (11%) patients progressed to develop greater immunoglobulin deficiencies. 6/6 patients have normal T cell subsets, B cell, and NK numbers. No lymphoma developed in the IgM-sd patients. CONCLUSIONS: IgM-sd is not rare. Most have respiratory symptoms. Many are stable over years but 11% progressed to develop greater immunoglobulin deficiencies.

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