IL-12Rß1 deficiency corresponding to concurrency of two diseases, mendelian susceptibility to mycobacterial disease and Crohn's disease.

BACKGROUND: The interleukin-12 receptor ß1 (IL-12Rß1) deficiency is a primary immunodeficiency (PID), affecting the immunological pathway of interleukin 12/interferon- γ (IL12/IFN-γ) axis and interleukin 23 receptor (IL23R). Defect in this pathway is mainly affecting the cellular immunity-related disorders. IL-12Rß1 is a receptor chain of both the IL-12 and the IL-23 receptors and thus, deficiency of IL-12Rß1 abolishes both IL-12 and IL-23 signaling. MATERIAL AND METHODS: In this study, we performed whole exon sequencing and confirmatory Sanger sequencing in IL-12Rß1. Evaluation of the IL12/IFN-γ axis was performed by assessment of patients' whole blood cell to IL12/IFN-γ responding. Total and surface IL-12Rß1expression was evaluated, in peripheral blood mononuclear cells (PBMCs) and T cell- derived PBMCs, and Th17 count was assessed. RESULTS: In the present study, we described a c.1791 + 2T > G mutation at a splicing site position in IL-12Rß1, using whole exome sequencing, and confirmed with targeted Sanger sequencing in a 26- year-old patient with Mendelian susceptibility to mycobacterial disease (MSMD) and Crohn's disease (CD). Complete lack of IL-12Rß1 protein expression was detected in patient's PBMCs, compared to the healthy control. Furthermore, no IL-12Rß1 protein was expressed on the cell surface. Interestingly, IL-12Rß1-mutant cells showed an impaired response to IL12, and Bacillus Calmette-Guérin stimulation, confirming that the mutation is causative in this patient. CONCLUSION: A 3'splicing site mutation in IL12Rß1, can be corresponding to the abolished expression of IL12Rß1 in patients' cells, and associated with an impaired IL12-mediated signaling, which may lead not only to MSMD, but also to inflammatory bowel disease (IBD).

Comparison of the Percentage of Regulatory T cells and their p-STAT5 Expression in Allergic and Non-Allergic Common Variable Immunodeficiency Patients.

BACKGROUND: Common Variable Immunodeficiency (CVID) is a primary immunodeficiency characterized by an immunologic deficiency in immunoglobulin production. Regulatory T cells (Tregs) play a key role in preventing the development allergic disorders. p-STAT5 is a known factor for the function and survival of Tregs. This study aimed to investigate the number of Tregs and their p-STAT5 expression in allergic and non-allergic CVID patients. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 10 healthy volunteers, 10 allergic patients, and 16 CVID patients (allergic and non-allergic) using Ficoll density centrifugation. The percentage of Tregs in PBMCs was analyzed by flow cytometry. Tregs were also isolated from participants using an immunomagnetic separation method and p-STAT5 expression was evaluated in Tregs using flow cytometry. RESULTS: The results revealed that Treg percentage was significantly lower in the CVID patients than the control groups (healthy and allergic individuals) (p<0.001). There was a significant reduction in Treg percentage in allergic patients compared to healthy subjects (p<0.05). No significant difference in Treg percentage between allergic and non-allergic CVID patients was observed. The expression of p-STAT5 in Tregs was significantly lower in CVID patients than the control groups (p<0.001). In addition, the expression of p-STAT5 in Tregs of allergic patients was significantly decreased compared to healthy subjects (p<0.001). However, the deference of p-STAT5 level was not statistically significant between allergic and non-allergic CVID patients. CONCLUSION: These findings suggest that p-STAT5 signaling defect and decreased Treg number may not participate in the development of allergy in CVID patients.

Recurrent Vulvovaginal Candidiasis: Could It Be Related to Cell-Mediated Immunity Defect in Response to Candida Antigen?

BACKGROUND: Recurrent vulvovaginal candidiasis (RVVC) is a common cause of morbidity affecting millions of women worldwide. Patients with RVVC are thought to have an underlying immunologic defect. This study has been established to evaluate cell-mediated immunity defect in response to candida antigen in RVVC cases. MATERIALS AND METHODS: Our cross-sectional study was performed in 3 groups of RVVC patients (cases), healthy individuals (control I) and known cases of chronic mucocutaneous candidiasis (CMC) (control II). Patients who met the inclusion criteria of RVVC were selected consecutively and were allocated in the case group. Peripheral blood mononuclear cells were isolated and labeled with CFSE and proliferation rate was measured in exposure to candida antigen via flow cytometry. RESULTS: T lymphocyte proliferation in response to candida was significantly lower in RVVC cases (n=24) and CMC patients (n=7) compared to healthy individuals (n=20, <0.001), but no statistically significant difference was seen between cases and control II group (P>0.05). Family history of primary immunodeficiency diseases (PID) differed significantly among groups (P=0.01), RVVC patients has family history of PID more than control I (29.2 vs. 0%, P=0.008) but not statistically different from CMC patients (29.2 vs. 42.9%, P>0.05). Prevalence of atopy was greater in RVVC cases compared to healthy individuals (41.3 vs. 15%, P=0.054). Lymphoproliferative activity and vaginal symptoms were significantly different among RVVC cases with and without allergy (P=0.01, P=0.02). CONCLUSION: Our findings revealed that T cells do not actively proliferate in response to Candida antigen in some RVVC cases. So it is concluded that patients with cell-mediated immunity defect are more susceptible to recurrent fungal infections of vulva and vagina. Nonetheless, some other cases of RVVC showed normal function of T cells. Further evaluations showed that these patients suffer from atopy. It is hypothesized that higher frequency of VVC in patients with history of atopy might be due to allergic response in mucocutaneous membranes rather than a functional impairment in immune system components.

Variations in T-helper 17 and Regulatory T Cells during The Menstrual Cycle in Peripheral Blood of Women with Recurrent Spontaneous Abortion.

BACKGROUND: Disorders in immune system regulation may result in pregnancy abnormalities such as recurrent spontaneous abortion (RSA). This study aims to determine the ratio of regulatory T (Treg) and T helper (Th) 17 cells in unexplained RSA (URSA) women during proliferative and secretory phases of their menstrual cycles compared to healthy non-pregnant women. MATERIALS AND METHODS: In this case control study, 25 women with URSA and 35 healthy, non-pregnant women were enrolled. The percentage of Th17 and Treg cells in participants peripheral blood were determined by flow cytometry. RESULTS: The percentage of Th17 cells and their related cytokines in serum (IL-17A) were higher in the proliferative and secretory phases of the menstrual cycles of URSA women compared to the control women. However, a lower percentage of Treg cells and their related cytokines in serum, transforming growth factor (TGF) ß1 and interleukin (IL)-10 were detected in the proliferative but not the secretory phase of the URSA group. The ratio of Th17/CD4+ Treg was higher in the URSA group than the control group. We observed an increased ratio of Th17/CD4+ Treg during the proliferative and secretory phases in URSA women. CONCLUSION: The imbalance between Th17 and Treg cells during the proliferative phase of menstrual cycles in the URSA group may be considered a cause for spontaneous abortion.