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Background: Common variable immunodeficiency (CVID) is considered the most symptomatic type of inborn errors of immunity in humans. Along with infectious complications, which have numerous consequences, noninfectious complications are a major challenge among CVID patients., Methods: All CVID patients registered in the national database were included in this retrospective cohort study. Patients were divided into 2 groups based on the presence of B-cell lymphopenia. Demographic characteristics, laboratory findings, noninfectious organ involvement, autoimmunity, and lymphoproliferative diseases were evaluated., Results: Among 387 enrolled patients, 66.4% were diagnosed with noninfectious complications and 33.6% with isolated infectious presentations. Enteropathy, autoimmunity, and lymphoproliferative disorders were reported in 35.1%, 24.3%, and 21.4% of patients, respectively. Some complications, including autoimmunity and hepatosplenomegaly, were reported to be significantly more frequent among patients with B-cell lymphopenia. As for organ involvement, the dermatologic, endocrine, and musculoskeletal systems were predominantly affected in CVID patients with B-cell lymphopenia. Among autoimmune manifestations, the frequency of rheumatologic, hematologic, and gastrointestinal autoimmunity was reported to be higher than that of other types of autoimmunity not associated with B cell-lymphopenia. Furthermore, hematological cancers, particularly lymphoma, were the most common type of malignancy. The mortality rate was 24.5%, and respiratory failure and malignancies were the most common causes of death, with no significant differences between the 2 groups., Conclusions: Considering that some of the noninfectious complications might be associated with B-cell lymphopenia, regular patient monitoring and follow-up with proper medication (in addition to immunoglobulin replacement therapy) are highly recommended to prevent sequelae and increase patient quality of life.

Background: Selective IgA deficiency is the most prevalent form of primary immunodeficiencies. The pathogenesis of the disease is still unknown. Several studies have suggested a defect in B cell responses to IL-10; however, the main reason for this defect has not been reported. Elucidating IL-10 signaling defects and their correlation with clinical manifestations could be helpful for better understanding and treatment of the disease., Methods: In this study, 15 SIgAD patients and 15 age- and sex-matched healthy controls were included. Surface expression of transforming growth factor β receptor II (TGF-β RII), IL-10R and IgA was assessed by flow cytometry in human purified B cells before and after stimulation by IL-10. Protein expression of STAT3, p-STAT3 and SOCS3 was measured by Western blotting analysis. TGF-β and IgA secretion was evaluated by ELISA. Finally, the measurement of B cell apoptosis was performed by flow cytometry., Results: The TGF-βRII expression level was decreased after stimulation with IL-10 in patients compared with controls. Notably, the TGF-β level were higher after stimulation with mCD40L and IL-10 in the control group as compared to stimulation with mCD40L alone. The IgA+ B cell percentage and IgA secretion levels were significantly increased in controls as compared with SIgAD patients. The relative concentration of the total STAT3 was decreased as compared with controls., Conclusion: The defect in IgA production in SIgAD patients could be due to inadequate B cell responses to IL-10 stimulation that probably originate from defective regulation of IL-10-mediated TGF-b ’symbol’ production TGF-β response by IL-10. Furthermore, it is suggested that the absence of STAT3 protein baseline expression could impair cytokine-mediated signaling such as thatinduced by IL-!0 and IL-21.

Common variable immunodeficiency (CVID) is the most prevalent form of symptomatic primary humoral immunodeficiencies characterized by failure in the final differentiation of B lymphocytes. The majority of CVID cases have no identified genetic defect, and epigenetic alteration could be involved in the pathogenesis of CVID. Hence, we aimed to evaluate the expression of hsa-miR-125b-5p -and, B lymphocyte-induced maturation protein-1(BLIMP-1) and interferon regulatory protein-4 (IRF-4) in a group of CVID patients with no definitive genetic diagnosis in comparison with healthy individuals. Ten CVID patients (all known genes excluded) and 10 age and sex-matched healthy controls participated in the study. B lymphocytes were isolated and expression of miR-125b-5p, IRF4, and BLIMP1 were evaluated by real-time polymerase chain reaction (RT-PCR). Moreover, B cell subsets were analyzed by flow cytometry. The results showed that the relative expression of miR-125b-5p in CVID patients was increased while it was decreased for the BLIMP1 and IRF4 transcription factors compared with the healthy controls. Although a reduction was observed in switched and non-switched memory B cells among all high-miR patients, these subsets were decreased in patients with normal miR expression (71.0% and 85.0%, respectively). Our results suggest that overexpression of miR-125b-5p affects the terminal differentiation of B cells in a selected group of CVID patients by downregulating the BLIMP-1 gene and more intensively for the IRF-4 gene expressions.

Background: Common variable immunodeficiency (CVID) is one of the most prevalent forms of primary immunodeficiency diseases (PID). CVID is characterized by failure in the final differentiation of B lymphocytes and impaired antibody production but the pathogenesis is not known in the majority of patients. We postulated that the expression pattern of miRNAs in unsolved CVID patients might be the underlying epigenetic cause of the disease. Therefore, we aimed to assess the expression of hsa-miR-210-5p and FOXP3 transcription factor in CVID cases in comparison with healthy individuals., Methods: Eleven CVID cases with no genetic defects (all PID known genes excluded) and 10 sex and age-matched healthy individuals were enrolled in the study. T lymphocytes were purified from PBMC, and expression levels of miR-210-5p and FOXP3 mRNA were evaluated by real-time PCR., Results: We demonstrated that miR-210 expression in patients was significantly higher than the control group (P = 0.03). FOXP3 expression was slightly lower in patients compared with healthy controls (P = 0.86). There was a negative correlation between miR and gene expression (r: -0.11, P = 0.73). Among various clinical complications, autoimmunity showed a considerable rate in high-miR patients (P = 0.12, 42.8%), while autoimmunity was not observed in normal miR-210 patients., Conclusions: Our results suggest a role for miR-210 in the pathogenesis of autoimmunity in CVID patients. Further studies would better elucidate epigenetic roles in CVID patients with no genetic defects., Competing Interests: The authors declare that they have no conflicts of interest.

Although it is estimated that COVID-19 life-threatening conditions may be diagnosed in less than 1:1000 infected individuals below the age of 50, but the real impact of this pandemic on pediatric patients with different types of primary immunodeficiency (PID) is not elucidated. The current prospective study on a national registry of PID patients showed that with only 1.23 folds higher incidence of infections, these patients present a 10-folds higher mortality rate compared to population mainly in patients with combined immunodeficiency and immune dysregulation. Therefore, further management modalities against COVID-19 should be considered to improve the survival rate in these two PID entities using hematopoietic stem cell transplantation and immunomodulatory agents.

Objectives: Human Ficolin-3 ( FCN3 ) is an oligomeric-structured lectin encoded by the FCN3 gene with a pivotal role in the lectin complement pathway. It has anti-microbial activities against bacterial and viral infections and restrains opportunistic pathogens. Mutation in the FCN3 gene is associated with variable clinical manifestations particularly immunologic (infections and autoimmunity) and neurologic complications., Methods: In this study, we report a 5-year-old boy with a biallelic mutation in the FCN3 gene using clinical and immunological and genetic evaluations (whole exome sequencing)., Results: Our case is the first national and the eighth case worldwide with a confirmed frameshift mutation associated with Ficolin-3 deficiency. He manifested refractory seizures since early infancy, meningitis, pyelonephritis and was diagnosed with severe primary immunodeficiency., Conclusion: Our case and literature review indicate Ficolin-3 deficiency should be considered in early-onset, premature neonate with a bacterial infection, neurological manifestation and systemic lupus erythematosus like presentations.

Background: Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency disorder mainly characterized by recurrent bacterial infections besides other immunological defects including loss of or dysfunction of B cells and decreased immunoglobulin levels. In this study, our aim is to evaluate clinical, immunological, and molecular data of patients with a primary clinical diagnosis of CVID and autoimmune phenotype with a confirmed genetic diagnosis., Methods: Among 297 patients with CVID, who were registered in the Iranian Primary Immunodeficiency Registry at Children's Medical Center Hospital in Iran, 83 patients have been genetically examined and 27 patients with autoimmunity and confirmed genetic mutations were selected for analysis. Whole-exome sequencing and confirmatory Sanger sequencing methods were used for the study population. A questionnaire was retrospectively filled for all patients to evaluate demographic, laboratory, clinical, and genetic data., Results: In the 27 studied patients, 11 different genetic defects were identified, and the most common mutated gene was LRBA, reported in 17 (63.0%) patients. Two patients (7.7%) showed autoimmune complications as the first presentation of immunodeficiency. Eleven patients (40.7%) developed one type of autoimmunity, and 16 patients (59.3%) progressed to poly-autoimmunity. Most of the patients with mono-autoimmunity (n = 9, 90.0%) primarily developed infectious complications, while in patients with poly-autoimmunity, the most common first presentation was enteropathy (n = 6, 37.6%). In 13 patients (61.9%), the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency. The most frequent autoimmune manifestations were hematologic (40.7%), gastrointestinal (48.1%), rheumatologic (25.9%), and dermatologic (22.2%) disorders. Patients with poly-autoimmunity had lower regulatory T cells than patients with mono-autoimmunity., Conclusion: In our cohort, the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency in most patients. This association highlights the fact that patients referring with autoimmune manifestations should be evaluated for humoral immunity., (© 2020 S. Karger AG, Basel.)

Interleukin-10 (IL-10) is a pleiotropic cytokine, which has both regulatory and stimulatory effects on different immune cell types. Different studies have reported the importance of IL-10 and Transforming growth factor-beta (TGF-β) in the regulation of B cell class switching the production of immunoglobulin A (IgA); however, the underlying mechanisms remain to be fully elucidated. The objective of this study was to investigate the TGF-β response during B stimulation of human B cells by IL-10. Pan B cells of healthy donors were negatively purified by a magnetic cell separation technique. B cells were cultured with multimeric CD40 ligand (mCD40L) and IL-10 for two and seven days. After harvesting in specific days, TGF-β receptor II and surface IgA expression was determined by flow cytometry, while IgA and TGF-β secretion was assessed by enzyme-linked immunosorbent assay. B cells endogenously expressed TGF-β receptor II and after 48 hours cultivation with mCD40L or mCD40L plus IL-10, both the expression of this receptor and the production of TGF-β were significantly increased. Notably, TGF-β levels following stimulation with mCD40L and IL-10 were higher than those produced by B cells stimulated with mCD40L alone. Furthermore, at day 7 and following IL-10 stimulation, there was a significant rise in the amount of IgA secretion by class-switched plasma cells, which was higher than stimulation with mCD40L alone. Our findings suggest that IL-10 can modulate TGF-β production and TGF-β receptor expression in mCD40-activated human B lymphocytes.

Background and Objective: APDS [Activated phosphoinositide 3-kinase (PI3K) δ Syndrome] is a newly found special form of primary immunodeficiency caused by mutations in genes encoding PI3Kδ subunits and over-activation of the PI3K signaling pathway. Gain-of-function and loss-of-function mutations in PIK3CD (encoding P110δ) and PIK3R1 (encoding p85α, p55α and p50α) lead to APDS1 and APDS2, respectively. The subsequent irregular PI3K downstream signaling cascade is associated with abnormalities in B cells and T cells and the consequent heterogeneous clinical manifestations including respiratory tract infections, autoimmunity, lymphoproliferation and not to mention primary antibody deficiency. In this study, we report a 12-year-old girl with a mutation in the PIK3R1 gene who manifested immunological phenotypes resembling hyper IgM syndrome along with a review of the literature of the previously reported patients., Methods: Whole exome sequencing was performed to detect the underlying genetic mutation in this patient., Results: A de novo heterozygous splice site mutation in the hot spot of the PIK3R1 gene within the intron 10 was found (c.1425+1G>A)., Conclusion: Further investigations are required for evaluation of the underlying genetic defects and the possible associations between genetic underpinning and heterogeneous severity and features of the disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Osteomyelitis (OM) is an atypical consequence of ankle-foot trauma which is associated with long-term mental and physical morbidity and persistent pain. This study aimed to assess the health status of OM patients with war-related ankle-foot injuries., Methods: A total of 1129 veterans with ankle-foot injuries participated in a case-control study (2014-2016). Thirty patients with chronic OM of the ankle-foot were compared with 90 non-OM participants as the control group. Quality of life (QOL), life satisfaction and the ability to perform basic and instrumental activities of daily living were measured using the following questionnaires: short-form health survey (SF-36), satisfaction with life scale (SWLS), activity of daily living (ADL) and instrumental activity of daily living (IADL), respectively. OM patients were categorized according to their risk factors as A, B and C hosts using a modified version of the Cierny and Mader classification system. The one sample t-test, 2-independent sample t-test, ANOVA, Pearson correlation coefficient and multiple linear regression analyses were applied to analyze the data., Results: Ankle-foot pain leading to surgery (P < 0.001) and orthosis usage (P = 0.039) were more common in OM patients. There was no significant difference between the two groups in the prevalence of pulmonary and cardiovascular diseases or kidney failure and other related diseases. OM patients showed a significantly lower level of mental health compared to non-OM respondents (P = 0.025). Approximately, 70.0% of ankle-foot injured veterans were dissatisfied with their life, and there was no difference between the two groups (P > 0.05). Mobility was significantly lower in the OM patients than in the control group (P = 0.023). Life satisfaction (P = 0.001) and the ability to perform daily activities were the determinants for poor physical (P = 0.018) and mental (P = 0.012) health-related quality of life. According to the Cierny and Mader classification system, they were all included in the type C host classification, with one major and/or three or more minor risk factors., Conclusions: A low level of quality and satisfaction of life and ability to perform activities of daily living were observed in OM patients with war-related ankle-foot injuries. Surgeries of the ankle and foot due to pain were much more common in OM patients than in non-OM participants. Since all the participants were classified as the C-host, health policy planning seems to be necessary.