The Autoimmune Manifestations in Patients with Genetic Defects in the B Cell Development and Differentiation Stages.

PURPOSE: Primary B cell defects manifesting as predominantly antibody deficiencies result from variable inborn errors of the B cell lineage and their development, including impairments in early bone marrow development, class switch recombination (CSR), or terminal B cell differentiation. In this study, we aimed to investigate autoimmunity in monogenic patients with B cell development and differentiation defects. METHODS: Patients with known genetic defects in the B cell development and differentiation were recruited from the Iranian inborn errors of immunity registry. RESULTS: A total of 393 patients with a known genetic defect in the B cell development and differentiation (257 males; 65.4%) with a median age of 12 (6-20) years were enrolled in this study. After categorizing patients, 109 patients had intrinsic B cell defects. More than half of the patients had defects in one of the ATM (85 patients), BTK (76 patients), LRBA (34 patients), and DOCK8 (33 patients) genes. Fifteen patients (3.8%) showed autoimmune complications as their first manifestation. During the course of the disease, autoimmunity was reported in 81 (20.6%) patients at a median age of 4 (2-7) years, among which 65 patients had mixed intrinsic and extrinsic and 16 had intrinsic B cell defects. The comparison between patients with the mentioned four main gene defects showed that the patient group with LRBA defect had a significantly higher frequency of autoimmunity compared to those with other gene defects. Based on the B cell defect stage, 13% of patients with early B cell defect, 17% of patients with CSR defect, and 40% of patients who had terminal B cell defect presented at least one type of autoimmunity. CONCLUSION: Our results demonstrated that gene mutations involved in human B cell terminal stage development mainly LRBA gene defect have the highest association with autoimmunity.

The role of lncRNA CERS6-AS1 in cancer and its molecular mechanisms: A systematic review and meta-analysis.

BACKGROUND: LncRNAs have the potential to play a regulatory role in different processes of cancer development and progression. We conducted a systematic review and meta-analysis of evidence on the clinical significance and prognostic value of lncRNA CERS6-AS1 in cancer. METHODS: This systematic review was conducted following PRISMA guidelines. Medline and Embase databases were searched using the relevant key terms covering lncRNA CERS6-AS1 and cancer. We pooled the estimated effect sizes and their 95 % confidence interval (CI) using random-effects models in STATA 16.0 (StataCorp, College Station, TX, USA). RESULTS: Eleven articles on pancreatic, colorectal, gastric, papillary thyroid, breast, and hepatocellular cancers fulfilled our eligibility criteria. Studies consistently found that lncRNA CERS6-AS1 expression is upregulated in all assessed cancers. Based on our meta-analysis, its aberrant expression was directly associated with unfavorable clinical outcomes, including higher stage (pooled Odds ratios (95 % CI): 3.15 (2.01-4.93; I2 = 0.0 %), tumor size (1.97 (1.27-3.05; I2 = 37.8 %), lymph node metastasis (6.48 (4.01-10.45; I2 = 0.40 %), and poor survival (Pooled log-rank test P-value < 0.001) in patients. Regarding potential mechanisms, functional studies revealed that LncRNA CERS6-AS1 is involved in cancer growth mainly by sponging miRNAs and regulating their downstream targets. CONCLUSION: Available evidence suggests that LncRNA CERS6-AS1 is upregulated in different cancers and has an oncogenic role. LncRNA CERS6-AS1 expression level might predict cancer prognosis, highlighting its potential application as a prognostic biomarker for cancer.

Autoimmunity in monogenic combined immune deficiencies with associated or syndromic features.

Background: Combined immune deficiencies (CIDs) with associated or syndromic features are a highly heterogeneous subgroup of inherited immune disorders. These patients represent specific clinical complications with an increased risk of autoimmune conditions. Methods: We analyzed data of monogenic patients with syndromic CIDs adopted from the Iranian inborn errors of immunity registry up to January 2022. A comprehensive comparison in terms of demographic, clinical, and immunological features was performed between patients with and without autoimmunity and also among four mutation groups with the most registered cases including ATM, STAT3 (AD-LOF), DNMT3B/ZBTB24, and WAS mutations. Results: A total of 137 patients with monogenic syndromic CIDs were included. Most commonly mutated genes were the ATM [80 (58.4%)] and STAT3 (AD-LOF) [19 (13.9%)], followed by DNMT3B [11 (8%)], and WAS [11 (8%)]. More than 18% of all patients with syndromic CIDs, including most DNMT3B/ZBTB24 mutations patients, were clinically diagnosed with antibody deficiencies before genetic evaluation. Patients with ATM and WAS mutations had the latest age of onset and the lowest age of diagnosis, respectively. Autoimmune disorders were diagnosed in 24 patients at a median age of 3.5 (2.6-6.0) years, 70.6% of which were diagnosed prior to the diagnosis of immunodeficiency. Lymphoproliferation, particularly hepatosplenomegaly, was significantly higher in patients with autoimmunity (p=0.004). Syndromic CID patients with autoimmunity had significantly lower IgG levels. Hematologic autoimmunity mainly immune thrombocytopenic purpura was the most frequent autoimmunity among major groups of ATM, STAT3 (AD-LOF), DNMT3B/ZBTB24, and WAS mutations, however ATM-mutated patients present more diversified involved organs including rheumatologic, gastrointestinal and dermatologic autoimmunity. Conclusion: About 18% of patients with monogenic syndromic CIDs developed autoimmunity, mainly in the form of hematological immune diseases. Autoimmunity could be an early-onset involvement with a potential diagnostic impact on suspicious cases of syndromic CIDs.