Common Variable Immunodeficiency Research Articles

Retraction Note: Rifaximin alters gut microbiota profile, but does not affect systemic inflammation - a randomized controlled trial in common variable immunodeficiency

Retraction Note: Rifaximin alters gut microbiota profile, but does not affect systemic inflammation - a randomized controlled trial in common variable immunodeficiency

Predominantly antibody deficiency and the association with celiac disease in Sweden: A nationwide case-control study

BackgroundPredominantly antibody deficiency (PAD) is associated with noninfectious inflammatory gastrointestinal disease. Population estimates of celiac disease (CeD) risk in those with PAD are limited. ObjectiveTo estimate population risk of PAD in individuals with CeD. MethodsWe conducted a nationwide case-control study in Swedish individuals who received a diagnosis of CeD between 1997 and 2017 (n = 34,980), matched to population comparators by age, sex, calendar year, and county. The CeD was confirmed through the Epidemiology Strengthened by histopathology Reports in Sweden study, which provided information on biopsy specimens from each of Sweden's pathology departments. PAD was identified using International Classification of Diseases, 10th Revision coding and categorized according to the International Union of Immunologic Societies. Logistic regression was used to calculate adjusted odds ratios (aORs) and 95% CIs. ResultsPAD was more prevalent in CeD than in population controls (n = 105 [0.3%] vs n = 57 [0.033%], respectively). This translated to an aOR of 8.23 (95% CI 5.95-11.48). The association was strongest with common variable immunodeficiency (aOR 17.25; 95% CI 6.86-52.40), and slightly lower in other PAD (aOR 8.39; 95% CI 5.79-12.32). The risk of CeD remained increased at least 5 years after diagnosis of PAD (aOR 4.79; 95% CI 2.89-7.97, P-heterogeneity ≤ 0.001). ConclusionPAD was associated with an increased risk of CeD. A particularly strong association was seen in those with CVID, although this should be interpreted cautiously given the limited understanding of the mechanisms of histopathologic changes in these patients.

Clinical and experimental treatment of primary humoral immunodeficiencies.

Selective IgA deficiency (sIgAD), common variable immunodeficiency (CVID), and transient hypogammaglobulinemia of infancy (THI) are the most frequent forms of primary antibody deficiencies. Difficulties in initial diagnosis, especially in the early childhood, the familiar occurrence of these diseases, as well as the possibility of progression to each other suggest common cellular and molecular patomechanism and a similar genetic background. In this review, we discuss both similarities and differences of these three humoral immunodeficiencies, focusing on current and novel therapeutic approaches. We summarize immunoglobulin substitution, antibiotic prophylaxis, treatment of autoimmune diseases, and other common complications, i.e. cytopenias, gastrointestinal complications, and granulomatous disease. We discuss novel therapeutic approaches such as allogenic stem cell transplantation and therapies targeting-specific proteins, dependent on the patient's genetic defect. The diversity of possible therapeutics models results from a great heterogeneity of the disease variants, implying the need of personalized medicine approach as a future of primary humoral immunodeficiencies treatment.

Nonparametric Bayes multiresolution testing for high-dimensional rare events

In a variety of application areas, there is interest in assessing evidence of differences in the intensity of event realizations between groups. For example, in cancer genomic studies collecting data on rare variants, the focus is on assessing whether and how the variant profile changes with the disease subtype. Motivated by this application, we develop multiresolution nonparametric Bayes tests for differential mutation rates across groups. The multiresolution approach yields fast and accurate detection of spatial clusters of rare variants, and our nonparametric Bayes framework provides great flexibility for modelling the intensities of rare variants. Some theoretical properties are also assessed, including weak consistency of our Dirichlet Process-Poisson-Gamma mixture over multiple resolutions. Simulation studies illustrate excellent small sample properties relative to competitors, and we apply the method to detect rare variants related to common variable immunodeficiency from whole exome sequencing data on 215 patients and over 60,027 control subjects.

IgD+IgM- B Cells in Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is the most frequent form of primary hypogammaglobulinemia in adults. In addition to recurrent infections and respiratory manifestations, CVID patients may present several non-infection complications such as autoimmune diseases. The mechanisms that lead to immune dysregulation in CVID are not completely understood. Given the role of IgD on naïve B cells in the maintenance of tolerance and secreted IgD in the respiratory mucosa, we evaluated the frequency of IgD+ naïve and IgD+ memory B cells in CVID patients. Here, no differences were observed in the percentages and proliferative responses of anergic IgD+IgM-CD27- B cells between CVID patients, with or without autoimmune disease, and the control group. Interestingly, in the compartment of memory B cells, the percentage of IgD+IgM- cells was higher only in CVID patients with allergic rhinitis/allergic asthma. Our results may indicate that anergic IgD+IgM-CD27- B cells may not be compromised in our CVID cohort. However, IgD+IgM- memory B cells may play a role in the immunopathogenesis of allergic rhinitis/allergic asthma in CVID patients. Further studies are needed to better understand the participation of IgD+IgM- memory B cells in the immunopathogenesis of allergic rhinitis/allergic asthma in CVID patients.

High Prevalence of Long COVID in Common Variable Immunodeficiency: An Italian Multicentric Study

The long-term effects of SARS-CoV-2 infection represent a relevant global health problem. Long COVID (LC) is defined as a complex of signs and symptoms developed during or after SARS-CoV-2 infection and lasting > 12 weeks. In common variable immunodeficiency (CVID) patients, we previously reported higher risk of hospitalization and death during SARS-CoV-2 infection, as well as prolonged swab positivity and frequent reinfections. The aim of the present study was to assess the risk of LC in an Italian cohort of CVID patients. We used a translated version of the survey proposed by Centers for Disease Control and Prevention (CDC) to collect data on LC. In the enrolled cohort of 175 CVID patients, we found a high prevalence of LC (65.7%). The most frequent LC symptoms were fatigue (75.7%), arthralgia/myalgia (48.7%), and dyspnea (41.7%). The majority of patients (60%) experienced prolonged symptoms, for at least 6 months after infection. In a multivariate analysis, the presence of complicated phenotype (OR 2.44, 95% CI 1.88–5.03; p = 0.015), obesity (OR 11.17, 95% CI 1.37–90.95; p = 0.024), and female sex (OR 2.06, 95% CI 1.09–3.89; p = 0.024) significantly correlated with the development of LC. In conclusion, in this multicenter observational cohort study, we demonstrated that CVID patients present an increased prevalence of LC when compared to the general population. Improved awareness on the risk of LC in CVID patients could optimize management of this new and alarming complication of SARS-CoV-2 infection.

Bone Mineral Density is Related to CD4+ T Cell Counts and Muscle Mass is Associated with B Cells in Common Variable Immunodeficiency Patients.

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by chronic/recurrent respiratory infections, bronchiectasis, autoimmunity, inflammatory, gastrointestinal diseases and malignancies associated with a chronic inflammatory state and increased risk of osteoporosis and muscle loss. The aim of this study was to evaluate bone mineral density (BMD), body composition and their relationship with lymphocyte subpopulations in CVID patients. Dual-energy X-ray absorptiometry was performed to assess BMD, lean mass, and fat mass in CVID patients. Peripheral blood CD4+, CD8+, and CD19+ cells were measured using flow cytometry. Thirty-three patients (37.3 ± 10.8 years old) were examined. Although only 11.8% of the individuals were malnourished (BMI <18.5 kg/m2), 27.7% of them had low skeletal muscle mass index (SMI), and 57.6% of them had low BMD. Patients with osteopenia/osteoporosis presented lower weight (p = 0.007), lean mass (p = 0.011), appendicular lean mass (p = 0.011), SMI (p = 0.017), and CD4+ count (p = 0.030). Regression models showed a positive association between CD4+ count and bone/muscle parameters, whereas CD19+ B cell count was only associated with muscle variables. Analysis of ROC curves indicated a cutoff value of CD4+ count (657 cells/mm3; AUC: 0.71, 95% CI 0.52-0.90) which was related to low BMD. Weight (p = 0.004), lean mass (p = 0.027), appendicular lean mass (p = 0.022), SMI (p = 0.029), total bone mineral content (p = 0.005), lumbar (p = 0.005), femoral neck (p = 0.035), and total hip BMD (p<0.001) were found to be lower in patients with CD4+ count below the cutoff. CVID patients presented with low BMD, which was associated with CD4+ count. Moreover, low muscle parameters were correlated with B cell count.

Equine common variable immunodeficiency: Lessons from 100 clinical cases

SummaryThe clinical manifestation of recurrent fevers and infections alerts the clinician to the possibility of an underlying immunodeficiency. Common variable immunodeficiency (CVID) in the horse is a rare late‐onset, nonfamilial immunological disorder of B cell depletion and/or dysfunction with resultant inadequate antibody production. The most common clinical presentations in horses with CVID are recurrent upper and/or lower respiratory infections, meningitis and/or ataxia, cholangiohepatitis, infectious colitis, infectious dermatitis and severe gastrointestinal parasitism. Immune‐mediated and lymphoproliferative conditions are additional clinical features. The diagnosis of CVID in horses is based on a persistent hypogammaglobulinaemia primarily caused by a serum IgG concentration below 10.00 g/L in at least two different measurements, often accompanied by a serum IgM concentration below 0.50 g/L. Most horses with CVID show a persistent peripheral blood B cell distribution below 6% of total circulating lymphocytes, indicating severe B cell paucity or depletion, but the B cell distribution can be within the normal reference interval. Post‐mortem findings add diagnostic information about the distribution of B and T cells in lymphoid tissues. Clinical management of horses with immunodeficiency is intense and expensive, and these factors weigh on the difficult decision of elective euthanasia. To date, no genetic mutation has been identified in horse patients with CVID, and the large number of breeds of single‐affected individuals in a same herd or immediate lineage from various parts of the United States and the world do not point at an obvious inheritable mechanism of disease or environmental risk factors. This article describes the clinical and immunological findings in 100 equine cases, and comparisons with the disease in human patients.

BIOLOGICS AND SMALL MOLECULES USED IN IBD MIMICS: HIGHLIGHTING THE IMPORTANCE OF DIAGNOSIS CONFIRMATION

Abstract INTRODUCTION Since 2009, inflammatory bowel disease (IBD) specialists have been utilizing “IBD Live,” a weekly live video conference with a global audience of 150-200 participants, to discuss the multidisciplinary management of their commonly seen and most challenging cases. While most cases presented were confirmed as IBD, a substantial number were mimics for which IBD was not the ultimate diagnosis. We previously categorized all IBD Live cases and identified the frequency of “IBD mimics.” Here, we examine the use of biologic medications for these cases which ultimately were determined to be something other than IBD. METHODS Cases have been recorded and archived since May 2018. 371 total cases from May 2018 through February 2023 were reviewed spanning 186 hours. 65 of those cases were determined to be IBD mimics, defined as those with features of IBD that ultimately resulted in a non-IBD diagnosis. IBD mimics were analysed and categorized in terms of their biologic usage. RESULTS 25 of the 65 mimics (38.5%) were treated with biologics for presumed IBD. 14 were treated with one biologic, 5 with two biologics, and 6 with three or more biologics. The biologics used in the management of these IBD mimics included infliximab (n=21), vedolizumab (n=12), adalimumab (n=11), ustekinumab (n=6), and certolizumab (n=1). Of the 25 cases of biologic usage without definitive confirmation of IBD, 6 ended up with a diagnosis where biologics were an appropriate treatment for the mimic. These mimics included drug-induced colitis (n=3), Behcet’s disease (n=1), segmental colitis associated with diverticulosis (SCAD; n=1), and CTLA-4 haploinsufficiency with autoimmune infiltrates (CHAI; n=1). Several of the IBD mimics were prescribed steroids, azathioprine, mercaptopurine, or methotrexate, and 3 were trialled on tofacitinib (for Sweet’s syndrome, PIK3cd, and SCAD). There were 3 patients with confirmed IBD, in remission on a biologic, who subsequently had symptoms concerning for an IBD flare. In each of these cases, IBD was not the cause of their symptoms (e.g., cecal volvulus). There were 4 patients with confirmed IBD, in remission off biologics, who later developed symptoms suspicious for an IBD flare. Each of these cases was trialled on biologics to treat the supposed flare; however, symptoms were ultimately found to be due to an IBD mimic (e.g., eosinophilic esophagitis). 33 of the 65 IBD mimics were never treated with biologics. DISCUSSION In a 5-year period at IBD Live, 17.5% of cases (65 of 371) were found to be IBD mimics. 38.5% (25 of 65) of these were treated with biologics. The diverse presentation of signs and symptoms of IBD and IBD mimics requires reassessment of the biologic therapy in patients without response. Often the biologic needs to be optimized for IBD, but in some cases, the diagnosis of IBD will need to be called into question. Table 1 IBD mimics and biologics used Abbreviations BADAS = bowel-associated dermatosis-arthritis syndrome, BCL = B-cell lymphoma, CD = Crohn’s Disease, CHAI = CTLA-4 haploinsufficiency with autoimmune infiltrates, C-MUSE = cryptogenic multifocal ulcerous stenosing enteritis, CMV = cytomegalovirus, CVID = common variable immunodeficiency, EGPA = eosinophilic granulomatosis with polyangiitis, GABA = gamma-aminobutyric acid, IBD = inflammatory bowel disease, IMHMV = idiopathic myointimal hyperplasia of the mesenteric veins, PIK3cd = phosphatidylinositol-4,5-bisphosphonate 3-kinase catalytic subunit delta, PNH = paroxysmal nocturnal hemoglobinuria, SCAD = segmental colitis associated with diverticulosis, STI = sexually transmitted infection, UC = Ulcerative Colitis. Image 1: Biologic usage in IBD mimics

Association Between Cytometric Biomarkers, Clinical Phenotype, and Complications of Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is a heterogeneous group of immune disorders. The patients are classified according to the clinical manifestation with the infection-only phenotype (CVIDinf) and CVID with immune dysregulation (CVIDid). We performed a retrospective clinical analysis of 64 CVID patients (34 males, 53.13%; mean age: 41.4 years; SD: ±21.4 years). We divided the patients into subgroups according to the clinical manifestation (CVIDinf andCVIDid) and according to B cell phenotypic profiling after performing flow cytometry with the use of the EUROclass classification. We compared clinical manifestations, selected laboratory parameters, and therapy in these groups. All CVIDid patients were tested after the manifestation of complications associated with immune dysregulation and in eight patients during the immunosuppressive treatment (systemic corticosteroids and hydroxychloroquine). Two-thirds of patients in our cohort had symptoms resulting from immune dysregulation. Almost half of the patients had autoimmune complications. A higher proportion of marginal zone B cells was associated with autoimmune complications. A lower percentage of naïve B cells was connected to autoimmunity, whereas a lower proportion of transitional B cells was associated with rheumatic diseases and splenomegaly. Patients with lymphadenopathy had a higher percentage of double-negative T cells and a lower percentage of switched memory B cells. We performed molecular-genetic testing in 28% (n = 17) of patients and found a causal pathogenic variant in 23.5% (n = 4) of this group. Based on our results, there is an association between specific cytometric parameters, clinical phenotype, and complications of CVID. The use of the subpopulations of B cells can be helpful in the diagnosis of these specific clinical complications in CVID patients and could help to personalise the therapeutic approach.

Role of Skewed X-Chromosome Inactivation in Common Variable Immunodeficiency.

The term common variable immunodeficiency (CVID) encompasses a clinically diverse group of disorders, mainly characterized by hypogammaglobulinemia, insufficient specific antibody production, and recurrent infections. The genetics of CVID is complex, and monogenic defects account for only a portion of cases, typically <30%. Other proposed mechanisms include digenic, oligogenic, or polygenic inheritance and epigenetic dysregulation. In this study, we aimed to assess the role of skewed X-chromosome inactivation (XCI) in CVID. Within our cohort of 131 genetically analyzed CVID patients, we selected female patients with rare variants in CVID-associated genes located on the X-chromosome. Four patients harboring heterozygous variants in BTK (n = 2), CD40LG (n = 1), and IKBKG (n = 1) were included in the study. We assessed XCI status using the HUMARA assay and an NGS-based method to quantify the expression of the 2 alleles in mRNA. Three of the 4 patients (75%) exhibited skewed XCI, and the mutated allele was predominantly expressed in all cases. Patient 1 harbored a hypomorphic variant in BTK (p.Tyr418His), patient 3 had a pathogenic variant in CD40LG (c.288+1G>A), and patient 4 had a hypomorphic variant in IKBKG (p.Glu57Lys) and a heterozygous splice variant in TNFRSF13B (TACI) (c.61+2T>A). Overall, the analysis of our cohort suggests that CVID in a small proportion of females (1.6% in our cohort) is caused by skewed XCI and highly penetrant gene variants on the X-chromosome. Additionally, skewed XCI may contribute to polygenic effects (3.3% in our cohort). These results indicate that skewed XCI may represent another piece in the complex puzzle of CVID genetics.

Influence of Splenomegaly and Splenectomy on the Immune Cell Profile of Patients with Common Variable Immunodeficiency Disease.

About 25% of patients with common variable immunodeficiency disease (CVID) have splenomegaly, necessitating sometimes splenectomy whom consequences on the immunological profile of CVID patients have never been studied. We analyzed 11 CVID patients' comprehensive blood immune cell phenotypes pre- and post-splenectomy. Flow cytometry analyses of immune cell populations. Among 89 CVID cohort patients, 41 with splenomegaly, splenomegaly was strongly associated with granulomatous disease, autoimmune disorders, lymphoid hyperplasia, and/or portal hypertension. CVID patients with splenomegaly have significant peripheral lymphopenia (p = 0.001), and significantly fewer peripheral class-switched memory B cells (smBs) (p = 0.001), CD4+ T lymphocytes (p = 0.001), NK (p = 0.0001) and dendritic cells (p ≤ 0.01), and significantly more circulating CD4+ and CD8+ (p = 0.00001) T cell subset activation (p = 0.00005), than CVID patients without splenomegaly. Examination of splenectomy impact on circulating lymphocyte subset distributions demonstrated the drastically enhanced total circulating lymphocyte count post-splenectomy, predominantly B lymphocytes and CD8+ T cells. However, splenectomy did not change B cell distribution, with smBs remaining persistently low, in contrast to complete inversion of the circulating T cell composition, with reversal of the CD4+/CD8+ ratio suggesting that amplification of the CD8+ T cell compartment is a CVID characteristic in patients with splenomegaly. Our results highlight this CD8+ amplification in CVID-splenomegaly patients that might be explained by a homing effect to the spleen and/or possible chronic virus replication, which in turn could induce T cell expansions. Splenectomizing CVID patients with splenomegaly restores the absolute circulating lymphocyte count, suggesting that the decreased T cell count in the presence of splenomegaly cannot be used as an exclusive criterion for combined immunodeficiency.

Shorter antitubercular therapy for extrapulmonary tuberculosis - a case report

IntroductionExtrapulmonary tuberculosis (EPTB) adds to India’s significant economic burden, with pericardial effusion being a potentially fatal complication. This case report highlights the need for early diagnosis and the feasibility of shorter-duration treatment for EPTB in developing countries.PresentationThis case report describes a 19-year-old male from Southeast Asia who had a history of bronchiectasis involving the left lower lobe and the right middle lobe, which was cystic in nature, as well as multiple episodes of non-tuberculous pneumonia. Currently, he presented with fever, hypotension, tachycardia, and acute kidney injury. Echocardiogram showed left ventricular dysfunction with a left ventricular ejection fraction (LVEF) of 45% and moderate pericardial effusion. Early signs of cardiac tamponade were noted, specifically the absence of respiratory variation in the right ventricle and left ventricle collapse. Emergent pericardiocentesis was performed, and hemorrhagic pericardial fluid was aspirated. Fluid analysis revealed high levels of LDH (5000 U/L), polymorphonuclear leukocytosis, and acid-fast bacilli that were visualized on microscopy, which led to the diagnosis of pericardial tuberculosis. A CT of the abdomen showed hepatosplenomegaly and polyserositis. Empirically, antitubercular therapy consisting of isoniazid, rifampin, pyrazinamide, and ethambutol was administered for 2 months and isoniazid along with rifampicin was given for the next 4 months. Serial echocardiograms in the following months showed an improvement in LVEF (55%) and decreased effusion. However, during this treatment period, due to frequent episodes of pneumonia, the evaluation of immunodeficiency disorders was performed and revealed low levels of IgG (4.741 g/L), IgA (0.238 g/L), and IgM (0.098 g/L). He was diagnosed with common variable immunodeficiency disease and received intravenous immunoglobulin therapy.ConclusionThis report emphasizes the timely identification of cardiac tamponade and the effective management of EPTB through a shorter-than-recommended course of antitubercular therapy, resulting in the alleviation of symptoms and better overall health outcomes.

Evaluation of the Effectiveness of the 6 Warning Signs of the European Society for Immunodeficiencies for Primary Immunodeficiencies in Older Adults

Introduction: Diagnostic delay in cases of primary immunodeficiency (PID) is a significant problem for clinicians, and most do not have sufficient awareness of this uncommon disorder. The European Society for Immunodeficiencies (ESID) has developed 6 warning signs to increase awareness of adult PIDs. The aim of this study was to determine the prevalence of PID in older adults regardless of the reason for presentation and to evaluate the effectiveness of the 6 warning signs of ESID in the diagnosis of PIDs. Methods: The study included 1,331 patients aged ≥65 years who presented at our clinic for any reason and were questioned about the ESID 6 warning signs for PIDs. After the exclusion of reasons for secondary immunodeficiency (SID), all the patients underwent immunological evaluation for the diagnosis of potential underlying PIDs. Results: After excluding 6 patients diagnosed with SID, PID was diagnosed in 16 (1.2%) of 1,325 older adults using ESID warning signs. The most common reasons for presentation were infection (69%) in the PID group and urticaria and/or angioedema (41.5%) in the non-PID group. The most common PID subgroup was common variable immunodeficiency (50%). In 12 of the patients diagnosed with PID, there was at least 1 positive ESID warning sign. In 4 patients, PID was determined despite negative ESID warning signs. The patients diagnosed with PID showed a significant, minimal level of agreement with questions 1 and 4 of the ESID warning signs (p < 0.001, ĸ = 0.204, p = 0.005, ĸ = 0.208, respectively). Conclusion: The ESID warning signs do not encompass all the symptoms and findings of PIDs. There is a need for more infection-centered questions to determine PIDs in older adults. Therefore, the ESID warning signs should be further developed.

Genetics and clinical phenotypes in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is one of the most common symptomatic groups of inborn errors of immunity. In addition to infections resulting from insufficient levels of immune globulins and antibodies, many patients develop inflammatory or autoimmune conditions, which are associated with increased mortality. This aspect of CVID has been the focus of many studies, and dissecting the clinical phenotypes of CVID, has had the goal of providing biomarkers to identify these subjects, potentially at the time of diagnosis. With the application of whole exome (WES) and whole genome analyses, an increasing number of monogenic causes of CVID have been elucidated. From the standpoint of the practicing physician, an important question is whether the clinical phenotype, particularly the occurrence of autoinflammation of autoimmunity, might suggest the likelihood of identifying a causative mutation, and if possible the gene most likely to underlie CVID. We addressed this question in a patient group of 405 subjects diagnosed with CVID from one medical center.

Inborn errors of immunity with kidney and urinary tract disorders: a review.

Human inborn errors of immunity (IEIs), previously referred to as primary immunodeficiency disorders (PIDs), are a heterogeneous spectrum of inherited abnormalities of the immune system with different organ involvement. The number of identified IEIs is rapidly increasing, highlighting the non-negligible role of an interdisciplinary approach in clinical diagnosis. Kidney disorders are one of the important comorbidities in some of the affected patients and play a significant role in the diagnosis and course of disease. According to recent studies, 22 types of human IEI with renal manifestations have been identified so far, including immunodeficiency with congenital thrombocytopenia, thymic defects with additional congenital anomalies, complement deficiencies, type 1 interferonopathies, immunity related to non-hematopoietic tissues, congenital neutropenia's, common variable immunodeficiency disorder (CVID) phenotype and immuno-osseous dysplasia. Based on this classification, we herein review IEIs with renal features and explain the genetic defect, inheritance, and type of renal manifestations.

Target genes regulated by CLEC16A intronic region associated with common variable immunodeficiency

BackgroundCLEC16A intron 19 has been identified as a candidate locus for common variable immunodeficiency (CVID). ObjectiveThe objective of this study is to elucidate the molecular mechanism by which variants at the CLEC16A intronic locus may contribute to the pathogenesis of CVID. MethodsWe performed fine-mapping of the CLEC16A locus in a CVID cohort, then deleted the candidate functional SNP in T-cell lines by the CRISPR-Cas9 technique and conducted RNA-seq to identify target gene(s). The interactions between the CLEC16A locus and its target genes were identified using Circularized Chromosome Conformation Capture. The transcription factor complexes mediating the chromatin interactions were determined by proteomic approach. The molecular pathways regulated by the CLEC16A locus were examined by RNA-seq and reverse phase protein array. ResultsOur study showed that the CLEC16A locus is an enhancer regulating expression of multiple target genes including a distant gene ATF7IP2 through chromatin interactions. Distinct transcription factor complexes mediate the chromatin interactions in an allele-specific manner. Disruption of the CLEC16A locus affects the AKT signaling pathway, as well as the molecular response of CD4+T cells to immune stimulation. ConclusionThrough multi-omics and targeted experimental approaches, we elucidated the underlying target genes and signaling pathways involved in the genetic association of CLEC16A with CVID, and highlighted plausible molecular targets for developing novel therapeutics.

Expression of IL-17RA in Innate Cells of Patients with Common Variable Immunodeficiency (CVID) and its Clinical Implications.

Background. Common Variable Immunodeficiency (CVID) is a primary immunodeficiency disorder characterized by B-cell dysfunction and immunoglobulin production deficiency. Dysregulation of interleukin-17 (IL-17) and its receptor IL-17RA have been reported in various immune disorders. This study aimed to investigate the expression of IL-17RA in innate immune cells of CVID patients and its correlation with clinical manifestations. Methods. A cross-sectional study included 22 CVID patients and 14 age- and sex-matched healthy controls. IL-17RA expression was assessed in various immune cell subsets using flow cytometry. Demographic and clinical data were collected, and statistical analysis was performed. Results. CVID patients had elevated IL-17RA expression in neutrophils, non-classical monocytes, and dendritic cells compared to healthy controls. Patients with a history of intestinal microbial colonization, particularly with Campylobacter jejuni and Giardia intestinalis, showed significantly higher IL-17RA expression in innate cells. Elevated IL-17RA expression in monocytes and dendritic cells also correlated with higher fecal calprotectin levels in CVID patients, regardless of microbial colonization. Conclusions. The study suggests that despite previous reports of reduced circulating Th17 cells and IL-17 levels in CVID patients, IL-17RA expression in innate cells may be elevated, potentially indicating altered IL-17 signaling. This heightened IL-17RA expression could contribute to a persistent pro-inflammatory state, possibly due to microbial translocation or other inflammatory factors. The association of IL-17RA expression with gastrointestinal microbial colonization and its correlation with fecal calprotectin underscores the complexity of IL-17RA's role in CVID pathophysiology. Further research in larger cohorts could elucidate the implications of IL-17RA expression in both infectious and non-infectious inflammatory aspects of CVID.

Complications of untreated hypogammaglobulinemia in a patient with common variable immunodeficiency – A case report

Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder characterized by decreased or undetectable serum levels of immunoglobulin G (IgG), decreased levels of IgA isotypes, and poor specific antibody production in response to vaccines and pathogens. Owing to hypogammaglobulinemia, patients have increased susceptibility to infections and a higher risk of malignancies. Here we present a case study of patient with a diagnosis of CVID, who refused immunoglobulin replacement therapy despite plenty of complications. Patient suffered from recurrent respiratory and digestive tract infections, diarrhea, malnutrition, infection of the central nervous system, and autoimmune complications. The complications of untreated hypogammaglobulinemia eventually led to the death of the patient at the age of 63 years. Patients with CVID have an increased susceptibility to chronic infections and subsequent complications; hence, proper treatment with immunoglobulin replacement therapy should be administered. Owing to the increased risk of autoimmunity and malignancy, regular surveillance should be conducted in patients with CVID. Understanding the natural history of untreated hypogammaglobulinemia emphasizes the need for early diagnosis, appropriate treatment, and vigilant follow-up in patients with CVID.

Pathogenic TNFRSF13B Variant in an Adult Japanese Patient with Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is a primary B cell immunodeficiency disorder. Symptoms do not develop immediately after birth, and patients are often diagnosed in childhood and adulthood. These patients often develop autoimmune diseases and malignant tumors. We herein report a 50-year-old woman with severe hypogammaglobulinemia and recurrent respiratory tract infections who was diagnosed with CVID. Target sequencing showed a TNFRSF13B heterozygous frameshift variant. The patient had many comorbidities, probably caused by a CVID-induced immune imbalance. Physicians who treat adult patients are often unaware of CVID. CVID should be recognized as a differential diagnosis in hypogammaglobulinemia and recurrent infections.