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Introduction: Inborn errors of immunity (IEIs) refer to a heterogeneous category of diseases with defects in the number and/or function of components of the immune system. Immunoglobulin A (IgA) deficiency is the most prevalent IEI characterized by low serum level of IgA and normal serum levels of IgG and/or IgM. Most of the individuals with IgA deficiency are asymptomatic and are only identified through routine laboratory tests. Others may experience a wide range of clinical features including mucosal infections, allergies, and malignancies as the most important features. IgA deficiency is a multi-complex disease, and the exact pathogenesis of it is still unknown., Areas Covered: This review compiles recent research on genetic and epigenetic factors that may contribute to the development of IgA deficiency. These factors include defects in B-cell development, IgA class switch recombination, synthesis, secretion, and the long-term survival of IgA switched memory B cells and plasma cells., Expert Opinion: A better and more comprehensive understanding of the cellular pathways involved in IgA deficiency could lead to personalized surveillance and potentially curative strategies for affected patients, especially those with severe symptoms.

Celiac disease is a common gastroenterological illness. Current diagnostics of the disease are based on serological markers and histology of duodenal biopsies. Hitherto, a strict gluten-free diet is the only effective treatment and is necessary for good control of the disease. Serological tests in current use have very high specificity and sensitivity for diagnostics, but in follow-up they have some limitations. Their levels do not accurately reflect mucosal healing, and they are unable to detect minimal transgressions in the diet. This problem is significant in patients with IgA deficiency, and there exist no robust follow-up tools for monitoring these patients' adherence to treatment. For their follow-up, we currently use IgG-based tests, and these antibodies persist for a long time even when a patient has stopped consuming gluten. More accurate and specific biomarkers are definitely needed. Adherence to a gluten-free diet is essential not only for intestinal mucosa healing and alleviation of symptoms but also for preventing complications associated with celiac disease. Here, we summarize current evidence regarding noninvasive biomarkers potentially useful for follow-up not only of patients with IgA deficiency but for all patients with celiac disease. We describe several very promising biomarkers with potential to be part of clinical practice in the near future.

Background: Whether coeliac disease in adults can be diagnosed with serology alone remains controversial. We aimed to evaluate the accuracy of serum anti-tissue transglutaminase IgA (tTG-IgA) in the diagnosis of coeliac disease., Methods: In this multicentre, prospective cohort study, adult participants (aged ≥18 years) with suspected coeliac disease without IgA deficiency who were not on a gluten-free diet and who had a local serum tTG-IgA measurement, were enrolled from Feb 27, 2018, to Dec 24, 2020, by 14 tertiary referral centres (ten from Europe, two from Asia, one from Oceania, and one from South America) to undergo local endoscopic duodenal biopsy. Local serum tTG-IgA was measured with 14 different test brands and concentration expressed as a multiple of each test's upper limit of normal (ULN), and defined as positive when greater than 1 times the ULN. The main study outcome was the reliability of serum tests for the diagnosis of coeliac disease, as defined by duodenal villous atrophy (Marsh type 3 or Corazza-Villanacci grade B). Histology was evaluated by the local pathologist, with discordant cases (positive tTG-IgA without duodenal villous atrophy or negative tTG-IgA with duodenal villous atrophy) re-evaluated by a central pathologist. The reliability of serum tests for the prediction of duodenal villous atrophy was evaluated according to sensitivity, specificity, positive predictive value, negative predictive value, and the area under the receiver operating characteristic curve (AUC) for categorical and continuous data., Findings: We enrolled 436 participants with complete local data on serum tTG-IgA and duodenal histology (296 [68%] women and 140 [32%] men; mean age 40 years [SD 15]). Positive serum tTG-IgA was detected in 363 (83%) participants and negative serum tTG-IgA in 73 (17%). Of the 363 participants with positive serum tTG-IgA, 341 had positive histology (true positives) and 22 had negative histology (false positives) after local review. Of the 73 participants with negative serum tTG-IgA, seven had positive histology (false negatives) and 66 had negative histology (true negatives) after local review. The positive predictive value was 93·9% (95% CI 89·2-98·6), the negative predictive value was 90·4% (85·5-95·3), sensitivity was 98·0% (95·3-100·0), and specificity was 75·0% (66·6-83·4). After central re-evaluation of duodenal histology in 29 discordant cases, there were 348 true positive cases, 15 false positive cases, 66 true negative cases, and seven false negative cases, resulting in a positive predictive value of 95·9% (92·0-99·8), a negative predictive value of 90·4% (85·5-95·3), a sensitivity of 98·0% (95·3-100·0), and a specificity of 81·5% (73·9-89·1). Either using the local or central definition of duodenal histology, the positive predictive value of local serum tTG-IgA increased when the serological threshold was defined at increasing multiples of the ULN (p<0·0001). The AUC for serum tTG-IgA for the prediction of duodenal villous atrophy was 0·87 (95% CI 0·81-0·92) when applying the categorical definition of serum tTG-IgA (positive [>1 × ULN] vs negative [≤1 × ULN]), and 0·93 (0·89-0·96) when applying the numerical definition of serum tTG-IgA (multiples of the ULN). Additional endoscopic findings included peptic gastritis (nine patients), autoimmune atrophic gastritis (three), reflux oesophagitis (31), gastric or duodenal ulcer (three), and Barrett's oesophagus (one). In the 1-year follow-up, a midgut ileum lymphoma was diagnosed in a woman on a gluten-free diet., Interpretation: Our data showed that biopsy could be reasonably avoided in the diagnosis of coeliac disease in adults with reliable suspicion of coeliac disease and high serum tTG-IgA., Funding: None., Competing Interests: Declaration of interests GLN is an employee of Werfen. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The prevalence of Celiac Disease (CD) in Juvenile Idiopathic Arthritis (JIA) has been reported to be 0.1-7% in various small studies. As a result of the limited number of research and their inconclusive results there are no clear recommendations for routine CD screening in asymptomatic patients with JIA. Our aim is to estimate the prevalence of IgA deficiency and tissue transglutaminase (tTG) IgA in a cohort of JIA followed in two large academic medical centers., Methods: Serum was collected and stored from all subjects and analyzed in a reference laboratory for total IgA (Quantitative Nephelometry) and tTG IgA antibody levels (Semi-Quantitative Enzyme-Linked Immunosorbent Assay). Fisher's exact tests were performed for statistical significance. Risk estimates (odds ratios) with 95% confidence intervals were calculated., Results: 808 JIA cases and 140 controls were analyzed. Majority were non-Hispanic whites (72% vs. 68% p = 0.309). A total of 1.2% of cases were IgA deficient compared to none of the controls (p = 0.373). After excluding IgA deficient subjects, 2% of cases had tTG IgA ≥ 4u/mL compared to 3.6% of controls (p = 0.216) (OR = 0.5; 95% C.I = 0.1-1.4); and 0.8% of cases had tTG IgA > 10u/mL compared to 1.4% of controls (p = 0.627) (OR = 0.5; 95%C.I = 0.1-2.9)., Conclusions: Using the largest JIA cohort to date to investigate prevalence of celiac antibodies, the prevalence of positive tTG IgA was 0.8% and of IgA deficiency was 1.2%. The results did not demonstrate a higher prevalence of abnormal tTG IgA in JIA. The study did not support the routine screening of asymptomatic JIA patients for CD., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Secretory IgA interacts with commensal bacteria, but its impact on human mycobiota ecology has not been widely explored. In particular, whether human IgA-deficiency is associated with gut fungal dysbiosis remains unknown., Objectives: Our goal was to study the impact of IgA on gut mycobiota ecology., Methods: The Fungi-Flow method was used to characterize fecal, systemic, and maternal IgA, IgM, and IgG responses against 14 representative fungal strains (yeast/spores or hyphae forms) in healthy donors (HDs) (n = 34, 31, and 20, respectively) and to also compare gut mycobiota opsonization by secretory antibodies in HDs (n = 28) and patients with selective IgA deficiency (SIgAd) (n = 12). Stool mycobiota composition was determined by internal transcribed spacer gene sequencing in HDs (n = 23) and patients with SIgAd (n = 17). Circulating CD4 + T-cell cytokine secretion profiles were determined by intracellular staining. The impact of secretory IgA, purified from breast milk (n = 9), on Candidaalbicans growth and intestinal Caco-2 cell invasion was tested in vitro., Results: Homeostatic IgA binds commensal fungi with a body fluid-selective pattern of recognition. In patients with SIgAd, fungal gut ecology is preserved by compensatory IgM binding to commensal fungi. Gut Calbicans overgrowth nevertheless occurs in this condition but only in clinically symptomatic patients with decreased T H 17/T H 22 T-cell responses. Indeed, secretory IgA can reduce in vitro budding and invasion of intestinal cells by Calbicans and therefore exert control on this pathobiont., Conclusion: IgA has a selective impact on Calbicans ecology to preserve fungal-host mutualism., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The ability of most patients with selective immunoglobulin A (IgA) deficiency (SIgAD) to remain apparently healthy has been a persistent clinical conundrum. Compensatory mechanisms, including IgM, have been proposed, yet it remains unclear how secretory IgA and IgM work together in the mucosal system and, on a larger scale, whether the systemic and mucosal anti-commensal responses are redundant or have unique features. To address this gap in knowledge, we developed an integrated host-commensal approach combining microbial flow cytometry and metagenomic sequencing (mFLOW-Seq) to comprehensively define which microbes induce mucosal and systemic antibodies. We coupled this approach with high-dimensional immune profiling to study a cohort of pediatric patients with SIgAD and household control siblings. We found that mucosal and systemic antibody networks cooperate to maintain homeostasis by targeting a common subset of commensal microbes. In IgA-deficiency, we find increased translocation of specific bacterial taxa associated with elevated levels of systemic IgG targeting fecal microbiota. Associated features of immune system dysregulation in IgA-deficient mice and humans included elevated levels of inflammatory cytokines, enhanced follicular CD4 T helper cell frequency and activation, and an altered CD8 T cell activation state. Although SIgAD is clinically defined by the absence of serum IgA, the symptomatology and immune dysregulation were concentrated in the SIgAD participants who were also fecal IgA deficient. These findings reveal that mucosal IgA deficiency leads to aberrant systemic exposures and immune responses to commensal microbes, which increase the likelihood of humoral and cellular immune dysregulation and symptomatic disease in patients with IgA deficiency.

The increase in life expectancy can be a consequence of the world's socioeconomic, sanitary and nutritional conditions. Some studies have demonstrated that individuals with a satisfactory diet variety score present a lower risk of malnutrition and better health status. Zinc and selenium are important micronutrients that play a role in many biochemical and physiological processes of the immune system. Deficient individuals can present both innate and adaptive immunity abnormalities and increased susceptibility to infections. Primary immunodeficiency diseases, also known as inborn errors of immunity, are genetic disorders classically characterized by an increased susceptibility to infection and/or dysregulation of a specific immunologic pathway. IgA deficiency (IgAD) is the most common primary antibody deficiency. This disease is defined as serum IgA levels lower than 7 mg/dL and normal IgG and IgM levels in individuals older than four years. Although many patients are asymptomatic, selected patients suffer from different clinical complications, such as pulmonary infections, allergies, autoimmune diseases, gastrointestinal disorders and malignancy. Knowing the nutritional status as well as the risk of zinc and selenium deficiency could be helpful for the management of IgAD patients., Objectives: to investigate the anthropometric, biochemical, and nutritional profiles and the status of zinc and selenium in patients with IgAD., Methods: in this descriptive study, we screened 16 IgAD patients for anthropometric and dietary data, biochemical evaluation and determination of plasma and erythrocyte levels of zinc and selenium., Results: dietary intake of zinc and selenium was adequate in 75% and 86% of the patients, respectively. These results were consistent with the plasma levels (adequate levels of zinc in all patients and selenium in 50% of children, 25% of adolescents and 100% of adults). However, erythrocyte levels were low for both micronutrients (deficiency for both in 100% of children, 75% of adolescents and 25% of adults)., Conclusion: our results highlight the elevated prevalence of erythrocyte zinc and selenium deficiency in patients with IgAD, and the need for investigation of these micronutrients in their follow-up.

SARS-CoV-2, the agent responsible for COVID-19, has wreaked havoc around the globe. Hundreds of millions of individuals have been infected and well over six million have died from COVID-19. Many COVID-19 survivors have ongoing physical and psychiatric morbidity, which will remain for the rest of their lives. Early in the pandemic, it became apparent that older individuals and those with comorbidities including obesity, diabetes mellitus, coronary artery disease, hypertension, and renal and pulmonary disease were at increased risk of adverse outcomes. It is also clear that some immunodeficient patients, such as those with innate or T cell-immune defects, are at greater risk from COVID-19. Selective IgA deficiency (sIgAD) is generally regarded as a mild disorder in which most patients are asymptomatic because of redundancy in protective immune mechanisms. Recent data indicate that patients with sIgAD may be at high risk of severe COVID-19. SARS-CoV-2 gains entry primarily through the upper respiratory tract mucosa, where IgA has a critical protective role. This may underlie the vulnerability of sIgAD patients to adverse outcomes from COVID-19. This perspective highlights the need for ongoing research into mucosal immunity to improve COVID-19 treatments for patients with sIgAD., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The diagnosis of celiac disease (CD) at the first diagnostic step requires the detection of specific class A antibodies to tissue transglutaminase type-2 (TG2 IgA) and the measurement of total immunoglobulin A (tIgA) to exclude IgA deficiency. The aim of the study was to evaluate the new quantitative immunoassay panel allowing for the detection of celiac-specific antibodies with the simultaneous determination of tIgA from the same sample of blood at one time. This retrospective study included 104 pediatric patients divided into groups with recognized CD and IgA deficiency (n = 20; 19%), immunocompetent children with CD (n = 28; 27%), children with IgA deficiency and without CD (n = 28; 27%), and the control group of immunocompetent children without CD (n = 28; 27%). Intestinal biopsy with histopathological evaluation (except five patients with CD who were diagnosed without biopsy) and measurement of reference celiac specific antibodies were performed in all children. Multiparametric quantitative immunoassay Polycheck ® Celiac IgA plus total IgA test was used to evaluate its usefulness in CD screening and IgA deficiency diagnosis. The statistical analysis showed the high sensitivity and specificity of both TG2 IgA and tIgA on the multiparametric panel (sensitivity 96% and 100%; specificity 100% and 79%, respectively). The accuracy and area under the ROC curve for tIgA were 0.904 and 0.955, while for TG2 IgA they were 0.982 and 1.000, respectively. Although the sensitivity of IgA antibodies against deaminated gliadin peptides was low (20%), the specificity reached 100%. The study showed that Polycheck ® Celiac IgA plus total IgA test is a specific and sensitive tool for simultaneous serological CD screening and recognition of IgA deficiency.

IgA deficiency is the commonest immunodeficiency affecting up to 1 in 700 individuals. The effects of IgA deficiency are difficult to see in many individuals, are mild in many fewer and severe in fewer still. While monovalent IgA is found in serum, dimeric IgA is secreted through mucosal surfaces where it helps to maintain epithelial homeostasis. Studies with knockout mice have taught us that there are subtle inflammatory consequences of removing secretory IgA (sIgA), and the best explanation for these changes can be related by the loss of the 'excretory' immune system. The excretion of antigens is a logical process in regulating the immune system, given the long half-life of complement fixing antibodies. But the function of IgA as an immune or inflammation regulator may go beyond antigen removal., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Strugnell.)

Background: The spontaneously hypertensive rat (SHR) is extensively used to study hypertension. Gut microbiota dysbiosis is a notable feature in SHR for reasons unknown. Immunoglobulin A (IgA) is a major host factor required for gut microbiota homeostasis. We hypothesized that inadequate IgA contributes to gut microbiota dysbiosis in SHR., Methods: IgA was measured in feces, cecum, serum, liver, gut-associated lymphoid tissue, and milk from SHR and Wistar Kyoto rats. IgA regulatory factors like IgM, IgG, and pIgR (polymeric immunoglobulin receptor) were analyzed. IgA and IgG antibodies and blood pressure (BP) were measured before and after administrating a bacterial antigen (ie, flagellin)., Results: Compared with Wistar Kyoto rats, SHR displayed remarkably near-deficient IgA levels accompanied by compensatory increases in serum IgM and IgG and gut-liver pIgR expression. Inadequate milk IgA in SHR emphasized this immune defect stemmed from the neonatal stage. Reduced IgA + B cells in circulation and Peyer patches indicated a possible reason for the lower IgA in SHR. Noteworthy, a genetic insufficiency was unlikely because administering flagellin to SHR induced anti-flagellin IgA antibodies. This immune response surprisingly accelerated hypertension development in SHR, suggesting IgA quiescence may help maintain lower BP., Conclusions: This study is the first to reveal IgA deficiency in SHR as one host factor associated with gut microbiota dysbiosis and invigorates future research to determine the pathophysiological role of IgA in hypertension.

Although some adults infected with influenza 2009 A(H1N1)pdm09 viruses mounted high hemagglutination inhibition (HAI) antibody response, they still suffered from severe disease, or even death. Here, we analyzed antibody profiles in patients (n = 31, 17-65 years) admitted to intensive care units (ICUs) with lung failure and invasive mechanical ventilation use due to infection with A(H1N1)pdm09 viruses during 2009-2011. We performed a comprehensive analysis of the quality and quantity of antibody responses using HAI, virus neutralization, biolayer interferometry, enzyme-linked-lectin and enzyme-linked immunosorbent assays. At time of the ICU admission, 45% (14/31) of the patients had HAI antibody titers ≥ 80 in the first serum (S1), most (13/14) exhibited narrowly-focused HAI and/or anti-HA-head binding antibodies targeting single epitopes in or around the receptor binding site. In contrast, 42% (13/31) of the patients with HAI titers ≤ 10 in S1 had non-neutralizing anti-HA-stem antibodies against A(H1N1)pdm09 viruses. Only 19% (6/31) of the patients showed HA-specific IgG1-dominant antibody responses. Three of 5 fatal patients possessed highly focused cross-type HAI antibodies targeting the (K130 + Q223)-epitopes with extremely low avidity. Our findings suggest that narrowly-focused low-quality antibody responses targeting specific HA-epitopes may have contributed to severe infection of the lower respiratory tract., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objectives: (1) To describe the prevalence of IgA deficiency (IgAD), uveitis, coeliac disease (CD) and thyroid disorders in a multicentric cohort of patients diagnosed with JIA and, (2) to evaluate whether patients with JIA and IgAD present other autoimmune diseases more frequently than patients with normal serum levels of IgA., Methods: Retrospective chart review of a cohort of patients diagnosed with JIA followed at the paediatric rheumatology units of two hospitals in Madrid, Spain., Results: A total of 193 patients were included. Of them, 123 were females (64%). Median age at disease onset was 5.6 years (IQR 2.5-9.7) and the median time of follow-up was 5.1 years (IQR 2.2-8.1). The three most common ILAR categories were oligoarticular (53%), polyarticular RF negative (20%) and enthesitis related arthritis (10%). Serum IgA levels were available in 172/193 (89%); 25/172 (15%) had selective (<7mg/dl, n=8) or partial (7-69mg/dl, n=17) IgAD. All the patients had periodic eye exams. Eighteen children (9%) had anterior uveitis, 15/18 chronic and 3/18 acute. Serum anti transglutaminase IgA, or IgG in IgAD were obtained in 135/193 (70%). Four children (3%) were diagnosed with CD either by intestinal biopsy (n=3) or by the combination of characteristic clinical, serological and genetic features (n=1); two of them had IgAD (p=0.12; OR=6.4; 95% CI 0.9-47.6). Only 1/153 (0.7%) patient had hyperthyrotropinemia with positive anti-thyroid antibodies and required replacement therapy., Conclusion: Patients with JIA frequently present autoimmune comorbidities. IgAD does not seem to increase their prevalence, with the possible exception of CD., (Copyright © 2022 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

The majority of primary immunodeficiencies (PIDs) are antibody deficiencies (PADs), and not all of them are rare diseases; As an example, Caucasian individuals suffer from selective IgA deficiency at a frequency of 1:500. In addition to infections, symptomatic patients with PAD are more likely to develop neoplastic, autoimmune, and allergic diseases. In the event that PAD is neglected or delayed for more than ten years, complications develop, eventually resulting in death. No studies have been conducted to devise and report detailed ready-to-use protocols for managing PAD to date. This study aimed to propose protocols and guidelines for the adult PAD patients' standard care. Preparing the protocol, we considered the frequency and type of laboratory tests, imaging, endoscopic examinations, specialist consultations, and standardized recommendations for further care in the place of residence.  As a result of the proposed monitoring scheme, patients can be provided with complete care in terms of their underlying conditions and comorbidities, as well as early detection of complications. This protocol will serve as a guide for physicians dealing with these patients and enable comparisons of patient groups across a variety of treatment centers, even far away from each other. A national consultant in the field of clinical immunology verified the protocol mainly developed by Polish experts from reference immunology centres for adults.

IgA deficiency is more common in patients with coeliac disease (CD). Total IgA levels are often recommended as part of first line coeliac testing along with anti-tissue transglutaminase (tTG) IgA, to identify these patients and reduce falsely negative results. This study aimed to identify patients with complete IgA deficiency by determining a cut-off threshold on chemiluminescent tTG IgA testing. A chemiluminescent assay QUANTA Flash h-tTG was reviewed using the BIO-FLASH automated platform. tTG relative light units (RLU) were analysed in relation to total IgA levels. Correlation analysis was performed and distributions of tTG RLU were compared between the IgA deficient and IgA detectable groups, and ROC analysis was performed to identify a suitable threshold. A total of 203 samples were reviewed in our initial cohort. There was a strong correlation between IgA and tTG RLU levels (Pearson correlation coefficient 0.495, p<0.001). There was a statistically significant difference of 170.57 RLU between the means of the IgA deficient and IgA detectable group (p<0.001, 156.50-184.64). A receiver operating characteristic (ROC) curve was generated with area under the curve of 0.997. A cut-off of less than 300 tTG RLU for identification of IgA deficiency was chosen, which had a sensitivity and specificity of 100% and 98.9%, respectively. A prospective validation cohort was conducted which confirmed the initial results. Our study has validated an algorithm to identify complete IgA deficiency by implementing a threshold of 300 RLU during tTG IgA testing by chemiluminescent immunoassay. This approach resulted in a sensitivity of 100% to detect patients with complete IgA deficiency. Widespread uptake would result in improved workflow, workload and turnaround time, and reduce the need for unnecessary blanket testing of total IgA in the screening for coeliac disease., (Copyright © 2022 Royal College of Pathologists of Australasia. All rights reserved.)

Purpose: Selective IgA deficiency (IgAD) is the most common primary immunodeficiency, frequently leading to only minor clinical complaints. IgAD may be associated with autoimmune diseases such as celiac disease (CeD). Although IgAD is thought to precede CeD and autoimmunity, the association between the two conditions has not been clarified., Methods: Routine techniques were used to measure serum IgA and celiac diagnostic markers as transglutaminase 2 IgA (TG2-IgA) and deamidated gliadin IgG and for immunohistochemistry for IgG, IgM, and IgA., Results: We report two childhood cases of complete IgA deficiency that evolved after the diagnosis of CeD and the start of a gluten-free diet. Histology showed persistence of IgA in the intestinal mucosa., Conclusion: Both children with CeD showed IgA deficiency that unexpectedly developed after the initiation of a gluten-free diet. This supports IgA deficiency as a process that develops gradually and occurs due to specific defects in immunoregulation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Inborn errors of immunity, mainly Predominantly Antibody deficiencies with normal IgG levels are unrecognized in adults with lung diseases such as bronchiectasis or recurrent pneumonia., Objective: To determine IgM, IgA, IgG2 subclass deficiencies, and Specific antibody deficiency (anti-pneumococcal polysaccharide antibodies) in adults with non-cystic fibrosis bronchiectasis or recurrent pneumonia., Methods: Cross-sectional study. Consecutive patients with non-cystic fibrosis bronchiectasis or recurrent pneumonia were recruited in Cali, Colombia. IgG, IgA, IgM, and IgE, IgG2subclass and IgG anti-pneumococcal serum levels were measured., Results: Among the 110 participants enrolled, Antibody deficiencies with normal serum IgG levels were found in 11(10%) cases. IgA deficiency (3 cases), IgM deficiency (2 cases) and IgG2 deficiency (2 cases) were the most frequent primary immunodeficiencies. In addition, IgG2+IgA deficiency, Ataxia-telangiectasia, Hyper-IgE syndrome and Specific Antibody Deficiency(anti-polysaccharides) were found in one case each., Conclusions: Predominantly antibody deficiencies with normal IgG levels are an important etiology of non-cystic fibrosis bronchiectasis and recurrent pneumonia in adults., Competing Interests: Conflict of interest: Los autores no presentan conflictos de intereses asociados con esta publicación y que no ha habido un apoyo financiero significativo para este trabajo que pueda haber influido en su resultado., (Copyright © 2022 Colombia Medica.)

Background: Primary antibody deficiencies (PADs) without an identified monogenetic origin form the largest and most heterogeneous group of primary immunodeficiencies. These patients often remain undiagnosed for years and many present to medical attention in adulthood after several infections risking structural complications. Not much is known about their treatment, comorbidities, or prognosis, nor whether the various immunological forms (decreased total IgG, IgG subclass(es), IgM, IgA, specific antibody responses, alone or in combination(s)) should be considered as separate, clearly definable subgroups. The unclassified primary antibody deficiency (unPAD) study aims to describe in detail all PAD patients without an identified specific monogenetic defect regarding their demographical, clinical, and immunological characteristics at presentation and during follow-up. In constructing these patterns, the unPAD study aims to reduce the number of missed and unidentified PAD patients in the future. In addition, this study will focus on subclassifying unPAD to support the identification of patients at higher risk for infection or immune dysregulation related complications, enabling the development of personalized follow-up and treatment plans., Methods and Analysis: We present a protocol for a multicenter observational cohort study using the ESID online Registry. Patients of all ages who have given informed consent for participation in the ESID online Registry and fulfill the ESID Clinical Working Definitions for 'unclassified antibody deficiency', 'deficiency of specific IgG', 'IgA with IgG subclass deficiency', 'isolated IgG subclass deficiency', 'selective IgM deficiency', 'selective IgA deficiency' or 'common variable immunodeficiency' will be included. For all patients, basic characteristics can be registered at first registration and yearly thereafter in level 1 forms. Detailed characteristics of the patients can be registered in level 2 forms. Consecutive follow-up forms can be added indefinitely. To ensure the quality of the collected data, all data will be fully monitored before they are exported from the ESID online Registry for analysis. Outcomes will be the clinical and immunological characteristics of unPAD at presentation and during follow-up. Subgroup analyses will be made based on demographical, clinical and immunological characteristics., Competing Interests: The authors have declared that no competing interests exist.

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.

Background: Specific Antibody Deficiency (SAD) is a primary immunodeficiency disease (PID) characterized by the occurrence of recurrent infections and inadequate antibody response to polysaccharide new antigens., Objective: This study aims to determine the titer of specific antibodies against unconjugated 23-valent pneumococcal polysaccharide vaccine (PPSV-23), the presence of SAD, and its association with clinical and laboratory findings in Ataxia-telangiectasia (A-T) and selective immunoglobulin A deficiency (SIgAD) patients., Methods: 32 A-T patients and 43 SIgAD patients were included in this cross-sectional study. Samples of the patients were obtained before and three weeks after vaccination with PPSV-23. Specific immunoglobulin G (IgG) directed towards pneumococcal capsular antigen and specific antibodies against whole pneumococcal antigens was measured., Results: Comparison of the response to vaccination revealed that 81.3% of A-T patients and 18.6% of the SIgAD patients had an inadequate response to PPSV-23 (p<0.001). The prevalence of recurrent infection (p=0.034) and pneumonia (p=0.003) in SIgAD patients was significantly higher in non-responders than responders. Likewise, the number of marginal zone B cells (p=0.037), transitional B cells (p=0.019), plasmablasts (p=0.019), CD8+ naïve T cells (p=0.036), and percentage of CD8+ T cells (p=0.047), switched memory B cells (SMB) (p=0.026) and immunoglobulin M (IgM) memory B cells (p=0.022) in SIgAD patients were significantly lower in non-responder group than responder group. In contrast, the percentage of CD4 T+ cells in A-T patients was lower in the non-responder group than responders (p=0.035)., Conclusion: SAD is more frequent in A-T patients than SIgAD patients. The role of SMB and T cells should not be underestimated in SAD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978)., (© 2021. The Author(s).)

Selective IgA deficiency (SIgAD) is defined by the European Society for Immunodeficiencies (ESID) as a serum IgA of less than 0.07g/L in patients greater than 4 years old with normal levels of IgG and IgM, normal vaccine responses, and with the exclusion of secondary causes of hypogammaglobulinemia. When serum IgA level is higher than 0.07g/L but two standard deviations below normal for age, the condition may be referred to as partial IgA deficiency, which is quite common. SIgAD is the most common primary immunodeficiency in Europe (1/600 in France) and most patients with SIgAD are asymptomatic (75-90%). The clinical complications associated with SIgAD include recurrent respiratory infections (in particular involving Haemophilus influenza and Streptococcus pneumoniae) and gastrointestinal (mainly due to Giardialamblia), autoimmune and allergic manifestations (anaphylaxis if blood products with IgA are administrated), inflammatory gastrointestinal disease. There is no specific treatment for SIgAD and each patient must be managed individually. While asymptomatic subjects do not need any treatment, it is still necessary for them to be up-to-date with vaccinations. If the patient experiences recurrent infections, prophylactic antibiotics may be beneficial. Immunoglobulin replacement therapy should be considered in patients with SIgAD and concomitant IgG subclass deficiency. Treatment for autoimmune and allergic manifestations is based on current standards of care for specific disease entities. To improve quality of life and reduce morbidity, an interdisciplinary team approach is essential., (Copyright © 2021 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

A large repertoire of IgA is produced by B lymphocytes with T-independent and T-dependent mechanisms useful in defense against pathogenic microorganisms and to reduce immune activation. IgA is active against several pathogens, including rotavirus, poliovirus, influenza virus, and SARS-CoV-2. It protects the epithelial barriers from pathogens and modulates excessive immune responses in inflammatory diseases. An early SARS-CoV-2 specific humoral response is dominated by IgA antibodies responses greatly contributing to virus neutralization. The lack of anti-SARS-Cov-2 IgA and secretory IgA (sIgA) might represent a possible cause of COVID-19 severity, vaccine failure, and possible cause of prolonged viral shedding in patients with Primary Antibody Deficiencies, including patients with Selective IgA Deficiency. Differently from other primary antibody deficiency entities, Selective IgA Deficiency occurs in the vast majority of patients as an asymptomatic condition, and it is often an unrecognized, Studies are needed to clarify the open questions raised by possible consequences of a lack of an IgA response to SARS-CoV-2., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Quinti, Mortari, Fernandez Salinas, Milito and Carsetti.)

Objective: The aim: To present data on the possibility of occurrence and active progression of generalized periodontitis in persons with secretory immunoglobulin A deficiency and possible methods of its correction., Patients and Methods: Мaterials and methods: Analytical elaboration of scientific and medical literature based on the immunological aspect of generalized periodontitis., Conclusion: Conclusions: The deficiency of secretory immunoglobulin A may occur in cases of primary or secondary insufficiency of the immune system. Selective IgA deficiency is an example of primary insufficiency of the immune system. Secondary immunodeficiency disorders is a clinical and immunological syndrome that develops against the background of a previously normally functioning immune system, characterized by a steady decrease in quantitative or functional indicators of specific or(and) nonspecific factors of immunoresistance. Insufficient awareness of dentists about certain aspects of the etiology and pathogenesis of generalized periodontitis leads to deterioration of treatment results.

OBJECTIVE To study the profile of associated autoimmune diseases in a series of patients with systemic lupus erythematosus (SLE) and see if such associations are linked to IgA deficiency. METHODS Two hundred eighty-one patients with SLE were studied for Ig A levels by nephelometry. Levels equal to or under 0.05g/dL were considered as IgA deficiency. Epidemiological and clinical data, including the presence of associated autoimmune diseases, were extracted from the patient's charts. RESULTS Ig A deficiency was found in 6% of the patients. In 30.2% of SLE patients, there was at least one more autoimmune disease; Hashimoto thyroiditis and Sjögren's syndrome were the most common. No association between the occurrence of associated autoimmune disease with IgA deficiency was found. CONCLUSIONS There is a high prevalence of autoimmune diseases associated with SLE. IgA deficiency does not affect the presence of these associations.

Background: IgA deficiency associated with glomerulonephritis is rare. In particular, there is no prior report regarding the association between IgA deficiency and membranoproliferative glomerulonephritis (MPGN) in children. Herein, we describe the case of a 5-year-old girl with selective IgA deficiency and MPGN., Case Presentation: The patient presented with persisting urinary abnormality and hypocomplementemia following a group A treptococcal infection. Renal biopsy revealed the presence of diffuse mesangial hypercellularity, endocapillary proliferation, and focal thickening of the walls of the glomerular capillaries using light microscopy, with IgG and moderate C3 deposits observed using immunofluorescence. Electron microscopy images revealed nodular deposits in the subendothelial areas, with hump-shaped subepithelial deposits. The pathological diagnosis was confirmed as MPGN. Treatment using oral prednisolone (PSL), mizoribine (MZR), and angiotensin-converting enzyme inhibitors reduced the proteinuria. The PSL dose was gradually tapered, with the low dose of PSL and MZR continued for 4 years. Histological findings were improved on repeated renal biopsy, and PSL and MZR administration was discontinued., Conclusions: We report a rare case of MPGN related to a streptococcal infection in a child. The clinical presentation included selective IgAD, with several pathological findings and a clinical course typical of glomerulopathy. The patient was successfully treated using multidrug therapy.

Immunoglobulin A (IgA) is the principal antibody in secretions that bathe the gastrointestinal and respiratory mucosal surfaces and acts as an important first line of defense against invasion of pathogenic micro-organisms. The reported prevalence rate of complete IgA deficiency in healthy children ranges from 1:170 to 1:400, and as a solitary condition, it is often considered of limited clinical importance. However, patients with IgA deficiency can develop recurrent respiratory and gastrointestinal infections, as well as allergic and autoimmune diseases. In children referred for recurrent respiratory tract infections, the observed prevalence rate increases more than tenfold. This review discusses several aspects of IgA deficiency in children, including immunologic and microbiome changes in early childhood and the potential consequences of this condition in later life. It illustrates the importance of early identification of children with impaired IgA production who deserve appropriate clinical care and follow-up., (Copyright © 2019. Published by Elsevier Inc.)

In a recently published article we report the metagenomic analysis of human gut microbiomes evolved in the absence of immunoglobulin A (IgA). We show that human IgA deficiency is not associated with massive quantitative perturbations of gut microbial ecology. While our study underlines a rather expected pathobiont expansion, we at the same time highlight a less expected depletion in some typically beneficial symbionts. We also show that IgM partially supply IgA deficiency, explaining the relatively mild clinical phenotype associated with the early steps of this condition. Microbiome studies in patients should consider potential issues such as cohort size, human genetic polymorphism and treatments. In this commentary, we discuss how such issues were taken into account in our own study.

Background: Transfusion-associated anaphylaxis has been associated with anti-immunoglobulin A (anti-IgA) of IgG class in patients with IgA deficiency. In recent years, however, the frequency and clinical impact of this syndrome has been questioned. We present a case of recurrent red blood cell (RBC) transfusion-associated anaphylactoid reactions (rigors, hypertension, transient monocytopenia, and neutropenia) associated with anti-IgA., Case Report: An 88-year-old woman developed anemia after a traumatic right humerus fracture. After receiving approximately 100 mL of RBCs she developed rigors and hypertension; her absolute neutrophil and monocyte counts decreased by 73 and 100%, respectively. All symptoms and signs resolved, and her blood counts normalized. A second RBC transfusion was given, with recurrence of rigors, hypertension, neutropenia, and monocytopenia (69 and 100% declines, respectively), along with fever. All tests for hemolysis were negative. She then received two transfusions of washed RBCs, without incident. The patient was found to be deficient in IgA (<0.05 mg/dL). Further, anti-IgA of IgG class antibodies were detected in high levels by enzyme-linked immunosorbent assay (>1000 U/mL). We reviewed case reports, case series, and reviews of IgA deficiency-associated reactions, examining whether hypertensive reactions and acute neutropenia and/or monocytopenia have been associated with anti-IgA reactions., Results: Reports of reactions associated with anti-IgA emphasize hypotension and are generally classified as "anaphylactic or anaphylaxis." No previous reports described neutropenia or monocytopenia., Conclusion: Our case suggests that adverse transfusion reactions associated with anti-IgA of IgG class may sometimes be characterized by anaphylactoid features such as rigors and hypertension, with transient monocytopenia and neutropenia., (© 2018 AABB.)

The use of broad-spectrum antibiotics in empirical antimicrobial therapy is a lifesaving strategy for patients in intensive care. At the same time, antibiotics dramatically increase the risk for nosocomial infections, such as hospital‑acquired pneumonia caused by Pseudomonas aeruginosa, and other antibiotic-resistant bacteria. In this issue of the JCI, Robak and colleagues identified a mechanism by which depletion of resident gut and lung microbiota by antibiotic treatment results in secondary IgA deficiency and impaired anti-P. aeruginosa host defense. Impaired defenses could be improved by substitution of polyclonal IgA via the intranasal route in a mouse model of pneumonia. Importantly, antibiotic treatment caused lung IgA deficiency that involved reduced TLR-dependent production of a proliferation-inducing ligand (APRIL) and B cell-activating factor (BAFF) in intensive care unit patients. These patients might therefore benefit from future strategies to increase pulmonary IgA levels.

The clinical importance of immunoglobulin A (IgA) deficiency in otherwise healthy individuals is not well described. We aimed to investigate the self-reported mental and physical health and the risk of infection in IgA-deficient blood donors compared to healthy control blood donors. Infectious events, recorded in public health registries either as prescriptions filled of any antimicrobial medicine or as hospital infections, were compared between 177 IgA-deficient blood donors and 1770 control blood donors. A subset of the IgA-deficient donors were further characterized by self-reported health (Short Form-12, n = 28) and circulating C-reactive protein (CRP) (n = 10). IgA-deficient individuals had lower self-reported mental health (p = 0.01) and higher CRP (p < 0.05). A strong trend was found regarding prescription of antimicrobial medicine (hazard ratio = 1.19, p = 0.05). No association was found with hospital infections (hazard ratio = 1.02, p = 0.95) or self-reported physical health (p = 0.86). IgA-deficient blood donors have impaired self-reported mental health, enhanced inflammation and possibly an increased risk of infection. Despite these findings, this study does not provide sufficient evidence to warrant specific health precautions for donors with IgA deficiency., (© 2018 APMIS. Published by John Wiley & Sons Ltd.)

We present the case of a 67-year-old man who suffered an acute anaphylactic reaction during red cell transfusion due to the presence of anti-IgA antibodies. The incidence and clinical relevance of anti-IgA antibodies in IgA deficiency is reviewed, and the wider investigation and management of acute transfusion reactions is also discussed. This case highlights the need to consider the potential risks of blood component transfusion against the purported benefit., (© Royal College of Physicians 2018. All rights reserved.)

Common variable immunodeficiency (CVID) and immunoglobulin A deficiency (IgAD) are the most prevalent primary immunodeficiency disorders. High rates of familial inheritance have been described in CVID and IgAD, but it is unknown in different ethnic populations. We aimed to determine the prevalence of familial cases and whether they showed more severe clinical characteristics than sporadic ones in Turkish patients. A total of 40 CVID and 70 IgAD patients and their 251 first-degree relatives (FDRs) were evaluated. Demographic, clinical, and laboratory data were reviewed. A familial case was defined as a patient with at least one affected FDR (A-FDR). The rate of parental consanguinity was 19.1%. There were 37 familial cases (37/110) (33.6%) with at least one A-FDR. There were 48 A-FDRs who had immunoglobulins lower than age-related normals (48/251) (19.1%). Pulmonary infections were significantly higher in familial cases. To our knowledge, this study includes the highest number of CVID/IgAD patients and their FDRs in literature. Familial cases are at least 30% of the IgAD and CVID patients, and they have more frequent lower respiratory tract infections than sporadic ones, so these patients have to be evaluated depending on their being familial or sporadic for better management. The risk of carrying any immunologic alterations in relatives of patients with IgAD and CVID is approximately 20%. Although most A-FDRs are asymptomatic, considering the risk of progression to CVID by age, we highly recommend routine screening for FDRs.

Background: Brucella has been known to cause pyrexia of unknown origin., Case Characteristics: 9-year-old boy with fever and abdominal pain; multiple abscesses within the liver on ultrasonography., Observations: IgM Antibodies against Brucella were raised in his serum sample, and Brucella serum agglutination test was positive. Immunological work-up suggested selective IgA deficiency. Reduction in size following treatment with trimethoprim-sulphamethoxazole, amikacin and doxycycline., Message: Brucellosis should be considered as an etiology of liver abscess in patients not responding to conventional antibiotics.

Background: IgA deficiency is the most common primary immunodeficiency. Early diagnosis and clinical follow-up may improve the quality of life of patients with IgA deficiency. To this end, IgA deficiency should be further studied and better understood on its clinical manifestations., Objective: To determine IgA deficiency clinical manifestations., Methods: Cross-sectional, retrospective, exploratory study, where the medical records of 39 patients with IgA deficiency were analyzed., Results: Among the analyzed cases, 10 patients were diagnosed with total IgA deficiency and 29 patients with partial IgA deficiency. Partial and total IgA deficiency main clinical manifestations were allergic rhinoconjunctivitis and allergic asthma. In total IgA deficiency, in addition to allergic diseases, a statistically significant number (p < 0.05) of cases of infection-related rhinosinusitis, tonsillitis and conjunctivitis were also observed., Conclusion: This study showed that the main clinical manifestations in IgA deficiency were allergic rhinoconjunctivitis and allergic asthma. In addition, patients with total IgA deficiency showed a significant increase in infection-related rhinosinusitis, tonsillitis and conjunctivitis, when compared with patients with partial IgA deficiency.

Lamotrigine (LTG) is an anti-epileptic drug and mood-stabilizing agent, whose adverse effects include skin rash and dizziness. Interactions with the immune system are rare, and only a few cases linking hypogammaglobulinemia to LTG treatment have been previously described. In this report, we describe a case in which a patient developed hypogammaglobulinemia, and a subsequent immunoglobulin A (IgA) deficiency, following LTG treatment. As a result of her immunodeficiency, the patient presented with a severe urinary tract infection and required intravenous immunoglobulin. Serum levels of immunoglobulin G and M had recovered by seven months and one month after the discontinuation of LTG, respectively; however, IgA levels remained low (less than 4mg/dL) two years post-treatment. While previous reports have demonstrated IgA deficiencies in patients prescribed other antiepileptic drugs, this is the first case of an IgA deficiency following LTG administration., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Unlabelled: Objective：To calculate the prevalence of IgAD in a replicate cohort of the Chinese Han population in Shanghai area by screening blood donors and to study the genetic difference of IgAD individuals in the Mongoloid population., Methods: The prevalence of IgAD in a large number of Chinese blood donors (n=61624) in Shanghai area was investigated. The immunoglobulin class, IgG subclass and anti-IgA serum levels were measured among the IgAD donors. These donors were subsequently tissue typed and the allele frequency was compared with the Shanghai bone marrow donor HLA registry., Results: Thirty-one IgAD blood donors were identified, giving a prevalence of 1:2000(31/61624). Most IgAD donors had serum IgG levels above the normal range with no major IgG subclass deficiency and 3 donors was positive for anti-IgA. Two-thirds of the IgAD donors carried Caucasian IgAD associated risk haplotypes, including DRB1*0301-DQB1*0201, DRB1*0701-DQB1*020 and DRB1*0102-DQB1*0501, giving a significantly higher frequency of these haplotypes as compared to the Shanghai bone marrow donor HLA registry., Conclusion: The prevalence of IgAD in Chinese Han population is markedly lower than that in Caucasians. The low prevalence of IgAD can potentially be due to the low frequency of the disease associated risk haplotypes in China. However, potential risks exist in performing blood transfusion to IgAD persons, and measures should be taken to reduce IgA anaphylaxis. Meanwhile, it is necessary to set up a Shanghai rare blood bank of IgAD donor for patients to meet the needs of IgA-poor transfusion.

Common variable immunodeficiency (CVID) and selective IgA deficiency (SIgAD) are the most common primary immunodeficiencies in human. Both diseases share clinical manifestation and molecular defects. Increased apoptosis may be one of the mechanisms involved in the pathogenesis of CVID and SIgAD. Elevated apoptosis in this disorder leads to defective long-term survival of B-cells, reduced antibody production, decreased lymphocyte proliferation and defective cytokine secretion. For the first time, we reviewed the role of apoptosis in CVID and SIgAD., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Selective immunoglobulin A deficiency (SIgAD), the most common primary immunodeficiency, is often asymptomatic. High rates of familial clustering have been described in SIgAD, but the causative genetic defect and mechanism of inheritance are unknown., Objectives: To determine whether familial SIgAD cases show more severe clinical and immunological characteristics than sporadic ones; to investigate the utility of screening first-degree relatives (FDRs) of these patients, and to determine whether symptoms in affected family members are important enough to justify screening., Patients and Methods: Descriptive, cross-sectional study (October 2010-September 2011) of all patients with SIgAD and followed up in our center. Demographic, clinical, and analytical data were reviewed. A familial case was defined as an SIgAD patient with at least one affected FDR., Results: Of the 130 participants, 42 were SIgAD patients and 88 FDR. There were 13 (31%) familial cases and and 14 (16%) affected FDRs. Six family members had to be analyzed in order to detect one affected one. There were no clinical differences between familial and sporadic SIgAD cases. The percentages of intestinal disease (p=001, OR=9.57, 95%CI 2.59-35.3), hospitalizations (p=045, OR=4.01; 95%CI 1.10-14.67], and need for chronic treatment (p=006, OR=5.5; 95%CI 1.57-19.54) were higher in affected FDRs than in unaffected ones., Conclusions: The symptoms were not more severe in familial than sporadic SIgAD cases. Nonetheless, the elevated prevalence of affected FDRs with significant morbidity may justify routine screening of close family members of these patients., (Copyright © 2015 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: To explore the risk of infections in individuals with IgA deficiency compared to general population controls., Methods: In this nationwide prospective population-based cohort study, we used data on IgA levels (<0.07 g/L) from six university hospitals in Sweden to identify 2100 individuals with IgA deficiency. Individuals were diagnosed between 1980 and 2010. For each patient with IgA deficiency we identified 10 controls from the general population, matched on age, sex, and place of residence (n = 18,653). Data on infections were obtained from the Swedish National Patient Register (including inpatient and hospital-based outpatient care) between 2001 and 2010. We defined infections as having a record of a relevant international classification of disease (ICD) code. Prevalences and prevalence ratios (PRs) were calculated., Results: Individuals with IgA deficiency were more likely to have a record of any infection (36.1 vs. 18.8% in controls) corresponding to a PR of 2.4 (95%CI 2.2-2.6). We also noted statistically significant associations with IgA deficiency (all P-values <0.05) and respiratory tract infections (17.8 vs. 6.3% in controls; PR = 3.2), gastrointestinal infections (6.0 vs. 1.8% in controls; PR = 3.5), skin infections (4.1 vs. 2.2% in controls; PR = 1.9), joint infections (0.48 vs. 0.24% in controls; PR = 2.0; P = 0.052), sepsis (1.5 vs. 0.45% in controls; PR = 3.4), meningitis (0.38 vs. 0.12%, PR = 3.2), mastoiditis/otitis (2.1 vs. 1.1% in controls; PR = 2.0), and urinary tract infections (6.1 vs. 3.4% in controls; PR = 1.8)., Conclusions: Individuals with IgA deficiency are at an increased risk of infections requiring hospital care.

Background and Aims: Multiple European studies report increased prevalence of selective immunoglobulin A deficiency (SIgAD) and partial immunoglobulin A deficiency (PIgAD) in patients with celiac disease (CD). However; prospective data representing North American adults are lacking. While SIgAD precludes the use of IgA-tissue-transglutaminase antibody (IgA-tTG), the effect of PIgAD on IgA-tTG sensitivity is not well documented. We aim to determine the prevalence and impact of IgA deficiency on CD presentation and diagnosis in North American adult patients., Methods: We reviewed 1000 consecutive patients undergoing IgA-tTG testing and 243 healthy controls. Eligible sera were tested for IgA-tTG, serum immunoglobulins, and IgA/IgG-deamidated gliadin peptide (IgA/IgG-DGP)., Results: Prevalence of SIgAD was marginally higher in patients with CD (1.9%) compared with healthy controls (0.4%, P = 0.24) and patients without CD (0.7%, P = 0.173). Prevalence of PIGAD was similar in patients with CD (4.8%) compared with healthy controls (5.9%, P = 0.57) and patients without CD (7.2%, P = 0.22). One (16.7%) of 6 patients with CD with SIgAD and all 15 (100%) with PIGAD tested IgA-tTG positive prior to gluten-free diet initiation. Patients with CD with SIGAD showed lower frequency of gastrointestinal symptoms (33% vs 82%, P = 0.01) and more co-morbid autoimmune disease (67% vs 23%, P = 0.03) when compared with patients with CD with normal IgA., Conclusions: The prevalence of SIgAD in North American patients with CD is comparable with European data but not significantly different than control populations. Patients with CD with SIgAD exhibit decreased IgA-tTG sensitivity and lack of gastrointestinal symptoms. PIgAD is common in patients with gastrointestinal disorders but does not alter CD presentation or IgA-tTG sensitivity., (© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)