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Since the start of the COVID-19 pandemic, in a short span of 3 years, vaccination against SARS-CoV-2 has resulted in the end of the pandemic. Patients with inborn errors of immunity (IEI) are at an increased risk for SARS-CoV-2 infection; however, serious illnesses and mortality, especially in primary antibody deficiencies (PADs), have been lower than expected and lower than other high-risk groups. This suggests that PAD patients may mount a reasonable effective response to the SARS-CoV-2 vaccine. Several studies have been published regarding antibody responses, with contradictory reports. The current study is, perhaps, the most comprehensive study of phenotypically defined various lymphocyte populations in PAD patients following the SARS-CoV-2 vaccine. In this study, we examined, following two vaccinations and, in a few cases, prior to and following the 1st and 2nd vaccinations, subsets of CD4 and CD8 T cells (Naïve, T CM , T EM , T EMRA ), T follicular helper cells (T FH1 , T FH2 , T FH17 , T FH1/17 ), B cells (naïve, transitional, marginal zone, germinal center, IgM memory, switched memory, plasmablasts, CD21 low ), regulatory lymphocytes (CD4Treg, CD8Treg, T FR , Breg), and SARS-CoV-2-specific activation of CD4 T cells and CD8 T cells (CD69, CD137), SARS-CoV-2 tetramer-positive CD8 T cells, and CD8 CTL. Our data show significant alterations in various B cell subsets including Breg, whereas only a few subsets of various T cells revealed alterations. These data suggest that large proportions of PAD patients may mount significant responses to the vaccine.

DNA repair defects are heterogenous conditions characterized by a wide spectrum of clinical phenotypes. The common presentations of DNA repair defects include increased risk of cancer, accelerated aging, and defects in the development of various organs and systems. The immune system can be affected in a subset of these disorders leading to susceptibility to infections and autoimmunity. Infections in DNA repair defects may occur due to primary defects in T, B, or NK cells and other factors such as anatomic defects, neurologic disorders, or during chemotherapy. Consequently, the characteristics of the infections may vary from mild upper respiratory tract infections to severe, opportunistic, and even fatal infections with bacteria, viruses, or fungi. Here, infections in 15 rare and sporadic DNA repair defects that are associated with immunodeficiencies are discussed. Because of the rarity of some of these conditions, limited information is available regarding infectious complications.

Purpose: CD8 cytotoxic T cells (CTLs) play a critical role in the clearance of virally infected cells. SARS-CoV-2-specific CD8 T cells and functional CTLs in natural infections and following COVID-19 vaccine in primary antibody deficiency (PAD) have not been reported. In this study, we evaluated T cell response following COVID-19 or COVID-19 mRNA vaccination in patients with PADs by assessing SARS-CoV-2 tetramer-positive CD8 T cells and functional CTLs., Methods: SARS-CoV-2-specific CD8 and functional CTLs were examined in a patient with X-linked agammaglobulinemia (XLA) and a patient with common variable immunodeficiency (CVID) following COVID-19 infection, and in 5 patients with CVID and 5 healthy controls 1 month following 2nd dose of COVID-19 mRNA vaccine (Pfizer-BioNTech). Cells were stained with SARS-CoV-2 spike protein-specific tetramers, and for functional CTLs (CD8 + CD107a + granzyme B + perforin + ), with monoclonal antibodies and isotype controls and analyzed by flow cytometry., Results: SARS-CoV-2-specific tetramer + CD8 T cells and functional CTLs in the patient with XLA following COVID-19 infection were higher, as compared to healthy control subject following COVID-19 infection. On the other hand, SARS-CoV2-tetramer + CD8 T cells and functional CTLs were lower in CVID patient following COVID19 infection as compared to healthy control following COVID-19 infection. SARS-CoV2-tetramer + CD8 T cells and functional CTLs were significantly lower in SARS-CoV2-naive CVID patients (n = 10) following vaccination when compared to SARS-CoV-2-naive healthy vaccinated controls (n = 10)., Conclusions: CVID is associated with reduced SARS-CoV-2-specific CD8 T cells and functional CTLs in both natural SARS-CoV-2 infection and in response to SARS-CoV-2 mRNA vaccine, whereas natural infection in XLA is associated with a robust SARS-CoV-2-specific CD8 and functional CTL responses., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The role of CD4 T regulatory cells is well established in peripheral tolerance and the pathogenesis of the murine model and human autoimmune diseases. CD4 T regulatory cells (CD4 Tregs) have been investigated in common variable immunodeficiency (CVID). Recently, additional members have been added to the club of regulatory lymphocytes. These include CD8 T regulatory (CD8 Tregs), B regulatory (Bregs), and T follicular helper regulatory (T FR ) cells. There are accumulating data to suggest their roles in both human and experimental models of autoimmune disease. Their phenotypic characterization and mechanisms of immunoregulation are evolving. Patients with CVID may present or are associated with an increased frequency of autoimmunity and autoimmune diseases. In this review, we have primarily focused on the characteristics of CD4 Tregs and new players of the regulatory club and their changes in patients with CVID in relation to autoimmunity and emphasized the complexity of interplay among various regulatory lymphocytes. We suggest future careful investigations of phenotypic and functional regulatory lymphocytes in a large cohort of phenotypic and genotypically defined CVID patients to define their role in the pathogenesis of CVID and autoimmunity associated with CVID., 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 © 2022 Gupta, Demirdag and Gupta.)

Introduction: As the prevalence of food allergies (FAs) increases worldwide, our understanding of their pathophysiology and risk factors is markedly expanding. In the past few decades, an increasing number of genes have been linked to FA. Identification of such genes may help in predicting the genetic risk for FA development, age of onset, clinical manifestation, causative allergen(s), and possibly the optimal treatment strategies. Furthermore, identification of these genetic factors can help to understand the complex interactions between genes and the environment in predisposition to FA., Areas Covered: We outline the recent important progress in determining genetic variants and disease-associated genes in IgE-mediated FA. We focused on the monogenic inborn errors of immunity (IEI) where FA is one of the clinical manifestations, emphasizing the genes and gene variants, which were linked to FA with some of the most robust evidence., Expert Opinion: Genetics play a significant role, either directly or along with environmental factors, in the development of FA. As a multifactorial disease, it is expected that multiple genes and genetic loci contribute to the risk for FA development. Identification of the involved genes should contribute to the area of FA regarding pathogenesis, prediction, recognition, prognosis, prevention, and possibly therapeutic interventions.

Purpose of Review: Primary immunodeficiency diseases (PIDs), also called inborn errors of immunity (IEI), are genetic disorders classically characterized by an increased susceptibility to infection and/or disruption in the regulation of an immunologic pathway. This review summarizes and highlights the new IEI disorders in the IUIS 2019 report and 2020 interim report and discusses the directions for the future management of PIDs., Recent Findings: Since 2017, the International Union of Immunologic Societies (IUIS) IEI committee has updated the IUIS classification of IEIs with 88 new gene defects and 75 new immune disorders. The increased utilization of genetic testing and advances in the strategic evaluation of genetic variants have identified, not only novel IEI disorders, but additional genetic causes for known IEI disorders. Investigation of potential immune susceptibilities during the ongoing COVID-19 pandemic suggests that defects in Type I interferon signalling may underlie more severe disease., Summary: The rapid discovery of new IEIs reflects the growing trend of applying genetic testing modalities as part of medical diagnosis and management.In turn, elucidating the pathophysiology of these novel IEIs have enhanced our understanding of how genetic mutations can modulate the immune system and their consequential effect on human health and disease., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by pathogenic variants in the BTK gene, resulting in impaired B cell differentiation and maturation. Over 900 variants have already been described in this gene, however, new pathogenic variants continue to be identified. In this report, we describe 22 novel variants in BTK, associated with B cell deficiency with hypo- or agammaglobulinemia in male patients or in asymptomatic female carriers. Genetic data was correlated with BTK protein expression by flow cytometry, and clinical and family history to obtain a comprehensive assessment of the clinico-pathologic significance of these new variants in the BTK gene. For one novel missense variant, p.Cys502Tyr, site-directed mutagenesis was performed to determine the impact of the sequence change on protein expression and stability. Genetic data should be correlated with protein and/or clinical and immunological data, whenever possible, to determine the clinical significance of the gene sequence alteration., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined., Objective: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors., Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed., Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS., Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Infliximab is a highly effective monoclonal antibody against tumor necrosis factor, which is a major inflammatory mediator in certain gastrointestinal, rheumatic, and skin diseases. In some patients, infliximab infusion causes systemic adverse reactions that often lead to discontinuation of therapy even in responsive patients., Objective: To investigate the frequency and characteristics of adverse reactions to infliximab at the authors' institution and the outcome of their management, including desensitization., Methods: This was a single-center retrospective study of patients who were treated with infliximab, primarily for inflammatory bowel disease, from January 1, 2000 to March 31, 2014. Data included age, sex, underlying disease, infliximab therapy duration before the first reaction, manifestation of reaction, onset, and management., Results: There were 336 patients with inflammatory bowel disease who were treated with infliximab during the study period. Thirty patients (8.9%) developed a systemic adverse reaction to infliximab, which was discontinued in 15 patients (50%) and was continued in 3 patients after premedication and/or decreased infusion rate. Twelve patients (40%) underwent infliximab desensitization with gradually increasing doses starting at a dilution of 0.1 mg/mL to reach the full treatment dose over approximately 4 to 6 hours. It was successful in all 12 patients, who continued to receive up to 26 infliximab infusions, mostly without premedication., Conclusion: Infliximab can trigger systemic reactions that hinder its administration. The present desensitization protocol appears to be safe and effective and it can be considered in patients whose inflammatory bowel disease responds well to infliximab but who develop systemic adverse reactions., (Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Chronic rhinosinusitis (CRS) and asthma frequently coexist in children and adults. However, the precise pathophysiologic mechanism of this interaction is still poorly understood, especially in children, owing to the lack of direct measurements of mucosal inflammation in the upper airways., Objective: To determine the pathophysiologic mechanism by analyzing the expression of a large array of inflammatory cytokines and chemokines in the sinus and adenoid tissues surgically removed from pediatric patients with CRS refractory to medical management., Methods: Twenty-eight children 2 to 12 years old diagnosed with CRS with or without asthma and 10 controls were included in this prospective, nonrandomized study. Mucosal expression of 40 inflammatory cytokines was measured with a multiplex assay and was normalized to total tissue protein., Results: Compared with children with CRS and without asthma, children with CRS and asthma had significantly higher sinus levels of tumor necrosis factor-α and adenoid levels of epidermal growth factor, eotaxin, fibroblast growth factor-2, growth-related oncogene, and platelet-derived growth factor-AA., Conclusion: The inflammatory response in the upper airway mucosa of children with asthma and CRS was similar, but more severe, compared with children with CRS without asthma. This observation is consistent with the hypothesis that asthma in these patients is caused or exacerbated by severe upper airway disease and supports the concept that treating sinus disease is paramount in the management of chronic asthma in children using, for the first time, direct measurements of airway inflammation in children., (Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Recurrent otitis media in children is considered one of the warning signs of primary immunodeficiencies (PIDs), particularly antibody deficiencies. Infants who have the most serious and potentially lethal form of PID, severe combined immunodeficiency (SCID), sometimes present with recurrent otitis media. Most of the time, because of the severity of the immune defect, they develop more serious and systemic infections. SCID is distinct among the PIDs and considered a pediatric emergency. Diagnosing SCID during the newborn period is crucial because survival completely depends on early diagnosis and treatment. Mortality declines significantly if immune reconstitution is established before 3.5 months of age, particularly before severe infections have occurred. However, most patients are diagnosed after they have suffered chronic or recurrent infections and developed permanent sequelae. Without institution of population-based newborn screening, most infants will miss the opportunity to live a healthy life.

We report a 16-year-old male patient who presented with headache, behavior changes, and fever. His cerebral spinal fluid and blood cultures grew Cryptococcus neoformans. His laboratory evaluation was negative for human immunodeficiency virus infection but flow cytometry revealed low CD4(+) count of 39 cells/mm(3) and CD4:CD8 ratio of 0.43. He was initially treated with antifungal agents with only partial clinical improvement, and he was discharged to home on oral fluconazole and prophylactic co-trimoxazole. After discharge, he continued to have persistent headache and recurrent episodes of vomiting. He was readmitted several times because of worsening of meningitis symptoms and received prolonged courses of multiple antifungal therapy, with clearance of infection from the central nervous system. He was subsequently placed on prophylactic therapy with fluconazole. His peripheral CD4(+) cell count remained low after resolution of his meningitis. Eight months after the initial diagnosis, recombinant IL-2 therapy was initiated and within a few months, his CD4(+) cell count started to increase. Treatment with rIL-2 and prophylactic antifungal therapy continued and he has been asymptomatic for almost 20 months so far. This case is the first reported pediatric idiopathic CD4(+) T-lymphocytopenia case with cryptococcal meningitis that was successfully treated by the addition of rIL-2 therapy to antifungal therapy.