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© 2015, The Author(s).We report the updated classification of primary immunodeficiencies compiled by the Primary Immunodeficiency Expert Committee (PID EC) of the International Union of Immunological Societies (IUIS). In the two years since the previous ve

© 2015 Springer Science+Business Media New York There are now nearly 300 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. For each of these five categories, a gr

Cellular metabolism is highly dynamic during hematopoiesis, yet the regulatory networks that maintain metabolic homeostasis during differentiation are incompletely understood. Here, we have studied the grave immunodeficiency syndrome reticular dysgenesis caused by loss of mitochondrial adenylate kinase 2 (AK2) function. By coupling single-cell transcriptomics in reticular dysgenesis patient samples with a CRISPR model of this disorder in primary human hematopoietic stem cells, we found that the consequences of AK2 deficiency for the hematopoietic system are contingent on the effective engagement of metabolic checkpoints. In hematopoietic stem and progenitor cells, including early granulocyte precursors, AK2 deficiency reduced mechanistic target of rapamycin (mTOR) signaling and anabolic pathway activation. This conserved nutrient homeostasis and maintained cell survival and proliferation. In contrast, during late-stage granulopoiesis, metabolic checkpoints were ineffective, leading to a paradoxical upregulation of mTOR activity and energy-consuming anabolic pathways such as ribonucleoprotein synthesis in AK2-deficient cells. This caused nucleotide imbalance, including highly elevated AMP and IMP levels, the depletion of essential substrates such as NAD+ and aspartate, and ultimately resulted in proliferation arrest and demise of the granulocyte lineage. Our findings suggest that even severe metabolic defects can be tolerated with the help of metabolic checkpoints but that the failure of such checkpoints in differentiated cells results in a catastrophic loss of homeostasis., (Copyright © 2024 American Society of Hematology.)

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2 , which encodes G αi2 , a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating G αi2 mutations had clinical presentations that included impaired immunity. Mutant G αi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G αi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)-activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT S6 signaling to drive cellular growth and proliferation.

Abstract: Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder associated with autosomal recessive variants in genes required for perforin-mediated lymphocyte cytotoxicity. A rapid diagnosis is crucial for successful treatment. Although defective cytotoxic T lymphocyte (CTL) function causes pathogenesis, quantification of natural killer (NK)-cell exocytosis triggered by K562 target cells currently represents a standard diagnostic procedure for primary HLH. We have prospectively evaluated different lymphocyte exocytosis assays in 213 patients referred for evaluation for suspected HLH and related hyperinflammatory syndromes. A total of 138 patients received a molecular diagnosis consistent with primary HLH. Assessment of Fc receptor-triggered NK-cell and T-cell receptor (TCR)-triggered CTL exocytosis displayed higher sensitivity and improved specificity for the diagnosis of primary HLH than routine K562 cell-based assays, with these assays combined providing a sensitivity of 100% and specificity of 98.3%. By comparison, NK-cell exocytosis after K562 target cell stimulation displayed a higher interindividual variability, in part explained by differences in NK-cell differentiation or large functional reductions after shipment. We thus recommend combined analysis of TCR-triggered CTL and Fc receptor-triggered NK-cell exocytosis for the diagnosis of patients with suspected familial HLH or atypical manifestations of congenital defects in lymphocyte exocytosis., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Background: Dedicator of cytokinesis 8 (DOCK8)-deficient patients have severe eczema, elevated IgE, and eosinophilia, features of atopic dermatitis (AD)., Objective: We sought to understand the mechanisms of eczema in DOCK8 deficiency., Methods: Skin biopsy samples were characterized by histology, immunofluorescence microscopy, and gene expression. Skin barrier function was measured by transepidermal water loss. Allergic skin inflammation was elicited in mice by epicutaneous sensitization with ovalbumin (OVA) or cutaneous application of Staphylococcus aureus., Results: Skin lesions of DOCK8-deficient patients exhibited type 2 inflammation, and the patients' skin was colonized by Saureus, as in AD. Unlike in AD, DOCK8-deficient patients had a reduced FOXP3:CD4 ratio in their skin lesions, and their skin barrier function was intrinsically intact. Dock8 -/- mice exhibited reduced numbers of cutaneous T regulatory (Treg) cells and a normal skin barrier. Dock8 -/- and mice with an inducible Dock8 deletion in Treg cells exhibited increased allergic skin inflammation after epicutaneous sensitization with OVA. DOCK8 was shown to be important for Treg cell stability at sites of allergic inflammation and for the generation, survival, and suppressive activity of inducible Treg cells. Adoptive transfer of wild-type, but not DOCK8-deficient, OVA-specific, inducible Treg cells suppressed allergic inflammation in OVA-sensitized skin of Dock8 -/- mice. These mice developed severe allergic skin inflammation and elevated serum IgE levels after topical exposure to Saureus. Both were attenuated after adoptive transfer of WT but not DOCK8-deficient Treg cells., Conclusion: Treg cell dysfunction increases susceptibility to allergic skin inflammation in DOCK8 deficiency and synergizes with cutaneous exposure to Saureus to drive eczema in DOCK8 deficiency., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Aims: To understand the characteristics of combined immunodeficiency disorders that affect cellular and humoral immunity (CID) in the Arabian Peninsula., Methods: Retrospective study of 236 patients with CID from the region were enrolled from 2004 to 2022., Results: 236 patients were included with a majority being profound CID. Among patients with a family history of CID, the ages at onset and diagnosis, and the delay in diagnosis were lower compared to those with no family history of CID, but this did not affect time to transplant. HSCT was performed for 51.27% of the patients with median time from diagnosis to HSCT of 6.36 months. On multivariate analysis, patients who underwent early transplant had increased odds of having CD3 count ≤1000 cell/μl, diagnosed by screening or erythroderma., Conclusion: There is a delay in diagnosis and treatment of CID in our region. Establishing newborn screening programs and HSCT units in our region are the urgent need., Competing Interests: Declaration of Competing Interest none., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The recently emerged novel coronavirus, "severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)," caused a highly contagious disease called coronavirus disease 2019 (COVID-19). It has severely damaged the world's most developed countries and has turned into a major threat for low- and middle-income countries. Since its emergence in late 2019, medical interventions have been substantial, and most countries relied on public health measures collectively known as nonpharmaceutical interventions (NPIs). We aimed to centralize the accumulative knowledge of NPIs against COVID-19 for each country under one worldwide consortium. International COVID-19 Research Network collaborators developed a cross-sectional online survey to assess the implications of NPIs and sanitary supply on the incidence and mortality of COVID-19. The survey was conducted between January 1 and February 1, 2021, and participants from 92 countries/territories completed it. The association between NPIs, sanitation supplies, and incidence and mortality were examined by multivariate regression, with the log-transformed value of population as an offset value. The majority of countries/territories applied several preventive strategies, including social distancing (100.0%), quarantine (100.0%), isolation (98.9%), and school closure (97.8%). Individual-level preventive measures such as personal hygiene (100.0%) and wearing facial masks (94.6% at hospitals; 93.5% at mass transportation; 91.3% in mass gathering facilities) were also frequently applied. Quarantine at a designated place was negatively associated with incidence and mortality compared to home quarantine. Isolation at a designated place was also associated with reduced mortality compared to home isolation. Recommendations to use sanitizer for personal hygiene reduced incidence compared to the recommendation to use soap. Deprivation of masks was associated with increased incidence. Higher incidence and mortality were found in countries/territories with higher economic levels. Mask deprivation was pervasive regardless of economic level. NPIs against COVID-19 such as using sanitizer, quarantine, and isolation can decrease the incidence and mortality of COVID-19., (© 2022 Wiley Periodicals LLC.)

Human inborn errors of immunity (IEI) are a group of 485 distinct genetic disorders affecting children and adults. Signs and symptoms of IEI are heterogeneous, and accurate diagnosis can be challenging and depends on the available human expertise and laboratory resources. The Middle East and North Africa (MENA) region has an increased prevalence of IEI because of the high rate of consanguinity with a predominance of autosomal recessive disorders. This area also exhibits more severe disease phenotypes compared with other regions, probably due to the delay in diagnosis. The MENA-IEI registry network has designed protocols and guidelines for the diagnosis and treatment of IEI, taking into consideration the variable regional expertise and resources. These guidelines are primarily meant to improve the care of patients within the region, but can also be followed in other regions with similar patient populations., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Hereditary angioedema (HAE), a potentially life-threatening genetic disorder due to C1 inhibitor deficiency in most cases, is characterized by sudden and/or recurrent attacks of angioedema (subcutaneous/submucosal swellings). The global World Allergy Organization (WAO)/European Academy of Allergy and Clinical Immunology (EAACI) International guideline for HAE management is comprehensive, but the implementation of this guideline may require regional adaptation considering the diversity in disease awareness, type of medical care systems, and access to diagnostics and treatment. The aim of this Delphi initiative was to build on the global guideline and provide regional adaptation to address the concerns and specific needs in the Middle East., Methods: The Consensus panel comprised 13 experts from the Middle East (3 from the United Arab Emirates, 3 from Saudi Arabia, 2 from Lebanon, 2 from Kuwait, 2 from Oman and 1 from Qatar) who have more than 2 decades of experience in allergy and immunology and are actively involved in managing HAE patients. The process that was carried out to reach the consensus recommendation included: 1.) A systematic literature review for articles related to HAE management using Ovid MEDLINE. 2.) The development of a questionnaire by an internationally acclaimed expert, with 10 questions specific to HAE management in the Middle East. 3.) Experts received the questionnaire via email individually and their answers were recorded (email/interview). 4.) A virtual consensus meeting was organized to discuss the questionnaire, make amends if needed, vote, and achieve consensus., Results: The questionnaire comprised 10 questions, each with 2 or more statements/recommendations on which the regional experts voted. A consensus was reached based on a 70% agreement between the participants. The key highlights include: 1) HAE experts in the Middle East emphasized the importance of a positive family history for arriving at a diagnosis of HAE. 2) The number of episodes per month or per 6-month period and severity should be used, together with other markers, to determine the need for prophylaxis. 3) Disease status should be monitored by periodic visits and the use of patient-reported outcome measures such as the angioedema activity score and the angioedema control test. 4) Attenuated androgens and tranexamic acid may be considered for long-term prophylaxis, if lanadelumab, C1-Inhibitor or berotralstat are not available., Conclusion: This consensus recommendation may help to educate healthcare practitioners in the Middle East and unify their approach to the diagnosis and management of HAE., (© 2022 The Authors.)

Background: There is an increased demand for hematopoietic stem cell transplant (HSCT) to treat various diseases including combined immunodeficiencies (CID), with limited worldwide availability. Variables affecting the decision regarding CID patients' prioritization for HSCT are not known. We aimed to determine general, clinical, and immunologic factors associated with the higher risk of early death (≤6 months after diagnosis) in untransplanted CID patients., Methods: Data collection was done retrospectively from five centers and included general patients' information, and clinical and laboratory variables. Inclusion criteria were untransplanted patients who are either dead or alive with a follow-up period ≥6 months after diagnosis., Results: Two hundred and thirty-six CID patients were reported by participating centers, of whom 111 were included in the study with a cumulative follow-up period of 278.6 years. Seventy-two patients died with the median age of death of 10.5 months. 35.1% of the patients succumbed within 6 months after the diagnosis. Having a history of Candida infections, sepsis or hepatomegaly was associated with an increased risk of early death. None of the other general or clinical variables was associated with such risk. Bivariate analysis of lymphocyte subsets showed that patients with the following counts: CD3 +  < 100, CD4 +  < 200, CD8 +  < 50, or CD16 + CD56 + <200 cells/μl had increased risk of early death. In adjusted analysis, increased risk of early death was observed among patients with CD3 + count <100 cells/μl., Conclusion: Combined immunodeficiencies patients with a history of Candida infections, sepsis, hepatomegaly, or severe T-lymphopenia should be given priority for HSCT to avoid early death., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Aims: To present the details of Bacillus Calmette-Guérin (BCG)-vaccine associated complications (VACs) in combined immunodeficiencies (CID) patients., Methods: Five centers participated in this retrospective study and completed a data form, which included general patients' information, clinical and laboratory data., Results: Among 236 CID patients, 127 were BCG vaccinated. 41.9% of patients with family history of CID and 17.1% who were diagnosed by screening were BCG vaccinated. Twenty-three patients (18.1%) developed BCG-VACs. The median age of VACs was 6 months and the median time from vaccination to complications was 6 months. The highest rate of BCG-VACs was recorded in patients receiving the Russian BCG strain compared to the Tokyo and Danish strains. Univariate analysis of T-lymphocyte subsets showed increased odds of BCG complications in patients with CD3+, CD4+, and CD8+ counts of ≤250 cells/µL. Only CD8 + count ≤250 cells/µL had increased such odds on multivariate analysis. VACs were disseminated in 13 and localized in 10 patients. Localized complication occurred earlier after vaccination (median: 4 months) compared with disseminated ones (median: 7 months). There were no significant associations between sex, administered vaccine strain, serum immunoglobulins levels, lymphocyte subsets counts, and the chance of having either localized or disseminated BCG-related complications., Coclusions: Although contraindicated, many patients with CID continue to be vaccinated with BCG. Low CD8 + count is a risk factor for BCG-related complications and localized complications occurred earlier than disseminated ones. Considerations should be undertaken by health care authorities especially in countries with high incidence of CID to implement newborn screening, delay the time of BCG vaccine administration beyond 6 months of age and to use the relatively safer strains like the Danish and Tokyo ones., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Monogenic immune dysregulation diseases (MIDD) are caused by defective immunotolerance. This study was designed to increase knowledge on the prevalence and spectrum of MIDDs, genetic patterns, and outcomes in Middle East and North Africa (MENA). MIDD patients from 11 MENA countries (Iran, Turkey, Kuwait, Oman, Algeria, Egypt, United Arab Emirates, Tunisia, Jordan, Qatar, and Azerbaijan) were retrospectively evaluated. 343 MIDD patients (58% males and 42% female) at a median (IQR) age of 101 (42-192) months were enrolled. The most common defective genes were LRBA (23.9%), LYST (8.2%), and RAB27A (7.9%). The most prevalent initial and overall manifestations were infections (32.2% and 75.1%), autoimmunity (18.6% and 41%), and organomegaly (13.3% and 53.8%), respectively. Treatments included immunoglobulin replacement therapy (53%), hematopoietic stem cell transplantation (HSCT) (14.3%), immunosuppressives (36.7%), and surgery (3.5%). Twenty-nine (59.2%) patients survived HSCT. Along with infectious complications, autoimmunity and organomegaly may be the initial or predominant manifestations of MIDD., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases., (© 2022. The Author(s).)

Background: Lymphocyte differentiation is regulated by coordinated actions of cytokines and signaling pathways. IL-21 activates STAT1, STAT3, and STAT5 and is fundamental for the differentiation of human B cells into memory cells and antibody-secreting cells. While STAT1 is largely nonessential and STAT3 is critical for this process, the role of STAT5 is unknown., Objectives: This study sought to delineate unique roles of STAT5 in activation and differentiation of human naive and memory B cells., Methods: STAT activation was assessed by phospho-flow cytometry cell sorting. Differential gene expression was determined by RNA-sequencing and quantitative PCR. The requirement for STAT5B in B-cell and CD4 + T-cell differentiation was assessed using CRISPR-mediated STAT5B deletion from B-cell lines and investigating primary lymphocytes from individuals with germline STAT5B mutations., Results: IL-21 activated STAT5 and strongly induced SOCS3 in human naive, but not memory, B cells. Deletion of STAT5B in B-cell lines diminished IL-21-mediated SOCS3 induction. PBMCs from STAT5B-null individuals contained expanded populations of immunoglobulin class-switched B cells, CD21 lo Tbet + B cells, and follicular T helper cells. IL-21 induced greater differentiation of STAT5B-deficient B cells into plasmablasts in vitro than B cells from healthy donors, correlating with higher expression levels of transcription factors promoting plasma cell formation., Conclusions: These findings reveal novel roles for STAT5B in regulating IL-21-induced human B-cell differentiation. This is achieved by inducing SOCS3 to attenuate IL-21 signaling, and BCL6 to repress class switching and plasma cell generation. Thus, STAT5B is critical for restraining IL-21-mediated B-cell differentiation. These findings provide insights into mechanisms underpinning B-cell responses during primary and subsequent antigen encounter and explain autoimmunity and dysfunctional humoral immunity in STAT5B deficiency., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) reports here the 2022 updated phenotypic classification, which accompanies and complements the most-recent genotypic classification. This phenotypic classification is aimed for clinicians at the bedside and focuses on clinical features and laboratory phenotypes of specific IEI. In this classification, 485 IEI underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity and auto-inflammation are described, including 55 novel monogenic defects and 1 autoimmune phenocopy. Therefore, all 485 diseases of the genetic classification are presented in this paper in the form of colored tables with essential clinical or immunological phenotype entries., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an 'experiment of nature' to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent 'domino effect' that impacts stringency of tolerance and B cell fate in the periphery., (© 2022. The Author(s).)

Background: Allergies have long been observed in Inborn Errors of Immunity (IEI) and might even be the first presentation resulting in delayed diagnosis or misdiagnosis in some cases. However, data on the prevalence of allergic diseases among IEI patients are limited and contradictory., Objective: To provide a worldwide view of allergic diseases, across a broad spectrum of IEI, and their impact on the timely diagnosis of IEI., Methods: This is a worldwide study, conceived by the World Allergy Organization (WAO) Inborn Errors of Immunity Committee. A questionnaire was developed and pilot-tested and was sent via email to collect data from 61 immunology centers known to treat pediatric and/or adult IEI patients in 41 countries. In addition, a query was submitted to The United States Immunodeficiency Network (USIDNET) at its website., Results: Thirty centers in 23 countries caring for a total 8450 IEI patients responded. The USIDNET dataset included 2332 patients. Data from responders showed that a median (IQR) of 16.3% (10-28.8%) of patients experienced allergic diseases during the course of their IEI as follows: 3.6% (1.3-11.3%) had bronchial asthma, 3.6% (1.9-9.1%) atopic dermatitis, 3.0% (1.0-7.8%) allergic rhinitis, and 1.3% (0.5-3.3%) food allergy. As per the USIDNET data, the frequency of allergy among IEI patients was 68.8% (bronchial asthma in 46.9%). The percentage of IEI patients who presented initially with allergic disorders was 8% (5-25%) and diagnosis delay was reported in 7.5% (0.9-20.6%). Predominantly antibody deficiencies had the highest frequency of allergic disease followed by combined immunodeficiency with a frequency of 40.3% (19.2-62.5%) and 20.0% (10-32%) respectively. As per the data of centers, anaphylaxis occurred in 25/8450 patients (0.3%) whereas per USIDNET dataset, it occurred in 249/2332 (10.6%); drugs and food allergy were the main causes in both datasets., Conclusions: This multinational study brings to focus the relation between allergic diseases and IEI. Major allergies do occur in IEI patients but were less frequent than the general population. Initial presentation with allergy could adversely affect the timely diagnosis of IEI. There is a need for policies to raise awareness and educate primary care and other referring specialties on the association of allergic diseases with IEI. This study provides a network among centers for future prospective studies in the field., Competing Interests: The authors declare that they have no competing interests., (© 2022 The Authors.)

Rubella virus (RuV) has recently been found in association with granulomatous inflammation of the skin and several internal organs in patients with inborn errors of immunity (IEI). The cellular tropism and molecular mechanisms of RuV persistence and pathogenesis in select immunocompromised hosts are not clear. We provide clinical, immunological, virological, and histological data on a cohort of 28 patients with a broad spectrum of IEI and RuV-associated granulomas in skin and nine extracutaneous tissues to further delineate this relationship. Combined immunodeficiency was the most frequent diagnosis (67.8%) among patients. Patients with previously undocumented conditions, i.e., humoral immunodeficiencies, a secondary immunodeficiency, and a defect of innate immunity were identified as being susceptible to RuV-associated granulomas. Hematopoietic cell transplantation was the most successful treatment in this case series resulting in granuloma resolution; steroids, and TNF-α and IL-1R inhibitors were moderately effective. In addition to M2 macrophages, neutrophils were identified by immunohistochemical analysis as a novel cell type infected with RuV. Four patterns of RuV-associated granulomatous inflammation were classified based on the structural organization of granulomas and identity and location of cell types harboring RuV antigen. Identification of conditions that increase susceptibility to RuV-associated granulomas combined with structural characterization of the granulomas may lead to a better understanding of the pathogenesis of RuV-associated granulomas and discover new targets for therapeutic interventions., Competing Interests: MA is employed by Sidra Medicine and Hamad Medical Corporation, Qatar. HB is employed by Labor Berlin GmbH, Germany. JH received grants from Immune Deficiency Foundation, the US immunodeficiency network, Chao-physician Scientist award, the Texas Medical Center Digestive Diseases Center and the Jeffrey Modell Foundation. JH received honorarium, consultation fees from Horizon, Pharming, Baxalta, CSL Behring, the National guard, and Al-Faisal University Hospital. TPA received consultation fees from Horizon, Pharming, CSL Behring. The remaining 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 Perelygina, Faisthalab, Abernathy, Chen, Hao, Bercovitch, Bayer, Noroski, Lam, Cicalese, Al-Herz, Nanda, Hajjar, Vanden Driessche, Schroven, Leysen, Rosenbach, Peters, Raedler, Albert, Abraham, Rangarjan, Buchbinder, Kobrynski, Pham-Huy, Dhossche, Cunningham Rundles, Meyer, Theos, Atkinson, Musiek, Adeli, Derichs, Walz, Krüger, von Bernuth, Klein, Icenogle, Hauck and Sullivan.)

Objectives: To report the phenotypic, genetic findings and outcome of children with lupus manifestations associated with primary immunodeficiency diseases (PIDs)., Methods: Data are retrospectively collected on patients with lupus manifestations and PIDs seen between 1998 and 2019. Data comprised the clinical findings and genetic testing, the response to treatment and the accrual damage related to SLE., Results: A total of 39 patients (22 female) were reviewed. Thirty-four patients had lupus manifestations and six patients with SLE-like manifestations. Genetic analysis was performed in 25 patients. Complement deficiency was the most frequent PIDs; 26 patients were C1q deficient, three patients had C3 deficiency, two patients had C4 deficiency and one patient with heterozygous C8b variant. The other seven patients had different PIDs genetic defects that include SCID caused by PNP deficiency, CGD, CVID ( PIK3CD) , IL-2RB mutation, DNase II deficiency, STAT1 mutation, ISG15 mutation and Griscelli syndrome type 3. Mucocutaneous lesions, arthritis and lung involvement were the main clinical features. 84.1% experienced recurrent infections. The mean accrual damage was 2.7 ± 2.2. There were five deaths because of infection., Conclusion: This study suggests that patients with lupus manifestations and early onset disease, family history of SLE or recurrent infections should undergo immunological work-up and genetic testing to rule out PIDs.

Background and Objectives: Reports on skin manifestations in inborn errors of immunity (IEI) are based on retrospective analysis, small series, or isolated case reports. The present prospective study aimed to determine the spectrum of skin manifestations in children with IEI and their relevance to specific molecular defects., Materials and Methods: The data were obtained from the Kuwait National Primary Immunodeficiency Disorders Registry during the period of 2004-2020., Results: A total of 313 pediatric cases of IEI, 71% diagnosed at molecular level, were registered with a cumulative follow-up period of 29,734 months. Skin manifestations were seen in 40.3% of the patients, and they were among the presenting manifestations in 33%. Patients with skin manifestations were older at both onset and diagnosis ages of IEI symptoms, but this was statistically significant for the latter only. The diagnosis delay was significantly longer in patients with skin manifestations. There was a statistically significant association between having skin manifestations and IEI category, being more common in patients with complement deficiencies, combined immunodeficiencies, and diseases of immune dysregulation. There was no statistically significant association between having skin manifestations and both gender and survival. Skin infections were the most frequent manifestations followed by eczema and autoimmune associations. Among IEI with more than 10 cases, skin lesions were a consistent finding in dedicator of cytokinesis 8 (DOCK8) deficiency, hyper IgE syndrome, ataxia-telangiectasia, and recombination activation gene (RAG)1 deficiency., Conclusions: Skin manifestations are common in IEI patients, and they had significant diagnosis delay and referral to specialists. Improvement of awareness about IEI is needed among pediatricians and dermatologists., 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 Al-Herz, Zainal and Nanda.)

Background: Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis., Methods: We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers., Results: We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG)., Conclusions: This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation., (© 2021. The Author(s).)

Autosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor T H 17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.

The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.

Background: Iron uptake mediated by transferrin receptor 1 (TfR1), encoded by the TFRC gene, is essential for lymphocyte development and proliferation. Autosomal-recessive mutations in the human TFRC gene cause a combined immunodeficiency characterized by defective T- and B-cell proliferation as well as impaired class-switching. Clinical presentations have been severe in all reported cases, with symptoms including recurrent sinopulmonary infections, hypogammaglobulinemia, chronic diarrhea, and intermittent cytopenias., Objective: To describe outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with TFRC deficiency., Methods: Retrospective chart review study of 5 patients with TFRC deficiency who underwent allogeneic HSCT between July 2011 and May 2018 at Boston Children's Hospital., Results: Intermittent thrombocytopenia and neutropenia were a predominant feature of the clinical presentation in our cohort, and 3 patients who underwent bone marrow evaluation before HSCT were found to have signs of dysmyelopoiesis and dysplasia. One patient, who had a transplant at age 11 years, developed a clonal cytogenetic abnormality concerning for myelodysplastic syndrome. All 5 patients tolerated myeloablative conditioning regimens and had robust donor cell engraftment with resolution of cytopenias and independence from intravenous immunoglobulin substitution. All 5 patients were alive at a median follow-up of 47.1 months posttransplant (range, 15.7-85.4) and none had developed acute or chronic graft-versus-host disease., Conclusions: Allogeneic HSCT is curative for TFRC deficiency and rescues all known disease manifestations. Patients with TFRC deficiency may have a predisposition to malignant transformation of hematopoietic cells and may benefit from HSCT earlier in their disease course., (Copyright © 2020. Published by Elsevier Inc.)

Background: Severe early-onset erythroderma and gut inflammation, with massive tissue infiltration of oligoclonal activated T cells are the hallmark of Omenn syndrome (OS)., Objective: The impact of altered gut homeostasis in the cutaneous manifestations of OS remains to be clarified., Methods: We analyzed a cohort of 15 patients with OS and the 129Sv/C57BL/6 knock-in Rag2 R229Q/R229Q (Rag2 R229Q ) mouse model. Homing phenotypes of circulating lymphocytes were analyzed by flow cytometry. Inflammatory cytokines and chemokines were examined in the sera by ELISA and in skin biopsies by immunohistochemistry and in situ RNA hybridization. Experimental colitis was induced in mice by dextran sulfate sodium salt., Results: We show that memory/activated T cells from patients with OS and from the Rag2 R229Q mouse model of OS abundantly express the skin homing receptors cutaneous lymphocyte associated antigen and CCR4 (Ccr4), associated with high levels of chemokine C-C motif ligands 17 and 22. Serum levels of LPS are also elevated. A broad T h 1/T h 2/T h 17 inflammatory signature is detected in the periphery and in the skin. Increased Tlr4 expression in the skin of Rag2 R229Q mice is associated with enhanced cutaneous inflammation on local and systemic administration of LPS. Likewise, boosting colitis in Rag2 R229Q mice results in increased frequency of Ccr4 + splenic T cells and worsening of skin inflammation, as indicated by epidermal thickening, enhanced epithelial cell activation, and dermal infiltration by T h 1 effector T cells., Conclusions: These results support the existence of an interplay between gut and skin that can sustain skin inflammation in OS., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: During the last 4 decades, registration of patients with primary immunodeficiencies (PID) has played an essential role in different aspects of these diseases worldwide including epidemiological indexes, policymaking, quality controls of care/life, facilitation of genetic studies and clinical trials as well as improving our understanding about the natural history of the disease and the immune system function. However, due to the limitation of sustainable resources supporting these registries, inconsistency in diagnostic criteria and lack of molecular diagnosis as well as difficulties in the documentation and designing any universal platform, the global perspective of these diseases remains unclear., Areas Covered: Published and unpublished studies from January 1981 to June 2020 were systematically reviewed on PubMed, Web of Science and Scopus. Additionally, the reference list of all studies was hand-searched for additional studies. This effort identified a total of 104614 registered patients and suggests identification of at least 10590 additional PID patients, mainly from countries located in Asia and Africa. Molecular defects in genes known to cause PID were identified and reported in 13852 (13.2% of all registered) patients., Expert Opinion: Although these data suggest some progress in the identification and documentation of PID patients worldwide, achieving the basic requirement for the global PID burden estimation and registration of undiagnosed patients will require more reinforcement of the progress, involving both improved diagnostic facilities and neonatal screening.

Objectives: To present a prospective report on the characteristics of autoimmune manifestations in patients with primary immunodeficient children registered in the Kuwait National PIDs Registry (KNPIDR). Methods: The data were obtained from the Kuwait National Primary Immunodeficiency Disorders Registry during the period of January 2004 to December 2019. Results: A total of 286 PID children were registered in KNPIDR during the study period with a predominance of immunodeficiencies affecting cellular and humoral immunity followed by combined immunodeficiencies with associated syndromic features and diseases of immune dysregulation. Fifty-seven (19.9%) patients presented with a total of 107 autoimmune manifestations. There was no significant statistical association between autoimmune manifestations and gender. Patients with autoimmune manifestations were older at onset of PID symptoms compared to those with no such manifestations, but this did not reach level of significance. The diagnosis delay was longer in patients with autoimmune manifestations compared to those with no such manifestations ( p = 0.038). Forty-seven percent of these manifestations were among the presenting symptoms while 53% were documented later during the course of the disease. Fifty-seven percent of the patients developed 1 autoimmune manifestation, 30% developed 2 such manifestations, and 16% had ≥3 autoimmune manifestations. The most common autoimmune manifestation was cytopenia, followed by gastrointestinal manifestations and manifestations of the skin, hair, and nails. Autoimmune cytopenia were more common in patients with immune dysregulation syndromes, while gastrointestinal and skin manifestations predominate in patients with immunodeficiencies affecting cellular and humoral immunity and endocrine manifestations were more common in immune dysregulation syndromes. There were significant statistical associations between developing autoimmune manifestations and death as well as PID categories, being more common in patients with immune dysregulation. The frequency of autoimmunity was high among patients with RAG, WAS, STAT5b, NF-κB2, Fas, FasL, LRBA, APECED, IL-10, and C4 deficiencies. Conclusions: Autoimmunity is frequent in patients with PIDs in Kuwait. This should prompt the suspicion of a PID in patients who present initially with autoimmunity, especially autoimmune cytopenia. Such patients should be managed with extra care since they are at a higher risk of death., (Copyright © 2020 Massaad, Zainal and Al-Herz.)

Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to clinical disease caused by the Bacille Calmette-Guérin (BCG) vaccine and environmental mycobacteria. The known genetic etiologies of MSMD are inborn errors of IFN-γ immunity due to mutations of 15 genes controlling the production of or response to IFN-γ. Since the first MSMD-causing mutations were reported in 1996, biallelic mutations in the genes encoding IFN-γ receptor 1 (IFN-γR1) and IFN-γR2 have been reported in many patients of diverse ancestries. Surprisingly, mutations of the gene encoding the IFN-γ cytokine itself have not been reported, raising the remote possibility that there might be other agonists of the IFN-γ receptor. We describe 2 Lebanese cousins with MSMD, living in Kuwait, who are both homozygous for a small deletion within the IFNG gene (c.354&#95;357del), causing a frameshift that generates a premature stop codon (p.T119Ifs4*). The mutant allele is loss of expression and loss of function. We also show that the patients' herpesvirus Saimiri-immortalized T lymphocytes did not produce IFN-γ, a phenotype that can be rescued by retrotransduction with WT IFNG cDNA. The blood T and NK lymphocytes from these patients also failed to produce and secrete detectable amounts of IFN-γ. Finally, we show that human IFNG has evolved under stronger negative selection than IFNGR1 or IFNGR2, suggesting that it is less tolerant to heterozygous deleterious mutations than IFNGR1 or IFNGR2. This may account for the rarity of patients with autosomal-recessive, complete IFN-γ deficiency relative to patients with complete IFN-γR1 and IFN-γR2 deficiencies.

Novel coronavirus disease (COVID-19), named a pandemic by the WHO, is the current global health crisis. National and international collaboration are indispensable for combating COVID-19 and other similar potential outbreaks. International efforts to tackle this complex problem have led to remarkable scientific advances. Yet, as a global society, we can and must take additional measures to fight this pandemic. Undoubtedly, our approach toward COVID-19 was not perfect, and testing has not been deployed fast enough to arrest the epidemic early on. It is critical that we revise our approaches to be more prepared for pandemics as a united body by promoting global cooperation and commitment.

MHC class II deficiency is a rare, but life-threatening, primary combined immunodeficiency. Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in the previously published result was poor. We analyzed the outcome of 25 patients with MHC class II deficiency undergoing first HCT at Great North Children's Hospital between 1995 and 2018. Median age at diagnosis was 6.5 months (birth to 7.5 years). Median age at transplant was 21.4 months (0.1-7.8 years). Donors were matched family donors (MFDs; n = 6), unrelated donors (UDs; n = 12), and haploidentical donors (HIDs; n = 7). Peripheral blood stem cells were the stem cell source in 68% of patients. Conditioning was treosulfanbased in 84% of patients; 84% received alemtuzumab (n = 14) or anti-thymocyte globulin (n = 8) as serotherapy. With a 2.9-year median follow-up, OS improved from 33% (46-68%) for HCT before 2008 (n = 6) to 94% (66-99%) for HCT after 2008 (n = 19; P = .003). For HCT after 2008, OS according to donor was 100% for MFDs and UDs and 85% for HIDs (P = .40). None had grade III-IV acute or chronic graft-versus-host disease. Latest median donor myeloid and lymphocyte chimerism were 100% (range, 0-100) and 100% (range, 64-100), respectively. Latest CD4+ T-lymphocyte number was significantly lower in transplant survivors (n = 14) compared with posttransplant disease controls (P = .01). All survivors were off immunoglobulin replacement and had protective vaccine responses to tetanus and Haemophilus influenzae. None had any significant infection or autoimmunity. Changing transplant strategy in Great North Children's Hospital has significantly improved outcomes for MHC class II deficiency., (© 2020 by The American Society of Hematology.)

Background: Patients with signal transducer and activator of transcription 5b (STAT5b) deficiency have impairment in T-cell homeostasis and natural killer (NK) cells which leads to autoimmunity, recurrent infections, and combined immune deficiency., Objective: In this study we characterized the NK cell defect in STAT5b-deficient human NK cells, as well as Stat5b -/- mice., Methods: We used multiparametric flow cytometry, functional NK cell assays, microscopy, and a Stat5b -/- mouse model to elucidate the effect of impaired and/or absent STAT5b on NK cell development and function., Results: This alteration generated a nonfunctional CD56 bright NK cell subset characterized by low cytokine production. The CD56 dim NK cell subset had decreased expression of perforin and CD16 and a greater frequency of cells expressing markers of immature NK cells. We observed low NK cell numbers and impaired NK cell maturation, suggesting that STAT5b is involved in terminal NK cell maturation in Stat5b -/- mice. Furthermore, human STAT5b-deficient NK cells had low cytolytic capacity, and fixed-cell microscopy showed poor convergence of lytic granules. This was accompanied by decreased expression of costimulatory and activating receptors. Interestingly, granule convergence and cytolytic function were restored after IL-2 stimulation., Conclusions: Our results show that in addition to the impaired terminal maturation of NK cells, human STAT5b mutation leads to impairments in early activation events in NK cell lytic synapse formation. Our data provide further insight into NK cell defects caused by STAT5b deficiency., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)