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Human ADA2 deficiency (DADA2) is an inborn error of immunity with a broad clinical phenotype which encompasses vasculopathy including livedo racemosa and lacunar strokes, as well as hemato-immunological features. Diagnosis is based on the combination of decreased serum ADA2 activity and the identification of biallelic deleterious alleles in the ADA2 gene. DADA2 carriers harbor a single pathogenic variant in ADA2 and are mostly considered healthy and asymptomatic. However, some DADA2 carriers present a phenotype compatible with DADA2. Here, we report ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant (p.G47R, p.G47V, p.R169Q, p.H424N) was identified. To test whether being heterozygote for specific variants could explain the patients' phenotype, we investigated the effect of the ADA2 missense variants p.G47A, p.G47R, p.G47V, p.G47W, p.R169Q, p.E328K, p.T360A, p.N370K, p.H424N and p.Y453C on ADA2 protein expression, secretion and enzymatic activity. Functional studies indicate that they exert a dominant negative effect on ADA2 enzymatic activity, dimerization and/or secretion. At the molecular level, heterozygosity for these variants mimics what is observed in DADA2. We conclude that humans with heterozygous dominant negative missense variants in ADA2 are at risk of DADA2., Competing Interests: Conflict-of-interest statement: LRD KU Leuven receives advisory board honorary from Boehringer-Ingelheim and Takeda for IM. IM is the chair of the CSL Behring Chair in Primary Immunodeficiencies, paid to KU Leuven.

Purpose of Review: In this review, an update is provided on the current knowledge and pending questions about human adenosine deaminase type 2 deficiency. Patients have vasculitis, immunodeficiency and some have bone marrow failure. Although the condition was described ten years ago, the pathophysiology is incompletely understood RECENT FINDINGS: Endothelial instability due to increased proinflammatory macrophage development is key to the pathophysiology. However, the physiological role of ADA2 is a topic of debate as it is hypothesized that ADA2 fulfils an intracellular role. Increasing our knowledge is urgently needed to design better treatments for the bone marrow failure. Indeed, TNFi treatment has been successful in treating DADA2, except for the bone marrow failure. Major advances have been made in our understanding of DADA2. More research is needed into the physiological role of ADA2., (© 2024. The Author(s).)

The study of primary immunodeficiencies or inborn errors of immunity continues to drive our knowledge of the function of the human immune system. From the outset, the study of inborn errors has focused on unraveling genetic etiologies and molecular mechanisms. Aided by the continuous growth in genetic diagnostics, the field has moved from the study of an infection dominated phenotype to embrace and unravel diverse manifestations of autoinflammation, autoimmunity, malignancy, and severe allergy in all medical disciplines. It has now moved from the study of ultrarare presentations to producing meaningful impact in conditions as diverse as inflammatory bowel disease, neurological conditions, and hematology. Beyond offering immunogenetic diagnosis, the study of underlying inborn errors of immunity in these conditions points to targeted treatment which can be lifesaving., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mutations in the N-terminal WD40 domain of coatomer protein complex subunit α (COPA) cause a type I interferonopathy, typically characterized by alveolar hemorrhage, arthritis, and nephritis. We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity. We showed that these CTD COPA mutations disrupt the integrity and the function of coat protein complex I (COPI). In COPAR1142X and COPAR1058C fibroblasts, we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect. The disturbed intracellular trafficking resulted in a cGAS/STING-dependent upregulation of the type I IFN signaling in patients and patient-derived cell lines, albeit through a distinct molecular mechanism in comparison with mutations in the WD40 domain of COPA. We showed that CTD COPA mutations induce an activation of ER stress and NF-κB signaling in patient-derived primary cell lines. These results demonstrate the importance of the integrity of the CTD of COPA for COPI function and homeostatic intracellular trafficking, essential to ER homeostasis. CTD COPA mutations result in disease by increased ER stress, disturbed intracellular transport, and increased proinflammatory signaling.

The DNA polymerase δ complex (PolD), comprising catalytic subunit POLD1 and accessory subunits POLD2, POLD3, and POLD4, is essential for DNA synthesis and is central to genome integrity. We identified, by whole exome sequencing, a homozygous missense mutation (c.1118A > C; p.K373T) in POLD3 in a patient with Omenn syndrome. The patient exhibited severely decreased numbers of naïve T cells associated with a restricted T-cell receptor repertoire and a defect in the early stages of TCR recombination. The patient received hematopoietic stem cell transplantation at age 6 months. He manifested progressive neurological regression and ultimately died at age 4 years. We performed molecular and functional analysis of the mutant POLD3 and assessed cell cycle progression as well as replication-associated DNA damage. Patient fibroblasts showed a marked defect in S-phase entry and an enhanced number of double-stranded DNA break-associated foci despite normal expression levels of PolD components. The cell cycle defect was rescued by transduction with WT POLD3. This study validates autosomal recessive POLD3 deficiency as a novel cause of profound T-cell deficiency and Omenn syndrome., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by variants in Bruton's tyrosine kinase (BTK). XLA patients require lifelong immunoglobulin replacement therapy (IgRT). Only few XLA patients are indicated for allogeneic hematopoietic cell transplantation (HCT) because of severe complications. Accordingly, the published transplantation experience in XLA is minimal. We aimed to collect clinical data of XLA patients who received HCT in an international framework and to establish appropriate transplantation criteria and methods for XLA patients., Methods: XLA patients were recruited through a questionnaire and a literature review. The data are on patient characteristics and transplantation methods and outcomes., Results: In this study, twenty-two XLA patients who underwent HCT were recruited. The indication for HCT was recurrent or life-threatening infection in sixteen patients, malignancy in three, and other factors in three. A myeloablative conditioning, reduced toxicity myeloablative conditioning (RT-MAC), and reduced intensity conditioning (RIC) were selected in four, ten, and eight patients, respectively. Engraftment was achieved in 21 patients (95%). In all patients, 2-year overall survival (OS) and event-free survival (EFS) were 86% and 77%, respectively. In patients who received RT-MAC or RIC using treosulfan, busulfan, or melphalan, 2-year OS and EFS were 82% and 71%, respectively. Finally, twenty-one patients (95%) obtained complete or stable high-level mixed chimerism (50-95%), and the 1-year discontinuation rate of IgRT was 89%., Conclusion: Based on the concept in which IgRT is the standard treatment for XLA, HCT may be an effective and safe alternative treatment option for XLA patients, and IgRT can be discontinued following transplantation. It is ideal to perform HCT in XLA patients for whom transplantation is indicated before they develop organ damage., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Deficiency of human adenosine deaminase type 2 (DADA2) is a complex systemic autoinflammatory disorder characterized by vasculopathy, immune dysregulation, and hematologic abnormalities. The most notable neurological manifestations of DADA2 are strokes that can manifest with various neurological symptoms and are potentially fatal. However, neurological presentations can be diverse. We here present a review of the neurological manifestations of DADA2 to increase clinical awareness of DADA2 as the underlying diagnosis. We reviewed all published cases of DADA2 from 1 January 2014 until 19 July 2022 found via PubMed. A total of 129 articles describing the clinical features of DADA2 were included in the analysis. Six hundred twenty-eight patients diagnosed with DADA2 were included in the review. 50.3% of patients had at least signs of one reported neurological event, which was the initial or sole manifestation in 5.7% and 0.6%, respectively. 77.5% of patients with neurological manifestations had at least signs of one cerebrovascular accident, with lacunar strokes being the most common and 35.9% of them having multiple stroke episodes. There is a remarkable predilection for the brain stem and deep gray matter, with 37.3% and 41.6% of ischemic strokes, respectively. Other neurological involvement included neuropathies, focal neurological deficits, ophthalmological findings, convulsions, and headaches. In summary, neurological manifestations affect a significant proportion of patients with DADA2, and the phenotype is broad. Neurological manifestations can be the first and single manifestation of DADA2. Therefore, stroke, encephalitis, posterior reversible encephalopathy syndrome, mononeuropathy and polyneuropathy, and Behçet's disease-like presentations should prompt the neurologist to exclude DADA2, especially but not only in childhood., (© 2023. The Author(s).)

Background: Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking., Objectives: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS., Methods: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs., Results: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS., Conclusions: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Objectives: Antibody response on polysaccharide- and protein-based vaccines is useful to test B cell functionality. As only few studies have explored the value of studying immune response to both vaccines, we evaluated the clinical value of anti-polysaccharide and anti-protein Luminex-based multiplex assays in context of primary immunodeficiency (PID) diagnosis., Methods: A 10-plex Luminex-based assay detecting antibodies to ten pneumococcal polysaccharide (PnPS) serotypes [present in unconjugated Pneumovax, not in 13-valent pneumococcal conjugated vaccine (PCV)] and a 5-plex assay detecting antibodies to five protein antigens (present in DTap/Tdap) were clinically validated in healthy individuals (n=99) and in retrospective (n=399) and prospective (n=108) patient cohorts. Clinical features of individuals with impaired response to PnPS and/or proteins were compared to those with normal response., Results: Antigen-specific antibody thresholds were determined in healthy individuals. Individuals with impaired anti-PnPS responses and deficient immunoglobulin levels suffered more from autoimmune diseases and had lower B cell levels compared to individuals with impaired anti-PnPS response with normal immunoglobulin levels. Individuals with combined impaired response to PnPS and proteins showed more severe clinical manifestations compared to individuals with isolated impaired response to PnPS or proteins. Eight of the 11 individuals with severely impaired responses to both PnPS and proteins had common variable immunodeficiency. Evaluation of the anti-PnPS response to four serotypes not contained in 20-valent PCV was comparable to evaluation to ten serotypes not contained in 13-valent PCV., Conclusions: Multiplexed assessment of anti-PnPS and anti-protein responses combined with immunoglobulin quantification provides useful clinical information to support PID diagnosis., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Severe congenital neutropenia presents with recurrent infections early in life as a result of arrested granulopoiesis. Multiple genetic defects are known to block granulocyte differentiation; however, a genetic cause remains unknown in approximately 40% of cases., Objective: We aimed to characterize a patient with severe congenital neutropenia and syndromic features without a genetic diagnosis., Methods: Whole exome sequencing results were validated using flow cytometry, Western blotting, coimmunoprecipitation, quantitative PCR, cell cycle and proliferation analysis of lymphocytes and fibroblasts and granulocytic differentiation of primary CD34 + and HL-60 cells., Results: We identified a homozygous missense mutation in DBF4 in a patient with mild extra-uterine growth retardation, facial dysmorphism and severe congenital neutropenia. DBF4 is the regulatory subunit of the CDC7 kinase, together known as DBF4-dependent kinase (DDK), the complex essential for DNA replication initiation. The DBF4 variant demonstrated impaired ability to bind CDC7, resulting in decreased DDK-mediated phosphorylation, defective S-phase entry and progression and impaired differentiation of granulocytes associated with activation of the p53-p21 pathway. The introduction of wild-type DBF4 into patient CD34 + cells rescued the promyelocyte differentiation arrest., Conclusion: Hypomorphic DBF4 mutation causes autosomal-recessive severe congenital neutropenia with syndromic features., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival.

X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4-dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8-207.8, P < 0.001). The patients' susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia., (© 2023 García García et al.)

Since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/coronavirus disease 2019 (COVID-19) pandemic, global sequencing efforts have led in the field of inborn errors of immunity, and inspired particularly by previous research on life-threatening influenza, they have revealed that known and novel inborn errors affecting type I interferon immunity underlie critical COVID-19 in up to 5% of cases. In addition, neutralizing autoantibodies against type I interferons have been identified in up to 20% of patients with critical COVID-19 who are older than 80 years and 20% of fatal cases, with a higher prevalence in men and individuals older than 70 years. Also, inborn errors impairing regulation of type I interferon responses and RNA degradation have been found as causes of multisystem inflammatory syndrome in children, a life-threatening hyperinflammatory condition complicating otherwise mild initial SARS-CoV-2 infection in children and young adults. Better understanding of these immunologic mechanisms can aid in designing treatments for severe COVID-19, multisystem inflammatory syndrome in children, long COVID, and neuro-COVID., (Copyright © 2023. Published by Elsevier Inc.)

Encephalitis and encephalopathy in children represent a diagnostic challenge. We describe a patient with relapsing encephalitis in whom the differential diagnosis included acute disseminated encephalomyelitis, human herpesvirus 6 encephalitis, and hemophagocytic lymphohistiocytosis (HLH). Because of its rarity, HLH is often overlooked as a differential diagnosis in encephalitis, especially in the isolated CNS forms. As this case illustrates, inborn errors of immunity can underlie isolated encephalitis and should be included in the differential diagnosis of these presentations., (© 2022 American Academy of Neurology.)

Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5-13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 × 10-11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie ∼10% of hospitalizations for COVID-19 pneumonia in children., (© 2022 ZHANG et al.)

Autosomal recessive IRF7 deficiency was previously reported in three patients with single critical influenza or COVID-19 pneumonia episodes. The patients' fibroblasts and plasmacytoid dendritic cells produced no detectable type I and III IFNs, except IFN-β. Having discovered four new patients, we describe the genetic, immunological, and clinical features of seven IRF7-deficient patients from six families and five ancestries. Five were homozygous and two were compound heterozygous for IRF7 variants. Patients typically had one episode of pulmonary viral disease. Age at onset was surprisingly broad, from 6 mo to 50 yr (mean age 29 yr). The respiratory viruses implicated included SARS-CoV-2, influenza virus, respiratory syncytial virus, and adenovirus. Serological analyses indicated previous infections with many common viruses. Cellular analyses revealed strong antiviral immunity and expanded populations of influenza- and SARS-CoV-2-specific memory CD4+ and CD8+ T cells. IRF7-deficient individuals are prone to viral infections of the respiratory tract but are otherwise healthy, potentially due to residual IFN-β and compensatory adaptive immunity., (© 2022 Campbell et al.)

Purpose of Review: The severe acute respiratory syndrome (SARS)-coronavirus 2 (CoV2)/COVID-19 pandemic has reminded us of the fundamental and nonredundant role played by the innate and adaptive immune systems in host defense against emerging pathogens. The study of rare 'experiments of nature' in the setting of inborn errors of immunity (IEI) caused by monogenic germline variants has revealed key insights into the molecular and cellular requirements for immune-mediated protection against infectious diseases. This review will provide an overview of the discoveries obtained from investigating severe COVID-19 in patients with defined IEI or otherwise healthy individuals., Recent Findings: Genetic, serological and cohort studies have provided key findings regarding host defense against SARS-CoV2 infection, and mechanisms of disease pathogenesis. Remarkably, the risk factors, severity of disease, and case fatality rate following SARS-CoV2 infection in patients with IEI were not too dissimilar to that observed for the general population. However, the type I interferon (IFN) signaling pathway - activated in innate immune cells in response to viral sensing - is critical for anti-SARS-CoV2 immunity. Indeed, genetic variants or autoAbs affecting type I IFN function account for up to 20% of all cases of life-threatening COVID-19., Summary: The analysis of rare cases of severe COVID-19, coupled with assessing the impact of SARS-CoV2 infection in individuals with previously diagnosed IEI, has revealed fundamental aspects of human immunology, disease pathogenesis and immunopathology in the context of exposure to and infection with a novel pathogen. These findings can be leveraged to improve therapies for treating for emerging and established infectious diseases., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused extreme concern for patients with inborn errors of immunity (IEIs). In the first 6  months of the pandemic, the case fatality rate among patients with IEIs resembled that of the general population (9%). This review aims at summarizing what we have learned about the course and outcome of coronavirus disease 2019 (COVID-19) in patients with different IEIs and what this can potentially teach us about the immune mechanisms that could confer protection or predisposition to severe disease., Recent Findings: A total of 649 patients with IEI and COVID-19 have been reported in the last year and a half, spanning all groups of the International Union of Immunological Societies classification of IEIs. For most patients, the underlying IEI does not represent an independent risk factor for severe COVID-19. In fact, some IEI may even be protective against the severe disease due to impaired inflammation resulting in less immune-mediated collateral tissue damage., Summary: We review the characteristics of SARS-CoV-2 infection in a large number of patients with IEI. Overall, we found that combined immunodeficiencies, immune dysregulation disorders, and innate immune defects impairing type I interferon responses are associated with severe disease course., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Deficiency of adenosine deaminase type 2 (ADA2) (DADA2) is a rare inborn error of immunity caused by deleterious biallelic mutations in ADA2. Clinical manifestations are diverse, ranging from severe vasculopathy with lacunar strokes to immunodeficiency with viral infections, hypogammaglobulinemia and bone marrow failure. Limited data are available on the phenotype and function of leukocytes from DADA2 patients. The aim of this study was to perform in-depth immunophenotyping and functional analysis of the impact of DADA2 on human lymphocytes., Methods: In-depth immunophenotyping and functional analyses were performed on ten patients with confirmed DADA2 and compared to heterozygous carriers of pathogenic ADA2 mutations and normal healthy controls., Results: The median age of the patients was 10 years (mean 20.7 years, range 1-44 years). Four out of ten patients were on treatment with steroids and/or etanercept or other immunosuppressives. We confirmed a defect in terminal B cell differentiation in DADA2 and reveal a block in B cell development in the bone marrow at the pro-B to pre-B cell stage. We also show impaired differentiation of CD4 + and CD8 + memory T cells, accelerated exhaustion/senescence, and impaired survival and granzyme production by ADA2 deficient CD8 + T cells. Unconventional T cells (i.e. iNKT, MAIT, Vδ2 + γδT) were diminished whereas pro-inflammatory monocytes and CD56 brigh t immature NK cells were increased. Expression of the IFN-induced lectin SIGLEC1 was increased on all monocyte subsets in DADA2 patients compared to healthy donors. Interestingly, the phenotype and function of lymphocytes from healthy heterozygous carriers were often intermediate to that of healthy donors and ADA2-deficient patients., Conclusion: Extended immunophenotyping in DADA2 patients shows a complex immunophenotype. Our findings provide insight into the cellular mechanisms underlying some of the complex and heterogenous clinical features of DADA2. More research is needed to design targeted therapy to prevent viral infections in these patients with excessive inflammation as the overarching phenotype., (© 2021. The Author(s).)

Purpose: Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2., Methods: We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS)., Results: Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2-28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5-16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT., Conclusion: HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency., Clinical Implications: HCT is a definitive cure for DADA2 with > 95% survival., (© 2021. The Author(s).)

Background: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense., Objective: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2., Methods: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI., Results: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died., Conclusions: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The technological advances in diagnostics and therapy of primary immunodeficiency are progressing at a fast pace. This review examines recent developments in the field of inborn errors of immunity, from their definition to their treatment. We will summarize the challenges posed by the growth of next-generation sequencing in the clinical setting, touch briefly on the expansion of the concept of inborn errors of immunity beyond the classic immune system realm, and finally review current developments in targeted therapies, stem cell transplantation, and gene therapy., Competing Interests: Competing interests: IM is supported by a CSL Behring Chair in Primary Immunodeficiency (paid to institution). GB declares that she has no competing interests.No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed., (Copyright: © 2020 Bucciol G and Meyts I.)

Background: The correlation between different methods for the detection of pneumococcal polysaccharide vaccine (PPV) responses to diagnose specific polysaccharide antibody deficiency (SAD) is poor and the criteria for defining a normal response lack consensus. We previously proposed fifth percentile (p5) values of PPV responses as a new cutoff for SAD., Objective: To analyze the association of SAD (determined by either World Health Organization (WHO)-standardized ELISA or multiplex bead-based assay) with abnormal response to Salmonella (S.) typhi Vi vaccination in a cohort of patients with recurrent infections., Methods: Ninety-four patients with a clinical history suggestive of antibody deficiency received PPV and S. typhi Vi vaccines. Polysaccharide responses to either 3 or 18 pneumococcal serotypes were measured by either the WHO ELISA or a multiplex in-house bead-based assay. Anti-S. typhi Vi IgG were measured by a commercial ELISA kit. Allohemagglutinins (AHA) were measured by agglutination method., Results: Based on the American Academy of Allergy, Asthma and Immunology (AAAAI) criteria for WHO ELISA, 18/94 patients were diagnosed with SAD and 22/93 based on serotype-specific p5 cutoffs for bead-based assay. The association between the two methods was significant, with 10 subjects showing abnormal response according to both techniques. Abnormal response to S. typhi Vi vaccination was found in 7 patients, 6 of which had SAD. No correlation was found between polysaccharide response and AHA, age, or clinical phenotype., Conclusion: The lack of evidence-based gold standards for the diagnosis of SAD represents a challenge in clinical practice. In our cohort, we confirmed the insufficient correlation between different methods of specific PPV response measurement, and showed that the S. typhi Vi response was not contributive. Caution in the interpretation of results is warranted until more reliable diagnostic methods can be validated.

Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease. Severe illness by MMR vaccines can be caused by inborn errors of type I and/or III interferon (IFN) immunity (mutations in IFNAR2 , STAT1 , or STAT2 ). Adverse reactions to the YF vaccine have remained unexplained. We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients' fibroblast phenotypes are rescued with WT IFNAR1 Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals., (© 2019 Hernandez et al.)

DOCK2 is a guanine-nucleotide-exchange factor for Rac proteins. Activated Rac serves various cellular functions including the reorganization of the actin cytoskeleton in lymphocytes and neutrophils and production of reactive oxygen species in neutrophils. Since 2015, six unrelated patients with combined immunodeficiency and early-onset severe viral infections caused by bi-allelic loss-of-function mutations in DOCK2 have been described. Until now, the function of phagocytes, specifically neutrophils, has not been assessed in human DOCK2 deficiency. Here, we describe a new kindred with four affected siblings harboring a homozygous splice-site mutation (c.2704-2 A > C) in DOCK2. The mutation results in alternative splicing and a complete loss of DOCK2 protein expression. The patients presented with leaky severe combined immunodeficiency or Omenn syndrome. The novel mutation affects EBV-B cell migration and results in NK cell dysfunction similar to previous observations. Moreover, both cytoskeletal rearrangement and reactive oxygen species production are partially impaired in DOCK2-deficient neutrophils.

Inherited defects in genes encoding for proteins that are involved in the assembly and dynamics of the actin skeleton have increasingly been identified in patients presenting with primary immunodeficiencies. In this review, we summarize a subset of the recently described conditions, emphasizing the clinical features as well as the immunophenotype and pathophysiology., (© 2019 Australasian Society for Immunology Inc.)

Innate immunity contributes to host defense through all cell types and relies on their shared germline genetic background, whereas adaptive immunity operates through only 3 main cell types, αβ T cells, γδ T cells, and B cells, and relies on their somatic genetic diversification of antigen-specific responses. Human inborn errors of innate immunity often underlie infectious diseases. The range and nature of infections depend on the mutated gene, the deleteriousness of the mutation, and other ill-defined factors. Most known inborn errors of innate immunity to infection disrupt the development or function of leukocytes other than T and B cells, but a growing number of inborn errors affect cells other than circulating and tissue leukocytes. Here we review inborn errors of innate immunity that have been recently discovered or clarified. We highlight the immunologic implications of these errors., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Next-generation sequencing, especially whole exome sequencing (WES), has revolutionized the molecular diagnosis of inborn errors of immunity. This review summarizes the generation and analysis of next-generation sequencing data., Recent Findings: The focus is on prioritizing strategies for unveiling the potential disease-causing variant. We also highlighted oversights and imperfections of WES and targeted panel sequencing, as well as the need for functional validation., Summary: The information is crucial for a judicious use of WES by researchers, but even more so by the clinical immunologist.