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Cells of the innate and adaptive immune systems depend on proper actin dynamics to control cell behavior for effective immune responses. Dysregulated actin networks are known to play a pathogenic role in an increasing number of inborn errors of immunity. The WAVE regulatory complex (WRC) mediates branched actin polymerization, a process required for key cellular functions including migration, phagocytosis, vesicular transport, and immune synapse formation. Recent reports of pathogenic variants in NCKAP1L, a hematopoietically restricted gene encoding the HEM1 protein component of the WRC, defined a novel disease involving recurrent bacterial and viral infections, autoimmunity, and excessive inflammation (OMIM 141180). This review summarizes the diverse clinical presentations and immunological phenotypes observed in HEM1-deficient patients. In addition, we integrate the pathophysiological mechanisms described in current literature and highlight the outstanding questions for diagnosis and management of the HEM1 actin immunodysregulatory disorder.

[Purpose] STAT1 gain-of-function (GOF) and dominant-negative (DN) STAT3 syndromes share clinical manifestations including infectious and inflammatory manifestations. Targeted treatment with Janus-kinase (JAK) inhibitors shows promising results in treating STAT1 GOF-associated symptoms while management of DN STAT3 patients has been largely supportive. We here assessed the impact of ruxolitinib on the JAK-STAT1/3 pathway in DN STAT3 patients' cells., [Methods] Using flow cytometry, immunoblot, qPCR, and ELISA techniques, we examined the levels of basal STAT1 and phosphorylated STAT1 (pSTAT1) of cells obtained from DN STAT3, STAT1 GOF patients, and healthy donors following stimulation with type I/II interferons (IFNs) or interleukin (IL)-6. We also describe the impact of ruxolitinib on cytokine-induced STAT1 signaling in these patients., [Results] DN STAT3 and STAT1 GOF resulted in a similar phenotype characterized by increased STAT1 and pSTAT1 levels in response to IFNα (CD3+ cells) and IFNγ (CD14+ monocytes). STAT1-downstream gene expression and C-X-C motif chemokine 10 secretion were higher in most DN STAT3 patients upon stimulation compared to healthy controls. Ex vivo treatment with the JAK1/2-inhibitor ruxolitinib reduced cytokine responsiveness and normalized STAT1 phosphorylation in DN STAT3 and STAT1 GOF patient’ cells. In addition, ex vivo treatment was effective in modulating STAT1 downstream signaling in DN STAT3 patients., [Conclusion] In the absence of effective targeted treatment options for AD-HIES at present, modulation of the JAK/STAT1 pathway with JAK inhibitors may be further explored particularly in those AD-HIES patients with autoimmune and/or autoinflammatory manifestations., This work was supported by the Job Research Foundation (NY, United States); Consejería de Salud de la Junta de Andalucía (SA0051/2020 to O.N.); Agencia de Innovación y Desarrollo de Andalucía (PI-0184-2018 to P.O.), Instituto de Salud Carlos III, Madrid, Spain [Sara Borrell, CD20/00124 to P.B.L, Juan Rodés JR18/00042 to P.O, FIS PI19/01471].

We describe the successful use of the novel antifungal drug fosmanogepix to treat a chronic case of multidrug-resistant cutaneous Fusarium suttonianum infection in a pediatric patient with STAT3 Hyper-IgE Syndrome and end-stage kidney disease on peritoneal dialysis.

The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system. During homeostasis TH1 cells activate a cell-intrinsic inflammatory shutdown program and shift to IL-10 production. Chauss et al. find that this TH1 homeostatic program is dependent on vitamin D signaling and is disrupted in severe COVID-19.

Background SARS-CoV-2 vaccination is recommended in patients with inborn errors of immunity (IEIs); however, little is known about immunogenicity and safety in these patients. Objective We sought to evaluate the impact of genetic diagnosis, age, and treatment on antibody response to COVID-19 vaccine and related adverse events in a cohort of patients with IEIs. Methods Plasma was collected from 22 health care worker controls, 81 patients with IEIs, and 2 patients with thymoma; the plasma was collected before immunization, 1 to 6 days before the second dose of mRNA vaccine, and at a median of 30 days after completion of the immunization schedule with either mRNA vaccine or a single dose of Johnson & Johnson’s Janssen vaccine. Anti-spike (anti-S) and anti-nucleocapsid antibody titers were measured by using a luciferase immunoprecipitation systems method. Information on T- and B-cell counts and use of immunosuppressive drugs was extracted from medical records, and information on vaccine-associated adverse events was collected after each dose. Results Anti-S antibodies were detected in 27 of 46 patients (58.7%) after 1 dose of mRNA vaccine and in 63 of 74 fully immunized patients (85.1%). A lower rate of seroconversion (7 of 11 [63.6%]) was observed in patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy. Previous use of rituximab and baseline counts of less than 1000 CD3+ T cells/mL and less than 100 CD19+ B cells/mL were associated with lower anti-S IgG levels. No significant adverse events were reported. Conclusion Vaccinating patients with IEIs is safe, but immunogenicity is affected by certain therapies and gene defects. These data may guide the counseling of patients with IEIs regarding prevention of SARS-CoV-2 infection and the need for subsequent boosts.

Purpose: Though copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. Thus, we sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with suspected or known IEI. Methods: We performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings. Results: Of the 332 probands, 134 (40.4%) received molecular diagnoses. Of these, 116/134 (86.6%) were diagnosed by ES alone. An additional 15/134 (11.2%) were diagnosed by CMA alone, including two likely de novochanges. Three (2.2%) participants had diagnostic molecular findings from both ES and CMA, including two compound heterozygotes and one patient with two distinct diagnoses. Half of the participants with CMA contribution to diagnosis had CNVs in at least one non-immune gene, highlighting the clinical complexity of these cases. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5%. Conclusion: Pairing ES and CMA can provide a comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. Such a combined approach to genetic testing helps untangle complex phenotypes, not only by clarifying the differential diagnosis, but in some cases by identifying multiple diagnoses contributing to the overall clinical presentation.

BACKGROUNDRare diseases collectively impose significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans.METHODSWe established a clinical genomics and genetic counselling facility, within a multidisciplinary tertiary paediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population.RESULTSWe present data on 529 patients with rare diseases (47% females; Average age, 4 years) representing 41 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 35.7% (95% CI, 31.8% - 39.9%) and was higher for genomic sequencing-based testing than chromosomal microarrays (41.2% versus 16.9%, P=0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 124 Mendelian disorders identified in this cohort, the majority (N = 110) were encountered only once, and those with recessive inheritance accounted for ~60% of sequencing diagnoses. Of patients with positive genetic findings (N = 189), 71.9% were less than 5 years of age, and 65.6% were offered modified management and/or intervention plans. Interestingly, 18.5% of patients with positive genetic findings received delayed diagnoses (age range 7 – 37 years), most likely due to lack of access to genomic investigations in this region. One such genetic finding ended over a 10-year long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders.CONCLUSIONSEarly access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this historically underrepresented population.

The hyper-IgE syndromes (HIES) are a heterogeneous group of inborn errors of immunity sharing manifestations including increased infection susceptibility, eczema, and raised serum IgE. Since the prototypical HIES description 55 years ago, areas of significant progress have included description of key disease-causing genes and differentiation into clinically distinct entities. The first two patients reported had what is now understood to be HIES from dominant-negative mutations in signal transduction and activator of transcription 3 (STAT3-HIES), conferring a broad immune defect across both innate and acquired arms, as well as defects in skeletal, connective tissue, and vascular function, causing a clinical phenotype including eczema, staphylococcal and fungal skin and pulmonary infection, scoliosis and minimal trauma fractures, and vascular tortuosity and aneurysm. Due to the constitutionally expressed nature of STAT3, initial reports at treatment with allogeneic stem cell transplantation were not positive and treatment has hinged on aggressive antimicrobial prophylaxis and treatment to prevent the development of end-organ disease such as pneumatocele. Research into the pathophysiology of STAT3-HIES has driven understanding of the interface of several signaling pathways, including the JAK-STAT pathways, interleukins 6 and 17, and the role of Th17 lymphocytes, and has been expanded by identification of phenocopies such as mutations in IL6ST and ZNF341. In this review we summarize the published literature on STAT3-HIES, present the diverse clinical manifestations of this syndrome with current management strategies, and update on the uncertain role of stem cell transplantation for this disease. We outline key unanswered questions for further study.

Dominant negative (DN) mutations in signal transducer and activator of transcription 3 (STAT3) are known to cause hyper-IgE syndrome, a rare primary immunodeficiency. STAT3 DN patients are prone to develop fungal infections, including chronic mucocutaneous candidiasis due to impaired IL-17-mediated immunity, and pulmonary aspergillosis. Despite having preserved phagocyte functions, STAT3 DN patients present connective tissue abnormalities and a defect in the immunological skin barrier. Fusarium species are ubiquitous molds, whose potential to infect humans depends on the host's innate and cellular immune status. Our aim was to describe four STAT3 DN patients with fusariosis confined to the skin. Medical records were reviewed and summarized. Four patients, aged 4, 11, 30, and 33 years, presented with chronic skin lesions which started in the extremities. Two patients had remote lesions, and none had systemic involvement. Skin biopsies showed mycelial threads with deep inflammatory-occasionally granulomatous-infiltrates, reaching the dermis; cultures grew Fusarium solani. Response to treatment was heterogeneous, often requiring multimodal therapies, including topical antifungal preparations. In this work, we describe primary invasive cutaneous fusariosis as a syndromic entity in four STAT3 DN patients.

Most of the currently known heterozygous pathogenic

Background Recent case reports have described the efficacy of daratumumab to treat refractory pure red cell aplasia (PRCA) following major ABO mismatched allogeneic hematopoietic stem cell transplantation (HSCT). In this report, we describe the use of daratumumab as a first-line agent for treatment of delayed red blood cell (RBC) engraftment following a major ABO mismatched pediatric HSCT and provide a review of the literature. Study design and materials We report on a 14-year-old with DOCK8 deficiency who underwent a myeloablative, haploidentical bone marrow transplant from her major ABO mismatched sister (recipient O+, donor A+) for treatment of her primary immunodeficiency. Despite achieving full donor chimerism, she had delayed RBC engraftment requiring ongoing transfusions. Due to iron deposition, symptomatic anemia, and persistence of anti-A iso-hemagglutinins despite discontinuation of immunosuppression, treatment for delayed RBC engraftment with the CD38-targeted monoclonal antibody daratumumab was selected as a less immunosuppressive agent that could more selectively target iso-hemagglutinin producing plasma cells without causing broad B-cell aplasia. Results Clinical effect with daratumumab was demonstrated by reduced iso-hemagglutinin titer, increased reticulocytosis, normalization of her hemoglobin, and transfusion independence. In the 11-month follow-up period to date, no additional transfusions or immunosuppression have been necessary, despite persistence of low-level anti-A iso-hemagglutinin. Conclusion Our experience suggests that daratumumab was an effective first-line therapy for delayed RBC engraftment and that earlier consideration for daratumumab in treatment of delayed RBC engraftment may be warranted.

Loss of function mutations in STAT3 (STAT3-LOF; autosomal dominant hyper-IgE (Job’s) syndrome) are associated with a variety of musculoskeletal manifestations, including scoliosis, osteoporosis, and minimal trauma fractures. This retrospective magnetic resonance (MR) imaging study sought to characterize an unusual pattern of cervical spine degeneration among a cohort of STAT3-LOF patients. Cervical spine MR images of the STAT3-LOF cohort (n = 38) were assessed for a variety of degenerative changes and compared to age-matched groups of controls (n = 42) without known immune or musculoskeletal abnormalities. A unique pattern of premature cervical spine degeneration was identified among the STAT3-LOF cohort which included straightening and eventual reversal of the normal cervical lordosis, mainly due to multi-level spondylolisthesis, as well as early development of spinal canal narrowing, cord compression, and myelomalacia. Cervical spine degeneration in the STAT3-LOF cohort was significantly worse than controls in both the 30–45 and 45 + age groups. Moderate to severe degenerative changes were present after age 30, and markedly worsened over time in several cases. Bone mineral density (BMD) had a moderate negative correlation with cervical degeneration severity and a strong negative correlation with age among STAT3-LOF participants. Cervical degeneration in STAT3-LOF appears to be progressive and could result in cord compromise if left unaddressed. Focused history and physical examination for signs of neurologic compromise as well as periodic MR imaging are thus recommended for the evaluation of premature cervical spine degeneration in STAT3-LOF patients after age 30 so that timely surgical interventions may be considered to prevent spinal cord damage and permanent neurological deficits.

Summary: We characterized Mycobacterium bovis BCG isolates found in lung and brain samples from a previously vaccinated patient with IFNγR1 deficiency. The isolates collected displayed distinct genomic and phenotypic features consistent with host adaptation and associated changes in antibiotic susceptibility and virulence traits. Background: We report a case of a patient with partial recessive IFNγR1 deficiency who developed disseminated BCG infection after neonatal vaccination (BCG-vaccine). Distinct M. bovis BCG-vaccine derived clinical strains were recovered from the patient’s lungs and brain. Methods: BCG strains were phenotypically (growth, antibiotic susceptibility, lipid) and genetically (whole genome sequencing) characterized. Mycobacteria cell infection models were used to assess apoptosis, necrosis, cytokine release, autophagy, and JAK-STAT signaling. Results: Clinical isolates BCG-brain and BCG-lung showed distinct Rv0667 rpoB mutations conferring high- and low-level rifampin resistance; the latter displayed clofazimine resistance through Rv0678 gene (MarR-like transcriptional regulator) mutations. BCG-brain and BCG-lung showed mutations in fadA2, fadE5, and mymA operon genes, respectively. Lipid profiles revealed reduced levels of PDIM in BCG-brain and BCG-lung and increased TAGs and Mycolic acid components in BCG-lung, compared to parent BCG-vaccine. In vitro infected cells showed that the BCG-lung induced a higher cytokine release, necrosis, and cell-associated bacterial load effect when compared to BCG-brain; conversely, both strains inhibited apoptosis and altered JAK-STAT signaling. Conclusions: During a chronic-disseminated BCG infection, BCG strains can evolve independently at different sites likely due to particular microenvironment features leading to differential antibiotic resistance, virulence traits resulting in dissimilar responses in different host tissues.

BACKGROUNDIdiopathic CD4 lymphopenia (ICL) is defined by persistently low CD4+ cell counts (

The differential diagnosis of eosinophilia is broad and includes infections, malignancies, and atopy as well as inborn errors of immunity (IEI). Certain types of IEIs are known to be associated with elevated numbers of eosinophils and frequently elevated serum IgE, whereas for others the degree and frequency of eosinophilia are less established. The molecular defects underlying IEI are heterogeneous and affect different pathways, which highlights the complex regulations of this cell population within the immune system. In this review, we list and discuss clinical manifestations and therapies of immune deficiency or immune dysregulation disorders associated with peripheral blood or tissue eosinophilia with or without raised IgE levels. We present illustrative case vignettes for the most common entities and propose a diagnostic algorithm aiming to help physicians systematically to evaluate patients with eosinophilia and suspicion of an underlying IEI., This work was supported by the Job Research Foundation, New York (to P. Olbrich), Agencia de Innovación y Desarrollo de Andalucía (PI-0184-2018 to P. Olbrich), and Instituto de Salud Carlos III, Madrid, Spain (Juan Rodés JR18/00042, to P. Olbrich; and FIS PI19/01471, to P. Olbrich). This work was funded (in part) by the intramural research program of the National Institute of Allergy and Infectious diseases.

Inborn errors of immunity (IEIs) consist of numerous rare, inherited defects of the immune system that affect about 500,000 people in the United States. As advancements in diagnosis through genetic testing and treatment with targeted immunotherapy and bone marrow transplant emerge, increasing numbers of patients survive into adulthood posing fresh clinical challenges. A large spectrum of hepatobiliary diseases now present in those with immunodeficiency diseases, leading to morbidity and mortality in this population. Awareness of these hepatobiliary diseases has lagged the improved management of the underlying disorders, leading to missed opportunities to improve clinical outcomes. This review article provides a detailed description of specific liver diseases occurring in various inborn errors of immunity. A generalized approach to diagnosis and management of hepatic complications is provided, and collaboration with hepatologists, immunologists, and pathologists is emphasized as a requirement for optimizing management and outcomes.

Sterile alpha motif (SAM) and Src homology-3 (SH3) domain-containing 3 (SASH3), also called SH3-containing lymphocyte protein (SLY1), is a putative adaptor protein that is postulated to play an important role in the organization of signaling complexes and propagation of signal transduction cascades in lymphocytes. The SASH3 gene is located on the X-chromosome. Here, we identified 3 novel SASH3 deleterious variants in 4 unrelated male patients with a history of combined immunodeficiency and immune dysregulation that manifested as recurrent sinopulmonary, cutaneous, and mucosal infections and refractory autoimmune cytopenias. Patients exhibited CD4+ T-cell lymphopenia, decreased T-cell proliferation, cell cycle progression, and increased T-cell apoptosis in response to mitogens. In vitro T-cell differentiation of CD34+ cells and molecular signatures of rearrangements at the T-cell receptor α (TRA) locus were indicative of impaired thymocyte survival. These patients also manifested neutropenia and B-cell and natural killer (NK)-cell lymphopenia. Lentivirus-mediated transfer of the SASH3 complementary DNA–corrected protein expression, in vitro proliferation, and signaling in SASH3-deficient Jurkat and patient-derived T cells. These findings define a new type of X-linked combined immunodeficiency in humans that recapitulates many of the abnormalities reported in mice with Sly1–/– and Sly1Δ/Δ mutations, highlighting an important role of SASH3 in human lymphocyte function and survival.

Autosomal dominant (AD) NFKB1 deficiency is thought to be the most common genetic etiology of common variable immunodeficiency (CVID). However, the causal link between NFKB1 variants and CVID has not been demonstrated experimentally and genetically, as there has been insufficient biochemical characterization and enrichment analysis. We show that the cotransfection of NFKB1-deficient HEK293T cells (lacking both p105 and its cleaved form p50) with a κB reporter, NFKB1/p105, and a homodimerization-defective RELA/p65 mutant results in p50:p65 heterodimer–dependent and p65:p65 homodimer–independent transcriptional activation. We found that 59 of the 90 variants in patients with CVID or related conditions were loss of function or hypomorphic. By contrast, 258 of 260 variants in the general population or patients with unrelated conditions were neutral. None of the deleterious variants displayed negative dominance. The enrichment in deleterious NFKB1 variants of patients with CVID was selective and highly significant (P = 2.78 × 10−15). NFKB1 variants disrupting NFKB1/p50 transcriptional activity thus underlie AD CVID by haploinsufficiency, whereas neutral variants in this assay should not be considered causal.