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Mutations in genes encoding components of the immune system cause primary immunodeficiencies. Here, we study a patient with recurrent atypical mycobacterial infection and early-onset metastatic bladder carcinoma. Exome sequencing identified two homozygous missense germline mutations, P733L and P832S, in the JAK1 protein that mediates signalling from multiple cytokine receptors. Cells from this patient exhibit reduced JAK1 and STAT phosphorylation following cytokine stimulations, reduced induction of expression of interferon-regulated genes and dysregulated cytokine production; which are indicative of signalling defects in multiple immune response pathways including Interferon-γ production. Reconstitution experiments in the JAK1-deficient cells demonstrate that the impaired JAK1 function is mainly attributable to the effect of the P733L mutation. Further analyses of the mutant protein reveal a phosphorylation-independent role of JAK1 in signal transduction. These findings clarify JAK1 signalling mechanisms and demonstrate a critical function of JAK1 in protection against mycobacterial infection and possibly the immunological surveillance of cancer. JAK1 mediates intracellular signalling from multiple cytokine receptors. Here, Eletto et al . identify JAK1 mutations that disrupt multiple signalling pathways and are associated with primary immunodeficiency, atypical mycobacterial infection susceptibility and early-onset metastatic bladder carcinoma.

Non-canonical NF-κB-pathway signaling is integral in immunoregulation. Heterozygous mutations in have recently been established as a molecular cause of common variable immunodeficiency (CVID) and DAVID-syndrome, a rare condition combining deficiency of anterior pituitary hormone with CVID. Here, we investigate 15 previously unreported patients with primary immunodeficiency (PID) from eleven unrelated families with heterozygous -mutations including eight patients with the common p.Arg853 nonsense mutation and five patients harboring unique novel C-terminal truncating mutations. In addition, we describe the clinical phenotype of two patients with proximal truncating mutations. Cohort analysis extended to all 35 previously published -cases revealed occurrence of early-onset PID in 46/50 patients (mean age of onset 5.9 years, median 4.0 years). ACTH-deficiency occurred in 44%. Three mutation carriers have deceased, four developed malignancies. Only two mutation carriers were clinically asymptomatic. In contrast to typical CVID, most patients suffered from early-onset and severe disease manifestations, including clinical signs of T cell dysfunction e.g., chronic-viral or opportunistic infections. In addition, 80% of patients suffered from (predominately T cell mediated) autoimmune (AI) phenomena (alopecia > various lymphocytic organ-infiltration > diarrhea > arthritis > AI-cytopenia). Unlike in other forms of CVID, auto-antibodies or lymphoproliferation were not common hallmarks of disease. Immunophenotyping showed largely normal or even increased quantities of naïve and memory CD4 or CD8 T-cells and normal T-cell proliferation. NK-cell number and function were also normal. In contrast, impaired B-cell differentiation and hypogammaglobinemia were consistent features of -associated disease. In addition, an array of lymphocyte subpopulations, such as regulatory T cell, Th17-, cTFH-, NKT-, and MAIT-cell numbers were decreased. We conclude that heterozygous damaging mutations in represent a distinct PID entity exceeding the usual clinical spectrum of CVID. Impairment of the non-canonical NF-κB pathways affects function and differentiation of numerous lymphocyte-subpopulations and thus causes a heterogeneous, more severe form of PID phenotype with early-onset. Further characteristic features are multifaceted, primarily T cell-mediated autoimmunity, such as alopecia, lymphocytic organ infiltration, and in addition frequently ACTH-deficiency.

Autoimmune thrombocytopenia (AITP) is frequent in patients diagnosed with common variable immunodeficiency (CVID). High dose intravenous immunoglobulin treatment (IVIG) has conventionally been a cornerstone of the initial therapy for AITP. This study aimed to assess the safety and effectiveness of subcutaneous immunoglobulin (SCIG) compared to IVIG in preventing AITP in CVID patients. This prospective observational study enrolled 47 adult CVID patients concurrently diagnosed with AITP. Of the participants, 27 (57%) were treated with SCIG, while 20 (43%) received IVIG. AITP episodes were defined as platelet counts <50,000/µl with bleeding or <20,000/µl with or without bleeding, followed over a 64-month period. Among the 47 patients included, 12 (25.5%) experienced AITP episodes, with seven using SCIG and five using IVIG. No significant difference was observed in AITP occurrence between the two treatment groups (p-value=0.99). Neither splenomegaly nor the use of immunosuppressive therapies showed a correlation to the AITP bouts. Maintaining IgG trough levels above 7g/l arose as a key factor for preventing AITP in both treatment modalities. In conclusion, both SCIG and IVIG demonstrated comparable efficacy in the prevention of AITP in CVID patients. This study highlights the importance of monitoring IgG levels in the management of CVID patients with AITP.

Gain-of-function (GOF) mutations in cause a combined immunodeficiency characterized by chronic mucocutaneous candidiasis (CMC), recurrent infections, and autoimmunity. Mutations in the DNA-binding domain (DBD) have previously been associated with poor outcomes, but the contributions of specific variants to clinical phenotype remain unexplored. We performed a systematic literature review to identify patients with confirmed GOF mutations, integrating new cases with a previously reported international cohort. Clinical and genetic data were analyzed at both domain and mutation level to define genotype-phenotype correlations. A total of 533 unique patients from 36 countries were identified, harboring 135 distinct mutations. As previously reported, DBD mutations were associated with increased risk of systemic infections, bronchiectasis, autoimmunity, and reduced survival. However, mutation-level stratification revealed that the T385M variant accounted for much of this effect. Compared with both other DBD mutations and mutations elsewhere in , T385M conferred significantly higher rates of infection, bronchiectasis, autoimmunity, and premature death (p < 0.001). Conversely, certain coiled-coil (CC) domain mutations, such as R274Q, were associated with milder disease and improved survival. Our findings demonstrate that the adverse prognosis previously ascribed to DBD mutations in GOF is predominantly driven by the T385M variant. Mutation-specific, rather than domain-level, stratification is therefore essential for accurate risk assessment and clinical management. In particular, patients predicted to have severe disease, such as those with the T385M mutation should be considered early for curative interventional therapies such as stem cell transplant or gene therapy.

Dysregulation of autophagy and inflammasome activity contributes to the development of auto-inflammatory diseases. Emerging evidence highlights the importance of the actin cytoskeleton in modulating inflammatory responses. Here we show that deficiency of Wiskott–Aldrich syndrome protein (WASp), which signals to the actin cytoskeleton, modulates autophagy and inflammasome function. In a model of sterile inflammation utilizing TLR4 ligation followed by ATP or nigericin treatment, inflammasome activation is enhanced in monocytes from WAS patients and in WAS-knockout mouse dendritic cells. In ex vivo models of enteropathogenic Escherichia coli and Shigella flexneri infection, WASp deficiency causes defective bacterial clearance, excessive inflammasome activation and host cell death that are associated with dysregulated septin cage-like formation, impaired autophagic p62/LC3 recruitment and defective formation of canonical autophagosomes. Taken together, we propose that dysregulation of autophagy and inflammasome activities contribute to the autoinflammatory manifestations of WAS, thereby identifying potential targets for therapeutic intervention. Wiskott-Aldrich syndrome protein (WASp) is essential for controlling the cytoskeleton, but its function in innate immunity is unclear. Here the authors show that WASp deficiency is associated with dysregulated septin cage formation, excessive inflammasome activation, elevated immune cell death and reduced bacterial clearance.

Individuals with primary and secondary immunodeficiency (PID/SID) were shown to be at risk of poor outcomes during the early stages of the SARS-CoV-2 pandemic. SARS-CoV-2 vaccines demonstrate reduced immunogenicity in these patients. To understand whether the risk of severe COVID-19 in individuals with PID or SID has changed following the deployment of vaccination and therapeutics in the context of the emergence of novel viral variants of concern. The outcomes of two cohorts of patients with PID and SID were compared: the first, infected between March and July 2020, prior to vaccination and treatments, the second after these intervention became available between January 2021 and April 2022. 22.7% of immunodeficient patients have been infected at least once with SARS-CoV-2 since the start of the pandemic, compared to over 70% of the general population. Immunodeficient patients were typically infected later in the pandemic when the B.1.1.529 (Omicron) variant was dominant. This delay was associated with receipt of more vaccine doses and higher pre-infection seroprevalence. Compared to March-July 2020, hospitalization rates (53.3% vs 17.9%, p<0.0001) and mortality (Infection fatality rate 20.0% vs 3.4%, p=0.0003) have significantly reduced for patients with PID but remain elevated compared to the general population. The presence of a serological response to vaccination was associated with a reduced duration of viral detection by PCR in the nasopharynx. Early outpatient treatment with antivirals or monoclonal antibodies reduced hospitalization during the Omicron wave. Most individuals with immunodeficiency in the United Kingdom remain SARS-CoV-2 infection naïve. Vaccination, widespread availability of outpatient treatments and, possibly, the emergence of the B.1.1.529 variant have led to significant improvements in morbidity and mortality followings SARS-CoV-2 infection since the start of the pandemic. However, individuals with PID and SID remain at significantly increased risk of poor outcomes compared to the general population; mitigation, vaccination and treatment strategies must be optimized to minimize the ongoing burden of the pandemic in these vulnerable cohorts.

Common Variable Immunodeficiency Disorders (CVID) encompass a spectrum of immunodeficiency characterised by recurrent infections and diverse non-infectious complications (NICs). This study aimed to describe the clinical features and variation in NICs in CVID with and without interstitial lung disease (ILD) from a large UK national registry population. Retrospective, cross-sectional data from a UK multicentre database (previously known as UKPIN), categorising patients into those with CVID-ILD and those with NICs related to CVID but without pulmonary involvement (CVID-EP; EP= extra-pulmonary involvement only). 129 patients were included. Chronic lung diseases, especially CVID-ILD, are prominent complications in complex CVID, occurring in 62% of the cohort. Bronchiectasis was common (64% of the cohort) and associated with greater pulmonary function impairment in patients with CVID-ILD compared to those without bronchiectasis. Lymphadenopathy and the absence of gastrointestinal diseases were significant predictors of ILD in complex CVID. Although the presence of liver disease did not differ significantly between the groups, nearly half of the CVID-ILD patients were found to have liver disease. Patients with CVID-ILD were more likely to receive immunosuppressive treatments such as rituximab and mycophenolate mofetil than the CVID-EP group, indicating greater need for treatment and risk of complications. This study highlights the significant burden of CVID-ILD within the CVID population with NICs only. The lungs emerged as the most frequently affected organ, with ILD and bronchiectasis both highly prevalent. These findings emphasise the necessity of a comprehensive and multidisciplinary approach in managing CVID patients, considering their susceptibility to various comorbidities and complications.

Diarrhoea is the commonest gastrointestinal symptom in patients with common variable immunodeficiency (CVID). The aim of this study was to describe the prevalence and clinical presentation of chronic and recurrent diarrhoea in the Royal-Free-Hospital (RFH) London CVID cohort, including symptoms, infections, level of inflammation, and microbial diversity. A cross-sectional study of adult CVID patients (139 out of 172 diagnosed with CVID completed the screening questionnaire). Those with diarrhoea ≥6 days/month had stool and blood samples analysed and completed the short Inflammatory Bowel Disease Questionnaire (sIBDQ). BMI, spleen-size, lymphocytes and gut-microbial diversity were compared. Due to logistical and clinical restraints, not all patients could be analysed on all measures. 46/139 (33.1%) patients had current significant diarrhoea. In patients with past or present diarrhoea, BMI was lower (median 23.7 vs. 26, = 0.005), malabsorption more common (57.97 vs. 35.71%, = 0.011). CD4+ lymphocytes were higher in patients with diarrhoea ( = 0.028; = 138), but CD4+ naïve lymphocytes were significantly higher in non-diarrhoea patients ( = 0.009, = 28). Nine patients had confirmed or probable current gastrointestinal infections. Calprotectin was >60 μg/g in 13/29 with significant diarrhoea including 9 without infection. SIBDQ revealed a low median score of 4.74. Microbial alpha diversity was significantly lower in CVID patients compared to healthy household controls. There was no significant difference in alpha diversity in relation to antibiotic intake during the 6 weeks prior to providing samples. Patients with CVID and significant diarrhoea had infections, raised calprotectin, malabsorption, a lower BMI, an impaired quality of life (comparable to active IBD), and they differed from non-diarrhoea patients in their lymphocyte phenotyping. Furthermore, microbial diversity was altered. These findings strongly imply that there may be an inflammatory nature and a systemic predisposition to diarrhoea in CVID, which necessitates further investigation.

Common variable immunodeficiency (CVID) is traditionally characterised by recurrent infections and immune dysregulation, but growing evidence suggests an increased risk of endothelial dysfunction and premature atherosclerosis in this population. To evaluate cardiovascular risk in patients with CVID through integration of clinical risk factors, biomarkers of endothelial dysfunction, and radiographic surrogates of subclinical atherosclerosis. A total of 101 CVID patients and 56 matched household controls were recruited. Data collected included cardiovascular risk factors, blood biomarkers (D-dimer, von Willebrand factor [vWF], fibrinogen, ESR, CRP), and immunological profiles. Existing imaging was reviewed, including thoracic CT for assessment of coronary artery calcification (CAC) and FibroScan for controlled attenuation parameter (CAP) scores; aortic pulse wave velocity (aPWV) was measured in a subset of participants. Subgroup analysis compared infection-only versus inflammatory/complex phenotypes of CVID. CVID patients demonstrated high rates of hyperlipidaemia (38.6%), hypertension (23.8%), and diabetes/prediabetes (14.9%). CAC was present in 37%, with 82.4% having no known prior cardiovascular disease. Hepatic steatosis and elevated aPWV were observed in 30% and 6.5%, respectively. Patients with CAC were older and had higher rates of hypertension, diabetes, hyperlipidaemia, chronic kidney disease, elevated median vWF (227.5 vs 167 IU/dL, p=0.001), D-dimer (370.5 vs 271 ng/mL, p=0.011), and aPWV (8.2 vs 6.0 m/s, p=0.006). Patients with an inflammatory phenotype had higher vWF (224 vs 163 IU/dL, p<0.001) and D-dimer (314 vs 205 ng/mL, p=0.043) levels than those with infection-only CVID. CVID is associated with a substantial burden of cardiovascular risk factors and subclinical atherosclerosis, especially in the inflammatory phenotype.

The International Patient Organisation for Primary Immunodeficiencies (IPOPI) held its second Global Multi-Stakeholders’ Summit, an annual stimulating and forward-thinking meeting uniting experts to anticipate pivotal upcoming challenges and opportunities in the field of primary immunodeficiency (PID). The 2023 summit focused on three key identified discussion points: (i) How can immunoglobulin (Ig) therapy meet future personalized patient needs? (ii) Pandemic preparedness: what’s next for public health and potential challenges for the PID community? (iii) Diagnosing PIDs in 2030: what needs to happen to diagnose better and to diagnose more? Clinician-Scientists, patient representatives and other stakeholders explored avenues to improve Ig therapy through mechanistic insights and tailored Ig preparations/products according to patient-specific needs and local exposure to infectious agents, amongst others. Urgency for pandemic preparedness was discussed, as was the threat of shortage of antibiotics and increasing antimicrobial resistance, emphasizing the need for representation of PID patients and other vulnerable populations throughout crisis and care management. Discussion also covered the complexities of PID diagnosis, addressing issues such as global diagnostic disparities, the integration of patient-reported outcome measures, and the potential of artificial intelligence to increase PID diagnosis rates and to enhance diagnostic precision. These proceedings outline the outcomes and recommendations arising from the 2023 IPOPI Global Multi-Stakeholders’ Summit, offering valuable insights to inform future strategies in PID management and care. Integral to this initiative is its role in fostering collaborative efforts among stakeholders to prepare for the multiple challenges facing the global PID community.