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In addition to susceptibility to infections, conventional primary immunodeficiency disorders (PIDs) and inborn errors of immunity (IEI) can cause immune dysregulation, manifesting as lymphoproliferative and/or autoimmune disease. Autoimmunity can be the prominent phenotype of PIDs and commonly includes cytopenias and rheumatological diseases, such as arthritis, systemic lupus erythematosus (SLE), and Sjogren’s syndrome (SjS). Recent advances in understanding the genetic basis of systemic autoimmune diseases and PIDs suggest an at least partially shared genetic background and therefore common pathogenic mechanisms. Here, we explore the interconnected pathogenic pathways of autoimmunity and primary immunodeficiency, highlighting the mechanisms breaking the different layers of immune tolerance to self-antigens in selected IEI.

To assess the clinical relevance of diagnosing and classifying isolated IgG deficiency and combined IgG/IgM deficiency separately from CVID. In a retrospective cohort of patients with primary hypogammaglobulinemia, we evaluated and compared the clinical spectrum and immunological findings of patients with CVID, isolated IgG deficiency, and combined IgG/IgM deficiency. In comparison to CVID, respiratory tract infections and gastrointestinal infections were less common in isolated IgG or combined IgG/IgM deficiency, while recurrent mucocutaneous herpes simplex virus reactivations were more common. With respect to immune dysregulation, splenomegaly and immune thrombocytopenic purpura were more frequently observed in CVID. Comparison of immunophenotypic data, revealed relatively lower class-switch memory B cell counts in CVID, while patients with IgG deficiency displayed lower transitional B cells. Survival analysis for these cohorts reveals a significant divergence in long-term outcomes, demonstrating that patients with CVID experience markedly lower overall survival rates. Comparison of CVID with isolated IgG deficiency or combined IgG/IgM deficiency revealed distinct immunophenotypic profiles, differences in both infectious and non-infectious manifestations, and markedly worse clinical outcomes in CVID. These findings suggest that CVID and unclassified antibody deficiencies - manifesting as isolated IgG deficiency or combined IgG/IgM deficiency - occupy different immunological niches. Consequently, our data support maintaining CVID as a distinct diagnostic entity, separate from IgG and IgG/IgM deficiencies, and highlight the need for tailored diagnostic approaches and follow-up strategies for these different forms of primary antibody deficiency.

The aim of the present study was to investigate the clinical spectrum of IgG subclass deficiencies (IgGSDs) and assess the relative clinical significance of diagnosing each specific IgGSD disorder as compared to the common variable immunodeficiency (CVID). The clinical spectrum and immunological findings from 96 patients, diagnosed with diverse IgGSDs, were retrospectively evaluated. Specific IgGSDs were compared with each other and a cohort of 270 patients with CVID. In comparison to CVID, recurrent lower respiratory tract infections (LRTIs) and bronchiectasis were rarer in IgGSDs, while recurrent mucocutaneous herpes simplex virus reactivations were more common. With respect to autoimmunity, IgGSDs were associated with arthritis, while autoimmune cytopenias were less frequently observed than in CVID. Among IgGSDs, herpes zoster was more common in IgG3SD. Arthritis was more prevalent in IgG1 + 3SD. Given its association with LRTI, splenomegaly, immune thrombocytopenic purpura, and the lower class-switched memory B-cell counts, IgG2 + 4SD is the IgGSD that rather resembles CVID. Comparative evaluation of phenotypes and treatments of patients with IgGSDs and CVID reveals distinct features, suggesting the differential clinical significance of diagnosing IgGSDs. The differential clinical expressions of IgGSDs highlight the need for studying each IgGSD separately in order to optimize disorder-specific follow-up procedures and prophylactic anti-infective measures.

The aim of this study was to investigate the prevalence of cancer and associating clinical, immunological, and genetic factors in a German cohort of patients with common variable immunodeficiency (CVID). In this retrospective monocenter cohort study, we estimated the standardized incidence ratio (SIR) for different forms of cancer diagnosed in CVID patients. Furthermore, we evaluated the likely association of infectious and non-infectious CVID-related phenotypes with the diagnosis of cancer by calculation of the odds ratio. The genetic background of CVID in patients with cancer was evaluated with sequential targeted next-generation sequencing (tNGS) and whole-exome sequencing (WES). Patients' family history and WES data were evaluated for genetic predisposition to cancer. A total of 27/219 patients (12.3%) were diagnosed with at least one type of cancer. Most common types of cancer were gastric cancer (SIR: 16.5), non-melanoma skin cancer (NMSC) (SIR: 12.7), and non-Hodgkin lymphoma (NHL) (SIR: 12.2). Immune dysregulation manifesting as arthritis, atrophic gastritis, or interstitial lung disease (ILD) was associated with the diagnosis of cancer. Furthermore, diagnosis of NMSC associated with the diagnosis of an alternative type of cancer. Studied immunological parameters did not display any significant difference between patients with cancer and those without. tNGS and/or WES yielded a definite or likely genetic diagnosis in 11.1% of CVID patients with cancer. Based on identified variants in cancer-associated genes, the types of diagnosed cancers, and family history data, 14.3% of studied patients may have a likely genetic susceptibility to cancer, falling under a known hereditary cancer syndrome. Gastric cancer, NMSC, and NHL are the most frequent CVID-associated types of cancer. Manifestations of immune dysregulation, such as arthritis and ILD, were identified as risk factors of malignancy in CVID, whereas studied immunological parameters or the identification of a monogenic form of CVID appears to have a limited role in the evaluation of cancer risk in CVID.

The signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) syndrome (STAT3-GOF) is an inborn error of immunity (IEI) characterized by diverse manifestations of immune dysregulation that necessitate systemic immunomodulatory treatment. The blockade of the interleukin-6 receptor and/or the inhibition of the Janus kinases has been commonly employed to treat diverse STAT3-GOF-associated manifestations. However, evidence on long-term treatment outcome, especially in the case of adult patients, is scarce. Clinical data, including laboratory findings and medical imaging, were collected from all seven patients, diagnosed with STAT3-GOF, who have been treated at the Hannover University School, focusing on those who received a Janus kinase (JAK) inhibitor (JAKi). Previously published cases of STAT3-GOF patients who received a JAKi were evaluated, focusing on reported treatment efficacy with respect to diverse STAT3-GOF-associated manifestations of immune dysregulation and safety. Five out of seven patients diagnosed with STAT3-GOF were treated with a JAKi, each for a different indication. Including these patients, outcomes of JAKi treatment have been reported for a total of 41 patients. Treatment with a JAKi led to improvement of diverse autoimmune, inflammatory, or lymphoproliferative manifestations of STAT3-GOF and a therapeutic benefit could be documented for all except two patients. Considering all reported manifestations of immune dysregulation in each patient, complete remission was achieved in 10/41 (24.4%) treated patients. JAKi treatment improved diverse manifestations of immune dysregulation in the majority of STAT3-GOF patients, representing a promising therapeutic approach. Long-term follow-up data are needed to evaluate possible risks of prolonged treatment with a JAKi.

Background Homozygous or compound heterozygous variants in RNU4ATAC , which transcribes a non-coding RNA component of the minor spliceosome, have been associated with a spectrum of disorders, collectively known as RNU4ATAC -related spliceosomeopathies. The phenotypic spectrum of RNU4ATAC -related disease is characterized by dysmorphic features, growth delay, neurological and skeletal features, whose severity ranges from the microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) to the milder Roifman syndrome. Objectives To characterize the clinical spectrum and evaluate long-term outcomes of RNU4ATAC -related diseases. Methods We evaluated the phenotypic features of four novel patients with deleterious RNU4ATAC variants, diagnosed by means of whole genome sequencing. Same features were evaluated in previously published cases, identified by literature research on PubMed. Results We identified four novel cases with deleterious compound heterozygous variants in RNU4ATAC , which were not restricted to the 5’ stem-loop, including three adult patients. Reported cases expand the clinical spectrum of RNU4ATAC -related disorders, highlighting renal disease, autoimmunity and systemic inflammation as possibly more frequent yet previously under-recognized features. Immunological investigations reveal enhanced HLA-DR and PD-1 expression in T cells from tested patients, suggesting T cell activation and exhaustion. Reevaluation of all previously published cases confirms the strong correlation of RNU4ATAC variants located exclusively at the 5’ stem-loop with severe lethal disease falling under MOPD1. Genotypes carrying at least one variant that spares the 5′ stem-loop are associated with a milder phenotype and later onset. Conclusion Homozygous or compound heterozygous RNU4ATAC variants affecting the 5’ stem-loop region are associated with severe phenotypes and adverse disease courses. In contrast, genotypes sparing the critical 5′ stem-loop region of RNU4ATAC can cause a complex phenotype that is not necessarily dominated by dysmorphic features or growth failure, but rather by immunodeficiency and immune dysregulation.

Activated phosphoinositide 3-kinase delta syndrome (APDS) is an inborn error of immunity first described in 2013. With an estimated prevalence of 1-2 per 1,000,000 individuals, it is considered an ultra-rare disease. The aim of this survey was to explore the diagnostic and therapeutic challenges of patients with APDS from the patients` and physicians` perspective in Austria, Germany, and Switzerland. A qualitative case study approach was applied. Semi-structured interviews were conducted with six patients or legal guardians of children with APDS, and four clinical immunologists with direct experience in APDS care. Transcripts were analyzed using inductive content analysis. The interviews revealed a median diagnostic delay of several years, mainly due to the rarity and phenotypic heterogeneity of APDS and the involvement of multiple specialties prior to referral to an immunologist. Many patients initially received symptomatic treatment before an underlying immune disorder was suspected. Physicians emphasized the decisive role of genetic testing for confirmation, while patients frequently described the diagnosis as a \"lucky coincidence\". Both groups highlighted structural barriers including limited awareness, fragmented care, and delayed access to targeted therapy. Early recognition of APDS requires specific education across specialties, wider access to genetic testing, and the development of standardized diagnostic and disease activity tools. Strengthening interdisciplinary care pathways and timely initiation of APDS-specific therapy may substantially improve outcomes in this ultra-rare immunodeficiency.

Adult-onset primary immunodeficiency is characterized by recurrent infections, hypogammaglobulinemia, and poor antibody response to vaccines. In this study, we have analyzed targeted gene panel sequencing results of 270 patients diagnosed with antibody deficiency and identified five disease-associated variants in in five unrelated families. We detected two single base pair deletions and two single base pair insertions, causing severe protein truncations, and one missense mutation. Immunoblotting, lymphocyte stimulation, immunophenotyping, and ectopic expression assays demonstrated the functional relevance of mutations. Besides antibody deficiency, clinical manifestations included infections, autoimmune features, lymphoproliferation, lymphoma, Addison's disease, type 2 diabetes and asthma. Although partial clinical penetrance was observed in almost all pedigrees, all carriers presented a deficiency in certain serum immunoglobulins and the majority showed a lack of memory B cells (CD19 CD27 ). Among all tested genes, alterations were the most common monoallelic cause of antibody deficiency in our cohort.

IntroductionThe diagnosis and treatment of inborn errors of immunity (IEI) is a major challenge as the individual conditions are rare and often characterized by a variety of symptoms, which are often non disease-specific. Ideally, patients are treated in dedicated centers by physicians who specialize in the management of primary immune disorders. In this study, we used the example of Activated PI3Kδ syndrome (APDS), a rare IEI with an estimated prevalence of 1:1,000,000. We conducted surveys by questionnaire and interviewed physicians at different IEI centers in Germany.MethodsWe queried structural aspects of IEI care in Germany, diagnostic procedures in IEI care (including molecular diagnostics), distribution of APDS patients, APDS symptoms and severity, treatment algorithms in APDS, the role of stem cell transplantation and targeted therapies in IEI with focus on APDS. We were especially interested in how genetic diagnostics may influence treatment decisions, e.g. with regard to targeted therapies.Results/discussionMost centers care for both pediatric and adult patients. A total of 28 APDS patients are currently being treated at the centers we surveyed. Patient journeys vary considerably, as does severity of disease. Genetic diagnosis continues to gain importance - whole genome sequencing is likely to become routine in IEI in the next few years. According to the experts interviewed, stem cell transplantation and - with new molecules being approved - targeted therapies, will gain in importance for the treatment of APDS and IEI in general.