Explore the vast range of titles available.

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.

Since Tregs, particularly those committed in the thymus (tTregs), play a non-redundant role in the control of autoimmune and inflammatory diseases, it is critical to identify the relevant network of epigenomic interactions governing tTregs and their possible alterations in IEI.Raposo et al.used the genome-wide expression (RNA-seq) and chromatin accessibility maps (ATAC-seq) of purified CD4 single-positive (CD4SP) Tregs and conventional T cells (Tconv) from human thymuses to define their expression signature and quantify genome-wide transcription factor (TF) binding. [...]measurement of autoantibodies might be a useful screening test for autoimmune diseases in PID patients. Since some ICF patients suffer from recurrent viral and/or fungal infections, ICF patients have been suspected of having concomitant T-cell immunodeficiency. In this Research Topic,Lullo et al.provide a novel human model for ICF-2 subtype 2 (ICF-2), due to pathogenic variants of the ZBTB24 gene.

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.

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.

[This corrects the article DOI: 10.3389/fimmu.2021.767188.].

NF-κB1 deficiency is suggested to be the most common cause of common variable immunodeficiency (CVID). NFKB1 encodes for the p105 precursor protein of NF-κB1, which is converted into the active transcriptional subunit p50 through proteasomal processing of its C-terminal half upon stimulation and is implicated in the canonical NF-kB pathway. Rare monoallelic NFKB1 variants have been shown to cause (haplo) insufficiency. Our report describes a novel NFKB1 missense variant (c.691C>T, p.R230C; allele frequency 0.00004953) in a family vulnerable to meningitis, sepsis, and late-onset hypogammaglobulinemia. We investigated the pathogenic relevance of this variant by lymphocyte stimulation, immunophenotyping, overexpression study and immunoblotting. The ectopic expression of p50 for c.691 C>T restricted transcriptionally active p50 in the cytoplasm, and immunoblotting revealed reduced p105/50 expression. This study shows that the deleterious missense variant in NFKB1 adversely affects the transcriptional and translational activity of NFκB1, impairing its function. Patients immunological parameters show a progressive course of hypogammaglobulinemia, which may partially account for the incomplete disease penetrance and suggest the need for closer immunological monitoring of those mutation carriers.

ObjectiveThe clinical spectrum of primary antibody deficiencies (PADs) and especially common variable immunodeficiency (CVID) includes various autoimmune disorders. We studied the prevalence and the features of articular rheumatic disease in a cohort of patient with PADs.MethodsIn this retrospective cohort study, complete clinical data of 268 patients with PADs, mainly consisting of patients with CVID, visiting the immunology outpatient clinic of a German tertiary hospital between 2018 and 2021 were collected. Those included case history, physical examination, laboratory as well as radiological findings.ResultsInflammatory arthritis was diagnosed in 16.4% of studied patients and was significantly more common among patients with PAD-associated enteropathy (OR 13.39, p=0.0001), splenomegaly (OR 6.09, p=0.0001) or atopic diseases (OR 3.31, p=0.021). Given HLA-B27 status, the involvement of the axial skeleton and the presence of features, such as anterior uveitis, inflammatory bowel disease, psoriasis and/or dactylitis, 75% of studied patients fulfilled the Assessment of Spondyloarthritis International Society classification criteria.ConclusionPAD-associated arthritis frequently shares features with spondyloarthritis (SpA) and enteropathic arthritis. The latter may suggest the interconnected pathomechanisms of inflammatory arthritis in SpA and PADs.