Explore the vast range of titles available.

Activated PI3Kδ syndrome (APDS) is a rare inborn error of immunity (IEI) characterized primarily by frequent infections, lymphoproliferation and autoimmunity. Since its initial description in 2013, APDS has become part of the growing group of nearly 500 IEIs affecting various components of the immune system. The two subtypes of APDS - APDS1 and APDS2 - are caused by variants in the PIK3CD and PIK3R1 genes, respectively. Due to the rarity of the disease and the heterogeneous clinical picture, many patients are not diagnosed until years after symptom onset. Another challenge is the large number of PIK3CD and PIK3R1 variants whose functional significance for developing APDS is inconclusive. Treatment of APDS has so far been mostly symptom-oriented with immunoglobulin replacement therapy, immunosuppressive therapies and antibiotic or antiviral prophylaxes. Additionally, allogeneic stem cell transplantation as well as new targeted therapies are options targeting the root cause that may improve patients’ quality of life and life expectancy. However, the clinical course of the disease is difficult to predict which complicates the choice of appropriate therapies. This review article discusses diagnostic procedures and current and future treatment options, and highlights the difficulties that physicians, patients and their caretakers face in managing this complex disease. This article is based on cohort studies, the German and US guidelines on the management of primary immunodeficiencies as well as on published experience with diagnosis and compiled treatment experience for APDS.

Graft-versus-host disease (GvHD) of the skin is a severe allo-immune reaction and complication following allogeneic stem cell transplantation. Over the past years, intensive pre-clinical research has led to an improved understanding of the pathophysiology of acute and to a lesser extend chronic GvHD. This has translated into the approval of several new agents for the treatment of both forms of GvHD. This review summarizes the most recent advances in underlying pathomechanisms, clinical trials and newly approved agents for GvHD, with a special focus on skin involvement.

The discovery of Suppressor of Cytokine Signaling 1 (SOCS1) in 1997 marked a significant milestone in understanding the regulation of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways. Subsequent research deciphered its cellular functions, and recent insights into SOCS1 deficiencies in humans underscored its critical role in immune regulation. In humans, SOCS-haploinsufficiency (SOCS1-HI) presents a diverse clinical spectrum, encompassing autoimmune diseases, infection susceptibility, and cancer. Variability in disease manifestation, even within families sharing the same genetic variant, raises questions about clinical penetrance and the need for individualized treatments. Current therapeutic strategies include JAK inhibition, with promising results in controlling inflammation in SOCS1-HI patients. Hematopoietic stem cell transplantation and gene therapy emerge as promising avenues for curative treatments. The evolving landscape of SOCS1 research, emphasizes the need for a nuanced understanding of genetic variants and their functional consequences.

Although negative selection of developing B cells in the periphery is well described, yet poorly understood, evidence of naive B cell positive selection remains elusive. Using 2 humanized mouse models, we demonstrate that there was strong skewing of the expressed immunoglobulin repertoire upon transit into the peripheral naive B cell pool. This positive selection of expanded naive B cells in humanized mice resembled that observed in healthy human donors and was independent of autologous thymic tissue. In contrast, negative selection of autoreactive B cells required thymus-derived Tregs and MHC class II-restricted self-antigen presentation by B cells. Indeed, both defective MHC class II expression on B cells of patients with rare bare lymphocyte syndrome and prevention of self-antigen presentation via HLA-DM inhibition in humanized mice resulted in the production of autoreactive naive B cells. These latter observations suggest that Tregs repressed autoreactive naive B cells continuously produced by the bone marrow. Thus, a model emerged, in which both positive and negative selection shaped the human naive B cell repertoire and that each process was mediated by fundamentally different molecular and cellular mechanisms.

DNA damage is a constant event in every cell caused by exogenous factors such as ultraviolet and ionizing radiation (UVR/IR) and intercalating drugs, or endogenous metabolic and replicative stress. Proteins of the DNA damage response (DDR) network sense DNA lesions and induce cell cycle arrest, DNA repair, and apoptosis. Genetic defects of DDR or DNA repair proteins can be associated with immunodeficiency, bone marrow failure syndromes, and cancer susceptibility. Although various diagnostic tools are available to evaluate DNA damage, their quality to identify DNA repair deficiencies differs enormously and depends on affected pathways. In this study, we investigated the DDR biomarkers γH2AX (Ser139), p-ATM (Ser1981), and p-CHK2 (Thr68) using flow cytometry on peripheral blood cells obtained from patients with combined immunodeficiencies due to non-homologous end-joining (NHEJ) defects and ataxia telangiectasia (AT) in response to low-dose IR. Significantly reduced induction of all three markers was observed in AT patients compared to controls. However, delayed downregulation of γH2AX was found in patients with NHEJ defects. In contrast to previous reports of DDR in cellular models, these biomarkers were not sensitive enough to identify ARTEMIS deficiency with sufficient reliability. In summary, DDR biomarkers are suitable for diagnosing NHEJ defects and AT, which can be useful in neonates with abnormal TREC levels (T cell receptor excision circles) identified by newborn screening. We conclude that DDR biomarkers have benefits and some limitations depending on the underlying DNA repair deficiency.

Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-α or anti-IFN-ω antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.

Autoinflammatory diseases are a heterogenous group of disorders defined by fever and systemic inflammation suggesting involvement of genes regulating innate immune responses. Patients with homozygous loss‐of‐function variants in the OTU‐deubiquitinase OTULIN suffer from neonatal‐onset OTULIN‐related autoinflammatory syndrome (ORAS) characterized by fever, panniculitis, diarrhea, and arthritis. Here, we describe an atypical form of ORAS with distinct clinical manifestation of the disease caused by two new compound heterozygous variants (c.258G>A (p.M86I)/c.500G>C (p.W167S)) in the OTULIN gene in a 7‐year‐old affected by a life‐threatening autoinflammatory episode with sterile abscess formation. On the molecular level, we find binding of OTULIN to linear ubiquitin to be compromised by both variants; however, protein stability and catalytic activity is most affected by OTULIN variant p.W167S. These molecular changes together lead to increased levels of linear ubiquitin linkages in patient‐derived cells triggering the disease. Our data indicate that the spectrum of ORAS patients is more diverse than previously thought and, thus, supposedly asymptomatic individuals might also be affected. Based on our results, we propose to subdivide the ORAS into classical and atypical entities. Synopsis The OTULIN‐Related Autoinflammatory Syndrome (ORAS) is known to be caused by homozygous variants in the OTULIN gene. This study discovers that two new compound‐heterozygous variants in OTULIN are associated with an atypical, but potentially fatal, late‐onset form of ORAS. Atypical ORAS is characterized by multiorgan abscess formation and bears the risk of being clinically inapparent. OTULIN variants p.M86I and p.W167S disrupt OTULIN function leading to increased levels of linear ubiquitin linkages in patient‐derived fibroblasts and B cells. Molecularly, atypical ORAS resembles classical ORAS with enhanced TNF production in monocytes, but diminished TNF‐induced gene activation and sensitization to TNF‐mediated cell death (in the presence of cycloheximide) in fibroblasts. Anti‐TNF therapy with Adalimumab resulted in normalization of the patient's inflammatory plasma protein profile suggesting that patients with atypical ORAS might benefit from TNF‐blocking agents as seen in patients with classical ORAS. Graphical Abstract The OTULIN‐Related Autoinflammatory Syndrome (ORAS) is known to be caused by homozygous variants in the OTULIN gene. This study discovers that two new compound‐heterozygous variants in OTULIN are associated with an atypical, but potentially fatal, late‐onset form of ORAS.

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.

Graft failure requires urgent salvage HSCT, but there is no universally accepted approach for this situation. We investigated T-cell replete haploidentical HSCT with post-transplantation cyclophosphamide following serotherapy-based, radiation-free, reduced intensity conditioning in children with non-malignant disorders who had rejected their primary graft. Twelve patients with primary or secondary graft failure received T-cell replete bone marrow grafts from haploidentical donors and post-transplantation cyclophosphamide. The recommended conditioning regimen comprised rituximab 375 mg/m2, alemtuzumab 0.4 mg/kg, fludarabine 150 mg/m2, treosulfan 20–24 g/m2 and cyclophosphamide 29 mg/kg. After a median follow-up of 26 months (7–95), eleven of twelve patients (92%) are alive and well with complete donor chimerism in ten. Neutrophil and platelet engraftment were observed in all patients after a median of 18 days (15–61) and 39 days (15–191), respectively. Acute GVHD grade I was observed in 1/12 patients (8%) and mild chronic GVHD in 1/12 patients (8%). Viral reactivations and disease were frequent complications at 75% and 42%, respectively, but no death from infectious causes occurred. In summary, this retrospective analysis demonstrates that a post-transplantation cyclophosphamide-based HLA-haploidentical salvage HSCT after irradiation-free conditioning results in excellent engraftment and overall survival in children with non-malignant diseases.

DNA damage occurs constantly in every cell triggered by endogenous processes of replication and metabolism, and external influences such as ionizing radiation and intercalating chemicals. Large sets of proteins are involved in sensing, stabilizing and repairing this damage including control of cell cycle and proliferation. Some of these factors are phosphorylated upon activation and can be used as biomarkers of DNA damage response (DDR) by flow and mass cytometry. Differential survival rates of lymphocyte subsets in response to DNA damage are well established, characterizing NK cells as most resistant and B cells as most sensitive to DNA damage. We investigated DDR to low dose gamma radiation (2Gy) in peripheral blood lymphocytes of 26 healthy donors and 3 patients with ataxia telangiectasia (AT) using mass cytometry. γH2AX, p-CHK2, p-ATM and p53 were analyzed as specific DDR biomarkers for functional readouts of DNA repair efficiency in combination with cell cycle and T, B and NK cell populations characterized by 20 surface markers. We identified significant differences in DDR among lymphocyte populations in healthy individuals. Whereas CD56 + CD16 + NK cells showed a strong γH2AX response to low dose ionizing radiation, a reduced response rate could be observed in CD19 + CD20 + B cells that was associated with reduced survival. Interestingly, γH2AX induction level correlated inversely with ATM-dependent p-CHK2 and p53 responses. Differential DDR could be further noticed in naïve compared to memory T and B cell subsets, characterized by reduced γH2AX, but increased p53 induction in naïve T cells. In contrast, DDR was abrogated in all lymphocyte populations of AT patients. Our results demonstrate differential DDR capacities in lymphocyte subsets that depend on maturation and correlate inversely with DNA damage-related survival. Importantly, DDR analysis of peripheral blood cells for diagnostic purposes should be stratified to lymphocyte subsets.