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RELA-related disease is a rare, autosomal-dominant condition presenting with immune dysregulation and immunodeficiency. RELA encodes the p65 subunit, a component of the canonical NFκB pathway. The underlying pathogenesis, at least in part, involves impaired NFκB activation, increased susceptibility to TNFα-induced apoptosis, and hyperinflammation. To date, only a modest number of cases have been documented worldwide, and the full clinical and functional spectrum of disease remains incompletely defined. This study represents a large global cohort identified with RELA variants, comprising 40 patients from 30 institutions, expanding our previous report of a single large kindred (1). The clinical spectrum includes arthritis, mucocutaneous ulcers, uveitis, dermatitis, irritable bowel disease, recurrent infections, lymphopenia, hypogammaglobulinemia, recurrent fevers, and susceptibility to neoplasia. The patients represent 36 kindreds with 28 unique RELA variants, of which 15 are missense, 7 nonsense, and 6 frameshift variants. Fifteen are in the Rel homology domain, 7 in the transcriptional activation domain, and 6 in the C-terminal region proximal to TAD (Fig. 1). Functional studies assessed the canonical NFκB pathway in 27% of the cohort (n = 11; healthy controls = 40). Patient peripheral blood mononuclear cells (PBMCs) were used to quantify total and phosphorylated p65 (ph-p65, Ser529) by flow cytometry after stimulation with PMA (100 ng/ml) and ionomycin (1 uM). In 8 patients, we assessed the kinetics of IκBα degradation, required for p65 phosphorylation and nuclear translocation of p65/p50. All patients tested had decreased total p65, while 64% had decreased ph-p65 with altered phosphorylation kinetics. Nearly 45% had impaired IκBα degradation. One patient (P4) demonstrated increased IκBα degradation and ph-p65, while a related proband (P1) had decreased ph-p65. Additionally, P4 did not have the same mucocutaneous clinical phenotype as P1 despite sharing the same RELA variant. This could reflect the effect of other genetic modifiers, epigenetic, environmental, or stochastic variations, which could lead to variable expressivity and/or incomplete penetrance. All patients appeared to have haploinsufficiency, as none had normal levels of p65. This study expands the clinical and genetic spectrum of RELA-related disease and provides mechanistic insights into the impact of these variants on p65 phosphorylation and downstream function, resulting in variable expressivity. Figure 1. RelA protein structure. Represents unique variant locations and categories, key domains, and phosphorylation sites. Source: UniProt. Adapted from (2). BioRender.

Background Granulomatous-lymphocytic interstitial lung disease (GLILD) is a major cause of morbidity and mortality in common variable immunodeficiency (CVID), yet its pathophysiology remains incompletely understood, and no Food and Drug Administration (FDA)-approved therapies exist. Cellular senescence, a state associated with inflammation and fibrosis, has been implicated in chronic lung diseases, including idiopathic pulmonary fibrosis, where senolytic therapies have shown benefit. Cellular senescence has also been described in some cases of GLILD. Objective To evaluate the efficacy of fisetin, a senolytic flavonoid, compared with placebo in adults with CVID-associated GLILD. Methods We conducted a randomized, double-blind, placebo-controlled pilot trial in 10 adults with GLILD (Figure 1). Participants received fisetin 20 mg/kg or placebo on days 0–1 and 28–29, with follow-up over 180 days. Assessments included pulmonary function testing (PFT) and Short Form Health Survey (SF-36). Results Fisetin was well tolerated, with no adverse events. SF-36 Mental Health scores were numerically higher in fisetin participants (day 28: −0.28; day 180: 0.00) than placebo (day 28: −0.56; day 180: −0.28). Mental Component Summary scores remained stable in the fisetin group (−0.65 to −0.70) but declined in the placebo group (−1.09 to −1.94). All other SF-36 domains were comparable between groups. Mean spirometry measures were stable in both groups. With fisetin, lung volumes increased over time, with increases in mean total lung capacity (5.46 to 5.76 L), residual volume (1.69 to 2.09 L), and residual volume (RV)/total lung capacity (TLC) (0.31 to 0.37). In contrast, the placebo group demonstrated decreases in total lung capacity (4.72 to 4.62 L), residual volume (1.89 to 1.72 L), and RV/TLC (0.41 to 0.38). Diffusion capacity corrected increased from baseline to day 90 in the fisetin group (13.9 to 15.9) and remained stable at day 180, whereas it declined in the placebo group by day 180 (19.1 to 17.6). Discussion In this randomized pilot study, fisetin was well tolerated and showed benefit in diffusion capacity, lung volumes, and mental health–related outcomes compared to placebo in GLILD. The temporal pattern of changes suggests that alternative dosing strategies may warrant further evaluation, in addition to potentially larger future studies. Figure 1. CONSORT flow diagram.

Introduction Individuals with inborn errors of immunity (IEI) are increasingly reaching reproductive age, yet guidance on fertility preservation, genetic counseling, medication adjustments in pregnancy and breastfeeding, monitoring for complications, and multidisciplinary coordination is lacking. This joint effort between two committees of the Clinical Immunology Society (CIS), the Women of the Clinical Immunology Society (WCIS) and the Adult Immune Deficiency Committee (AID) survey aimed to characterize current reproductive care practices for IEI patients. Methods A survey was disseminated to 809 CIS members. The response rate was 6.43% (52 respondents). The 24-item questionnaire addressed management of pregnancy in IEI, medications adjustment, participation in hematopoietic stem cell transplant (HSCT) care and fertility preservation, and maternal/neonatal outcomes. Results Because survey items were optional, the number of respondents varies by question. Forty-two participants completed core items: 64% (27/42) allergists/immunologists, 71% (30/42) practicing at academic centers, and 48% (20/42) with >50% immunology-focused practices. Most respondents (78%, 41/52) currently or previously cared for pregnant/planning IEI patients. Preconception counseling was common (90%, 37/41), yet only 2% (1/41) have access to a formal reproductive multidisciplinary team. Among clinicians involved in HSCT care, 45% (13/29) referred patients for fertility preservation. More than half, 52% (22/42), observed reduced fertility in IEI patients, and 56% (20/36) observed adverse maternal outcomes. Medication management varied: 61% (24/39) discontinued known teratogenic medications, and 64% (25/39) adjusted dosing during pregnancy. Regarding immunoglobulin replacement therapy, 79% adjusted dosing based on IgG levels and 42% increased dosing by trimester. Conclusions This CIS survey reveals practice variability and notable gaps in reproductive health support for individuals with IEIs. Due to the relatively low response rate, generalizability across providers and practice settings is challenging. However, the results of this survey suggest that although most clinicians provide preconception counseling and manage IgG and immunomodulatory therapy during pregnancy, formal multidisciplinary structures are rare. High rates of reported fertility concerns and maternal complications underscore the need for enhanced collaboration with obstetrics/gynecology and the development of structured, evidence-based, multidisciplinary guidelines for reproductive care in IEI. Tabular data are included as downloadable supplement files.

Background T cell–mediated hepatitis is an uncommon cause of acute pediatric liver injury. Most patients respond to steroids, but management of refractory disease remains challenging. We describe four patients with non-monogenic CD8+ T cell–mediated hepatitis with close temporal presentation and variable response to therapies. All four patients had severe elevations in liver enzymes, synthetic dysfunction, hyperbilirubinemia, cytopenias, elevations in cytokines (supplemental table), and CD8+ T cell predominance on biopsy, without meeting criteria for autoimmune hepatitis. All underwent next-generation or whole-exome sequencing; no monogenic causes were elucidated. Broad infectious workup was unrevealing. Case 1 A 17-year-old male with epilepsy presented with abdominal pain and jaundice, with labs and biopsy consistent with portal and lobular hepatitis with CD8+ T cell predominance. Bone marrow aspirate (BMA) was reassuring. Hepatitis was refractory despite corticosteroids, tacrolimus, sirolimus, anakinra, intravenous immune globulin (IVIG), and anti-thymocyte globulin (ATG). Infliximab led to dramatic but incomplete improvement. He remains on steroids, tacrolimus, and infliximab, with planned hematopoietic stem cell transplantation (HSCT). Case 2 A 7-year-old female with type 1 diabetes presented with jaundice and abdominal pain, with labs and biopsy consistent with CD8+ T cell hepatitis. Steroids induced a partial response, while infliximab led to marked improvement. She transitioned to azathioprine and maintains normal liver enzymes. Case 3 A 5-year-old male with autism presented with fevers and abdominal distention, with labs and biopsy consistent with portal and lobular hepatitis with CD8+ T cell predominance. IVIG/steroids provided only a transient improvement. Tacrolimus normalized labs and enabled steroid discontinuation. Case 4 An 11-month-old healthy female presented with jaundice. Labs and biopsy were consistent with giant cell hepatitis with CD8+ T cell predominance, and no evidence of autoimmune hemolytic anemia. She was listed for liver transplantation. Partial steroid response prompted tacrolimus initiation, leading to normalization of labs and removal from transplant listing. Conclusion CD8+ T cell–mediated hepatitis may progress rapidly and be steroid refractory. Early initiation of infliximab or tacrolimus may prevent progression to liver failure. Case one represents a severe presentation with limited response; however, most avoided liver or hematopoietic stem cell transplantation. All cases presented within a three-month window, suggesting a possible infectious trigger. Tabular data are included as downloadable supplement files.

Introduction Hyperuricemia, pulmonary hypertension, renal failure, alkalosis (HUPRA) syndrome is a mitochondrial disease caused by mutations in SARS2 (seryl-tRNA synthetase 2), which plays a role in protein synthesis. Limited case reports describe an association of HUPRA with immunodeficiency; however, no in-depth immune phenotyping has been described. We present a case of HUPRA with recurrent infections and lymphopenia, with clinical improvement on immunoglobulin replacement therapy (IgRT). Case Description An 11-month-old male born at 29 weeks’ gestational age with pulmonary hypertension (PH) and tracheostomy dependence was admitted with recurrent fevers and worsening PH. History revealed prior Enterococcus faecalis bacteremia as well as Staphylococcus aureus and Pseudomonas aeruginosa tracheitis. Laboratory evaluation revealed mildly low IgG with normal IgM and IgA. Lymphocyte subsets revealed T cell, B cell, and natural killer cell lymphopenias, with CD4+ T cell compartment skewing to a memory phenotype, normal total switched memory B cells, and normal T follicular helper cells. Vaccine titers were not obtained, given receipt of only one set of vaccines. T cell proliferations were reassuring. Genetic testing revealed compound heterozygous mutations in SARS2, confirming a diagnosis of HUPRA. He is being treated with IgRT with significant clinical improvement. Discussion In case series, up to half of patients with HUPRA can present with increased infections, often with leukopenia. Multiple studies have shown that aminoacyl-tRNA synthetases can play a role in immune cell development, regulation, and autoimmunity through interactions with innate and adaptive immune responses. Additionally, hyperuricemia is known to induce innate and adaptive immune responses. It is difficult to know how these findings relate to the function of SARS2 or patients with HUPRA. Our patient was found to have multilineage lymphopenia with mildly low IgG, with significant clinical improvement on IgRT. More in-depth evaluations are needed to better understand the pathophysiology of immune dysfunction with SARS2 deficiency. This case provides in-depth immune phenotyping and a potential treatment option for others with HUPRA. Tabular data are included as downloadable supplement files.

Introduction BACH2-related immunodeficiency and autoimmunity (BRIDA) increases the risk of developing B cell lymphoma. We present a case of a patient with a known history of common variable immunodeficiency (CVID) and BACH2 variant of uncertain significance, presenting with hypercalcemia and acute kidney injury (AKI), found to have T cell histiocyte-rich large B cell lymphoma of the spleen. Case Description 46-year-old male with CVID-like clinical picture with variant of uncertain significance in BACH2 (Combined Annotation Dependent Depletion [CADD] 25.2, allele frequency 2) and granulomatous-lymphocytic interstitial lung disease (GL-ILD), admitted for acute kidney injury with hypercalcemia. He is pancytopenic, hypercalcemic, with marked splenomegaly on CT. PET-CT showed retroperitoneal and iliac chain lymphadenopathy along with mixed changes of osseous/marrow lesions with new lesions in the thoracic spine and left mid femur. There is a notable improvement in GL-ILD on CT chest while the patient is on prednisone. Renal biopsy showed acute tubular injury with increased deposition of calcium phosphate, along with moderate interstitial fibrosis and tubular atrophy with mild fibrointimal thickening of arteries. No monoclonal protein detected in the serum, negative JC virus, BK virus, EBV, CMV, and HIV. Splenic biopsy showed B cell lymphoma with features of micronodular T cell/histiocyte-rich large B cell lymphoma of the spleen. Patient initiated on rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone treatment protocol. Discussion BACH2 is a regulator of T and B cell differentiation and maturation. The effect of BACH2 on T cells involves limiting the differentiation of regulatory T (Treg) cells, which aid in preventing autoimmunity. BACH2 mutations have been described in the literature in patients with CVID and autoimmunity, such as ulcerative colitis. Lymphoma can cause hypercalcemia, which can lead to acute kidney injury. This patient has a variant of uncertain significance in BACH2 with CADD 25.2, allele frequency 2. His clinical picture of CVID, acute kidney injury in the setting of hypercalcemia, and newfound B cell lymphoma of the spleen may be due to this variant of uncertain significance. Further studies need to be conducted to better understand this gene and its role in CVID and B cell lymphoma. Tabular data are included as downloadable supplement files.

Abstract The discovery of pathogenic neuroglial surface-directed autoantibodies (NGSAbs) has fundamentally transformed clinical neurology, by enabling molecular-level diagnoses in potentially treatable, yet previously unrecognized, diseases. Annual descriptions of novel CNS-targeting antibodies create a continuous stream of new conditions in which to evaluate distinct phenotypes, specific tumour associations and immunotherapy responses. Alongside this clinical growth, increasing basic knowledge has highlighted origins and mechanisms underlying disease causation, most comprehensively interrogated in the well-established autoantibody-mediated conditions of autoimmune encephalitis (AE), neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). The corresponding most common ‘big six’ autoantigens are LGI1, the N-methyl-D-aspartate (NMDA) receptor, CASPR2, IgLON5, in forms of AE, AQP4 and MOG. Each of these autoantigens associates with a homogenous set of basic clinical features, across age, sex, tumour associations and ethnicities, coupled with partly distinctive profiles of triggers and predispositions, paradigms of immune tolerance escape in the periphery, how cells and autoantibodies gain access to the CNS, and discrete mechanisms by which the CNS autoantibodies induce neuroglial dysfunction. These observations lead us to reconstruct a proposed chronological series of events as the ‘cascade to pathogenicity’, which together culminate in a rare CNS disease. By extension, we hypothesize elucidating the underlying biology of each condition will present differing precision medicine approaches to optimize patient care. Despite distinctions, there are also clinical and biological overlaps between these diseases, collectively creating opportunities to compare and contrast their individual features. Here, in each condition, we review current knowledge regarding the similarities and differences between the triggering events, underlying immunological processes and pathogenic mechanisms of autoantibodies. In some instances, we identify scientific clues that drive hypothetical pathways of pathogenesis and, for others, highlight striking observations that aim to generate hypothesis-driven next steps. Our aim is to construct a model across the major autoantibody-mediated CNS diseases to highlight distinct components of cascades to pathogenicity, which may offer targeted therapeutic approaches to improve patient outcomes, and identify key areas and questions for future research.

Abstract Context Bilateral adrenalectomy (BLA) and autoimmune adrenal insufficiency (AAI) are 2 major causes of primary adrenal insufficiency (PAI). Comparative data between etiologies are limited. Objective To compare management, quality of life (QoL), and frequency of adrenal crises between participants post-BLA vs AAI. Methods We conducted a dual-center, cross-sectional study of adults with AAI or BLA between 2018 and 2025. All participants completed questionnaires on management, adrenal crises, and the Addison Disease-specific QoL Questionnaire (AddiQoL). Results Of 343 participants, 203 had AAI (median age 54 years, 72% women) and 139 had BLA (median age 57 years, 76% women). AddiQoL scores were similar between participants with AAI and BLA (median 84 vs 83, P = .947), but better in participants post-BLA for pheochromocytoma versus hypercortisolism (median 88 vs 81, P = .031). Participants with AAI reported a higher number of adrenal crises within the past year than those post-BLA (25% vs 13%, P = .022). In multivariable analyses of age, sex, glucocorticoid dose and type, PAI type, AddiQoL score, and autoimmune comorbidities, only PAI type was associated with higher number of reported adrenal crisis within the last year (AAI vs BLA: odds ratios of 2.1-2.2, P < .05 for all models). Conclusion QoL was comparable between participants with AAI and BLA, though patients post-BLA for pheochromocytoma reported better QoL than patients post-BLA for hypercortisolism. Adrenal crises were more common in participants with AAI than those post-BLA, a finding that was not explained by patients’ glucocorticoid management, underscoring the need for tailored crisis prevention strategies.

Abstract Aims We hypothesized that targeting interleukin-6—a cytokine central to NOD-like receptor protein 3 (NLRP3) inflammasome activation that is associated with both the onset and progression of heart failure (HF)—may be beneficial in patients with HF and circulating evidence of cardiovascular inflammation but without overtly reduced ejection fraction (EF). We describe the rationale and design of two clinical trials (ATHENA and HERMES) investigating ziltivekimab, a human monoclonal antibody directed against the interleukin-6 ligand, in patients with HF and mildly reduced or preserved EF (HFmrEF/HFpEF) and cardiovascular inflammation. Methods ATHENA (n = 673) and HERMES (n = 4900) are international, multi-centre, double-blind, placebo-controlled trials randomizing adults with HFpEF/HFmrEF and cardiovascular inflammation (high-sensitivity C-reactive protein ≥2 mg/l) to ziltivekimab 15 mg or placebo, administered subcutaneously once monthly on top of standard of care. Eligible participants have a left ventricular EF >40%, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), and serum high-sensitivity C-reactive protein ≥2 mg/l. The primary endpoint in ATHENA is the change in Kansas City Cardiomyopathy Questionnaire—Clinical Summary Score at 12 months. The primary endpoint in HERMES is time to first composite of cardiovascular death, hospitalization for HF, or urgent HF visit. ATHENA has a fixed duration of 12 months, whereas the HERMES trial is event driven (∼845 adjudicated primary events) with a minimum exposure of 6 months from randomization to the last treatment visit. Conclusion ATHENA and HERMES will investigate the effect of ziltivekimab in HFpEF/HFmrEF and cardiovascular inflammation. ATHENA will determine the effect of ziltivekimab on health status. HERMES will determine the efficacy and safety of ziltivekimab on morbidity and mortality.