Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and widespread inflammation. NK cells display marked functional impairment in SLE, including defective cytotoxicity and cytokine production, but the underlying mechanisms remain poorly defined. Here, we show that mitochondrial dysfunction and impaired mitophagy are key contributors to NK cell abnormalities in SLE. Using complementary structural, metabolic, and proteomic analyses, we found that SLE NK cells accumulate enlarged and dysfunctional mitochondria, exhibit impaired lysosomal acidification, and release mitochondrial DNA into the cytosol — features consistent with defective mitochondrial quality control. Transcriptional and proteomic profiling revealed downregulation of key mitophagy-related genes and pathways. These abnormalities correlated with reduced NK cell degranulation and cytokine production. We then tested whether enhancing mitochondrial quality control could restore NK cell function. The mitophagy activator Urolithin A improved mitochondrial and lysosomal parameters and rescued NK cell effector responses in vitro. Hydroxychloroquine partially restored mitochondrial recycling and reduced cytosolic mtDNA. These findings suggest that defective mitophagy and mitochondrial dysfunction are major contributors to NK cell impairment in SLE and that targeting mitochondrial quality control may represent a promising strategy for restoring immune balance in this disease.

Immunodeficiencies in adults are increasingly recognized yet often remain underdiagnosed, leading to significant morbidity from recurrent infections, autoimmunity, and malignancy. Both primary immunodeficiencies (PIDs), now known as inborn errors of immunity (IEI), and secondary immunodeficiencies (SIDs) contribute to immune dysfunction in adults. Although SIDs are more common in adults due to factors like medications, malignancies, metabolic disorders, chronic conditions, and protein-losing conditions, IEI—particularly common variable immunodeficiency (CVID)—can also manifest in adulthood with diverse clinical features. Early recognition is crucial, with key warning signs including recurrent sinopulmonary infections, unexplained autoimmunity, poor vaccine responses, chronic diarrhea, bronchiectasis, and persistent lymphadenopathy. The diagnostic approach should be systematic. It begins with a detailed patient history and status followed by the evaluation of immunoglobulin levels, lymphocyte subsets, vaccine-specific antibody responses, and exclusion of secondary causes. Genetic testing, increasingly accessible, plays an important role in confirming the diagnosis of IEI and guiding prognosis and treatment. Management strategies focus on treating the underlying condition in SIDs. Preventive measures, including antimicrobial prophylaxis, vaccination, and immunoglobulin replacement therapy (IGRT) in patients with significant antibody deficiencies, are essential for reducing infections and complications in high-risk patients. Given the growing recognition of adult-onset immunodeficiency, clinicians should maintain a high index of suspicion and adopt a structured diagnostic and management approach to improve patient outcomes and quality of life.

Introduction:Systemic lupus erythematosus (SLE) is characterized by dysregulated humoral immunity, leading to the generation of autoreactive B cells that can differentiate both within and outside of lymph node (LN) follicles. Methods:Here, we employed spatial transcriptomics and multiplex imaging to investigate the follicular immune landscaping and the in situ transcriptomic profile in LNs from SLE individuals. Results:Our spatial transcriptomic analysis revealed robust type I IFN and plasma cell signatures in SLE compared to reactive, control follicles. Cell deconvolution revealed that follicular T cell subsets are mainly affected by the type I IFN fingerprint of SLE follicles. Dysregulation of TFH differentiation was documented by i) the significant reduction of Bcl6hi TFH cells, ii) the reduced cell density of potential IL-4 producing TFH cell subsets associated with the impaired transcriptomic signature of follicular IL-4 signaling and iii) the loss of their correlation with GC-B cells. This profile was accompanied by a marked reduction of Bcl6hi B cells and an enrichment of extrafollicular CD19hiCD11chiTbethi, age-associated B cells (ABCs), known for their autoreactive potential. The increased prevalence of follicular IL-21hi cells further reveals a hyperactive microenvironment in SLE compared to control. Discussion:Taken together, our findings highlight the altered immunological landscape of SLE follicles, likely fueled by potent inflammatory signals such as sustained type I IFN and/or IL-21 signaling. Our work provides novel insights into the spatial molecular and cellular signatures of SLE follicular B and TFH cell dynamics, and points to druggable targets to restore immune tolerance and enhance vaccine responses in SLE patients.

ABSTRACTObjectivesNatural Killer (NK) cell dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis, but the underlying mechanisms remain poorly understood. This study investigates immunometabolic alterations in NK cells from SLE patients and explores therapeutic strategies for their restoration.MethodsWe characterized mitochondrial structure and function in NK cells from the peripheral blood of SLE patients and healthy controls using flow cytometry, electron microscopy, and proteomics. Key mitophagy-related gene expressions were quantified using qPCR. The ability of hydroxychloroquine (HCQ) to restore mitochondrial recycling and NK cell function were assessedin vitro.ResultsSLE NK cells displayed accumulated enlarged, hyperpolarized mitochondria with cristae disorganization, and reduced mitophagy. Impaired lysosomal acidification and mtDNA extrusion into the cytosol were also observed. Treatment with HCQ restored mitochondrial recycling, and NK cell effector functions, including cytokine production and cytotoxicity by acidifying lysosomes.ConclusionsThis study identifies mitochondrial recycling dysfunction as a driver of NK cell abnormalities in SLE patients. HCQ can correct these abnormalities by acidifying the lysosomes and highlights the potential of HCQ to restore NK cell functionality. These findings provide new insights into the immunometabolic mechanisms underlying SLE and suggest avenues for targeted therapeutic interventions.WHAT IS KNOWN ON THE TOPIC➢ SLE is a complex inflammatory disease characterized by the development of autoreactive cells and a breakdown of self-tolerance (1, 2).➢ Natural Killer (NK) cells, pivotal players in the innate immune system, exhibit reduced numbers, diminished cytotoxicity, and impaired cytokine production in SLE patients (3-5).➢ Peripheral CD56dimCD57+NK cells from SLE patients exhibit increased endogenous apoptosis and higher levels of mitochondrial (mt)ROS, contributing to their altered function (6).WHAT THE STUDY ADDS➢ This study reveals a full spectrum of immunometabolic alterations in Natural Killer (NK) cells from SLE patients, including hyperpolarized mitochondria accumulation, cristae disorganization and impaired mitophagy. These results identify mitochondrial recycling dysfunction as a central factor in NK cell abnormalities in SLE.➢ It demonstrates for the first time that hydroxychloroquine (HCQ), a standard treatment for SLE, effectively restores mitochondrial recycling in NK cells by modulating lysosomal acidification, reducing cytosolic leakage of mtDNA and enhancing the expression of mitophagy-related genes.➢ These results highlight a new mechanism by which HCQ attenuates immune dysregulation, making it a potential targeted approach for treating the specific dysfunction of NK cells in SLE.HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY➢ Understanding how mitochondrial recycling dysfunction impacts SLE pathogenesis can pave the way for the development of targeted therapies and improved disease management for SLE patients.

Recurrent miscarriage is a distressing condition with limited therapeutic options. Chronic histiocytic intervillositis of unknown etiology (CIUE) is a rare inflammatory placental disorder characterized by maternal immune cell infiltration of the intervillous space, fibrin deposition, and ischemic tissue damage, leading to pregnancy loss. The condition likely reflects an immune response against paternal alloantigens, with histopathological features resembling antibody-mediated rejection in solid organ transplantation. We investigated two women with recurrent CIUE-related pregnancy losses. Detailed immunological profiling included anti-human leukocyte antigen (HLA) antibody characterization, compatibility testing, and histopathological examination of previous placentas, as well as screening for other causes of recurrent pregnancy losses. Based on evidence of antibody-mediated alloimmune injury, we implemented a targeted immunosuppressive regimen derived from transplantation medicine, combining intravenous immunoglobulins (IVIG), tacrolimus, corticosteroids, and hydroxychloroquine, with close pregnancy monitoring. The first patient, after six consecutive CIUE-related pregnancy losses, underwent preconception desensitization and continued treatment throughout pregnancy. Early signs of placental dysfunction prompted therapy intensification, leading to delivery of a viable infant at 33 + 2 weeks. Placental histology showed only minor residual CIUE lesions. The second patient, with two pregnancy losses and a fetal demise from CIUE, began treatment at 6 weeks’ gestation and delivered a healthy infant at 36 weeks. In both cases, therapy was generally well tolerated, with gestational diabetes as the main complication, and no major maternal or neonatal adverse events. These cases support the concept that CIUE represents a breakdown of maternal immune tolerance toward paternal antigens, mediated by fetal-specific anti-HLA antibodies—akin to solid organ graft rejection. An immunosuppressive protocol adapted from transplantation medicine achieved two successful live births after multiple CIUE-related pregnancy losses. Targeting antibody-mediated alloimmunity may represent a promising therapeutic strategy for selected patients with recurrent miscarriages due to CIUE. Further studies are warranted to define optimal regimens and identify predictors of response.

Background: Beta-lactam antibiotics are the most frequent drug family to cause allergic reactions. Herein, we examined the frequency of confirmed allergies to beta-lactam, as well as the sensitivity and negative predictive value (NPV) of skin testing in an adult population referred to a university allergy clinic in Switzerland. Methods: This is a retrospective analysis of the clinical records of patients who were investigated for a label of allergy to beta-lactam (penicillin, cephalosporin or carbapenem) between January 1 2011 and December 31 2018. Results: 582 patients were identified with a documented allergy to beta-lactam and 477 patients were systemically investigated by skin tests and/or drug challenge to confirm or rule out allergy. 262 patients reported a history of immediate reactions, 137 of delayed reactions, and 114 of unknown reactions. 88 (18.4%) patients had confirmed to any beta-lactam antibiotics; 64 (13.4%) with an immediate- and 24 (5%) with a delayed-type reaction. Most frequently identified allergy was penicillin (65 patients), followed by cephalosporin (21 patients) and carbapenem (2 patients). NPV of skin tests for all beta-lactam were 97.7% and 92.5% for immediate- and delayed-type reactions, respectively, and 96.3% and 92.1% when only penicillin was considered. Systemic allergic reaction occurred in 0.6% of skin tests and in 3.1% of drug challenges. Conclusions: Only 18% of patients with beta-lactam allergy label have a confirmed allergy and non-allergic patients can be safely delabelled through allergic workup based on skin tests and drug challenge. This approach supports the policy of saving second-line antibiotics through systemic allergy work-up.

STUDY AIMS: VEXAS syndrome is a recently discovered monogenic auto-inflammatory disease caused by a somatic mutation in the UBA1 gene that manifests with rheumatologic and haematologic features. In this report, we present the first Swiss cohort, detailing its manifestations and treatment outcomes among Swiss patients. METHODS: Data were retrospectively collected from nine hospitals across Switzerland, representing a broad geographic distribution. Treating physicians completed a standardised case report form for each patient. The principal investigator and the co-investigators collected and analysed all case report forms. RESULTS: We identified 23 patients between July 2022 and 2023, of which 17 are described. All were male. They presented with skin manifestations (88%), general symptoms (82%), venous thromboembolism (59%), ocular manifestation (59%), lung infiltrates (59%) and articular manifestations (47%). Central nervous system and kidney manifestations were very rare, and heart and digestive manifestations were absent. Macrocytic anaemia was present in all patients throughout the disease progression but only in two-thirds of patients (12/17, 71%) at the time of diagnosis. Clinical response was reached in all cases treated with ruxolitinib (4/4, 100%), upadacitinib (1/1, 100%), azacytidine (5/5, 100%) and haematopoietic stem cell transplantation (2/2, 100%). All deaths were attributed to infections (5/5, 100%). CONCLUSION: This study corroborates the clinical spectrum of VEXAS syndrome described in other cohorts. It suggests that VEXAS syndrome is not limited to patients with macrocytic anaemia. In this study, azacytidine has been used effectively among patients with myelodysplastic syndrome. In addition, Janus kinase (JAK) inhibitors, particularly ruxolitinib, have been successfully used even in those without myelodysplastic syndrome. We report two successful treatments by haematopoietic stem cell transplantation.

VEXAS syndrome, a monogenic X-linked disorder resulting from mutations in the UBA1 gene, has emerged as a key model for unraveling the links between systemic inflammatory or autoimmune diseases (SIAD) and myelodysplastic syndromes (MD). This syndrome is characterized by the presence of vacuoles, X-linked inheritance, autoinflammation, and somatic mutation patterns, highlighting a unique intersection between genetic and immunological dysregulation. Apart from VEXAS, 10% to 30% of individuals diagnosed with MDS exhibit SIAD phenotypes, a significant increase compared to the 5% incidence in the general population. In this comprehensive review, we aim to elucidate the molecular mechanisms driving the pro-inflammatory environment in MDS, focusing on the contribution of VEXAS syndrome to this complex interplay. We examine how UBA1 mutations disrupt cellular homeostasis, triggering inflammatory pathways. Furthermore, we explore the broader implications of these findings for the pathogenesis of MDS, proposing that the inflammatory dysregulation of VEXAS may shed light on mechanisms of disease progression and identify potential therapeutic targets in MDS. Through an integrated analysis of genetic, immunological, and clinical data, this review seeks to deepen our understanding of the complex relationship between systemic inflammation and hematological malignancies, paving the way for new diagnostic and therapeutic strategies.

Infective endocarditis is a rare but life-threatening condition, occasionally linked to diverse immunologic manifestations, including mixed cryoglobulinemia. This can lead to cryoglobulinemic vasculitis, which has the potential for widespread organ damage. Although some cases have highlighted the relationship between infective endocarditis and cryoglobulinemic vasculitis, no comprehensive epidemiological evaluation or optimal treatment strategies have been advanced for such a combination. We present a case of methicillin-sensitive Staphylococcus aureus infective endocarditis associated with cryoglobulinemic vasculitis and conduct a literature review to compare management and outcomes in similar cases. Our patient presented with classical Meltzer’s triad and mild renal involvement. Cryoimmunofixation confirmed type III cryoglobulinemia, and serum cytokines showed elevated IL-6 levels. The differential diagnosis included infective endocarditis and chronic active hepatitis C virus infection. Rapid symptom resolution after antibiotic treatment identified infective endocarditis as the likely cause of cryoglobulinemic vasculitis. Our case and review of the literature highlight that early identification of the cause of cryoglobulinemic vasculitis is crucial for selecting appropriate treatment and preventing recurrence or morbidity.