Inborn errors of immunity (IEIs) are rare genetic anomalies that cause defective immune function. Over 500 IEIs have been identified to date, affecting millions of patients globally. These IEIs reveal the complex interplay between genetics, the environment and microorganisms that determine immune disease phenotypes. Progress in understanding the molecular and cellular mechanisms of IEIs provides a genetic framework for a functional understanding of the human immune system, disease pathogenesis and successful therapeutic interventions. This Review describes how IEIs impact infectious diseases, particularly coronavirus disease 2019, inflammatory bowel disease and cancer. Cui et al. discuss new molecular and cellular insights underlying the pathogenesis of rare human diseases that arise from genetic inborn errors of immunity.

Chronic stimulation in the tumor microenvironment can induce exhausted CD8+ T (Tex) cells that have limited tumoricidal activity. Here, we show an inverse correlation between signal strength and Tex cell differentiation by using patient-derived mutations in the T cell receptor (TCR)-signaling protein CARD11. Strong TCR signaling of the E134G mutant inhibits Tex cell differentiation and increases tumor growth. Conversely, reduced TCR signaling by the K215M mutant promotes Tex cell differentiation with better tumor control. These effects are a result of a restrained tumor-specific TCR clonal repertoire of Tex cells that reduces immunopathology but compromises tumoricidal activity. Mechanistically, CARD11 is a TCR signal-strength sensor, controlling the TCR repertoire of Tex cells by regulating the trafficking and homeostasis of the TCR complex. Expanding the TCR repertoire during Tex cell differentiation by fine-tuning the CARD11-mediated TCR signal strength reinvigorated antitumor function and indicates a strategy for improving cancer immunotherapy.

Anti-CTLA-4 Abs (ACAs) are a breakthrough for cancer therapy, but their potential is limited by immunotherapy-related adverse events (irAE). We previously reported that ACAs with acidic pH-sensitive binding to CTLA-4 exhibit higher antitumor activity with fewer irAE. We now test a panel of variants of Ipilimumab (Ipi), the first ACA cancer therapeutic, for tumoricidal efficacy and irAE. Surprisingly, not all pH-sensitive Ipi variants exhibited an enhanced therapeutic index. Ipi13, which retained binding to CTLA-4 at pH 6.0 but dissociated at lower pH, showed no enhancement. By contrast, Ipi25, which dissociates from CTLA-4 at pH 6.0, the pH of the early endosome (EE), showed greater tumor regression and less severe irAE. Confocal microscopy showed that Ipi13 maintained colocalization with CTLA-4 at the late endosomes (LE) and lysosomes resulting in lysosomal degradation of CTLA-4. Conversely, Ipi25 did not colocalize with CTLA-4 in LE or lysosomes after endocytosis but allowed both proteins to transfer to recycling endosomes. EE dissociation was also characteristic of variants of Tremelimumab (Treme), another clinical ACA, that showed better efficacy and fewer side effects. Thus, our data reveal the significance of early intracellular dissociation from CTLA-4 to improve ACAs for safer and more effective cancer immunotherapy.

BackgroundPrevious genetic and epidemiological studies have examined subpopulations from the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) patient cohort, but an encompassing analysis of the study population has not yet been carried out.ObjectiveThis retrospective study examines patterns of multiple sclerosis (MS) prevalence in 13,663 cohort members, including 4,821 persons with MS or suspected MS and 8,842 family members.MethodsWe grouped participants into epidemiologic subgroups based on age of MS onset, clinical stage at diagnosis, symptom type at disease onset, sex, proband status, disability as measured by the EDSS, and ancestry based on reported ethnicity.ResultsWe observed a 2.7:1 MS prevalence ratio of women to men, though disease severity was greater for male patients. Variation in the age of disease onset between patients was only slightly associated with sex and strongly associated with disease type. Specific types of clinical symptoms at disease onset were associated with the prognosis. Regional residence did not correlate with disease onset, type, or severity.ConclusionPopulation trends, as presented here, are not explained by environmental factors alone, highlighting the need for a comprehensive genetic analysis to understand disease variance across families.

Abstract Background CD55 deficiency with hyper-activation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) disease is a newly identified condition with an estimated worldwide prevalence of < 100 patients. Patient interviews can ensure that what is important to patients is assessed in a clinical trial program. Due to the rare and potentially fatal nature of CHAPLE disease, interviews were conducted as part of the pozelimab clinical trial, rather than in a separate study before the trial. The aim of the interviews was to identify the key disease-related signs, symptoms, and health-related quality-of-life (HRQoL) impacts that are important and relevant to patients with CHAPLE disease. Methods Interviews were conducted with patients and/or caregivers at two timepoints (screening and Week 24) during the pozelimab trial to document the signs/symptoms and HRQoL impacts of CHAPLE disease, and document the most bothersome sign/symptom at screening. At Week 24, interviews gathered additional information on the patient experience from caregivers and patients (note: the impact of pozelimab treatment was also collected, though these results are presented elsewhere). Results Ten patients, aged 3–19 years, were enrolled in the trial; caregivers contributed to nine interviews. Thirty-one signs‌/symptoms and 65 HRQoL impacts were reported during the interviews. Abdominal pain, diarrhea, facial and peripheral edema/‌swelling, nausea, and vomiting emerged as the core signs/‌symptoms of CHAPLE disease (i.e., experienced by ≥ 90% of patients prior to treatment). The remaining 25 signs/symptoms were experienced by four or fewer (n ≤ 4, ≤ 40.0%) patients, and 15 were only reported by one patient each. Abdominal pain and facial edema were reported as the most bothersome signs/‌symptoms (n = 9, 90.0% and n = 1, 10.0%, respectively). The most frequently reported (i.e., ≥ 80% of interviews) HRQoL impacts were restricted diet (n = 10, 100.0%), sleep disruptions (n = 10, 100.0%), missing school (n = 9, 90.0%), ability to get dressed independently (n = 8, 80.0%), and difficulty engaging in play activities (n = 8, 80.0%). Conclusions The main finding from these patient interviews is the identification of six core signs/symptoms of CHAPLE disease: abdominal pain, diarrhea, facial edema/swelling, peripheral edema/swelling, nausea, and vomiting. The severity of the core signs/symptoms leads to substantial impacts on patients’ lives. Trial registration ClinicalTrials.gov, NCT04209634. Registered 20 December 2019 https://classic.clinicaltrials.gov/ct2/show/NCT04209634 .

BACKGROUND:XMEN (X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV), and N-linked glycosylation defect) disease results from loss-of-function mutations in MAGT1, a protein that serves as a magnesium transporter and a subunit of the oligosaccharyltransferase (OST) complex. MAGT1 deficiency disrupts N-linked glycosylation, a critical regulator of immune function. XMEN results in recurrent EBV infections and a propensity for EBV-driven malignancies. Although XMEN is recognized as a systemic congenital disorder of glycosylation (CDG), its neurological involvement is rare and poorly characterized.CASES:Two young men, ages 32 and 33, are described here with truncating mutations in MAGT1, progressive behavioral changes, and neurodegenerative symptoms. These features manifested well into adulthood. Both patients still presented with many of the molecular and clinical hallmarks of the typical XMEN patient, including chronic EBV viremia and decreased expression of NKG2D.CONCLUSION:While previously unrecognized, XMEN may include prominent and disabling CNS manifestations. How MAGT1 deficiency directly or indirectly contributes to neurodegeneration remains unclear. Elucidating this mechanism may contribute to the understanding of neurodegeneration more broadly.

T cell receptor (TCR) engagement causes a global cellular response that entrains signaling pathways, cell cycle regulation, and cell death. The molecular regulation of mRNA translation in these processes is poorly understood. Using a whole-genome CRISPR screen for regulators of CD95 (FAS/APO-1)-mediated T cell death, we identified AMBRA1, a protein previously studied for its roles in autophagy, E3 ubiquitin ligase activity, and cyclin regulation. T cells lacking AMBRA1 resisted FAS-mediated cell death by down-regulating FAS expression at the translational level. We show that AMBRA1 is a vital regulator of ribosome protein biosynthesis and ribosome loading on select mRNAs, whereby it plays a key role in balancing TCR signaling with cell cycle regulation pathways. We also found that AMBRA1 itself is translationally controlled by TCR stimulation via the CD28-PI3K-mTORC1-EIF4F pathway. Together, these findings shed light on the molecular control of translation after T cell activation and implicate AMBRA1 as a translational regulator governing TCR signaling, cell cycle progression, and T cell death.

Preserving cells in a functional, non-senescent state is a major goal for extending human healthspans. Model organisms reveal that longevity and senescence are genetically controlled, but how genes control longevity in different mammalian tissues is unknown. Here, we report a new human genetic disease that causes cell senescence, liver and immune dysfunction, and early mortality that results from deficiency of GIMAP5, an evolutionarily conserved GTPase selectively expressed in lymphocytes and endothelial cells. We show that GIMAP5 restricts the pathological accumulation of long-chain ceramides (CERs), thereby regulating longevity. GIMAP5 controls CER abundance by interacting with protein kinase CK2 (CK2), attenuating its ability to activate CER synthases. Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by preventing CER overaccumulation and cell deterioration. Thus, GIMAP5 controls longevity assurance pathways crucial for immune function and healthspan in mammals.

Abstract Background CD55 deficiency with hyper-activation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) disease is ultra-rare (< 100 children or young adults worldwide) and potentially fatal. The study used mixed-methods approaches to assess how pozelimab impacts the signs and symptoms of CHAPLE disease from the patient perspective by combining within-trial interviews and clinical outcome assessments (COAs) (ClinicalTrials.gov, NCT04209634). Methods Interviews conducted with patients/caregivers at screening and week 24 assessed the signs and symptoms of CHAPLE disease, including those which were most bothersome, and evaluated the change. Patients/caregivers and clinicians completed the COAs; interview data contextualized the meaningfulness of change. Results Ten patients (aged 3–19 years) were enrolled; caregivers contributed to nine interviews. Abdominal pain, diarrhea, facial and peripheral edema, nausea, and vomiting are the core signs and symptoms of CHAPLE disease (≥ 90% patients experienced pre-treatment); the most bothersome signs and symptoms were abdominal pain (n = 9) and facial edema (n = 1). All core signs and symptoms were reported as resolved at week 24 interviews. Severity on global assessments changed from “mild” to “very severe” at baseline to “no signs or symptoms” at week 24. Interview results were generally consistent with sign- or symptom-specific COA scores. Conclusions Patients with CHAPLE disease treated with pozelimab for 24 weeks experienced complete resolution of core signs and symptoms. Mixed-methods approaches can contextualize the patient experience (how patients feel and function) in rare disease trials. Trial registration Clinicaltrials.gov, NCT04209634, registered December 24, 2019, https://classic.clinicaltrials.gov/ct2/show/NCT04209634.

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2, which encodes G(alpha i2), a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating G(alpha i2) mutations had clinical presentations that included impaired immunity. Mutant G(alpha i2) impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G(alpha i2) influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)-activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT S6 signaling to drive cellular growth and proliferation.

Spinal cord pathology is a major determinant of irreversible disability in progressive multiple sclerosis. The demyelinated lesion is a cardinal feature. The well-characterised anatomy of the spinal cord and new analytic approaches allows the systematic study of lesion topography and its extent of inflammatory activity unveiling new insights into disease pathogenesis. We studied cervical, thoracic, and lumbar spinal cord tissue from 119 pathologically confirmed multiple sclerosis cases. Immunohistochemistry was used to detect demyelination (PLP) and classify lesional inflammatory activity (CD68). Prevalence and distribution of demyelination, staged by lesion activity, was determined and topographical maps were created to identify patterns of lesion prevalence and distribution using mixed models and permutation-based voxelwise analysis. 460 lesions were observed throughout the spinal cord with 76.5% of cases demonstrating at least 1 lesion. The cervical level was preferentially affected by lesions. 58.3% of lesions were inflammatory with 87.9% of cases harbouring at least 1 inflammatory lesion. Topographically, lesions consistently affected the dorsal and lateral columns with relative sparing of subpial areas in a distribution mirroring the vascular network. The presence of spinal cord lesions and the proportion of active lesions related strongly with clinical disease milestones, including time from onset to wheelchair and onset to death. We demonstrate that spinal cord demyelination is common, highly inflammatory, has a predilection for the cervical level, and relates to clinical disability. The topography of lesions in the dorsal and lateral columns and relative sparing of subpial areas points to a role of the vasculature in lesion pathogenesis, suggesting short-range cell infiltration from the blood and signaling molecules circulating in the perivascular space incite lesion development. These findings challenge the notion that end-stage progressive multiple sclerosis is 'burnt out' and an outside-in lesional gradient predominates in the spinal cord. Taken together, this study provides support for long-term targeting of inflammatory demyelination in the spinal cord and nominates vascular dysfunction as a potential target for new therapeutic approaches to limit irreversible disability.

BACKGROUND:CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) is an ultra-rare genetic disorder characterised by intestinal lymphatic damage, lymphangiectasia, and protein-losing enteropathy caused by overactivation of the complement system. We assessed the efficacy and safety of pozelimab, an antibody blocking complement component 5. METHODS:This open-label, single-arm, historically controlled, multicentre phase 2 and 3 study evaluated ten patients with CHAPLE disease. This study was conducted at three hospitals in Thailand, Türkiye, and the USA. Patients aged 1 year or older with a clinical diagnosis of CHAPLE disease and a CD55 loss-of-function variant identified by genetic analysis and confirmed by flow cytometry or western blot of CD55 from peripheral blood cells were eligible for this study. Patients received a single intravenous loading dose of pozelimab 30 mg per kg of bodyweight, followed by a once-per-week subcutaneous dose over the treatment period based on bodyweight at a concentration of 200 mg/mL as either a single injection (<40 kg bodyweight) or two injections (≥40 kg bodyweight). The primary endpoint was proportion of patients with serum albumin normalisation with an improvement in active clinical outcomes and no worsening in inactive clinical outcomes (frequency of problematic abdominal pain, bowel movement frequency, facial oedema severity, and peripheral oedema severity) at week 24 compared with baseline, assessed in the full analysis set. This study is registered with ClinicalTrials.gov (NCT04209634) and is active but not recruiting. FINDINGS:11 patients were recruited between Jan 27, 2020, and May 12, 2021, ten of which were enrolled in the study and included in the analysis populations. The efficacy data corresponded to all patients completing the week 48 assessment and having at least 52 weeks of treatment exposure, and the safety data included an additional 90 days of follow-up and corresponded to all patients having at least 72 weeks of treatment. Patients were predominantly paediatric (with a median age of 8·5 years), and originated from Türkiye, Syria, Thailand, and Bolivia. Patients had markedly low weight-for-age and stature-for-age at baseline, and mean albumin at baseline was 2·2 g/dL, which was considerably less than the local laboratory reference range. After pozelimab treatment, all ten patients had serum albumin normalisation and improvement with no worsening in clinical outcomes. There was a complete inhibition of the total complement activity. Nine patients had adverse events; two were severe events, and one patient had an adverse event considered related to pozelimab. INTERPRETATION:Pozelimab inhibits complement overactivation and resolves the clinical and laboratory manifestations of CHAPLE disease. Pozelimab is the only currently approved therapeutic drug for patients with this life-threatening, ultra-rare condition. In patients with protein-losing enteropathy where known causes have been excluded, testing for a CD55 deficiency should be contemplated. A diagnosis of CHAPLE disease should lead to early consideration of treatment with pozelimab. FUNDING:Regeneron Pharmaceuticals and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Activated phosphoinositide 3-kinase delta (PI3K delta) syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoim-munity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3K delta signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3K delta. Here, 31 patients with APDS aged >= 12 years were enrolled in a global, phase 3, triple-blinded trial and randomized 2:1 to receive 70 mg leniolisib or placebo twice daily for 12 weeks. Coprimary outcomes were differences from baseline in the index lymph node size and the percentage of naive B cells in peripheral blood, assessed as proxies for immune dysregulation and deficiency. Both primary out-comes were met: the difference in the adjusted mean change (95% confidence interval [CI]) between leniolisib and placebo for lymph node size was -0.25 (-0.38, -0.12; P = .0006; N = 26) and for percentage of naive B cells, was 37.30 (24.06, 50.54; P = .0002; N = 13). Leniolisib reduced spleen volume compared with placebo (adjusted mean difference in 3-dimensional volume [cm3], -186; 95% CI, -297 to -76.2; P = .0020) and improved key immune cell subsets. Fewer patients receiving leniolisib reported study treatment-related adverse events (AEs; mostly grades 1-2) than those receiving placebo (23.8% vs 30.0%). Overall, leniolisib was well tolerated and significant improvement over placebo was notable in the coprimary endpoints, reducing lymphadenopathy and increasing the percentage of naive B cells, reflecting a favorable impact on the immune dysregulation and deficiency seen in patients with APDS. This trial was registered at www.clinicaltrials.gov as #NCT02435173.

Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated mucin or a Foxo3 inhibitor can ameliorate IBD.

Owing to advances in genomics that enable differentiation of molecular aetiologies, patients with monogenic inflammatory bowel disease (mIBD) potentially have access to genotype-guided precision medicine. In this Expert Recommendation, we review the therapeutic research landscape of mIBD, the reported response to therapies, the medication-related risks and systematic bias in reporting. The mIBD field is characterized by the absence of randomized controlled trials and is dominated by retrospective observational data based on case series and case reports. More than 25 off-label therapeutics (including small-molecule inhibitors and biologics) as well as cellular therapies (including haematopoietic stem cell transplantation and gene therapy) have been reported. Heterogeneous reporting of outcomes impedes the generation of robust therapeutic evidence as the basis for clinical decision making in mIBD. We discuss therapeutic goals in mIBD and recommend standardized reporting (mIBD REPORT (monogenic Inflammatory Bowel Disease Report Extended Phenotype and Outcome of Treatments) standards) to stratify patients according to a genetic diagnosis and phenotype, to assess treatment effects and to record safety signals. Implementation of these pragmatic standards should help clinicians to assess the therapy responses of individual patients in clinical practice and improve comparability between observational retrospective studies and controlled prospective trials, supporting future meta-analysis. In this Expert Recommendation, Uhlig and colleagues review the therapeutic landscape for monogenic inflammatory bowel disease and propose recommendations for standardized reporting of clinical outcomes.

Studies in model organisms have revealed that lifespan and senescence are genetically controlled, but how cellular longevity assurance pathways are regulated is unknown. Here, we report new insights into cell longevity and senescence through the investigation of a novel disease caused by mutations in GTPase of the immunity-associated protein 5 (GIMAP5). We identified 17 affected individuals in 9 kindreds with lymphopenia, liver disease, splenomegaly, thrombocytopenia, lymphadenopathy, lung infections, and lymphoma. GIMAP5is highly expressed in T and NK lymphocytes as well as endothelial cells (EC) and is famous as the gene mutated in the Biobreeding diabetic rat and Sphinx lymphopenic mice. Given the strong disease association, the mechanism of GIMAP5 is an important biological and medical question. We found that loss of GIMAP5 leads to the uncontrolled accumulation of long chain ceramides, which is associated with premature senescence and death of lymphocytes, resulting in severe and recurrent infections in patients. We further showed that Gimap5 deficiency in mice increases senescence markers in T cells and ECs of the lung and liver, suggesting that GIMAP5 is involved in the senescence mechanisms affecting multiple tissues. Therefore, our results illustrate the role of the GIMAP5 regulatory pathway in cell longevity and senescence and reveal new molecular targets for increasing the healthy functional lifespan of human cells. This research was supported by the Intramural Research Program of NIAID, NIH. This research was supported by the Intramural Research Program of NIAID, NIH.

Autoimmune central nervous system (CNS) demyelinating diseases are a major public health burden and poorly controlled by current immunosuppressants. More precise immunotherapies with higher efficacy and fewer side effects are sought. We investigated the effectiveness and mechanism of an injectable myelin-based antigenic polyprotein MMPt (myelin oligodendrocyte glycoprotein, myelin basic protein and proteolipid protein, truncated). We find that it suppresses mouse experimental autoimmune encephalomyelitis without major side effects. MMPt induces rapid apoptosis of the encephalitogenic T cells and suppresses inflammation in the affected CNS. Intravital microscopy shows that MMPt is taken up by perivascular F4/80 + cells but not conventional antigen-presenting dendritic cells, B cells, or microglia. MMPt-stimulated F4/80 + cells induce reactive T cell immobilization and apoptosis in situ, resulting in reduced infiltration of inflammatory cells and chemokine production. Our study reveals alternative mechanisms that explain how cognate antigen suppresses CNS inflammation and may be applicable for effectively and safely treating demyelinating diseases.