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J Clin Immunol. 2024 Feb 16;44(3):63. doi: 10.1007/s10875-024-01667-z.

ABSTRACT

Inflammatory bowel disease (IBD) occurring following allogeneic stem cell transplantation (aSCT) is a very rare condition. The underlying pathogenesis needs to be better defined. There is currently no systematic effort to exclude loss- or gain-of-function mutations in immune-related genes in stem cell donors. This is despite the fact that more than 100 inborn errors of immunity may cause or contribute to IBD. We have molecularly characterized a patient who developed fulminant inflammatory bowel disease following aSCT with stable 100% donor-derived hematopoiesis. A pathogenic c.A291G; p.I97M HAVCR2 mutation encoding the immune checkpoint protein TIM-3 was identified in the patient's blood-derived DNA, while being absent in DNA derived from the skin. TIM-3 expression was much decreased in the patient's serum, and in vitro-activated patient-derived T cells expressed reduced TIM-3 levels. In contrast, T cell-intrinsic CD25 expression and production of inflammatory cytokines were preserved. TIM-3 expression was barely detectable in the immune cells of the patient's intestinal mucosa, while being detected unambiguously in the inflamed and non-inflamed colon from unrelated individuals. In conclusion, we report the first case of acquired, "transplanted" insufficiency of the regulatory TIM-3 checkpoint linked to post-aSCT IBD.

PMID:38363399 | DOI:10.1007/s10875-024-01667-z

Immunity. 2024 Feb 13;57(2):256-270.e10. doi: 10.1016/j.immuni.2024.01.007.

ABSTRACT

Antibodies can block immune receptor engagement or trigger the receptor machinery to initiate signaling. We hypothesized that antibody agonists trigger signaling by sterically excluding large receptor-type protein tyrosine phosphatases (RPTPs) such as CD45 from sites of receptor engagement. An agonist targeting the costimulatory receptor CD28 produced signals that depended on antibody immobilization and were sensitive to the sizes of the receptor, the RPTPs, and the antibody itself. Although both the agonist and a non-agonistic anti-CD28 antibody locally excluded CD45, the agonistic antibody was more effective. An anti-PD-1 antibody that bound membrane proximally excluded CD45, triggered Src homology 2 domain-containing phosphatase 2 recruitment, and suppressed systemic lupus erythematosus and delayed-type hypersensitivity in experimental models. Paradoxically, nivolumab and pembrolizumab, anti-PD-1-blocking antibodies used clinically, also excluded CD45 and were agonistic in certain settings. Reducing these agonistic effects using antibody engineering improved PD-1 blockade. These findings establish a framework for developing new and improved therapies for autoimmunity and cancer.

PMID:38354703 | DOI:10.1016/j.immuni.2024.01.007

Arthritis Rheumatol. 2024 Feb 12. doi: 10.1002/art.42817. Online ahead of print.

ABSTRACT

OBJECTIVE: To describe the demographics, clinical features, disease course, and survival of polyarteritis nodosa (PAN) through an international collaboration (GLOBAL-PAN).

METHODS: Patients with PAN recruited between 1990 and 2020 from observational cohorts of 9 countries across Europe, Japan, and North America. Eligibility was retrospectively defined using the European Medicines Agency (EMA) classification algorithm. Patients with PAN related to hepatitis B virus (HBV) (n=12) and two monogenic diseases mimicking PAN, deficiency of adenosine deaminase 2 enzyme (n=16) or familial Mediterranean fever (n=11), were excluded. Data regarding organ involvement, relapse, disease-related damage, and survival were analyzed.

RESULTS: 358 patients (female/male: 174/184), including systemic PAN (sPAN, n=282) and cutaneous PAN (cPAN, n=76), were included. Twenty-five were pediatric-onset. Mean (SD) age at diagnosis was 44.3 (18.1) years. Constitutional symptoms (71.5%), cutaneous involvement (70.5%), musculoskeletal findings (69.1%), and neurologic features (48.0%) were common manifestations. Among patients with sPAN, gastrointestinal involvement, and proteinuria over 400 mg/day were reported in 52.2% and 11.2%, respectively. During a median (inter-quartile range) 59.6 (99.5) months of follow-up, relapse occurred in 48.5% of patients. One, 5- and 10-year survival rates for sPAN were 97.1%, 94.0%, and 89.0%, respectively. Predictors of mortality for sPAN included age ≥ 65 years at diagnosis, serum creatinine at diagnosis >140 μmol/L, gastrointestinal manifestations, and central nervous system (CNS) involvement .

CONCLUSION: The spectrum of PAN remains a complex, multi-faceted disease. Relapse is common. Age ≥ 65 years and serum creatinine >140 μmol/L at diagnosis, gastrointestinal and CNS involvement are independent predictors of mortality in sPAN.

PMID:38343337 | DOI:10.1002/art.42817

Nephrol Dial Transplant. 2024 Feb 10:gfae025. doi: 10.1093/ndt/gfae025. Online ahead of print.

ABSTRACT

The histopathological lesions, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), are entities without immune complex deposits which can cause podocyte injury, thus frequently grouped under the umbrella of podocytopathies. Whether MCD and FSGS may represent a spectrum of the same disease remains a matter of conjecture. Both frequently require repeated high-dose glucocorticoid therapy with alternative immunosuppressive treatments reserved for relapsing or resistant cases and response rates are variable. There is an unmet need to identify patients who should receive immunosuppressive therapies as opposed to those who would benefit from supportive strategies. Therapeutic trials focusing on MCD are scarce, and the evidence used for the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guideline for the management of glomerular diseases largely stems from observational and pediatric trials. In FSGS, the differentiation between primary forms and those with underlying genetic variants or secondary forms further complicates trial design. This article provides a perspective of the Immunonephrology Working Group (IWG) of the European Renal Association (ERA), and discusses the KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases focusing on the management of MCD and primary forms of FSGS in the context of recently published evidence, with a special emphasis on the role of rituximab, cyclophosphamide, supportive treatment options and ongoing clinical trials in the field.

PMID:38341276 | DOI:10.1093/ndt/gfae025

Dev Cell. 2024 Feb 2:S1534-5807(24)00031-5. doi: 10.1016/j.devcel.2024.01.011. Online ahead of print.

ABSTRACT

During kidney development, nephron epithelia arise de novo from fate-committed mesenchymal progenitors through a mesenchymal-to-epithelial transition (MET). Downstream of fate specification, transcriptional mechanisms that drive establishment of epithelial morphology are poorly understood. We used human iPSC-derived renal organoids, which recapitulate nephrogenesis, to investigate mechanisms controlling renal MET. Multi-ome profiling via snRNA-seq and ATAC-seq of organoids identified dynamic changes in gene expression and chromatin accessibility driven by activators and repressors throughout MET. CRISPR interference identified that paired box 8 (PAX8) is essential for initiation of MET in human renal organoids, contrary to in vivo mouse studies, likely by activating a cell-adhesion program. While Wnt/β-catenin signaling specifies nephron fate, we find that it must be attenuated to allow hepatocyte nuclear factor 1-beta (HNF1B) and TEA-domain(TEAD) transcription factors to drive completion of MET. These results identify the interplay between fate commitment and morphogenesis in the developing human kidney, with implications for understanding both developmental kidney diseases and aberrant epithelial plasticity following adult renal tubular injury.

PMID:38340720 | DOI:10.1016/j.devcel.2024.01.011

J Extracell Vesicles. 2024 Feb;13(2):e12412. doi: 10.1002/jev2.12412.

ABSTRACT

The COVID-19 pandemic highlighted the clear risk that zoonotic viruses pose to global health and economies. The scientific community responded by developing several efficacious vaccines which were expedited by the global need for vaccines. The emergence of SARS-CoV-2 breakthrough infections highlights the need for additional vaccine modalities to provide stronger, long-lived protective immunity. Here we report the design and preclinical testing of small extracellular vesicles (sEVs) as a multi-subunit vaccine. Cell lines were engineered to produce sEVs containing either the SARS-CoV-2 Spike receptor-binding domain, or an antigenic region from SARS-CoV-2 Nucleocapsid, or both in combination, and we tested their ability to evoke immune responses in vitro and in vivo. B cells incubated with bioengineered sEVs were potent activators of antigen-specific T cell clones. Mice immunised with sEVs containing both sRBD and Nucleocapsid antigens generated sRBD-specific IgGs, nucleocapsid-specific IgGs, which neutralised SARS-CoV-2 infection. sEV-based vaccines allow multiple antigens to be delivered simultaneously resulting in potent, broad immunity, and provide a quick, cheap, and reliable method to test vaccine candidates.

PMID:38339765 | PMC:PMC10858312 | DOI:10.1002/jev2.12412

JCI Insight. 2024 Feb 8:e174005. doi: 10.1172/jci.insight.174005. Online ahead of print.

ABSTRACT

Inappropriate immune activity is key in the pathogenesis of multiple diseases and is typically driven by excess inflammation and/or autoimmunity. IL-1 is often the effector due to its powerful role in both innate and adaptive immunity, and thus is tightly controlled at multiple levels. IL-1R2 antagonises IL-1, but effects of losing this regulation is unknown. We find IL-1R2 resolves inflammation by rapidly scavenging free IL-1. Specific IL-1R2 loss in germinal centre (GC) T follicular regulatory (Tfr) cells increases the GC response after a first, but not booster, immunisation, with more T follicular helper (Tfh) cells, GC B cells and antigen-specific antibodies, which is reversed upon IL-1 blockade. However, IL-1 signalling is not obligate for GC reactions, as wildtype and Il1r1-/- mice show equivalent phenotypes, suggesting GC IL-1 is normally restrained by IL-1R2. Fascinatingly, germline Il1r2-/- mice do not show this phenotype, but conditional Il1r2 deletion in adulthood recapitulates it, implying compensation during development counteracts IL-1R2 loss. Finally, patients with ulcerative colitis or Crohn's disease have lower serum IL-1R2. Together, we show that IL-1R2 controls important aspects of innate and adaptive immunity, and that IL-1R2 level may contribute to human disease propensity and/or progression.

PMID:38329807 | DOI:10.1172/jci.insight.174005

Front Immunol. 2024 Jan 23;15:1305586. doi: 10.3389/fimmu.2024.1305586. eCollection 2024.

ABSTRACT

INTRODUCTION: One of the unexpected outcomes of the COVID-19 pandemic was the relatively low levels of morbidity and mortality in Africa compared to the rest of the world. Nigeria, Africa's most populous nation, accounted for less than 0.01% of the global COVID-19 fatalities. The factors responsible for Nigeria's relatively low loss of life due to COVID-19 are unknown. Also, the correlates of protective immunity to SARS-CoV-2 and the impact of pre-existing immunity on the outcome of the COVID-19 pandemic in Africa are yet to be elucidated. Here, we evaluated the natural and vaccine-induced immune responses from vaccinated, non-vaccinated and convalescent individuals in Southern Nigeria throughout the three waves of the COVID-19 pandemic in Nigeria. We also examined the pre-existing immune responses to SARS-CoV-2 from samples collected prior to the COVID-19 pandemic.

METHODS: We used spike RBD and N- IgG antibody ELISA to measure binding antibody responses, SARS-CoV-2 pseudotype assay protocol expressing the spike protein of different variants (D614G, Delta, Beta, Omicron BA1) to measure neutralizing antibody responses and nucleoprotein (N) and spike (S1, S2) direct ex vivo interferon gamma (IFNγ) T cell ELISpot to measure T cell responses.

RESULT: Our study demonstrated a similar magnitude of both binding (N-IgG (74% and 62%), S-RBD IgG (70% and 53%) and neutralizing (D614G (49% and 29%), Delta (56% and 47%), Beta (48% and 24%), Omicron BA1 (41% and 21%)) antibody responses from symptomatic and asymptomatic survivors in Nigeria. A similar magnitude was also seen among vaccinated participants. Interestingly, we revealed the presence of preexisting binding antibodies (N-IgG (60%) and S-RBD IgG (44%)) but no neutralizing antibodies from samples collected prior to the pandemic.

DISCUSSION: These findings revealed that both vaccinated, non-vaccinated and convalescent individuals in Southern Nigeria make similar magnitude of both binding and cross-reactive neutralizing antibody responses. It supported the presence of preexisting binding antibody responses among some Nigerians prior to the COVID-19 pandemic. Lastly, hybrid immunity and heterologous vaccine boosting induced the strongest binding and broadly neutralizing antibody responses compared to vaccine or infection-acquired immunity alone.

PMID:38322252 | PMC:PMC10844438 | DOI:10.3389/fimmu.2024.1305586

EMBO Rep. 2024 Feb 6. doi: 10.1038/s44319-023-00040-2. Online ahead of print.

ABSTRACT

Cellular attachment of viruses determines their cell tropism and species specificity. For entry, vaccinia, the prototypic poxvirus, relies on four binding proteins and an eleven-protein entry fusion complex. The contribution of the individual virus binding proteins to virion binding orientation and membrane fusion is unclear. Here, we show that virus binding proteins guide side-on virion binding and promote curvature of the host membrane towards the virus fusion machinery to facilitate fusion. Using a membrane-bleb model system together with super-resolution and electron microscopy we find that side-bound vaccinia virions induce membrane invagination in the presence of low pH. Repression or deletion of individual binding proteins reveals that three of four contribute to binding orientation, amongst which the chondroitin sulfate binding protein, D8, is required for host membrane bending. Consistent with low-pH dependent macropinocytic entry of vaccinia, loss of D8 prevents virion-associated macropinosome membrane bending, disrupts fusion pore formation and infection. Our results show that viral binding proteins are active participants in successful virus membrane fusion and illustrate the importance of virus protein architecture for successful infection.

PMID:38321165 | DOI:10.1038/s44319-023-00040-2

Life Sci Alliance. 2024 Feb 5;7(4):e202302529. doi: 10.26508/lsa.202302529. Print 2024 Apr.

ABSTRACT

Bidirectional interactions between the immune system and the gut microbiota are key contributors to various physiological functions. Immune-associated diseases such as cancer and autoimmunity, and efficacy of immunomodulatory therapies, have been linked to microbiome variation. Although COVID-19 infection has been shown to cause microbial dysbiosis, it remains understudied whether the inflammatory response associated with vaccination also impacts the microbiota. Here, we investigate the temporal impact of COVID-19 vaccination on the gut microbiome in healthy and immuno-compromised individuals; the latter included patients with primary immunodeficiency and cancer patients on immunomodulating therapies. We find that the gut microbiome remained remarkably stable post-vaccination irrespective of diverse immune status, vaccine response, and microbial composition spanned by the cohort. The stability is evident at all evaluated levels including diversity, phylum, species, and functional capacity. Our results indicate the resilience of the gut microbiome to host immune changes triggered by COVID-19 vaccination and suggest minimal, if any, impact on microbiome-mediated processes. These findings encourage vaccine acceptance, particularly when contrasted with the significant microbiome shifts observed during COVID-19 infection.

PMID:38316462 | PMC:PMC10844540 | DOI:10.26508/lsa.202302529

J Biol Chem. 2024 Feb 1:105711. doi: 10.1016/j.jbc.2024.105711. Online ahead of print.

ABSTRACT

Cytosolic long double-stranded RNA (dsRNA), among the most potent proinflammatory signals, is recognized by MDA5. MDA5 binds dsRNA cooperatively, forming helical filaments. ATP hydrolysis by MDA5 fulfills a proofreading function by promoting dissociation of shorter endogenous dsRΝΑs from MDA5 while allowing longer viral dsRNAs to remain bound leading to activation of interferon-β responses. Here, we show that adjacent MDA5 subunits in MDA5-dsRNA filaments hydrolyze ATP cooperatively, inducing cooperative filament disassembly. Consecutive rounds of ATP hydrolysis amplify the filament footprint, displacing tightly bound proteins from dsRNA. Our electron microscopy and biochemical assays show that LGP2 binds to dsRNA at internal binding sites through noncooperative ATP hydrolysis. Unlike MDA5, LGP2 has low nucleic acid selectivity and can hydrolyze GTP and CTP as well as ATP. Binding of LGP2 to dsRNA promotes nucleation of MDA5 filament assembly resulting in shorter filaments. Molecular modeling identifies an internally bound MDA5-LGP2-RNA complex, with the LGP2 C-terminal tail forming the key contacts with MDA5. These contacts are specifically required for NTP-dependent internal RNA binding. We conclude that NTPase-dependent binding of LGP2 to internal dsRNA sites complements NTPase-independent binding to dsRNA ends, via distinct binding modes, to increase the number and signaling output of MDA5-dsRNA complexes.

PMID:38309507 | DOI:10.1016/j.jbc.2024.105711

Rheumatology (Oxford). 2024 Jan 30:keae049. doi: 10.1093/rheumatology/keae049. Online ahead of print.

ABSTRACT

OBJECTIVE: Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP.

METHODS: Patients with systemic sclerosis (SSc) and ≥7 RP attacks during the last screening week prior to a baseline visit were randomised to four weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud's Condition Score, with change in RP attacks/week as primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory endpoints included patients' and physicians' global impression of change, Assessment of Scleroderma-associated Raynaud's Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites.

RESULTS: Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). Mean weekly number of RP attacks (baseline; vipoglanstat 14.4[SD 6.7], placebo 18.2[12.6]) decreased by 3.4[95% CI -5.8;-1.0] and 4.2[-6.5;-2.0] attacks per week (p= 0.628) respectively. All patient reported outcomes improved, with no difference between the groups. Mean change in recovery of peripheral blood flow after cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in urine. Vipoglanstat was safe and well tolerated.

CONCLUSION: Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role.

PMID:38291895 | DOI:10.1093/rheumatology/keae049

J Virol. 2024 Jan 30:e0177723. doi: 10.1128/jvi.01777-23. Online ahead of print.

ABSTRACT

Rubella virus encodes a nonstructural polyprotein with RNA polymerase, methyltransferase, and papain-like cysteine protease activities, along with a putative macrodomain of unknown function. Macrodomains bind ADP-ribose adducts, a post-translational modification that plays a key role in host-virus conflicts. Some macrodomains can also remove the mono-ADP-ribose adduct or degrade poly-ADP-ribose chains. Here, we report high-resolution crystal structures of the macrodomain from rubella virus nonstructural protein p150, with and without ADP-ribose binding. The overall fold is most similar to macroD-type macrodomains from various nonviral species. The specific composition and structure of the residues that coordinate ADP-ribose in the rubella virus macrodomain are most similar to those of macrodomains from alphaviruses. Isothermal calorimetry shows that the rubella virus macrodomain binds ADP-ribose in solution. Enzyme assays show that the rubella virus macrodomain can hydrolyze both mono- and poly-ADP-ribose adducts. Site-directed mutagenesis identifies Asn39 and Cys49 required for mono-ADP-ribosylhydrolase (de-MARylation) activity.IMPORTANCERubella virus remains a global health threat. Rubella infections during pregnancy can cause serious congenital pathology, for which no antiviral treatments are available. Our work demonstrates that, like alpha- and coronaviruses, rubiviruses encode a mono-ADP-ribosylhydrolase with a structurally conserved macrodomain fold to counteract MARylation by poly (ADP-ribose) polymerases (PARPs) in the host innate immune response. Our structural data will guide future efforts to develop novel antiviral therapeutics against rubella or infections with related viruses.

PMID:38289106 | DOI:10.1128/jvi.01777-23

EMBO Rep. 2024 Jan 29. doi: 10.1038/s44319-024-00063-3. Online ahead of print.

ABSTRACT

The exquisite specificity of antibodies can be harnessed to effect targeted degradation of membrane proteins. Here, we demonstrate targeted protein removal utilising a protein degradation domain derived from the endogenous human protein Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9). Recombinant antibodies genetically fused to this domain drive the degradation of membrane proteins that undergo constitutive internalisation and recycling, including the transferrin receptor and the human cytomegalovirus latency-associated protein US28. We term this approach PACTAC (PCSK9-Antibody Clearance-Targeting Chimeras).

PMID:38287192 | DOI:10.1038/s44319-024-00063-3