Autoimmunity
Abstract
In Type 1 Diabetes (T1D), disease onset and immunotherapy responses vary widely, reflecting heterogeneous stage-specific immune dysregulation that remains undefined. To investigate this heterogeneity, we engineered microporous polycaprolactone scaffolds that form synthetic immunological niches (INs) subcutaneously and capture tissue-associated systemic immune changes. Building on our prior demonstration of IN-based longitudinal T1D monitoring, we use multimodal IN profiling to define the immune changes underlying divergent disease trajectories and immunotherapy responses. In non-obese diabetic (NOD) mice, longitudinal transcriptomic profiling of IN identified early myeloid associated changes, followed by increasing T cell-associated dysregulation that distinguished progressors from non-progressors. An early-stage IN-based T1D gene signature stratified NOD progressors from non-progressors by 6 weeks of age and was conserved across human T1D tissues, distinguishing T1D from non-diabetic individuals in spleen and pancreatic lymph node samples, but not in peripheral blood. Signature-based stratification revealed macrophage-associated TNFα pathway enrichment in pancreas of NOD progressors, which was validated in human T1D islets. Given the heterogeneous response to anti-TNFα therapy, IN profiling identified genesets associated with anti-TNFα efficacy and generated a response score that prospectively distinguished treatment-sensitive from resistant mice. These findings establish IN as a platform for detecting stage-wise immune dysregulation and stratifying immunotherapy response in T1D.
Authors
Jyotirmoy Roy, Yifei Jiang, Runbo Mao, Jessica L. King, Amod Talekar, Donglin Liu, Lillian Holman, Haoxuan Zeng, Xin Luo, Laila M. Rad, Peter Sajjakulnukit, Brianna Ha, Kai Liu, Elizabeth J. Bealer, Bryan Wonski, Kathryn Kang, Sean T. Carey, Luke F. Bugada, Brooke M. Smiley, Shahzad Sohail, Antonio D. Holmes, Dominik Awad, Aaron H. Morris, Costas A. Lyssiotis, Jie Liu, Lonnie D. Shea
Abstract
The establishment of mixed hematopoietic chimerism is a promising way to induce immune tolerance for islet replacement therapy and to treat the underlying autoimmunity in type 1 diabetes (T1D). Mixed chimerism not only promotes effective thymic negative selection of autoreactive cells but also restores regulatory T cell (Treg) function and peripheral tolerance. In the current study, we determined that a novel class of donor-derived CD8+CD44+CD122+ Tregs (d-CD8+CD122+ Tregs) plays a crucial role in controlling autoimmunity in non-obese diabetic (NOD) mice with induced mixed chimerism. Using adoptive T cell transfer experiments, we showed that d-CD8+CD122+ Tregs abrogate autoimmunity by suppressing the exogenously injected diabetogenic T cells in Recombination-Activating Gene deficient NOD mice. These d-CD8+CD122+ Tregs from NOD chimeras show upregulation of Helios, Programmed cell death protein 1, perforin, granzyme-B, CD39, Folate receptor 4, and downregulation of proinflammatory marker SCART1. Using in vitro assays, we show that d-CD8+CD122+ Tregs respond specifically to a Complementarity-Determining Region-3 peptide sequence derived from T cell receptors of islet antigen-specific autoreactive T cells. Similarly, we found that individuals with T1D have a deficiency in CD8+CD122+ Tregs, suggesting a potential loss of regulatory function accompanies disease onset. Revitalizing CD8+CD122+ Tregs may offer a new therapeutic strategy of restoring immune tolerance in autoimmune diabetes.
Authors
Shiva Pathak, Cameron S. Bader, Bettina P. Iliopoulou, Shobha Regmi, Pin-I Chen, Biki Gupta, Xiangni Wu, Blake Mosher, Alexandra Wells, Levon Witherspoon, Kayla C. Jenkins, William Harper, Emily Y. SooHoo, Abigail Twoy, Rizwan Ahmed, Suparna Dutt, Nadine Nagy, Kent P. Jensen, C. Garrison Fathman, Avnesh S. Thakor, Mark M. Davis, Everett H. Meyer
Abstract
BACKGROUND. Primary adrenal insufficiency (PAI) is commonly caused by autoimmunity in adults, known as autoimmune Addison’s disease (AAD). Autoantibodies against 21-hydroxylase are a hallmark of AAD but are absent in some patients diagnosed with AAD, posing a challenge to their clinical management. METHODS. We tested a polygenic risk score for AAD (PRS14AAD) to prioritize seronegative patients for etiologic reevaluation. The PRS14AAD was calculated in patients diagnosed with AAD but lacking 21-hydroxylase autoantibodies (n = 124). Patients with low (n = 35) or high (n = 10) genetic susceptibility to AAD underwent clinical re-evaluation and whole-genome sequencing. RESULTS. Of the 34 patients with low PRS14AAD, 14 (41%) were re-diagnosed with non-autoimmune adrenal insufficiency, whereas no alternative etiologies were identified in patients with high PRS14AAD. The low PRS group included six patients (17%) with confirmed monogenic PAI and eight patients (23%) with adrenal insufficiency due to either tuberculosis or non-primary causes. Notably, four of the six confirmed monogenic cases developed PAI in adulthood, consistent with late-onset disease caused by hypomorphic variants. Additionally, seven patients (20%) carried genetic variants suspected of causing monogenic disease. CONCLUSION. These findings support considering genetic evaluation in patients with seronegative PAI, regardless of the age at diagnosis.
Authors
Maribel Aranda-Guillén, Ileana Ruxandra Botusan, Venuja Fernando, Michela Barbaro, Maria Blomqvist, Ellen Christine Røyrvik, Anette Susanne Bøe Wolff, Eystein Sverre Husebye, Stephan Kemp, Anna Wedell, Olov Ekwall, Magnus Isaksson, Jeanette Wahlberg, Ola Lindgren, Jakob Skov, Ragnhildur Bergthorsdottir, Per Dahlqvist, Sophie Bensing, Olle Kämpe, Daniel Eriksson
Abstract
Primary central nervous system (CNS) vasculitis is a rare and devastating inflammatory cerebrovascular disease for which pathogenic mechanisms remain poorly defined, largely due to limited access to human tissue and the absence of validated experimental models. Here, we present a mouse model of CNS-restricted vasculitis based on inducible, endothelial-biased neoantigen expression, termed brain endothelial ovalbumin (BrEndO). In BrEndO mice, tamoxifen-induced ovalbumin (OVA) expression in cerebral endothelial cells (ECs) elicited a controlled endogenous CD8+ T cell response at the blood–brain barrier that remained clinically restrained. In contrast, peripheral immune activation through infection with OVA-expressing Listeria monocytogenes or systemic PD-L1 immune checkpoint blockade converted this regulated response into severe, CD8+ T cell–driven CNS vasculitis with vascular injury and parenchymal infiltration. Transcriptomic profiling of inflamed cerebral microvessels and spatial transcriptomic analyses demonstrated shared inflammatory and immune activation signatures between BrEndO mice and human primary CNS vasculitis brain biopsies. These findings identify antigen-specific endothelial immune recognition as a regulated process whose breakdown precipitates CNS-restricted vasculitis and establish BrEndO as an experimentally tractable platform to investigate mechanisms and modifiers of immune-mediated cerebrovascular inflammation.
Authors
Ines Sophie Schädlich, Du Huy Nguyen, Manja Wibke Thiem, Andreas Franzelin, Marcel Seungsu Woo, Alexandros Hadjilaou, Malte Borggrewe, Jiani Jiang, Mamta Panda, Enrico Maria Costanzo, Tina Fischer, Marco Er-Lukowiak, Yinghui Duan, Anne Rissiek, Alexander Winston Veltkamp, Friederike Raczkowski, Peter Ludewig, Markus Schwaninger, Dagmar Wirth, Gisa Tiegs, Thomas G. Oertner, Danny Schreier, Maike Frye, Amirrtavarshni Sivayoganathan, Christian F. Krebs, Sonja Johann, Barbara M. Braunger, Thomas Renné, Berta Puig, Anna Wiesner, Markus Glatzel, Hans-Willi Mittrücker, Björn Rissiek, Tim Magnus
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with alternating phases of heightened symptoms and periods of disease inactivity. Our investigation focuses on the distinct molecular profiles of resting naive B cells from both active and inactive SLE states in female adults, primarily of Black ancestry. We identified a distinct transcriptome and epigenome during inactive SLE. Transcriptional patterns indicated an increase in distinct cytokine signaling pathway expression in SLE B cells, encompassing both common and disease activity–specific components. Specifically, while both disease states exhibited interferon signatures, increased expression of IL-12, TNF-α/NF-κB, and CD40 signaling pathway genes was enriched in inactive disease. While some regions exhibited comparable epigenetic features in both disease states, such as TLR7 signaling genes, others were distinct. Chromatin accessibility in inactive disease indicated the involvement of MEF2 and bHLH family factors, such as E2A/E2-2, while active disease regions were defined by IRF family factors. This study illuminates both disease-associated programs and molecular changes to cell activation pathways capable of directing B cells toward diverse effector fates in active or inactive SLE. Our data also offer insights of particular importance for the design and monitoring of B cell–targeting treatments.
Authors
James R. Rose, Yusho Ishii, Arezou Khosroshahi, Sakeenah Hicks, Scott A. Jenks, Christopher D. Scharer, Ignacio Sanz, Jeremy M. Boss
Abstract
Effector CD8+ T cells are key drivers of type 1 diabetes (T1D) pathogenesis, yet questions remain regarding the molecular defects leading to altered cytotoxicity, peripheral tissue phenotype, and receptor specificity. We analyzed human pancreatic lymph nodes (pLNs) using mass cytometry and single-cell RNA-seq (scRNA-seq) with combined T cell receptor (TCR) profiling. Cytometric analysis revealed enrichment of T stem cell memory–like (TSCM-like) cells (CD8+CD45RA+CD27+CD28+CCR7+CXCR3+) in T1D pLNs. scRNA-seq indicated an elevated inflammatory cytokine gene signature (IFITM3, LTB) along with regulators of terminal differentiation (BCL6, BCL3), coupled with downregulation of exhaustion-associated genes (DUSP2, NR4A2, TSC22D3) in CD8+ T cells in T1D pLNs. Immune response enrichment analysis (IREA) indicated IL-15 signaling as a significant driver of these phenotypes. Integrated TCR and transcriptomics analysis revealed a cluster of diverse naive-like CD8+ T cell clones in T1D pLNs. Comparison of pLNs and pancreatic tissue slice isolates indicated sharing of effector CD8+ T cells, with enhanced terminal effector signatures within the pancreas relative to paired pLNs. Multiplex imaging revealed differential localization of T cell factor 1 (TCF1)- and thymocyte selection-associated high mobility group box protein (TOX)-expressing T cells in the pancreas, with islet-proximal TCF1+TOX+ cells displaying a mixture of activation and exhaustion-associated phenotypes. Thus, we provide multimodal cellular profiles enriched in T1D tissues for consideration in therapeutic targeting.
Authors
Leeana D. Peters, Howard R. Seay, Justin A. Smith, Amanda L. Posgai, Reed L. Berkowitz, Clive H. Wasserfall, Mark A. Atkinson, Rhonda Bacher, Maigan A. Brusko, Todd M. Brusko
Abstract
Membranous nephropathy (MN) is an autoimmune kidney disease and a major cause of nephrotic syndrome in adults. Although autoantibodies against phospholipase A2 receptor 1 (PLA2R) and complement activation are central to disease pathogenesis, the mechanisms by which anti-PLA2R antibodies activate complement at the podocyte surface remain incompletely defined. Here, we cloned 14 patient-derived anti-PLA2R monoclonal antibodies (mAbs) and found that they predominantly recognized the N-terminal cysteine-rich (CysR) and C-type lectin domain 1 (CTLD1) regions of PLA2R. Individual anti-PLA2R mAbs induced little or no complement-dependent cytotoxicity (CDC) of PLA2R-expressing podocytes in vitro. In contrast, paired mAbs targeting distinct epitopes, particularly CysR and CTLD1, markedly enhanced CDC. This effect was strongest for IgG1 and IgG3 antibodies, whereas IgG4 alone did not activate complement but modulated CDC in combination with IgG1. Purified IgG from patients with PLA2R-associated MN similarly induced CDC, which was augmented by addition of anti-PLA2R IgG1 and reduced by anti-PLA2R IgG4 or Fab fragments targeting CysR or CTLD1. In human PLA2R-expressing mice, paired anti-PLA2R antibodies increased glomerular complement deposition and induced albuminuria. These findings identify epitope pairing as a key determinant of complement activation in PLA2R-associated MN and support epitope-specific targeting strategies as a promising avenue for therapeutic intervention.
Authors
Tsai-Yi Wu, Kun-Hua Tu, Larissa Seifert, Kung-Wei Lin, Han-Po Shih, Yu-Fang Lo, Jhan-Jie Peng, Gunther Zahner, Oliver Kretz, You-Ning Lin, Chen-Xuan Kang, Jing-Ya Ding, Yi-Ran Tu, Li-Yi Ma, Ya-Ting Chuang, Chia-Chi Lo, Yu-Huan Tsai, Chih-Wei Yang, Nicola M. Tomas, Cheng-Lung Ku
Abstract
Multiple sclerosis (MS) is a complex inflammatory disease of the CNS resulting from an intricate interplay between genetic predisposition and environmental factors. Vitamin D (VD) deficiency is one of the established risk factors for MS. CD46 costimulation of CD4+ T cells induces a switch from Th1 to type I regulatory cells (Tr1), characterized by increased IL-10 production. This switch is impaired in MS T cells but can be restored by VD, which also strongly promotes expression of CD226 on CD46-activated T cells. The rs763361 polymorphism in the CD226 gene, resulting in a non-synonymous Gly307Ser variant, is associated with increased risk for MS. Herein, we show that expression of this CD226 risk allele disrupts the ability of CD46-activated T cells to operate the IFNγ/IL-10 switch upon VD exposure. Mechanistically, the risk variant impairs activation of the integrin LFA-1, which promotes the Tr1 phenotype. LFA-1-mediated Tr1 differentiation is also impaired in MS T cells expressing the CD226 risk allele upon CD46 and VD stimulation. Our study unveils how, in the context of MS susceptibility, a genetic polymorphism and an environmental factor act in concert to control the differentiation of Tr1 cells.
Authors
Saniya Kari, Aymeline Debonlier, Thibault Angles, Beatriz Chaves, Charles Grosjean, Florence Bucciarelli, Valérie Duplan-Eche, Lucie Nozeran, Jessica Lavery, Elena Morandi, Beatrice Pignolet, Max Mimpen, Joost Smolders, Roland Liblau, Abdelhadi Saoudi, Jan Damoiseaux, Frederick Masson, Loïc Dupré, Anne L. Astier
Abstract
Regulatory T (Treg) cells hold great promise as next-generation therapeutics for autoimmune diseases. However, maintaining their functional persistence within inflamed tissues remains a major translational challenge. Using an in vitro system that recapitulates the inflammatory CNS milieu of multiple sclerosis (MS), together with a pooled shRNA screen, we identify necroptotic signaling as a key driver of Treg cell death, thereby compromising Treg functional persistence under inflammatory conditions. We further demonstrate that Treg cells in both a mouse model of MS and patients with MS exhibit a preferential susceptibility to RIPK1 kinase-dependent necroptosis. Mechanistically, a FOXP3-driven low-glucose metabolic program renders Treg cells intrinsically susceptible to necroptosis by limiting O-GlcNAc modification on RIPK1. This vulnerability is not shared by conventional T cells under comparable inflammatory conditions. Finally, in combined with adoptive Treg cell transfer, we show that selective inhibition of necroptosis in Treg cells enhances their survival and suppressive function at sites of active inflammation, thereby reducing autoimmune pathology in mouse models of MS and systemic lupus erythematosus. Together, these findings identify necroptotic cell death as a barrier to Treg persistence within inflamed tissues and highlight the therapeutic potential of necroptosis-resistant Treg cells for the treatment of autoimmune diseases.
Authors
Qiaoyan Wu, Na Cui, Li Gao, Zhihui Lu, Xiang Ao, Rui Pang, Xingyan Li, Heling Pan, Daichao Xu, Peiying Li, Junying Yuan, Chengyu Zou
Abstract
Background Autoimmune diseases (ADs) often co-occur within individuals and families, indicating shared genetic risk factors. However, the composition of genetic overlap across autoimmunity is largely unknown. Methods This nationwide study included 6,336,615 individuals born in Sweden between 1932 and 1983, comprising 3,839,400 full-sibling pairs. Based on national heath-registers, 22 ADs were identified from 1969-2013. Aggregation and co-aggregation of ADs among siblings was used to estimate pairwise genetic correlations of ADs under a liability-threshold model. Network analysis and principal component analysis was used to characterize the structure of shared genetic risk across ADs. Results A total of 707,995 individuals (11.2%) were diagnosed with at least one AD. The studied ADs formed a network of significant genetic correlations (mean rg = 0.24, range 0.08-0.84) with clusters of more closely related ADs (rg ≥ 0.3). We found no evidence of a significant universal factor predisposing to autoimmunity. Conclusions This study demonstrates that ADs share substantial cluster-specific genetic overlap that largely aligns with affected tissue types, leading to distinct groupings of connective tissue diseases, gastrointestinal disorders, and endocrinopathies, whereas diseases of the nervous system show limited genetic cohesion. This suggests that shared biological mechanisms may drive coaggregation within disease groups. Clinically, these insights highlight the importance of monitoring patients and their relatives for related autoimmune disorders. Funding The Swedish Society of Medicine, Region Värmland's County Research Council, The Swedish Research Council, the Knut and Alice Wallenberg Foundation, The Regional Agreement on medical training and Clinical research (ALF) between Stockholm County Council and Karolinska Institutet
Authors
Daniel Eriksson, Ralf Kuja-Halkola, Marie E. Holmqvist, Henrik Larsson, Agnieszka Butwicka, Soffia Gudbjörnsdottir, Olle Kämpe, Sophie Bensing, Jakob Skov
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ISSN: 0021-9738 (print), 1558-8238 (online)