Autoimmunity
Abstract
Multiple sclerosis (MS) is a progressive, chronic, and highly disabling neuroinflammatory disorder characterized by demyelination and T cell–driven inflammation. Pathogenic T cells play a central role in MS, but effective therapeutic targeting remains challenging. Here, we identified ankyrin repeat domain–containing protein 55 (ANKRD55) as a key regulator of T cell function by single-cell transcriptomic analysis of cerebrospinal fluid and blood from MS patients. ANKRD55 was predominantly expressed in CD4+ T cells in both compartments. Genetic ablation of Ankrd55 led to a robustly reduced disease severity and neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a widely used animal model for MS. Furthermore, T cell–specific deficiency of Ankrd55 significantly impaired Th1 polarization and Th17 differentiation, reducing EAE pathogenicity. Mechanistically, we found that Ankrd55 deficiency disrupted T cell receptor (TCR) signaling integrity. We demonstrated that ANKRD55 regulates the formation of the immune synapse, an essential prerequisite for TCR activation, by interacting with subunits of the chaperonin-containing TCP1 (CCT) complex and modulating its activity, enhancing its assembly by competing with CCT5 for binding to TCP1, CCT3, and CCT6. This facilitates proper microtubule organization and TCR activation. These findings establish ANKRD55 as a critical regulator of TCR signaling and highlight its therapeutic potential in pathogenic T cell–driven autoimmune diseases.
Authors
Chuyu Wu, Meiling Jiang, Xue Yang, Yixuan Liu, Bin Huang, Yi Guo, Runjing Cao, Zhihui Cui, Guozhen Deng, Weiyan Wang, Mengdi Guo, Zhiyong Lin, Jiahui Fan, Lin-ming Zhang, Lorenzo Di Cesare Mannelli, Tao Pang, Chenhui Wang, Cun-Jin Zhang
Abstract
The current gold standard for assessing renal pathology in lupus nephritis (LN) is invasive and cannot be serially repeated. To assess if urine can serve as a liquid biopsy for underlying renal pathology, urine obtained from patients with LN at the time of renal biopsy were interrogated for 1,317 proteins, using an aptamer-based proteomic screen. Levels of 57 urine proteins were significantly elevated and correlated with pathology activity index (AI), notably endocapillary hypercellularity, fibrinoid necrosis, and cellular crescents. These included proteins pertaining to leukocyte/podocyte activation, neutrophil activation, endothelial activation, and markers of inflammation/anti-inflammation. In contrast, complement and coagulation cascade proteins, and proteins related to the extracellular matrix (ECM) emerged as the strongest urinary readouts of concurrent renal pathology chonicity index (CI), notably tubular atrophy and interstitial fibrosis. In vitro mechanistic studies revealed that complement proteins C3a and C5a increased the expression of profibrotic ECM proteins in macrophages and proximal tubule epithelial cells. Thus, carefully assembled panels of urinary proteins that are indicative of high renal pathology AI and/or CI may help monitor the status of renal pathology after therapy in patients with LN, in a noninvasive manner, without the need for repeat renal biopsies.
Authors
Ting Zhang, Jessica Castillo, Anto Sam Crosslee Louis Sam Titus, Kamala Vanarsa, Vedant Sharma, Sohan Kureti, Ramesh Saxena, Chandra Mohan
Abstract
Teplizumab, a humanized anti-CD3 monoclonal antibody, represents a breakthrough in autoimmune type 1 diabetes (T1D) treatment, by delaying clinical onset in stage 2 and slowing progression in early stage 3. However, therapeutic responses are heterogeneous. To better understand this variability, we applied single-cell transcriptomics to paired peripheral blood and pancreas samples from anti-mouse CD3-treated non-obese diabetic (NOD) mice and identified distinct gene signatures associated with therapy outcome, with consistent patterns across compartments. Success-associated signatures were enriched in NK/CD8⁺ T cells and other immune cell types, whereas resistance signatures were predominantly expressed by neutrophils. The immune communities underlying these response signatures were confirmed in human whole-blood sequencing data from the AbATE study at 6 months, which assessed teplizumab therapy in stage 3 T1D. Furthermore, baseline expression profiling in the human TN10 (stage 2) and AbATE (stage 3) cohorts identified immune signatures predictive of therapy response, T cell-enriched signatures in responders and neutrophil-enriched signatures in non-responders, highlighting the roles of both adaptive and innate immunity in determining teplizumab outcome. Using an elastic-net logistic regression model, we developed a 26-gene blood-based signature predicting teplizumab response (AUC = 0.97). These findings demonstrate the predictive potential of immune gene signatures and the value of transcriptomic profiling in guiding individualized treatment strategies with teplizumab in T1D.
Authors
Gabriele Sassi, Pierre Lemaitre, Laia Fernández Calvo, Francesca Lodi, Álvaro Cortés Calabuig, Samal Bissenova, Amber Wouters, Laure Degroote, Marijke Viaene, Niels Vandamme, Lauren Higdon, Peter S. Linsley, S. Alice Long, Chantal Mathieu, Conny Gysemans
Abstract
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of most insulin-producing β-cells, along with dysregulated glucagon secretion from pancreatic α-cells. We conducted an integrated analysis that combines electrophysiological and transcriptomic profiling, along with machine learning, of islet cells from T1D donors. The few surviving β-cells exhibit altered electrophysiological properties and transcriptomic signatures indicative of increased antigen presentation, metabolic reprogramming, and impaired protein translation. In α-cells, we observed hyper-responsiveness and increased exocytosis, which are associated with upregulated immune signaling, disrupted transcription factor localization and lysosome homeostasis, as well as dysregulation of mTORC1 complex signaling. Notably, key genetic risk signals for T1D were enriched in transcripts related to α-cell dysfunction, including MHC class I, which were closely linked with α-cell dysfunction. Our data provide what we believe are novel insights into the molecular underpinnings of islet cell dysfunction in T1D, highlighting pathways that may be leveraged to preserve residual β-cell function and modulate α-cell activity. These findings underscore the complex interplay between immune signaling, metabolic stress, and cellular identity in shaping islet cell phenotypes in T1D.
Authors
Theodore dos Santos, Xiao-Qing Dai, Robert C. Jones, Aliya F. Spigelman, Hannah M. Mummey, Jessica D. Ewald, Cara E. Ellis, James G. Lyon, Nancy Smith, Austin Bautista, Jocelyn E. Manning Fox, Norma F. Neff, Angela M. Detweiler, Michelle Tan, Rafael Arrojo e Drigo, Jianguo Xia, Joan Camunas-Soler, Kyle J. Gaulton, Stephen R. Quake, Patrick E. MacDonald
Abstract
Checkpoint inhibitors targeting CTLA-4 and PD-1 revolutionized the treatment of cancer patients, but their use is limited by the emergence of immune-related adverse events (irAE). We assessed autoreactive B cell frequencies in the blood of cancer patients before and after treatment with checkpoint inhibitors by testing the reactivity of recombinant antibodies cloned from single B cells. We found that anti-PD-1 and anti-CTLA-4 combination therapy induced the emergence of autoreactive mature naïve B cells, whereas central B-cell tolerance remained functional. In contrast, anti-PD-1 alone did not alter autoreactive B cell counterselection. Anti-CTLA-4 injections in humanized mice also resulted in the production of autoreactive B cells, whereas anti-PD-1 did not. We conclude that CTLA-4 but not PD-1 is required for the removal of developing autoreactive mature naïve B cells and that CTLA-4 blockade broadens the peripheral B cell repertoire which likely contains clones that promote not only irAEs but also anti-tumor responses.
Authors
Elif Çakan, Meng Wang, Yile Dai, Adrien Mirouse, Clarence Rachel Villanueva-Pachas, Delphine Bouis, Joshua M. Boeckers, Ruchi Gera, Sally Yraita, Leslie Clapp, Ana Luisa Perdigoto, Fabien R. Delmotte, Christopher Massad, Antonietta Bacchiocchi, Aaron M. Ring, Yuval Kluger, Harriet M. Kluger, Kevan C. Herold, Eric Meffre
Abstract
BACKGROUND. In human lupus nephritis (LuN), tubulointerstitial inflammation (TII) is prognostically more important than glomerular inflammation. However, a comprehensive understanding of both TII complexity and heterogeneity is lacking. METHODS. Herein, we used high-dimensional confocal microscopy, spatial transcriptomics and specialized computer vision techniques to quantify immune cell populations and localize these within normal and diseased renal cortex structures. With these tools, we compared LuN to renal allograft rejection (RAR) and normal kidney on 54 de-identified biopsies. RESULTS. In both LuN and RAR, the 33 characterized immune cell populations formed discrete subgroups whose constituents co-varied in prevalence across biopsies. In both diseases, these co-variant immune cell subgroups organized into the same unique niches. Therefore, inflammation could be resolved into trajectories representing the relative prevalence and density of cardinal immune cell members of each co-variant subgroup. Indeed, in any one biopsy, the inflammatory state could be characterized by quantifying constituent immune cell trajectories. Remarkably, LuN heterogeneity could be captured by quantifying a few myeloid immune cell trajectories while RAR was more complex with additional T cell trajectories. CONCLUSIONS. Our studies identify rules governing renal inflammation and thus provide an approach for resolving LuN into discrete mechanistic categories. FUNDING. NIH (U19 AI 082724 [MRC], R01 AI148705 [MRC and ASC]), Chan Zuckerberg Biohub (MRC) and Lupus Research Alliance (MRC)
Authors
Gabriel Casella, Madeleine S. Torcasso, Junting Ai, Thao P. Cao, Satoshi Hara, Michael S. Andrade, Deepjyoti Ghosh, Daming Shao, Anthony Chang, Kichul Ko, Anita S. Chong, Maryellen L. Giger, Marcus R. Clark
Abstract
Toll like receptor (TLR) 7 and 9, endosomal sensors for RNA and DNA, are key mediators of autoreactivity. Although generally considered homologous, they paradoxically have opposing effects on lupus: TLR7 exacerbates disease while TLR9 protects from disease. How they mediate opposing effects in autoimmunity remains undetermined. We hypothesized that differences in signaling qualities of the Toll-Interleukin 1 Receptor (TIR) domains of TLR7 and TLR9 could be responsible for their opposing effects. To test this, we introduced the TIR domain of TLR9 into the endogenous TLR7 locus and the TLR7 TIR domain into the endogenous TLR9 locus of mice, creating chimeric molecules termed TLR779 and TLR997. Lupus-prone MRL/lpr mice carrying Tlr779 had greatly ameliorated disease while MRL/lpr mice carrying Tlr997 had markedly exacerbated disease compared to respective TlrWT mice. These experiments establish that TLR7 and TLR9 TIR domains have divergent properties and control disease quality, thus explaining the longstanding “TLR paradox.”
Authors
Claire Leibler, Kayla B. Thomas, Coralie Josensi, Russell C. Levack, Shuchi Smita, Shinu John, Daniel J. Wikenheiser, Sheldon Bastacky, Sebastien Gingras, Kevin M. Nickerson, Mark J. Shlomchik
Abstract
Type 1 diabetes is characterized by the autoimmune destruction of pancreatic β cells, resulting in permanent loss of glucose homeostasis. Islet transplantation is a promising potential cure that remains hindered by immune rejection. We previously showed that ST8Sia6 expression on tumors reduced immune surveillance and hypothesized that this sialyltransferase could protect β cells from autoimmune destruction. Here, we demonstrate that ectopic expression of ST8Sia6 in β cells of female nonobese diabetic mice (NOD βST) decreased the spontaneous incidence of diabetes by 90% and preserved β cell mass. NOD βST mice had comparable insulitis at 8 weeks of age that did not progress over time compared with littermate controls. β Cell–autoreactive B and T cells were present in NOD βST mice, indicating a peripheral rather than central mechanism of immune tolerance. The islets of NOD βST mice displayed a dampened type 1 immune response and reduced IL-12p35 expression in dendritic cells compared with those of littermate controls. The peripheral protection persisted even after removal of ST8Sia6 expression at 20 weeks of age, indicating that transient expression was sufficient for establishment of tolerance. These results demonstrate that ST8Sia6 protects β cells from immune-mediated attack and rejection, highlighting its therapeutic potential for autoimmune disorders.
Authors
Justin Choe, Paul Belmonte, Sydney Crotts, Thanh Nguyen, David Friedman, Alexi Zastrow, Matthew Rajcula, Brady Hammer, Claire Wilhelm, Michael J. Shapiro, Aleksey Matveyenko, Virginia Smith Shapiro
Abstract
Chronic inflammatory diseases, like rheumatoid arthritis (RA) have been described to cause central nervous system (CNS) activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota-derived histamine as such factor. We show that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord and restore homeostatic microglia, thereby reducing inflammation in the joints. Selective histamine 3 receptor (H3R) signaling in the intestine is critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist-induced pro-resolving effects on arthritis. Moreover, therapeutic supplementation of the short-chain fatty acid (SCFA) propionate identified one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut-CNS-joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS.
Authors
Kerstin Dürholz, Leona Ehnes, Mathias Linnerbauer, Eva Schmid, Heike Danzer, Michael Hinzpeter-Schmidt, Lena Lößlein, Lena Amend, Michael Frech, Vugar Azizov, Fabian Schälter, Arne Gessner, Sébastien Lucas, Till-Robin Lesker, R. Verena Taudte, Jörg Hofmann, Felix Beyer, Hadar Bootz-Maoz, Yasmin Reich, Hadar Romano, Daniele Mauro, Ruth Beckervordersandforth, Maja Skov Kragsnaes, Torkell Ellingsen, Wei Xiang, Aiden Haghikia, Cezmi A. Akdis, Francesco Ciccia, Tobias Bäuerle, Kerstin Sarter, Till Strowig, Nissan Yissachar, Georg Schett, Veit Rothhammer, Mario M. Zaiss
Abstract
COPA syndrome is a monogenic disorder of immune dysregulation that leads to interstitial lung disease and high-titer autoantibodies. Constitutive activation of the innate immune molecule STING is centrally involved in disease. However, the mechanisms by which STING results in autoimmunity is not well understood in COPA syndrome and other STING-associated diseases. Prior studies show a cell autonomous role for STING in thymocyte development. Single cell data of human thymus demonstrates STING is highly expressed in medullary thymic epithelial cells (mTECs) and at levels much greater than T cells. Here, we show that in certain contexts activated STING exerts a functional role in the thymic epithelium to alter thymocyte selection and predisposes to autoimmunity. In CopaE241K/+ mice, activated STING in mTECs amplified interferon signaling, impaired macroautophagy and caused a defect in negative selection of T cell precursors. Wild-type mice given a systemic STING agonist phenocopied the selection defect and showed enhanced thymic escape of a T cell clone targeting a self-antigen also expressed in melanoma. Our work demonstrates STING activation in TECs shapes the T cell repertoire and contributes to autoimmunity, findings important for conditions that activate thymic STING.
Authors
Zimu Deng, Christopher S. Law, Santosh Kurra, Noa Simchoni, Anthony K. Shum
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ISSN: 0021-9738 (print), 1558-8238 (online)