Autoimmunity
Abstract
Type 1 diabetes (T1D) is precipitated by the autoimmune destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans. Chemokines have been identified as major conductors of islet infiltration by autoaggressive leukocytes, including antigen-presenting cells and islet autoantigen-specific T cells. We have previously generated a roadmap of gene expression in the islet microenvironment during T1D in a mouse model and found that most of the chemokine axes are chronically upregulated during T1D. The XCL1/XCR1 chemokine axis is of particular interest, since XCR1 is exclusively expressed on conventional dendritic cells type 1 (cDC1) that excel by their high capacity for T cell activation. Here we demonstrate cDC1 expressing XCR1 are present in and around the islets of patients with T1D and of islet-autoantibody positive individuals. Further, we show that XCL1 plays an important role in the attraction of highly potent dendritic cells expressing XCR1 to the islets in an inducible mouse model for T1D. XCL1-deficient mice display a diminished infiltration of XCR1+ cDC1 and subsequently a reduced magnitude and activity of islet autoantigen-specific T cells resulting in a profound decrease in T1D incidence. Interference with the XCL1/XCR1 chemokine axis might constitute a novel therapy for T1D.
Authors
Camilla Tondello, Christine Bender, Gregory J. Golden, Deborah Puppe, Elisa Blickberndt, Monika Bayer, Giulia K. Buchmann, Josef Pfeilschifter, Malte Bachmann, Edith Hintermann, Ralf P. Brandes, Michael R. Betts, Richard A. Kroczek, Urs Christen
Abstract
The mechanisms utilized by differentiating B cells to withstand highly damaging conditions generated during severe infections, like the massive hemolysis that accompanies malaria, are poorly understood. Here we demonstrate that ROCK1 regulates B cells differentiation in hostile environments replete with PAMPs (pathogen-associated molecular patterns) and high levels of heme by controlling two key heme-regulated molecules, BACH2 and Heme-regulated eIF2a kinase (HRI). ROCK1 phosphorylates BACH2 and protects it from heme-driven degradation. As B cells differentiate, furthermore, ROCK1 restrains their proinflammatory potential and helps them handle the heightened stress imparted by the presence of PAMPs and heme by controlling HRI, a key regulator of the integrated stress response and cytosolic proteotoxicity. ROCK1 controls the interplay of HRI with HSP90 and limits the recruitment of HRI and HSP90 to unique p62/SQSTM1 complexes that also contain critical kinases like mTORC1 and TBK1, and proteins involved in RNA metabolism, oxidative damage, and proteostasis like TDP-43. Thus, ROCK1 helps B cells cope with intense pathogen-driven destruction by coordinating the activity of key controllers of B cell differentiation and stress responses. These ROCK1-dependent mechanisms may be widely employed by cells to handle severe environmental stresses, and these findings may be relevant for immune-mediated and age-related neurodegenerative disorders.
Authors
Juan Rivera-Correa, Sanjay Gupta, Edd Ricker, Danny Flores-Castro, Daniel Jenkins, Stephen Vulcano, Swati P. Phalke, Tania Pannellini, Matthew M. Miele, Zhuoning Li, Nahuel Zamponi, Young-Bum Kim, Yurii Chinenov, Eugenia Giannopoulou, Leandro Cerchietti, Alessandra B. Pernis
Abstract
Autoimmune uveitis (AU) is a sight-threatening ocular autoimmune disorder that often manifests as retinal vasculitis. Increased neutrophil infiltration around retinal vessels has been reported during the progression of AU, while how they function is not fully recognized. Neutrophil extracellular traps (NETs), produced by activated neutrophils, have been suggested to be detrimental in autoimmune diseases. Here, we found that NETs were elevated in patients with active AU, and this was verified in an experimental AU (EAU) mouse model. Depletion of neutrophils or degradation of NETs with deoxyribonuclease-I (DNase I) could decrease CD4+ effector T cell (Teff) infiltration in retina and spleen to alleviate EAU. Moreover, we found that the expression of adhesion molecules, selectin, and antigen-presenting molecules was elevated in EAU retina and in retinal microvascular endothelial cells (RMECs) cocultured with NETs. The stimulated RMECs further facilitated CD4+ T cell adhesion, activation, and differentiation into Teffs. Mechanistically, NETs trigger RMEC activation by hastening cell senescence through the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. Slowing down senescence or inhibiting the cGAS/STING pathway in RMECs reduces the activation and differentiation of CD4+ T cells. These results suggest a deleterious role of NETs in AU. Targeting NETs would offer an effective therapeutic method.
Authors
Zuoyi Li, Zhuang Li, Yunwei Hu, Yanyan Xie, Yuxun Shi, Guanyu Chen, Jun Huang, Zhiqiang Xiao, Wenjie Zhu, Haixiang Huang, Minzhen Wang, Jianping Chen, Xiaoqing Chen, Dan Liang
Abstract
Deficits in IL-2 signaling can precipitate autoimmunity by altering the function and survival of FoxP3+ regulatory T cells (Tregs) while high concentrations of IL-2 fuel inflammatory responses. Recently, we showed that the non-beta IL-2 SYNTHORIN molecule SAR444336 (SAR’336) can bypass the induction of autoimmune and inflammatory responses by increasing its reliance on IL-2 receptor α chain subunit (CD25) to provide a bona fide IL-2 signal selectively to Tregs, making it an attractive approach for the control of autoimmunity. In this report, we further demonstrate that SAR’336 can support non-beta IL-2 signaling in murine Tregs and limit NK and CD8+ T cells’ proliferation and function. Using a murine model of spontaneous type 1 diabetes, we showed that the administration of SAR’336 slows the development of disease in mice by decreasing the degree of insulitis through the expansion of antigen-specific Tregs over Th1 cells in pancreatic islets. Specifically, SAR’336 promoted the differentiation of IL-33–responsive (ST2+), IL-10–producing GATA3+ Tregs over other Treg subsets in the pancreas, demonstrating the ability of this molecule to further orchestrate Treg adaptation. These results offer insight into the capacity of SAR’336 to generate highly specialized, tissue-localized Tregs that promote restoration of homeostasis during ongoing autoimmune disease.
Authors
Fernando Alvarez, Nicole V. Acuff, Glenn M. La Muraglia II, Nazila Sabri, Marcos E. Milla, Jill M. Mooney, Matthew F. Mackey, Mark Peakman, Ciriaco A. Piccirillo
Abstract
In systemic lupus erythematosus (lupus), environmental effects acting within a permissive genetic background lead to autoimmune dysregulation. Dysfunction of CD4+ T cells contributes to pathology by providing help to autoreactive B and T cells, and CD4+ T cell dysfunction coincides with altered DNA methylation and histone modifications of select gene loci. However, chromatin accessibility states of distinct T cell subsets and mechanisms driving heterogeneous chromatin states across patients remain poorly understood. We defined the transcriptome and epigenome of multiple CD4+ T cell populations from lupus patients and healthy individuals. Most lupus patients, regardless of disease activity, had enhanced chromatin accessibility bearing hallmarks of inflammatory cytokine signals. Single cell approaches revealed that chromatin changes extended to naive CD4+ T cells; uniformly affecting naive subpopulations. Transcriptional data and cellular and protein analyses suggested that the TNF family members, TNFɑ, LIGHT, and TWEAK, were linked to observed molecular changes and the altered lupus chromatin state. However, we identified a patient subgroup prescribed angiotensin receptor blockers (ARBs) which lacked TNF-linked lupus chromatin accessibility features. These data raise questions about the role of lupus-associated chromatin changes in naive CD4+ T cell activation and differentiation and implicate ARBs in the regulation of disease-driven epigenetic states.
Authors
Andrew P. Hart, Jonathan J. Kotzin, Steffan W. Schulz, Jonathan S. Dunham, Alison L. Keenan, Joshua F. Baker, Andrew D. Wells, Daniel P. Beiting, Terri M. Laufer
Abstract
Rheumatoid arthritis (RA) is one of the most common autoimmune disorders and is characterized by exacerbated joint inflammation that can lead to tissue remodeling and autoantigen generation. Despite the well-documented accumulation of the serine protease Granzyme B (GzmB) in the biospecimens of patients with RA, little is understood pertaining to its role in pathobiology. In the present study Tenascin-C (TN-C), a large extracellular matrix glycoprotein and an endogenous trigger of inflammation, was identified as a substrate for GzmB in RA. GzmB cleaves TN-C in vitro to generate three fragments: a 130 kDa fragment that remains anchored to the matrix, and two 70 and 30 kDa fragments that are released and solubilized. Mass spectrometry results seem to indicate that the 30 kDa fragment generated by GzmB most likely contains TN-C pro-inflammatory C-terminal fibrinogen-like domain. Soluble levels of GzmB and TN-C are also significantly elevated in the synovial fluids of RA patients compared to healthy controls, with two 70 kDa and 30 kDa soluble TN-C fragments detectable in the synovial fluids of RA patients. The molecular weights of these fragments coincide with those generated by GzmB in vitro, suggesting that GzmB also cleaves TN-C in RA patients. Granzyme K (GzmK), another member of the granzyme family, also cleaves TN-C in vitro. However, unlike GzmB, the molecular weights of TN-C fragments generated by GzmK in vitro do not correspond to fragments identified in patients. Altogether, our data supports the contribution of Granzyme B, but not Granzyme K, to RA through the cleavage of Tenascin-C.
Authors
Alexandre Aubert, Amy Liu, Martin Kao, Jenna Goeres, Katlyn C. Richardson, Lorenz Nierves, Karen Jung, Layla Nabai, Hongyan Zhao, Gertraud Orend, Roman Krawetz, Philipp F. Lange, Alastair Younger, Jonathan Chan, David J. Granville
Abstract
Systemic sclerosis (SSc) is characterized by immune system failure, vascular insult, autoimmunity, and tissue fibrosis. Transforming growth factor-beta (TGF-β) is a crucial mediator of persistent myofibroblast activation and aberrant extracellular matrix production in SSc. The factors responsible for this are unknown. By amplifying pattern recognition receptor signaling, Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) is implicated in multiple inflammatory conditions. In this study, we used novel ligand-independent TREM-1 inhibitors in order to investigate the pathogenic role of TREM-1 in SSc, using preclinical models of fibrosis, and explanted SSc skin fibroblasts. Selective pharmacological TREM-1 blockade prevented and reversed skin fibrosis induced by bleomycin in mice and mitigated constitutive collagen synthesis and myofibroblast features in SSc fibroblasts in vitro. Our results implicate aberrantly activated TREM-1 signaling in SSc pathogenesis, identify a unique approach to TREM-1 blockade, and suggest a potential therapeutic benefit for TREM-1 inhibition.
Authors
Swarna Bale, Priyanka Verma, Bharath Yalavarthi, Matija Bajželj, Syed A.M. Hasan, Jenna N. Silverman, Katherine Broderick, Kris A. Shah, Timothy Hamill, Dinesh Khanna, Alexander B. Sigalov, Swati Bhattacharyya, John Varga
Abstract
Rheumatoid Arthritis (RA) is an immune-mediated, chronic inflammatory condition. With modern therapeutics and evidence-based management strategies, achieving sustained remission is increasingly common. To prevent complications associated with prolonged use of immunosuppressants, drug tapering or withdrawal is recommended. However, due to the lack of tools that define immunological remission, disease flares are frequent, highlighting the need for a more precision medicine-based approach. Utilising high dimensional phenotyping platforms, we set out to define peripheral blood immunological signatures of sustained remission in RA. We identified that CD8+CD57+KIR2DL1+ NK cells are associated with sustained remission. Functional studies uncovered an NK cell subset characterized by normal degranulation responses and reduced pro-inflammatory cytokine expression, which was elevated in sustained remission. Furthermore, flow cytometric analysis of NK cells from synovial fluid combined with interrogation of a publicly available single cell RNA-seq dataset of synovial tissue from active RA identified a deficiency of the phenotypic characteristics associated with this NK cell remission signature. In summary, we have uncovered a novel RA remission signature associated with compositional changes in NK cell phenotype and function that has implications for understanding the impact of sustained remission on host immunity and distinct features which may define operational tolerance in RA.
Authors
Carl Coyle, Margaret Ma, Yann Abraham, Christopher B. Mahony, Kathryn Steel, Catherine Simpson, Nadia Guerra, Adam P. Croft, Stephen Rapecki, Andrew Cope, Rowann Bowcutt, Esperanza Perucha
Abstract
Sjögren’s disease is a chronic autoimmune disease characterized by symptoms of oral and ocular dryness and extra-glandular manifestations. Mouth dryness is not only due to reduced saliva volume but also to alterations in the quality of salivary mucins in these patients. Mucins play a leading role in mucosa hydration and protection, where sulfated and sialylated oligosaccharides retain water molecules at the epithelial surface. The correct localization of glycosyltransferases and sulfotransferases within the Golgi apparatus determines adequate O-glycosylation and sulfation of mucins, which depends on specific golgins that tether enzyme-bearing vesicles. Here, we show that a golgin called Giantin is mislocalized in salivary glands from patients with Sjögren’s disease and forms protein complexes with Gal3-O-sulfotransferases (Gal3STs), which change their localization in Giantin knockout and knockdown cells. Our results suggest that Giantin could tether Gal3ST-bearing vesicles and that its altered localization could affect Gal3ST activity, explaining the decreased sulfation of MUC5B observed in salivary glands from patients with Sjögren’s disease.
Authors
Matilde Nuñez, Patricia Carvajal, Sergio Aguilera, María-José Barrera, Soledad Matus, Alicia Couto, Malena Landoni, Gaelle Boncompain, Sergio González, Claudio Molina, Karina Pino, Sebastián Indo, Lourdes Figueroa, María-Julieta González, Isabel Castro
Abstract
Graves' disease (GD) is an autoimmune condition that can progress to Graves' Ophthalmopathy (GO), leading to irreversible damage to orbital tissues and potential blindness. The pathogenic mechanism is not fully understood. In this study, we conducted single-cell multi-omics analyses on healthy individuals, GD patients without GO, newly diagnosed GO patients, and treated GO patients. Our findings revealed gradual systemic inflammation during GO progression, marked by overactivation of cytotoxic effector T cell subsets, and expansion of specific T cell receptor clones. Importantly, we observed a decline in the immunosuppressive function of activated regulatory T cells (aTreg) accompanied by a cytotoxic phenotypic transition. In vitro experiments revealed that dysfunction and transition of GO-autoreactive Treg were regulated by the yinyang1 (YY1) upon secondary stimulation of thyroid stimulating hormone receptor (TSHR) under inflammatory conditions. Furthermore, adoptive transfer experiments of GO mouse model confirmed infiltration of these cytotoxic Treg into the orbital lesion tissues. Notably, these cells were found to upregulate inflammation and promote pathogenic fibrosis of orbital fibroblasts (OFs). Our results revealed the dynamic changes in immune landscape during GO progression and provided novel insights into the instability and phenotypic transition of Treg, offering potential targets for therapeutic intervention and prevention of autoimmune diseases.
Authors
Zhong Liu, Shurui Ke, Zhuoxing Shi, Ming Zhou, Li Sun, Qihang Sun, Bing Xiao, Dongliang Wang, Yanjing Huang, Jinshan Lin, Huishi Wang, Qikai Zhang, Caineng Pan, Xuanwei Liang, Rongxin Chen, Zhen Mao, Xianchai Lin
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