Autoimmunity
Abstract
Given the global surge in autoimmune diseases, it is critical to evaluate emerging therapeutic interventions. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leveraged advances in programmable-phage immunoprecipitation (PhIP-Seq) methodology to explore the modulation, or lack thereof, of autoantibody profiles, proteome-wide, in both health and disease. Using a custom set of over 730,000 human derived peptides, we demonstrated that each individual, regardless of disease state, possesses a distinct and complex constellation of autoreactive antibodies. For each individual, the set of resulting autoreactivites constituted a unique immunological fingerprint, or "autoreactome,” that was remarkably stable over years. Using the autoreactome as a primary output, we evaluated the relative effectiveness of various immunomodulatory therapies in altering autoantibody repertoires. We found that therapies targeting B-Cell Maturation Antigen (BCMA) profoundly altered an individual’s autoreactome, while anti-CD19 and CD20 therapies had minimal effects. These data both confirm that the autoreactome is comprised of autoantibodies secreted by plasma cells, and strongly suggest that BCMA or other plasma cell targeting therapies may be highly effective in treating currently refractory autoantibody mediated diseases.
Authors
Aaron Bodansky, David J.L. Yu, Alysa N. Rallistan, Muge Kalaycioglu, Jim Boonyaratanakornkit, Damian J. Green, Jordan Gauthier, Cameron J. Turtle, Kelsey C. Zorn, Brian O'Donovan, Caleigh Mandel-Brehm, James Asaki, Hannah Kortbawi, Andrew F. Kung, Elze Rackaityte, Chung-Yu Wang, Aditi Saxena, Kimberly de Dios, Gianvito Masi, Richard J. Nowak, Kevin C. O'Connor, Hao Li, Valentina E. Diaz, Rowan Saloner, Kaitlin B. Casaletto, Eva Q. Gontrum, Brandon J. Chan, Joel H. Kramer, Michael R. Wilson, Paul J. Utz, Joshua A. Hill, Shaun W. Jackson, Mark S. Anderson, Joseph L. DeRisi
Abstract
Authors
Jarmila Stremenova Spegarova, Praisoody Sinnappurajar, Dalila Al Julandani, Rokas Navickas, Helen Griffin, Manisha Ahuja, Angela Grainger, Katie Livingstone, Gillian I. Rice, Fraser Sutherland, Corinne Hayes, Simon Parke, Lewis Pang, Marion R. Roderick, Mary Slatter, Yanick Crow, Athimalaipet V. Ramanan, Sophie Hambleton
Abstract
Nuclear factor of activated T-cells 5 (NFAT5), an osmo-sensitive transcription factor, can be activated by isotonic stimuli, such as infection. It remains unclear, however, whether NFAT5 is required for damage-associated molecular pattern–triggered (DAMP-triggered) inflammation and immunity. Here, we found that several DAMPs increased NFAT5 expression in macrophages. In particular, serum amyloid A (SAA), primarily generated by the liver, substantially upregulated NFAT5 expression and activity through TLR2/4-JNK signalling pathway. Moreover, the SAA-TLR2/4-NFAT5 axis promoted migration and chemotaxis of macrophages in an IL-6– and chemokine ligand 2–dependent (CCL2-dependent) manner in vitro. Intraarticular injection of SAA markedly accelerated macrophage infiltration and arthritis progression in mice. By contrast, genetic ablation of NFAT5 or TLR2/4 rescued the pathology induced by SAA, confirming the SAA-TLR2/4-NFAT5 axis in vivo. Myeloid-specific depletion of NFAT5 also attenuated SAA-accelerated arthritis. Of note, inflammatory arthritis in mice strikingly induced SAA overexpression in the liver. Conversely, forced overexpression of the SAA gene in the liver accelerated joint damage, indicating that the liver contributes to bolstering chronic inflammation at remote sites by secreting SAA. Collectively, this study underscores the importance of the SAA-TLR2/4-NFAT5 axis in innate immunity, suggesting that acute phase reactant SAA mediates mutual interactions between liver and joints and ultimately aggravates chronic arthritis by enhancing macrophage activation.
Authors
Meiling Li, Yu-Mi Kim, Jung Hee Koh, Jihyun Park, H. Moo Kwon, Jong-Hwan Park, Jingchun Jin, Youngjae Park, Donghyun Kim, Wan-Uk Kim
Abstract
Altered tryptophan catabolism has been identified in inflammatory diseases like rheumatoid arthritis (RA) and spondyloarthritis (SpA), but the causal mechanisms linking tryptophan metabolites to disease are unknown. Using the collagen-induced arthritis (CIA) model we identified alterations in tryptophan metabolism, and specifically indole, that correlated with disease. We demonstrated that both bacteria and dietary tryptophan were required for disease, and indole supplementation was sufficient to induce disease in their absence. When mice with CIA on a low-tryptophan diet were supplemented with indole, we observed significant increases in serum IL-6, TNF, and IL-1β; splenic RORγt+CD4+ T cells and ex vivo collagen-stimulated IL-17 production; and a pattern of anti-collagen antibody isotype switching and glycosylation that corresponded with increased complement fixation. IL-23 neutralization reduced disease severity in indole-induced CIA. Finally, exposure of human colon lymphocytes to indole increased expression of genes involved in IL-17 signaling and plasma cell activation. Altogether, we propose a mechanism by which intestinal dysbiosis during inflammatory arthritis results in altered tryptophan catabolism, leading to indole stimulation of arthritis development. Blockade of indole generation may present a unique therapeutic pathway for RA and SpA.
Authors
Brenda J. Seymour, Brandon Trent, Brendan E. Allen, Adam J. Berlinberg, Jimmy Tangchittsumran, Widian K. Jubair, Meagan E. Chriswell, Sucai Liu, Alfredo Ornelas, Andrew Stahly, Erica E. Alexeev, Alexander S. Dowdell, Sunny L. Sneed, Sabrina Fechtner, Jennifer M. Kofonow, Charles E. Robertson, Stephanie M. Dillon, Cara C. Wilson, Robert M. Anthony, Daniel N. Frank, Sean P. Colgan, Kristine A. Kuhn
Abstract
The suppression mechanism of Tregs remains an intensely investigated topic. As our focus has shifted toward a model centered on indirect inhibition of DCs, a universally applicable effector mechanism controlled by the transcription factor forkhead box P3 (Foxp3) expression has not been found. Here, we report that Foxp3 blocked the transcription of ER Ca2+-release channel ryanodine receptor 2 (RyR2). Reduced RyR2 shut down basal Ca2+ oscillation in Tregs, which reduced m-calpain activities that are needed for T cells to disengage from DCs, suggesting a persistent blockage of DC antigen presentation. RyR2 deficiency rendered the CD4+ T cell pool immune suppressive and caused it to behave in the same manner as Foxp3+ Tregs in viral infection, asthma, hypersensitivity, colitis, and tumor development. In the absence of Foxp3, Ryr2-deficient CD4+ T cells rescued the systemic autoimmunity associated with scurfy mice. Therefore, Foxp3-mediated Ca2+ signaling inhibition may be a central effector mechanism of Treg immune suppression.
Authors
Xiaobo Wang, Shuang Geng, Junchen Meng, Ning Kang, Xinyi Liu, Yanni Xu, Huiyun Lyu, Ying Xu, Xun Xu, Xinrong Song, Bin Zhang, Xin Wang, Nuerdida Nuerbulati, Ze Zhang, Di Zhai, Xin Mao, Ruya Sun, Xiaoting Wang, Ruiwu Wang, Jie Guo, S.R. Wayne Chen, Xuyu Zhou, Tie Xia, Hai Qi, Xiaoyu Hu, Yan Shi
Abstract
C1q/TNF related protein 4 (CTRP4) is generally thought to be released extracellularly and plays a critical role in energy metabolism and protecting against sepsis. However, its physiological functions in autoimmune diseases have not been thoroughly explored. In this study, we demonstrated that Th17 cell-associated experimental autoimmune encephalomyelitis was greatly exacerbated in Ctrp4-/- mice compared to WT mice due to increased Th17 cell infiltration. The absence of Ctrp4 promoted the differentiation of naïve CD4+ T cells into Th17 cells in vitro. Mechanistically, CTRP4 interferes with the interaction between IL-6 and IL-6R by directly competing to bind with IL-6R leading to suppression of IL-6-induced activation of STAT3 pathway. Furthermore, the administration of recombinant CTRP4 protein ameliorated the disease symptoms. In conclusion, our results indicate that CTRP4, as an endogenous regulator of the IL-6 receptor signaling pathway, may be a potential therapeutic intervention for Th17 driven-autoimmune diseases.
Authors
Lulu Cao, Jinhai Deng, Wei Chen, Minwei He, Ning Zhao, He Huang, Lu Ling, Qi Li, Xiaoxin Zhu, Lu Wang
Abstract
Autoimmune polyendocrine syndrome type 1 (APS-1) is caused by mutations in the autoimmune regulator (AIRE) gene. Most patients present with severe chronic mucocutaneous candidiasis and organ-specific autoimmunity from early childhood, but the clinical picture is highly variable. AIRE is crucial for negative selection of T cells, and scrutiny of different patient mutations has previously highlighted many of its molecular mechanisms. In patients with a milder adult-onset phenotype sharing a mutation in the canonical donor splice site of intron 7 (c.879+1G>A), both the predicted altered splicing pattern with loss of exon 7 (AireEx7–/–) and normal full-length AIRE mRNA were found, indicating leaky rather than abolished mRNA splicing. Analysis of a corresponding mouse model demonstrated that the AireEx7–/– mutant had dramatically impaired transcriptional capacity of tissue-specific antigens in medullary thymic epithelial cells but still retained some ability to induce gene expression compared with the complete loss-of-function AireC313X–/– mutant. Our data illustrate an association between AIRE activity and the severity of autoimmune disease, with implications for more common autoimmune diseases associated with AIRE variants, such as primary adrenal insufficiency, pernicious anemia, type 1 diabetes, and rheumatoid arthritis.
Authors
Bergithe Eikeland Oftedal, Amund Holte Berger, Øyvind Bruserud, Yael Goldfarb, Andre Sulen, Lars Breivik, Alexander Hellesen, Shifra Ben-Dor, Rebecca Haffner-Krausz, Per M. Knappskog, Stefan Johansson, Anette S.B. Wolff, Eirik Bratland, Jakub Abramson, Eystein Sverre Husebye
Abstract
Authors
Alisa A. Mueller, Takanori Sasaki, Joshua W. Keegan, Jennifer P. Nguyen, Alec Griffith, Alice M. Horisberger, Thomas Licata, Elizabeth Fieg, Ye Cao, Mehreen Elahee, Kathryne E. Marks, Daimon P. Simmons, Lauren C. Briere, Laurel A. Cobban, J. Carl Pallais, Frances A. High, Melissa A. Walker, Jenny J. Linnoila, Jeffrey A. Sparks, V. Michael Holers, Karen H. Costenbader, Undiagnosed Diseases Network (UDN), David A. Sweetser, Joel B. Krier, Joseph Loscalzo, James A. Lederer, Deepak A. Rao
Abstract
A20 is a ubiquitin-modifying protein that negatively regulates NF-κB signaling. Mutations in A20/TNFAIP3 are associated with a variety of autoimmune diseases, including multiple sclerosis (MS). We found that deletion of A20 in central nervous system (CNS) endothelial cells (ECs) enhances experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. A20∆CNS-EC mice showed increased numbers of CNS-infiltrating immune cells during neuroinflammation and in the steady state. While the integrity of the blood-brain barrier (BBB) was not impaired, we observed a strong activation of CNS-ECs in these mice, with dramatically increased levels of the adhesion molecules ICAM-1 and VCAM-1. We discovered ICOSL as adhesion molecule expressed by A20-deficient CNS-ECs. Silencing of ICOSL in CNS microvascular ECs partly reversed the phenotype of A20∆CNS-EC mice without reaching statistical significance and delayed the onset of EAE symptoms in wildtype mice. In addition, blocking of ICOSL on primary mouse brain microvascular endothelial cells (pMBMECs) impaired the adhesion of T cells in vitro. Taken together, we here propose that CNS EC-ICOSL contributes to the firm adhesion of T cells to the BBB, promoting their entry into the CNS and eventually driving neuroinflammation.
Authors
Lisa Johann, Sasha Soldati, Kristin Müller, Josephine Lampe, Federico Marini, Matthias Klein, Eva Schramm, Nathalie Ries, Carsten Schelmbauer, Ilaria Palagi, Khalad Karram, Julian C. Assmann, Mahtab A. Khan, Jan Wenzel, Mirko H.H. Schmidt, Jakob Körbelin, Dirk Schlüter, Geert van Loo, Tobias Bopp, Britta Engelhardt, Markus Schwaninger, Ari Waisman
Abstract
Regulatory T cells (Tregs) are instrumental in maintaining immune tolerance and preventing destructive autoimmunity, but how heterogeneous Treg populations are established remains largely unknown. Here, we show that Zfp335 deletion in Tregs failed to differentiate into effector Tregs (eTregs) and lose Treg-suppressive function and that KO mice exhibited early-onset lethal autoimmune inflammation with unrestricted activation of conventional T cells. Single-cell RNA-Seq analyses revealed that Zfp335-deficient Tregs lacked a eTreg population and showed dramatic accumulation of a dysfunctional Treg subset. Mechanistically, Zfp335-deficient Tregs displayed reduced oxidative phosphorylation and dysfunctional mitochondrial activity. Further studies revealed that Zfp335 controlled eTreg differentiation by regulating fatty acid oxidation (FAO) through direct targeting of the FAO enzyme Hadha. Importantly, we demonstrate a positive correlation between ZNF335 and HADHA expression in human eTregs. Our findings reveal that Zfp335 controls FAO-driven eTreg differentiation to establish immune tolerance.
Authors
Xin Wang, Lina Sun, Biao Yang, Wenhua Li, Cangang Zhang, Xiaofeng Yang, Yae Sun, Xiaonan Shen, Yang Gao, Bomiao Ju, Yafeng Gao, Dan Liu, Jiapeng Song, Xiaoxuan Jia, Yanhong Su, Anjun Jiao, Haiyan Liu, Lianjun Zhang, Lan He, Lei Lei, WanJun Chen, Baojun Zhang
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ISSN: 0021-9738 (print), 1558-8238 (online)