Type 1 diabetes (T1D) patients show abnormalities in early B cell tolerance checkpoints, resulting in the accumulation of large numbers of autoreactive B cells in their blood. Treatment with rituximab, an anti-CD20 mAb that depletes B cells, has been shown to preserve β cell function in T1D patients and improve other autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. However, it remains largely unknown how anti–B cell therapy thwarts autoimmunity in these pathologies. Here, we analyzed the reactivity of Abs expressed by single, mature naive B cells from 4 patients with T1D before and 52 weeks after treatment to determine whether rituximab resets early B cell tolerance checkpoints. We found that anti–B cell therapy did not alter the frequencies of autoreactive and polyreactive B cells, which remained elevated in the blood of all patients after rituximab treatment. Moreover, the limited proliferative history of autoreactive B cells after treatment revealed that these clones were newly generated B cells and not self-reactive B cells that had escaped depletion and repopulated the periphery through homeostatic expansion. We conclude that anti–B cell therapy may provide a temporary dampening of autoimmune processes through B cell depletion. However, repletion with autoreactive B cells may explain the relapse that occurs in many autoimmune patients after anti–B cell therapy.
Nicolas Chamberlain, Christopher Massad, Tyler Oe, Tineke Cantaert, Kevan C. Herold, Eric Meffre, the Type 1 Diabetes TrialNet Pathway to Prevention Study Group
Vascular oxidative injury accompanies many common conditions associated with hypertension. In the present study, we employed mouse models with excessive vascular production of ROS (tgsm/p22phox mice, which overexpress the NADPH oxidase subunit p22
Jing Wu, Mohamed A. Saleh, Annet Kirabo, Hana A. Itani, Kim Ramil C. Montaniel, Liang Xiao, Wei Chen, Raymond L. Mernaugh, Hua Cai, Kenneth E. Bernstein, Jörg J. Goronzy, Cornelia M. Weyand, John A. Curci, Natalia R. Barbaro, Heitor Moreno, Sean S. Davies, L. Jackson Roberts II, Meena S. Madhur, David G. Harrison
Parasitic helminth worms, such as
Leticia Monin, Kristin L. Griffiths, Wing Y. Lam, Radha Gopal, Dongwan D. Kang, Mushtaq Ahmed, Anuradha Rajamanickam, Alfredo Cruz-Lagunas, Joaquín Zúñiga, Subash Babu, Jay K. Kolls, Makedonka Mitreva, Bruce A. Rosa, Rosalio Ramos-Payan, Thomas E. Morrison, Peter J. Murray, Javier Rangel-Moreno, Edward J. Pearce, Shabaana A. Khader
Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develop autoimmunity to FHL1, which is a muscle-specific protein. Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases or muscular dystrophies were largely anti-FHL1 negative. Anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. FHL1 showed an altered expression pattern, with focal accumulation in the muscle fibers of autoantibody-positive patients compared with a homogeneous expression in anti-FHL1–negative patients and healthy controls. We determined that FHL1 is a target of the cytotoxic protease granzyme B, indicating that the generation of FHL1 fragments may initiate FHL1 autoimmunity. Moreover, immunization of myositis-prone mice with FHL1 aggravated muscle weakness and increased mortality, suggesting a direct link between anti-FHL1 responses and muscle damage. Together, our findings provide evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, these results indicate that anti-FHL1 autoantibodies in peripheral blood have promising potential as a biomarker to identify a subset of severe IIM.
Inka Albrecht, Cecilia Wick, Åsa Hallgren, Anna Tjärnlund, Kanneboyina Nagaraju, Felipe Andrade, Kathryn Thompson, William Coley, Aditi Phadke, Lina-Marcela Diaz-Gallo, Matteo Bottai, Inger Nennesmo, Karine Chemin, Jessica Herrath, Karin Johansson, Anders Wikberg, A. Jimmy Ytterberg, Roman A. Zubarev, Olof Danielsson, Olga Krystufkova, Jiri Vencovsky, Nils Landegren, Marie Wahren-Herlenius, Leonid Padyukov, Olle Kämpe, Ingrid E. Lundberg
A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt. In stark contrast to Th17 cells and M1 macrophages, high salt blunted the alternative activation of BM-derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages. Salt-induced reduction of M(IL-4+IL-13) activation was not associated with increased polarization toward a proinflammatory M1 phenotype. In vitro, high salt decreased the ability of M(IL-4+IL-13) macrophages to suppress effector T cell proliferation. Moreover, mice fed a high salt diet exhibited reduced M2 activation following chitin injection and delayed wound healing compared with control animals. We further identified a high salt–induced reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR signaling, which indicates a mechanism by which NaCl inhibits full M2 macrophage activation. Collectively, this study provides evidence that high salt reduces noninflammatory innate immune cell activation and may thus lead to an overall imbalance in immune homeostasis.
Katrina J. Binger, Matthias Gebhardt, Matthias Heinig, Carola Rintisch, Agnes Schroeder, Wolfgang Neuhofer, Karl Hilgers, Arndt Manzel, Christian Schwartz, Markus Kleinewietfeld, Jakob Voelkl, Valentin Schatz, Ralf A. Linker, Florian Lang, David Voehringer, Mark D. Wright, Norbert Hubner, Ralf Dechend, Jonathan Jantsch, Jens Titze, Dominik N. Müller
Autosomal recessive mutations in proteasome subunit β 8 (
Anja Brehm, Yin Liu, Afzal Sheikh, Bernadette Marrero, Ebun Omoyinmi, Qing Zhou, Gina Montealegre, Angelique Biancotto, Adam Reinhardt, Adriana Almeida de Jesus, Martin Pelletier, Wanxia L. Tsai, Elaine F. Remmers, Lela Kardava, Suvimol Hill, Hanna Kim, Helen J. Lachmann, Andre Megarbane, Jae Jin Chae, Jilian Brady, Rhina D. Castillo, Diane Brown, Angel Vera Casano, Ling Gao, Dawn Chapelle, Yan Huang, Deborah Stone, Yongqing Chen, Franziska Sotzny, Chyi-Chia Richard Lee, Daniel L. Kastner, Antonio Torrelo, Abraham Zlotogorski, Susan Moir, Massimo Gadina, Phil McCoy, Robert Wesley, Kristina Rother, Peter W. Hildebrand, Paul Brogan, Elke Krüger, Ivona Aksentijevich, Raphaela Goldbach-Mansky
FOXP3+ Tregs are central for the maintenance of self-tolerance and can be defective in autoimmunity. In multiple sclerosis and type-1 diabetes, dysfunctional self-tolerance is partially mediated by a population of IFNγ-secreting Tregs. It was previously reported that increased NaCl concentrations promote the induction of proinflammatory Th17 cells and that high-salt diets exacerbate experimental models of autoimmunity. Here, we have shown that increasing NaCl, either in vitro or in murine models via diet, markedly impairs Treg function. NaCl increased IFNγ secretion in Tregs, and reducing IFNγ — either by neutralization with anti-IFNγ antibodies or shRNA-mediated knockdown — restored suppressive activity in Tregs. The heightened IFNγ secretion and loss of Treg function were mediated by the serum/glucocorticoid-regulated kinase (SGK1). A high-salt diet also impaired human Treg function and was associated with the induction of IFNγ-secreting Tregs in a xenogeneic graft-versus-host disease model and in adoptive transfer models of experimental colitis. Our results demonstrate a putative role for an environmental factor that promotes autoimmunity by inducing proinflammatory responses in CD4 effector cells and Treg pathways.
Amanda L. Hernandez, Alexandra Kitz, Chuan Wu, Daniel E. Lowther, Donald M. Rodriguez, Nalini Vudattu, Songyan Deng, Kevan C. Herold, Vijay K. Kuchroo, Markus Kleinewietfeld, David A. Hafler
Patients with mutations of the recombination-activating genes (
Jolan E. Walter, Lindsey B. Rosen, Krisztian Csomos, Jacob M. Rosenberg, Divij Mathew, Marton Keszei, Boglarka Ujhazi, Karin Chen, Yu Nee Lee, Irit Tirosh, Kerry Dobbs, Waleed Al-Herz, Morton J. Cowan, Jennifer Puck, Jack J. Bleesing, Michael S. Grimley, Harry Malech, Suk See De Ravin, Andrew R. Gennery, Roshini S. Abraham, Avni Y. Joshi, Thomas G. Boyce, Manish J. Butte, Kari C. Nadeau, Imelda Balboni, Kathleen E. Sullivan, Javeed Akhter, Mehdi Adeli, Reem A. El-Feky, Dalia H. El-Ghoneimy, Ghassan Dbaibo, Rima Wakim, Chiara Azzari, Paolo Palma, Caterina Cancrini, Kelly Capuder, Antonio Condino-Neto, Beatriz T. Costa-Carvalho, Joao Bosco Oliveira, Chaim Roifman, David Buchbinder, Attila Kumanovics, Jose Luis Franco, Tim Niehues, Catharina Schuetz, Taco Kuijpers, Christina Yee, Janet Chou, Michel J. Masaad, Raif Geha, Gulbu Uzel, Rebecca Gelman, Steven M. Holland, Mike Recher, Paul J. Utz, Sarah K. Browne, Luigi D. Notarangelo
Mucosal-associated invariant T cells (MAITs) have potent antimicrobial activity and are abundant in humans (5%–10% in blood). Despite strong evolutionary conservation of the invariant TCR-α chain and restricting molecule MR1, this population is rare in laboratory mouse strains (≈0.1% in lymphoid organs), and lack of an appropriate mouse model has hampered the study of MAIT biology. Herein, we show that MAITs are 20 times more frequent in clean wild-derived inbred CAST/EiJ mice than in C57BL/6J mice. Increased MAIT frequency was linked to one CAST genetic trait that mapped to the TCR-α locus and led to higher usage of the distal Vα segments, including Vα19. We generated a MAIThi congenic strain that was then crossed to a transgenic
Yue Cui, Katarzyna Franciszkiewicz, Yvonne K. Mburu, Stanislas Mondot, Lionel Le Bourhis, Virginie Premel, Emmanuel Martin, Alexandra Kachaner, Livine Duban, Molly A. Ingersoll, Sylvie Rabot, Jean Jaubert, Jean-Pierre De Villartay, Claire Soudais, Olivier Lantz
Polarized activation of adipose tissue macrophages (ATMs) is crucial for maintaining adipose tissue function and mediating obesity-associated cardiovascular risk and metabolic abnormalities; however, the regulatory network of this key process is not well defined. Here, we identified a PPARγ/microRNA-223 (miR-223) regulatory axis that controls macrophage polarization by targeting distinct downstream genes to shift the cellular response to various stimuli. In BM-derived macrophages, PPARγ directly enhanced miR-223 expression upon exposure to Th2 stimuli. ChIP analysis, followed by enhancer reporter assays, revealed that this effect was mediated by PPARγ binding 3 PPARγ regulatory elements (PPREs) upstream of the pre–miR-223 coding region. Moreover, deletion of miR-223 impaired PPARγ-dependent macrophage alternative activation in cells cultured ex vivo and in mice fed a high-fat diet. We identified
Wei Ying, Alexander Tseng, Richard Cheng-An Chang, Andrew Morin, Tyler Brehm, Karen Triff, Vijayalekshmi Nair, Guoqing Zhuang, Hui Song, Srikanth Kanameni, Haiqing Wang, Michael C. Golding, Fuller W. Bazer, Robert S. Chapkin, Stephen Safe, Beiyan Zhou