Autoimmune diseases, such as psoriasis and arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals, such as danger-associated molecular patterns (DAMPs), are indispensable for manifestation of local inflammation. S100A8/S100A9 complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP activities are barely understood. We now unravel for the first time, to our knowledge, a mechanism of autoinhibition in mice and humans restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry, and targeted mutations, we identified specific peptide sequences within the second calcium-binding EF-hands triggering TLR4/MD2-dependent inflammation. These binding sites are free when S100A8/S100A9 heterodimers are released at sites of inflammation. Subsequently, S100A8/S100A9 activities are locally restricted by calcium-induced (S100A8/S100A9)2 tetramer formation hiding the TLR4/MD2-binding site within the tetramer interphase, thus preventing undesirable systemic effects. Loss of this autoinhibitory mechanism in vivo results in TNF-α–driven fatal inflammation, as shown by lack of tetramer formation in crossing S100A9–/– mice with 2 independent TNF-α–transgene mouse strains. Since S100A8/S100A9 is the most abundant DAMP in many inflammatory diseases, specifically blocking the TLR4-binding site of active S100 dimers may represent a promising approach for local suppression of inflammatory diseases, avoiding systemic side effects.
Thomas Vogl, Athanasios Stratis, Viktor Wixler, Tom Völler, Sumita Thurainayagam, Selina K. Jorch, Stefanie Zenker, Alena Dreiling, Deblina Chakraborty, Mareike Fröhling, Peter Paruzel, Corinna Wehmeyer, Sven Hermann, Olympia Papantonopoulou, Christiane Geyer, Karin Loser, Michael Schäfers, Stephan Ludwig, Monika Stoll, Tomas Leanderson, Joachim L. Schultze, Simone König, Thomas Pap, Johannes Roth
Major histocompatibility (MHC) class II molecules are strongly associated with many autoimmune disorders. In type 1 diabetes, the DQ8 molecule is common, confers significant disease risk and is involved in disease pathogenesis. We hypothesized blocking DQ8 antigen presentation would provide therapeutic benefit by preventing recognition of self-peptides by pathogenic T cells. We used the crystal structure of DQ8 to select drug-like small molecules predicted to bind structural pockets in the MHC antigen-binding cleft. A limited number of the predicted compounds inhibited DQ8 antigen presentation in vitro with one compound preventing insulin autoantibody production and delaying diabetes onset in an animal model of spontaneous autoimmune diabetes. An existing drug of similar structure, methyldopa, specifically blocked DQ8 in recent-onset patients with type 1 diabetes along with reducing inflammatory T cell responses toward insulin, highlighting the relevance of blocking disease-specific MHC class II antigen presentation to treat autoimmunity.
David A. Ostrov, Aimon Alkanani, Kristen A. McDaniel, Stephanie Case, Erin E. Baschal, Laura Pyle, Samuel Ellis, Bernadette Pöllinger, Katherine J. Seidl, Viral N. Shah, Satish K. Garg, Mark A. Atkinson, Peter A. Gottlieb, Aaron W. Michels
Lupus nephritis (LN) often results in progressive renal dysfunction. The inactive Rhomboid 2 (iRhom2) is a newly identified key regulator of A disintegrin and metalloprotease 17 (ADAM17), whose substrates, such as TNF-α and heparin-binding EGF (HB-EGF), have been implicated in the pathogenesis of chronic kidney disease. Here we demonstrate that deficiency of iRhom2 protects the lupus-prone Fcgr2b–/– mice from developing severe kidney damage without altering anti-double stranded (ds) DNA Ab production, by simultaneously blocking the HB-EGF/EGFR and the TNF-α signaling in the kidney tissues. Unbiased transcriptome profiling of kidneys and kidney macrophages revealed that TNF-α and HB-EGF/EGFR signaling pathways are highly upregulated in Fcgr2b–/– mice; alterations that were diminished in the absence of iRhom2. Pharmacological blockade of either TNF-α or EGFR signaling protected Fcgr2b–/– mice from severe renal damage. Finally, kidneys from LN patients showed increased iRhom2 and HB-EGF expression, with interstitial HB-EGF expression significantly associated with chronicity indices. Our data suggest that activation of iRhom2/ADAM17-dependent TNF-α and EGFR signaling plays a crucial role in mediating irreversible kidney damage in LN, thereby uncovering a novel target for selective and simultaneous dual inhibition of two major pathological pathways in the effector arm of the disease.
Xiaoping Qing, Yurii Chinenov, Patricia Redecha, Michael Madaio, Joris J.T.H. Roelofs, Gregory Farber, Priya D. Issuree, Laura Donlin, David R. McIlwain, Tak W. Mak, Carl P. Blobel, Jane E. Salmon
In multiple sclerosis, the pathological interaction between autoreactive Th cells and mononuclear phagocytes in the CNS drives initiation and maintenance of chronic neuroinflammation. Here, we found that intrathecal transplantation of neural stem/precursor cells (NPCs) in mice with experimental autoimmune encephalomyelitis (EAE) impairs the accumulation of inflammatory monocyte-derived cells (MCs) in the CNS, leading to improved clinical outcome. Secretion of IL-23, IL-1, and TNF-α, the cytokines required for terminal differentiation of Th cells, decreased in the CNS of NPC-treated mice, consequently inhibiting the induction of GM-CSF–producing pathogenic Th cells. In vivo and in vitro transcriptome analyses showed that NPC-secreted factors inhibit MC differentiation and activation, favoring the switch toward an antiinflammatory phenotype. Tgfb2–/– NPCs transplanted into EAE mice were ineffective in impairing MC accumulation within the CNS and failed to drive clinical improvement. Moreover, intrathecal delivery of TGF-β2 during the effector phase of EAE ameliorated disease severity. Taken together, these observations identify TGF-β2 as the crucial mediator of NPC immunomodulation. This study provides evidence that intrathecally transplanted NPCs interfere with the CNS-restricted inflammation of EAE by reprogramming infiltrating MCs into antiinflammatory myeloid cells via secretion of TGF-β2.
Donatella De Feo, Arianna Merlini, Elena Brambilla, Linda Ottoboni, Cecilia Laterza, Ramesh Menon, Sundararajan Srinivasan, Cinthia Farina, Jose Manuel Garcia Manteiga, Erica Butti, Marco Bacigaluppi, Giancarlo Comi, Melanie Greter, Gianvito Martino
Autoreactive CD4 T cells that differentiate into pathogenic Th17 cells can trigger autoimmune diseases. Therefore, investigating the regulatory network that modulates Th17 differentiation may yield important therapeutic insights. miR-146a has emerged as a critical modulator of immune reactions, but its role in regulating autoreactive Th17 cells and organ-specific autoimmunity remains largely unknown. Here, we have reported that miR-146a–deficient mice developed more severe experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS). We bred miR-146a–deficient mice with 2D2 T cell receptor–Tg mice to generate 2D2 CD4 T cells that are deficient in miR-146a and specific for myelin oligodendrocyte glycoprotein (MOG), an autoantigen in the EAE model. miR-146a–deficient 2D2 T cells induced more severe EAE and were more prone to differentiate into Th17 cells. Microarray analysis revealed enhancements in IL-6– and IL-21–induced Th17 differentiation pathways in these T cells. Further study showed that miR-146a inhibited the production of autocrine IL-6 and IL-21 in 2D2 T cells, which in turn reduced their Th17 differentiation. Thus, our study identifies miR-146a as an important molecular brake that blocks the autocrine IL-6– and IL-21–induced Th17 differentiation pathways in autoreactive CD4 T cells, highlighting its potential as a therapeutic target for treating autoimmune diseases.
Bo Li, Xi Wang, In Young Choi, Yu-Chen Wang, Siyuan Liu, Alexander T. Pham, Heesung Moon, Drake J. Smith, Dinesh S. Rao, Mark P. Boldin, Lili Yang
In rheumatoid arthritis (RA), immunological triggers at mucosal sites, such as the gut microbiota, may promote autoimmunity that affects joints. Here, we used discovery-based proteomics to detect HLA-DR–presented peptides in synovia or peripheral blood mononuclear cells and identified 2 autoantigens, N-acetylglucosamine-6-sulfatase (GNS) and filamin A (FLNA), as targets of T and B cell responses in 52% and 56% of RA patients, respectively. Both GNS and FLNA were highly expressed in synovia. GNS appeared to be citrullinated, and GNS antibody values correlated with anti–citrullinated protein antibody (ACPA) levels. FLNA did not show the same results. The HLA-DR–presented GNS peptide has marked sequence homology with epitopes from sulfatase proteins of the Prevotella sp. and Parabacteroides sp., whereas the HLA-DR–presented FLNA peptide has homology with epitopes from proteins of the Prevotella sp. and Butyricimonas sp., another gut commensal. Patients with T cell reactivity with each self-peptide also had responses to the corresponding microbial peptides, and the levels were directly correlated. Furthermore, HLA-DR molecules encoded by shared-epitope (SE) alleles were predicted to bind these self- and microbial peptides strongly, and these responses were more common in RA patients with SE alleles. Thus, sequence homology between T cell epitopes of 2 self-proteins and a related order of gut microbes may provide a link between mucosal and joint immunity in patients with RA.
Annalisa Pianta, Sheila L. Arvikar, Klemen Strle, Elise E. Drouin, Qi Wang, Catherine E. Costello, Allen C. Steere
Design of efficacious Treg-based therapies and establishment of clinical tolerance in autoimmune diseases have proven to be challenging. The clinical implementation of Treg immunotherapy has been hampered by various impediments related to the stability and isolation procedures of Tregs as well as the specific in vivo targets of Treg modalities. Herein, we have demonstrated that Foxp3+ Tregs potently suppress autoimmune responses in vivo through inhibition of the autophagic machinery in DCs in a cytotoxic T-lymphocyte–associated protein 4–dependent (CTLA4-dependent) manner. Autophagy-deficient DCs exhibited reduced immunogenic potential and failed to prime autoantigen-specific CD4+ T cells to mediate autoimmunity. Mechanistically, CTLA4 binding promoted activation of the PI3K/Akt/mTOR axis and FoxO1 nuclear exclusion in DCs, leading to decreased transcription of the autophagy component microtubule-associated protein 1 light chain 3β (Lc3b). Human DCs treated with CTLA4-Ig, a fusion protein composed of the Fc region of IgG1 and the extracellular domain of CTLA4 (also known as abatacept, marketed as Orencia), demonstrated reduced levels of autophagosome formation, while DCs from CTLA4-Ig–treated rheumatoid arthritis patients displayed diminished LC3B transcripts. Collectively, our data identify the canonical autophagy pathway in DCs as a molecular target of Foxp3+ Treg–mediated suppression that leads to amelioration of autoimmune responses. These findings may pave the way for the development of therapeutic protocols that exploit Tregs for the treatment of autoimmunity as well as diseases in which disturbed tolerance is a common denominator.
Themis Alissafi, Aggelos Banos, Louis Boon, Tim Sparwasser, Alessandra Ghigo, Kajsa Wing, Dimitrios Vassilopoulos, Dimitrios Boumpas, Triantafyllos Chavakis, Ken Cadwell, Panayotis Verginis
A large proportion of human T cells are autoreactive to group 1 CD1 proteins, which include CD1a, CD1b, and CD1c. However, the physiological role of the CD1 proteins remains poorly defined. Here, we have generated a double-transgenic mouse model that expresses human CD1b and CD1c molecules (hCD1Tg) as well as a CD1b-autoreactive TCR (HJ1Tg) in the ApoE-deficient background (hCD1Tg HJ1Tg
Sreya Bagchi, Ying He, Hong Zhang, Liang Cao, Ildiko Van Rhijn, D. Branch Moody, Johann E. Gudjonsson, Chyung-Ru Wang
Despite the benefit of insulin, blockade of autoimmune attack and regeneration of pancreatic islets are ultimate goals for the complete cure of type 1 diabetes (T1D). Long-term consumption of ω-3 polyunsaturated fatty acids (PUFAs) is known to suppress inflammatory processes, making these fatty acids candidates for the prevention and amelioration of autoimmune diseases. Here, we explored the preventative and therapeutic effects of ω-3 PUFAs on T1D. In NOD mice, dietary intervention with ω-3 PUFAs sharply reduced the incidence of T1D, modulated the differentiation of Th cells and Tregs, and decreased the levels of IFN-γ, IL-17, IL-6, and TNF-α. ω-3 PUFAs exerted similar effects on the differentiation of CD4+ T cells isolated from human peripheral blood mononuclear cells. The regulation of CD4+ T cell differentiation was mediated at least in part through ω-3 PUFA eicosanoid derivatives and by mTOR complex 1 (mTORC1) inhibition. Importantly, therapeutic intervention in NOD mice through nutritional supplementation or lentivirus-mediated expression of an ω-3 fatty acid desaturase, m
Xinyun Bi, Fanghong Li, Shanshan Liu, Yan Jin, Xin Zhang, Tao Yang, Yifan Dai, Xiaoxi Li, Allan Zijian Zhao
Genetic variations in the
Mohd Hafeez Faridi, Samia Q. Khan, Wenpu Zhao, Ha Won Lee, Mehmet M. Altintas, Kun Zhang, Vinay Kumar, Andrew R. Armstrong, Carmelo Carmona-Rivera, Jessica M. Dorschner, Abigail M. Schnaith, Xiaobo Li, Yogita Ghodke-Puranik, Erica Moore, Monica Purmalek, Jorge Irizarry-Caro, Tingting Zhang, Rachael Day, Darren Stoub, Victoria Hoffmann, Shehryar Jehangir Khaliqdina, Prachal Bhargava, Ana M. Santander, Marta Torroella-Kouri, Biju Issac, David J. Cimbaluk, Andrew Zloza, Rajeev Prabhakar, Shashank Deep, Meenakshi Jolly, Kwi Hye Koh, Jonathan S. Reichner, Elizabeth M. Bradshaw, JianFeng Chen, Luis F. Moita, Peter S. Yuen, Wanxia Li Tsai, Bhupinder Singh, Jochen Reiser, Swapan K. Nath, Timothy B. Niewold, Roberto I. Vazquez-Padron, Mariana J. Kaplan, Vineet Gupta
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