Autoimmunity
Abstract
Authors
Sebastian Kämpf, Marjan Hematianlarki, Leon Altmann, Jessica M. Bright, Alyssa M. A. Toda, Zohreh Mirzapoor, Valentin Zollner, Anja Werner, Johanna Bulang, Barbara Radovani, Miriam Wöhner, William Avery, Mark J. Karbarz, Pamela B. Conley, Greg P. Coffey, Falk Nimmerjahn
Abstract
Systemic sclerosis (SSc) is a complex and heterogeneous condition characterized by progressive fibrosis in multiple organs. Recent studies implicate plasminogen activator inhibitor 1 (PAI-1) in the pathogenesis of SSc, and PAI-1 is considered as a potential target for therapy. Here, using single-cell and spatial RNA-seq analysis of skin biopsies from 18 healthy individuals and 22 SSc patients, we found elevated PAI-1 co-localizing to myofibroblasts with enriched extracellular matrix-associated biological processes. Treatment of SSc dermal fibroblasts with the small molecule PAI-1 inhibitor MDI-2517 reduced the expression of the profibrotic markers COL1A1 and ACTA2. To investigate the therapeutic potential of MDI-2517, we evaluated its efficacy in reducing fibrosis in a preclinical model of SSc. Treatment of mice with MDI-2517 significantly reduced both skin and lung fibrosis and was superior to treatment with either pirfenidone or mycophenolate mofetil. Additionally, MDI-2517 attenuated weight loss and significantly reduced the expression of key profibrotic markers. Compared to tiplaxtinin, another PAI-1 inhibitor previously shown to be effective in a model of SSc, MDI-2517 was found to have superior efficacy at a 10-fold lower dose. These findings highlight the role of PAI-1 in the pathogenesis of SSc, and the potential of MDI-2517 for the treatment of SSc.
Authors
Enming J. Su, Pei-Suen Tsou, Mark Warnock, Natalya Subbotina, Kris Mann, Sirapa Vichaikul, Alyssa Rosek, Lisa Leung, Xianying Xing, Enze Xing, Olesya Plazyo, Rachael Bogle, Lam C. Tsoi, Cory D. Emal, Dinesh Khanna, John Varga, Thomas H. Sisson, Johann E. Gudjonsson, Daniel A. Lawrence
Abstract
Degradation of cellular waste from phagocytosis, endocytosis and autophagy occurs through hydrolases that become activated during acidification of late endosomes and lysosomes (LELs). In a cross-sectional study we show diminished LEL acidification and the accumulation of surface-bound nucleosome on monocytes, dendritic cells, and B cells from SLE patients. Diminished acidification and exocytosis of undegraded IgG-ICs is evident in active, but not inactive disease. This is supported by our murine study where LEL acidification is diminished, promoting exocytosis and the accumulation of cell surface IgG-immune complexes. Mechanistically, LEL dysfunction is induced by chronic PI3k activation in lupus-prone MRL/lpr mice. We also show that on a non-autoimmune C57BL/6 background, deficiency in SHP-1 and inhibition of SHIP-1 activity is sufficient to recapitulate LEL dysfunction found in MRL/lpr mice. Non-acidic LELs are evident in 67% of patients, and associate with SLEDAI arthritis, rash, and nephritis. The high frequency of LEL dysfunction in SLE suggests it could serve as a biomarker identifying a specific disease endotype.
Authors
SunAh Kang, Andrew J. Monteith, Liubov Arbeeva, Karissa Grier, Shruti Saxena Beem, Anthony C. Trujillo, Xinyun Bi, Kai Sun, Rebecca E. Sadun, Mithu Maheswaranathan, Megan E.B. Clowse, Saira Z. Sheikh, Jennifer L. Rogers, Barbara J. Vilen
Abstract
In pemphigus, autoantibodies against the desmosomal cadherins desmoglein (DSG) DSG1 and DSG3 cause intraepidermal blistering. Recently, we found that increasing cAMP with the phosphodiesterase-4 inhibitor apremilast stabilizes keratinocyte cohesion in pemphigus. This effect is paralleled by phosphorylation of the desmosomal plaque protein plakoglobin (PG) at serine 665 (S665). Here, we investigated the relevance of PG phosphorylation at S665 for stabilization of keratinocyte cohesion and further characterized the underlying mechanisms. Ultrastructural analysis of a recently established PG-S665 phospho-deficient mouse model (PG-S665A) showed diminished keratin insertion. Accordingly, the protective effect of apremilast against pemphigus autoantibody-induced skin blistering was diminished, and apremilast failed to restore alterations of the keratin cytoskeleton in PG-S665A mice. Keratinocytes derived from PG-S665A mice revealed a disorganized keratin cytoskeleton and reduced single-molecule binding strength of DSG3. In line with this, in ex vivo human skin, increased cAMP augmented keratin insertion into desmosomal plaques. Additionally, PG phosphorylated at S665 colocalized with desmoplakin and keratin filaments anchoring to desmosomes and increased cAMP-accelerated assembly of desmosomes. Taken together, phosphorylation of PG at S665 was crucial for protective effects of apremilast in pemphigus and for maintenance of DSG3 binding and keratin filament anchorage to desmosomes.
Authors
Franziska Vielmuth, Anna M. Sigmund, Desalegn T. Egu, Matthias Hiermaier, Letyfee S. Steinert, Sina Moztarzadeh, Mariia Klimkina, Margarethe E.C. Schikora, Paulina M. Rion, Thomas Schmitt, Katharina Meier, Kamran Ghoreschi, Anja K.E. Horn, Mariya Y. Radeva, Daniela Kugelmann, Jens Waschke
Abstract
Adaptive immune responses are widely considered the primary drivers of chronic inflammation in autoimmune disease, yet increasing evidence suggests that dysregulated myeloid cells play a central role in sustaining tissue damage. Salt-inducible kinases (SIKs) regulate immune cell activation, and their pharmacological inhibition can promote a shift from proinflammatory toward an immunoregulatory phenotype. We investigated whether selective inhibition of SIK2 and SIK3 with GLPG3970 could reprogram monocytes, macrophages, and dendritic cells, and we assessed pharmacological effects on activated T and B cells. Preclinical studies in mouse models of colitis, psoriasis, and arthritis demonstrated that SIK2/SIK3 inhibition reduced inflammatory activity and promoted immunoregulatory and tolerogenic-associated pathways. Clinical signal-detection studies in ulcerative colitis, psoriasis, and rheumatoid arthritis revealed signs of clinical and biological activity in ulcerative colitis and psoriasis. These findings suggest that myeloid cell dysfunction and impaired myeloid phenotype switching contribute to chronic inflammation in autoimmune diseases and that therapeutic targeting of SIK2/SIK3 holds the potential to restore immune balance by converting proinflammatory into regulatory pathways. Collectively, this work supports SIK2/SIK3 inhibition as a potential treatment strategy for myeloid cell–driven chronic inflammatory conditions.
Authors
Steve De Vos, Nicolas Desroy, Susan J. Bellaire, Anna Pereira Fernandes, Stéphanie Lavazais, Didier Merciris, Carole Delachaume, Catherine Robin-Jagerschmidt, Adrien Cosson, Angela Lazaryan, Nancy Van Osselaer, David Amantini, Christophe Peixoto, Maikel L. Colli, Thomas Van Eeckhoutte, Tiina Hakonen, Magali Constant, Alberto Garcia-Hernandez, Rahul Barron, Geert D’Haens, Wulf O. Böcher
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and widespread inflammation. Natural killer (NK) cells display marked functional impairment in SLE, including defective cytotoxicity and cytokine production, but the underlying mechanisms remain poorly defined. Here, we show that mitochondrial dysfunction and impaired mitophagy are key contributors to NK cell abnormalities in SLE. Using complementary structural, metabolic, and proteomic analyses, we found that SLE NK cells accumulate enlarged and dysfunctional mitochondria, exhibit impaired lysosomal acidification, and release mitochondrial DNA into the cytosol—features consistent with defective mitochondrial quality control. Transcriptional and proteomic profiling revealed downregulation of key mitophagy-related genes and pathways. These abnormalities correlated with reduced NK cell degranulation and cytokine production. We then tested whether enhancing mitochondrial quality control could restore NK cell function. The mitophagy activator Urolithin A improved mitochondrial and lysosomal parameters and rescued NK cell effector responses in vitro. Hydroxychloroquine partially restored mitochondrial recycling and reduced cytosolic mtDNA. These findings suggest that defective mitophagy and mitochondrial dysfunction are major contributors to NK cell impairment in SLE and that targeting mitochondrial quality control may represent a promising strategy for restoring immune balance in this disease.
Authors
Natalia W. Fluder, Morgane Humbel, Emeline Recazens, Alexis A. Jourdain, Camillo Ribi, George C. Tsokos, Denis Comte
Abstract
Alveolar hemorrhage (AH) is a life-threatening condition with high mortality, yet the immunologic mechanisms governing disease severity remain poorly defined. Here, we demonstrate a protective role for T cell–intrinsic β-catenin stabilization in AH using a transgenic mouse model (CAT-Tg) in which β-catenin is stabilized under the Lck promoter. β-Catenin stabilization induced a distinct T cell phenotype marked by expansion of central effector memory cells (CD44+CD122+Eomes+T-bet+) and suppression of proinflammatory signaling, including reduced phosphorylation of STAT1, STAT3, and JAK1. Pristane-induced AH was attenuated in CAT-Tg mice, which exhibited reduced lung injury, decreased proteinuria, and diminished pulmonary proinflammatory cytokine production compared with wild-type controls. Protection was associated with a marked expansion of FOXP3+ regulatory T cells (Tregs). Mechanistically, β-catenin stabilization enhanced lung expression of Amphiregulin and BATF, mediators of Treg stability and tissue repair. Adoptive transfer of CAT-Tg–derived Tregs into wild-type mice conferred superior protection against AH, reducing lung inflammation and proteinuria. Transcriptomic analyses revealed enrichment of tissue repair and immune homeostasis pathways, including PI3K–Akt, angiogenesis, and STAT5 signaling. Collectively, these findings identify β-catenin as a regulator of a protective Amphiregulin–BATF–Treg axis, highlighting a immunomodulatory pathway with therapeutic potential for AH and inflammatory lung disease.
Authors
Fiona Mason, Hui Xiong, Ali Mobeen, Md Saddam Hossain, Sara Mahmudlu, Rosanne Trevail, Mikyal Mobeen, Li Chen, Sunny Lee, Tuncay Delibasi, Jyoti Misra Sen, Mobin Karimi
Abstract
Rheumatoid arthritis (RA) is characterized by joint inflammation and bone erosion. Understanding cytokine pathways, particularly those targeting TNF, is crucial for understanding pathology and advancing treatment development. Arid5a is a noncanonical RNA binding protein (RBP) that augments inflammation through stabilizing proinflammatory mRNAs and enhancing protein translation. We examined published datasets for ARID5A in human RA blood, T cells, and synovial tissues. A stromal cell line, epithelial cells, and primary synovial fibroblasts were used to assess the effect of TNF on Arid5a expression, localization, and function. To determine how TNF induces Arid5a, WT or Traf2–/– stromal cells were treated with NIK or IKK inhibitors. To evaluate the necessity of Arid5a in arthritis progression, Arid5a–/– mice were subjected to collagen-induced arthritis. ARID5A was elevated in patients with RA and reduced by anti-TNF therapy. TNF upregulated Arid5a through the NF-κB1/TRAF2 pathway, causing cytoplasmic relocalization. Arid5a stabilized proinflammatory transcripts and enhanced expression of chemokines that drive RA. Arid5a–/– mice were resistant to collagen-induced arthritis correlating with reduced Th17 cells in synovial tissue. Thus, Arid5a serves as a newly recognized signaling intermediate downstream of TNF that is elevated in human RA and drives pathology in murine CIA, potentially positioning this RBP as a possible therapeutic target.
Authors
Yang Li, Ipsita Dey, Shachi P. Vyas, Alzbeta Synackova, Decheng Li, Erik Lubberts, Dana P. Ascherman, Peter Draber, Sarah L. Gaffen
Abstract
Ulcerative colitis (UC) is a chronic inflammatory condition of the colon that primarily affects the mucosal layer. Previously, we identified autoantibodies against integrin αvβ6 in patients with UC. In this study, we established monoclonal antibodies (mAbs) from patients with UC to reveal the features and functions of these anti-integrin αvβ6 autoantibodies. We identified two shared heavy chain complementarity-determining region (CDR) 3 amino acid sequences among different patients with UC. Notably, several mAbs contained the RGD sequence in their heavy chain CDR3 that mimicked the key recognition sequence of integrin αvβ6 ligands such as fibronectin. Almost all mAbs selectively reacted with integrin αvβ6 in the presence of divalent cations (Ca²⁺ and Mg²⁺) and blocked fibronectin–integrin αvβ6 binding. MAbs that shared the same heavy chain CDR3 amino acid sequence showed differences in reactivity to integrin αvβ6, indicating that the reactivity of these mAbs is also affected by the light chain. Some of the mAbs showed varying degrees of cross-reactivity with integrin αvβ3. The identification of shared CDR3 amino acid sequences in anti-integrin αvβ6 antibodies from several patients with UC suggests a common mechanism underlying their production, which may help elucidate the pathogenesis of UC.
Authors
Masahiro Shiokawa, Yoshihiro Nishikawa, Ikuhisa Takimoto, Takeshi Kuwada, Sakiko Ota, Darryl Joy C. Juntila, Takafumi Yanaidani, Kenji Sawada, Ayako Hirata, Muneji Yasuda, Koki Chikugo, Risa Nakanishi, Masataka Yokode, Yuya Muramoto, Shimpei Matsumoto, Tomoaki Matsumori, Tsutomu Chiba, Hiroshi Seno
Abstract
CD4+ T cells predominate lymphocytic foci found in the salivary glands (SGs) of Sjögren’s disease (SjD) cases. Yet little is known about T cell receptor (TCR) repertoire features that distinguish cases from healthy controls (HCs), the relationship between SG and peripheral blood (PB) repertoires of cases, and antigens recognized by pathogenic T cell clones. We performed deep sequencing of bulk-sorted CD4+CD45RA– PB T cells from SjD cases and matched HCs, and single-cell TCR sequencing of the same T cell population from labial SG biopsies of these cases. We found that clonally expanded SG CD4+ T cells expressed complementarity-determining region 3 (CDR3) sequences that were also detected in multiple copies in the blood of the same individuals with SjD. SjD cases displayed a “private” and restricted PB TCR repertoire with reduced clonotype diversity. We identified SjD-associated TCR motifs with the same putative antigen specificity shared between SGs and PB of cases. Their abundances in PB correlated with reduced salivary flow, linking these T cells with pathogenic disease features. Finally, we discovered 2 Ro60 epitopes eliciting an HLA-restricted immune response from expanded SG T cell clones. The comprehensive characterization of SjD TCR repertoires enables the discovery of target antigens and therapeutic strategies.
Authors
Ananth Aditya Jupudi, Michelle L. Joachims, Christina Lawrence, Charmaine Lopez-Davis, Bhuwan Khatri, Astrid Rasmussen, Kiely Grundahl, R. Hal Scofield, Judith A. James, Joel M. Guthridge, Christopher J. Lessard, Linda F. Thompson, A. Darise Farris
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