The homeostasis of immunoglobulin G (IgG) is maintained by the neonatal Fc receptor, FcRn. Consequently, antagonism of FcRn to reduce endogenous IgG levels is an emerging strategy for treating antibody-mediated autoimmune disorders using either FcRn-specific antibodies or an engineered Fc fragment. For certain FcRn-specific antibodies, this approach has resulted in reductions in the levels of serum albumin, the other major ligand transported by FcRn. Cellular and molecular analyses of a panel of FcRn antagonists have been carried out to elucidate the mechanisms leading to their differential effects on albumin homeostasis. These analyses have identified two processes underlying decreases in albumin levels during FcRn blockade: increased degradation of FcRn and competition between antagonist and albumin for FcRn binding. These findings have potential implications for the design of drugs to modulate FcRn function.
Guanglong Ma, Andrew R. Crowley, Liesbeth Heyndrickx, Ilse Rogiers, Eef Parthoens, Jolien Van Santbergen, Raimund J. Ober, Vladimir Bobkov, Hans de Haard, Peter Ulrichts, Erik Hofman, Els Louagie, Bianca Balbino, E. Sally Ward
Mesenchymal stem cells (MSCs) have demonstrated potent immunomodulatory properties that have shown promise in the treatment of autoimmune diseases, including rheumatoid arthritis (RA). However, the inherent heterogeneity of MSCs triggered conflicting therapeutic outcomes, raising safety concerns and limiting their clinical application. This study aimed to investigate the potential of extracellular vesicles derived from human gingival mesenchymal stem cells (GMSC-EVs) as a therapeutic strategy for RA. Through in vivo experiments using an experimental RA model, our results demonstrated that GMSC-EVs selectively homed to inflamed joints and recovered Treg and Th17 cells balance, resulting in the reduction of arthritis progression. Our investigations also uncovered miR-148a-3p as a critical contributor to the Treg/Th17 balance modulation via IKKB/NF-κB signaling orchestrated by GMSC-EVs, which was subsequently validated in a model of human xenograft versus host disease (xGvHD). Furthermore, we successfully developed a humanized animal model by utilizing synovial fibroblasts obtained from patients with RA (RASFs). We found that GMSC-EVs impeded the invasiveness of RASFs and minimized cartilage destruction, indicating their potential therapeutic efficacy in the context of RA patients. Overall, the unique characteristics, including reduced immunogenicity, simplified administration, and inherent ability to target inflamed tissues, position GMSC-EVs as a viable alternative for RA and other autoimmune diseases.
Jingrong Chen, Xiaoyi Shi, Yanan Deng, Junlong Dang, Yan Liu, Jun Zhao, Liang Rongzhen, Donglan Zeng, Wenbin Wu, Yiding Xiong, Jia Yuan, Ye Chen, Julie Wang, Weidong Lin, Xiangfang Chen, Weishan Huang, Nancy Olsen, Yunfeng Pan, Qing-Ling Fu, Song Guo Zheng
Tregs have the potential to establish long-term immune tolerance in patients recently diagnosed with type 1 diabetes (T1D) by preserving β cell function. Adoptive transfer of autologous thymic Tregs, although safe, exhibited limited efficacy in previous T1D clinical trials, likely reflecting a lack of tissue specificity, limited IL-2 signaling support, and in vivo plasticity of Tregs. Here, we report a cell engineering strategy using bulk CD4+ T cells to generate a Treg cell therapy (GNTI-122) that stably expresses FOXP3, targets the pancreas and draining lymph nodes, and incorporates a chemically inducible signaling complex (CISC). GNTI-122 cells maintained an expression profile consistent with Treg phenotype and function. Activation of CISC using rapamycin mediated concentration-dependent STAT5 phosphorylation and, in concert with T cell receptor engagement, promoted cell proliferation. In response to the cognate antigen, GNTI-122 exhibited direct and bystander suppression of polyclonal, islet-specific effector T cells from patients with T1D. In an adoptive transfer mouse model of T1D, a mouse engineered-Treg analog of GNTI-122 trafficked to the pancreas, decreased the severity of insulitis, and prevented progression to diabetes. Taken together, these findings demonstrate in vitro and in vivo activity and support further development of GNTI-122 as a potential treatment for T1D.
Gene I. Uenishi, Marko Repic, Jennifer Y. Yam, Ashley Landuyt, Priya Saikumar-Lakshmi, Tingxi Guo, Payam Zarin, Martina Sassone-Corsi, Adam Chicoine, Hunter Kellogg, Martina Hunt, Travis Drow, Ritika Tewari, Peter J. Cook, Soo Jung Yang, Karen Cerosaletti, Darius Schweinoch, Benjamin Guiastrennec, Eddie James, Chandra Patel, Tiffany F. Chen, Jane H. Buckner, David J. Rawlings, Thomas J. Wickham, Karen T. Mueller
Understanding the immune responses to SARS-CoV-2 vaccination is critical to optimizing vaccination strategies for individuals with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here, we comprehensively analyzed innate and adaptive immune responses in 19 patients with SLE receiving a complete 2-dose Pfizer-BioNTech mRNA vaccine (BNT162b2) regimen compared with a control cohort of 56 healthy control (HC) volunteers. Patients with SLE exhibited impaired neutralizing antibody production and antigen-specific CD4+ and CD8+ T cell responses relative to HC. Interestingly, antibody responses were only altered in patients with SLE treated with immunosuppressive therapies, whereas impairment of antigen-specific CD4+ and CD8+ T cell numbers was independent of medication. Patients with SLE also displayed reduced levels of circulating CXC motif chemokine ligands, CXCL9, CXCL10, CXCL11, and IFN-γ after secondary vaccination as well as downregulation of gene expression pathways indicative of compromised innate immune responses. Single-cell RNA-Seq analysis reveals that patients with SLE showed reduced levels of a vaccine-inducible monocyte population characterized by overexpression of IFN-response transcription factors. Thus, although 2 doses of BNT162b2 induced relatively robust immune responses in patients with SLE, our data demonstrate impairment of both innate and adaptive immune responses relative to HC, highlighting a need for population-specific vaccination studies.
Kavita Y. Sarin, Hong Zheng, Yashaar Chaichian, Prabhu S. Arunachalam, Gayathri Swaminathan, Alec Eschholz, Fei Gao, Oliver F. Wirz, Brandon Lam, Emily Yang, Lori W. Lee, Allan Feng, Matthew A. Lewis, Janice Lin, Holden T. Maecker, Scott D. Boyd, Mark M. Davis, Kari C. Nadeau, Bali Pulendran, Purvesh Khatri, Paul J. Utz, Lisa C. Zaba
In autoimmunity, FOXP3+ regulatory T cells (Tregs) skew towards a pro-inflammatory, non-suppressive phenotype and are therefore unable to control the exaggerated autoimmune response. This largely impacts the success of autologous Treg therapy which is currently under investigation for autoimmune diseases, including multiple sclerosis (MS). There is a need to ensure in vivo Treg stability before successful application of Treg therapy. Using genetic fate-mapping mice, we demonstrate that inflammatory, cytokine-expressing exFOXP3 T cells accumulate in the central nervous system during experimental autoimmune encephalomyelitis. In a human in vitro model, we discovered that interaction with inflamed blood-brain barrier endothelial cells (BBB-ECs) induces loss-of-function by Tregs. Transcriptome and cytokine analysis revealed that in vitro migrated Tregs have disrupted regenerative potential, a pro-inflammatory Th1/17 signature and upregulate the mTORC1 signaling pathway. In vitro treatment of migrated human Tregs with the clinically-approved mTORC1 inhibitor rapamycin restored suppression. Finally, flow cytometric analysis indicated an enrichment of inflammatory, less suppressive CD49d+ Tregs in the cerebrospinal fluid of people with MS. In sum, interaction with BBB-ECs is sufficient to affect Treg function, and transmigration triggers an additive pro-inflammatory phenotype switch. These insights help improve the efficacy of autologous Treg therapy of MS.
Paulien Baeten, Ibrahim Hamad, Cindy Hoeks, Michael Hiltensperger, Bart Van Wijmeersch, Veronica Popescu, Lilian Aly, Veerle Somers, Thomas Korn, Markus Kleinewietfeld, Niels Hellings, Bieke Broux
Fibroblasts are stromal cells known to regulate local immune responses important for wound healing and scar formation; however, the cellular mechanisms driving damage and scarring in cutaneous lupus erythematosus (CLE) patients remain poorly understood. Dermal fibroblasts in systemic lupus erythematosus (SLE) patients are abnormally exposed to cytokines, but the impact of inflammatory mediators on fibroblast responses in non-scarring versus scarring CLE subtypes is unclear. Here, we examined responses to cytokines in dermal fibroblasts from non-lesional skin of 22 SLE patients with CLE and 34 healthy controls. Notably, inflammatory cytokine responses were exaggerated in SLE fibroblasts compared to healthy controls. In lesional CLE biopsies, these same inflammatory profiles were reflected in single cell RNA sequencing of SFRP2+ and inflammatory fibroblast subsets, and TGF-β was identified as a critical upstream regulator for inflammatory fibroblasts in scarring discoid lupus lesions. In vitro cytokine stimulation of non-lesional fibroblasts from patients who scar from CLE identified an upregulation of collagens, particularly in response to TGF-β, whereas inflammatory pathways were more prominent in non-scarring patients. Our study revealed that SLE fibroblasts are poised to hyper-respond to inflammation, with differential responses among scarring versus non-scarring disease, providing a potential skin-specific target for mitigating damage.
Suzanne K. Shoffner-Beck, Lisa Abernathy-Close, Stephanie Lazar, Feiyang Ma, Mehrnaz Gharaee-Kermani, Amy Hurst, Craig Dobry, Deepika Pandian, Rachael Wasikowski, Amanda Victory, Kelly Arnold, Johann E. Gudjonsson, Lam C. Tsoi, J. Michelle Kahlenberg
Linear ubiquitin chains, which are generated specifically by the linear ubiquitin assembly complex (LUBAC) ubiquitin ligase, play crucial roles in immune signaling, including NF-κB activation. LUBAC comprises catalytic large isoform of heme-oxidized iron regulatory protein 2 ubiquitin ligase 1 (HOIL-1L) interacting protein (HOIP), accessory HOIL-1L, and SHANK-associated RH domain-interacting protein (SHARPIN). Deletion of the ubiquitin ligase activity of HOIL-1L, an accessory ligase of LUBAC, augments LUBAC functions by enhancing LUBAC-mediated linear ubiquitination, which is catalyzed by HOIP. Here, we show that HOIL-1L ΔRING1 mice, which exhibit augmented LUBAC functions upon loss of the HOIL-1L ligase, developed systemic lupus erythematosus (SLE) and Sjögren’s syndrome in a female-dominant fashion. Augmented LUBAC activity led to hyperactivation of both lymphoid and myeloid cells. In line with the findings in mice, we sought to identify missense single nucleotide polymorphisms/variations of the RBCK1/HOIL-1L gene in humans that attenuate HOIL-1L ligase activity. We found that the R464H variant, which is encoded by rs774507518 within the RBCK1/HOIL-1L gene, attenuated HOIL-1L ligase activity and augmented LUBAC-mediated immune signaling, including that mediated by Toll-like receptors. We also found that rs774507518 was enriched significantly in patients with SLE, strongly suggesting that RBCK1/HOIL-1L is an SLE susceptibility gene and that augmented linear ubiquitin signaling generated specifically by LUBAC underlies the pathogenesis of this prototype systemic autoimmune disease.
Yasuhiro Fuseya, Keiichiro Kadoba, Xiaoxi Liu, Hiroyuki Suetsugu, Takeshi Iwasaki, Koichiro Ohmura, Takayuki Sumida, Yuta Kochi, Akio Morinobu, Chikashi Terao, Kazuhiro Iwai
Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%–40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL-16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.
Andrea Fava, Jill Buyon, Laurence Magder, Jeff Hodgin, Avi Rosenberg, Dawit S. Demeke, Deepak A. Rao, Arnon Arazi, Alessandra Ida Celia, Chaim Putterman, Jennifer H. Anolik, Jennifer Barnas, Maria Dall’Era, David Wofsy, Richard Furie, Diane Kamen, Kenneth Kalunian, Judith A. James, Joel Guthridge, Mohamed G. Atta, Jose Monroy Trujillo, Derek Fine, Robert Clancy, H. Michael Belmont, Peter Izmirly, William Apruzzese, Daniel Goldman, Celine C. Berthier, Paul Hoover, Nir Hacohen, Soumya Raychaudhuri, Anne Davidson, Betty Diamond, the Accelerating Medicines Partnership in RA/SLE network, Michelle Petri
Autoimmunity is characterized by loss of tolerance to tissue-specific as well as systemic antigens, resulting in complex autoantibody landscapes. Here, we introduce and extensively validate the performance characteristics of a murine proteome-wide library for phage display immunoprecipitation and sequencing (PhIP-seq), to profile mouse autoantibodies. This library was validated using seven genetic mouse lines across a spectrum of autoreactivity. Mice deficient in antibody production (Rag2–/– and µMT) were used to model non-specific peptide enrichments, while cross-reactivity was evaluated using anti-ovalbumin B cell receptor (BCR)-restricted OB1 mice as a proof of principle. The PhIP-seq approach was then utilized to interrogate three distinct autoimmune disease models. First, serum from Lyn–/– IgD+/– mice with lupus-like disease was used to identify nuclear and apoptotic bleb reactivities. Second, serum from non-obese diabetic (NOD) mice, a polygenic model of pancreas-specific autoimmunity, enriched peptides derived from both insulin and predicted pancreatic proteins. Lastly, Aire–/– mouse sera were used to identify numerous autoantigens, many of which were also observed in previous studies of humans with autoimmune polyendocrinopathy syndrome type 1 (APS1) carrying recessive mutations in AIRE. These experiments support the use of murine proteome-wide PhIP-seq for antigenic profiling and autoantibody discovery, which may be employed to study a range of immune perturbations in mouse models of autoimmunity profiling.
Elze Rackaityte, Irina Proekt, Haleigh S. Miller, Akshaya Ramesh, Jeremy F. Brooks, Andrew F. Kung, Caleigh Mandel-Brehm, David J.L. Yu, Colin R. Zamecnik, Rebecca Bair, Sara E. Vazquez, Sara Sunshine, Clare L. Abram, Clifford A. Lowell, Gabrielle Rizzuto, Michael R. Wilson, Julie Zikherman, Mark S. Anderson, Joseph L. DeRisi
The selective targeting of pathogenic T cells is a “holy grail” in the development of new therapeutics for T cell-mediated disorders including many autoimmune diseases and graft-versus-host disease. We describe the development of a CD6-targeted antibody-drug conjugate (CD6-ADC) by conjugating an inactive form of monomethyl auristatin E (MMAE), a potent mitotic toxin, onto a monoclonal antibody (mAb) against CD6, an established T cell surface marker. Even though CD6 is present on all T cells, only the activated (pathogenic) T cells vigorously divide and thus are susceptible to the anti-mitotic MMAE-mediated killing via the CD6-ADC. We found CD6-ADC selectively killed activated proliferating human T cells and antigen-specific mouse T cells in vitro. Furthermore, in vivo, whereas the CD6-ADC had no significant detrimental effect on normal T cells in naïve CD6 humanized mice, the same dose of CD6-ADC, but not the controls, efficiently treated two pre-clinical models of autoimmune uveitis and a model of graft-versus-host disease. These results provide evidence suggesting that CD6-ADC could be further developed as a novel therapeutic agent for the selective elimination of pathogenic T cells and treatment of many T cell-mediated disorders.
Lingjun Zhang, Liping Luo, Jin Y. Chen, Rupesh Singh, William M. Baldwin III, David A. Fox, Daniel J. Lindner, Daniel F. Martin, Rachel R. Caspi, Feng Lin
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