Inflammation
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal disease without any cure. Both human disease and animal models demonstrate dysregulated wound healing and unregulated fibrogenesis in a background of low-grade chronic T lymphocyte infiltration. Tissue-resident memory T cells (Trm) are emerging as important regulators of the immune microenvironment in response to pathogens, and we hypothesized that they might play a role in regulating the unremitting inflammation that promotes lung fibrosis. Herein, we demonstrate that lung-directed immunotherapy, in the form of i.n. vaccination, induces an antifibrotic T cell response capable of arresting and reversing lung fibrosis. In mice with established lung fibrosis, lung-specific T cell responses were able to reverse established pathology — as measured by decreased lung collagen, fibrocytes, and histologic injury — and improve physiologic function. Mechanistically, we demonstrate that this effect is mediated by vaccine-induced lung Trm. These data not only have implications for the development of immunotherapeutic regimens to treat IPF, but also suggest a role for targeting tissue-resident memory T cells to treat other tissue-specific inflammatory/autoimmune disorders.
Authors
Samuel L. Collins, Yee Chan-Li, MinHee Oh, Christine L. Vigeland, Nathachit Limjunyawong, Wayne Mitzner, Jonathan D. Powell, Maureen R. Horton
Abstract
IL-1β is a well-established inducer of both insulin resistance and impaired pancreatic islet function. Despite this, findings examining IL-1 receptor deficiency or antagonism in in vivo animal models, as well as in clinical studies of type 2 diabetic (T2D) patients, have led to conflicting results, suggesting that the actions of IL-1β on glycemic control may be pleiotropic in nature. In the present work, we find that the ability of IL-1β to amplify glucose-stimulated insulin secretion from human islets correlates with donor BMI. Islets from obese donors are sensitized to the insulinotropic effects of this cytokine, whereas the stimulatory effects of IL-1β are lost in islets from obese T2D patients, suggesting a role for IL-1 signaling in islet compensation. Indeed, mice deficient in IL-1 receptor type I become glucose intolerant more rapidly than their WT littermates and have impaired secretory responses during the acute stages of inflammatory and metabolic stress induced by LPS and high-fat diet, respectively. IL-1β directly enhances β cell insulin secretion by increasing granule docking and soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complex formation at the plasma membrane. Together, our study highlights the importance of IL-1β signaling in islet compensation to metabolic and inflammatory stress.
Authors
Catherine Hajmrle, Nancy Smith, Aliya F. Spigelman, Xiaoqing Dai, Laura Senior, Austin Bautista, Mourad Ferdaoussi, Patrick E. MacDonald
Abstract
Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatological condition. Although it has been proposed that JIA has an autoimmune component, the autoantigens are still unknown. Using biochemical and proteomic approaches, we identified the molecular chaperone transthyretin (TTR) as an antigenic target for B and T cell immune responses. TTR was eluted from IgG complexes and affinity purified from 3 JIA patients, and a statistically significant increase in TTR autoantibodies was observed in a group of 43 JIA patients. Three cryptic, HLA-DR1–restricted TTR peptides, which induced CD4+ T cell expansion and IFN-γ and TNF-α production in 3 out of 17 analyzed patients, were also identified. Misfolding, aggregation and oxidation of TTR, as observed in the synovial fluid of all JIA patients, enhanced its immunogenicity in HLA-DR1 transgenic mice. Our data point to TTR as an autoantigen potentially involved in the pathogenesis of JIA and to oxidation and aggregation as a mechanism facilitating TTR autoimmunity.
Authors
Cristina C. Clement, Halima Moncrieffe, Aditi Lele, Ginger Janow, Aniuska Becerra, Francesco Bauli, Fawzy A. Saad, Giorgio Perino, Cristina Montagna, Neil Cobelli, John Hardin, Lawrence J. Stern, Norman Ilowite, Steven A. Porcelli, Laura Santambrogio
Abstract
BACKGROUND. Kidney transplant biopsies offer an opportunity to understand the pathogenesis of organ fibrosis. We studied the relationships between the time of biopsy after transplant (TxBx), histologic fibrosis, diseases, and transcript expression.
METHODS. Expression microarrays from 681 kidney transplant indication biopsies taken either early (
RESULTS. Fibrosis was absent at transplantation but was present in some early biopsies by 4 months after transplant, apparently as a self-limited response to donation implantation injury not associated with progression to failure. The molecular phenotype of early biopsies represented the time sequence of the response to wounding: immediate expression of acute kidney injury transcripts, followed by fibrillar collagen transcripts after several weeks, then by the appearance of immunoglobulin and mast cell transcripts after several months as fibrosis appeared. Fibrosis in late biopsies correlated with injury, fibrillar collagen, immunoglobulin, and mast cell transcripts, but these were independent of time. Pathway analysis revealed epithelial response-to-wounding pathways such as Wnt/β-catenin.
CONCLUSION. Fibrosis in late biopsies had different associations because many kidneys had potentially progressive diseases and subsequently failed. Molecular correlations with fibrosis in late biopsies were independent of time, probably because ongoing injury obscured the response-to-wounding time sequence. The results indicate that fibrosis in kidney transplants is driven by nephron injury and that progression to failure reflects continuing injury, not autonomous fibrogenesis.
TRIAL REGISTRATION. INTERCOM study (www.clinicalTrials.gov; NCT01299168).
FUNDING. Canada Foundation for Innovation and Genome Canada.
Authors
Jeffery M. Venner, Konrad S. Famulski, Jeff Reeve, Jessica Chang, Philip F. Halloran
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