Examining the mechanisms underlying Libby Amphibole associated autoimmunity

Despite decades of research, the mechanistic understanding of asbestos related diseases, and especially asbestos-associated autoimmunity, remains incomplete. Since autoimmune disease (AID) is chronic and often fatal, there exists a critical need for novel therapeutics designed to slow or prevent disease development. However, without a better understanding of the molecular mechanisms precipitating autoantibody production and function, development of such therapeutics is unlikely. Citrullination of native proteins has been described in multiple AIDs and has been suggested as a mechanism by which neo-antigens are generated. Citrullination, or the post-translational modification of arginine to citrulline, can alter protein function and is facilitated by the peptidylarginase deiminase (PAD) enzyme family. Our preliminary data show increased expression of citrullinated residues and PAD4 in the lungs of mice exposed to Libby amphibole (LA) asbestos. We further show that citrullination (cit) enhances the binding of asbestos- associated autoantibodies to mesothelial cells, and we identify plasminogen (PLG) as a potential PAD4 target. Work by us and others has implicated anti-PLG antibodies in several fibrotic disorders, including LA-associated pleural fibrosis. Our preliminary data further show that anti-PLG antibodies promote the secretion of the collagen cross-linking enzyme Lysyl oxidase- like 1 (LOXL1), thus suggesting a mechanistic link between these autoantibodies and fibrosis. Given these data, we formulated our central hypothesis that LA exposure induces PAD4 expression and protein citrullination associated with autoimmune responses and that LA- associated anti-PLG antibodies exert their pathogenic effects by modulating LOXL1 activity. We will test this hypothesis with three specific aims designed to 1) confirm PAD4 enzyme contribution to LA-induced citrullination and autoimmune responses, 2) identify additional mesothelial protein targets of citrullination, and 3) determine the mechanisms underlying collagen I deposition associated with anti-PLG antibodies. Lastly, we will use a Vertically Integrated Project (VIP) model to engage undergraduate students in authentic research experiences while providing mentoring opportunities to graduate students. Together these data will 1) provide important information concerning the role of PAD4 in driving LA-associated citrullination and AID, 2) identify novel cellular targets of asbestos-associated autoantibodies, and 3) provide mechanistic data concerning anti-PLG induced fibrosis, while also providing opportunities for 20-25 undergraduate and 4-6 graduate students to engage in authentic, rigorous biomedical research at a university with a strong commitment to experiential learning. Project Number: 1R16AI192264-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Kinta Serve | Institution: IDAHO STATE UNIVERSITY, POCATELLO, ID | Award Amount: $138,803 | Activity Code: R16 | Study Section: Special Emphasis Panel[ZAI1 KLM-D (M1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R16AI19226401