8074 Investigating Viral Infections, Systemic Inflammation, and their Complex Interplay in Type 1 Diabetes Pathogenesis

Abstract Disclosure: K. Girdhar: None. E. Elko: None. A. Pina: None. M. Atkinson: None. J. Ludvigsson: None. J. Ladner: None. E. Altindis: None. Type 1 diabetes (T1D) is an autoimmune disorder characterized by the immune-mediated destruction of insulin-producing beta cells. The etiological factors triggering the immunogenicity of endogenous β-cell antigens remain a focal point of investigation. Viral infections, particularly enteroviruses, coxsackieviruses, and rotaviruses, have been proposed as potential contributors to T1D onset and progression. However, the causal relationship between viral infections and T1D pathogenesis remains elusive. To address this, we conducted an in-depth analysis of viral infection histories of T1D patients and pediatric T1D progressors compared to the controls. To this end, we employed highly multiplexed serology using PepSeq sequencing, an in vitro platform designed for conducting proteomic assays against customizable targets via DNA-barcoded peptides. Utilizing samples from the All Babies in Sweden (ABIS) study (n=58) and the TrialNet study (n=116 new-onset T1D, n=25 established T1D, n=128 controls), we assessed seropositivity against 79 different human viruses. Contrary to previous reports, no significant differences were identified in viral infection histories between T1D individuals and controls. Subsequent analyses of enriched Peptide Count and Viral Homology Search (VHS) species provided further confirmation of the absence of distinctions in T1D progression. Next, we determined whether there are any differences in the markers of systematic inflammation in spite of their similar viral history profile. Therefore, we employed Luminex assays to investigate cytokine profiles in established T1D individuals (n=25). While we could not identify any differences when we compared T1D patients to controls, we identified notable sex-specific differences. Anti-inflammatory cytokines (IL-4, IL-13, IL-22) were lower in female T1D patients compared to female controls. Likewise, female T1D patients had higher pro-inflammatory cytokines (IL-17E, TNF-β). On the other hand, male T1D patients exhibited increased levels of epidermal growth factor and platelet-derived growth factor compared to male controls, with IL-22 uniquely elevated. Our findings challenge the direct association between viral infections and T1D, highlighting the importance of investigating alternative factors. Moreover, the observed sex-specific cytokine alterations underscore the complex interplay between immune responses and T1D, emphasizing the need for sex-specific therapeutic strategies. This research contributes valuable insights into the intricate dynamics of viral infections, systemic inflammation, and their potential roles in T1D pathogenesis. Presentation: 6/2/2024