Using Immunosignatures to Identify LCMV Infection and an Investigation into Autoimmunity in a Mouse Model of Noonan Syndrome

Quantifying and tracking viruses can be complicated for a number of reasons. Viruses can move rapidly through populations, leave little trace, or if a trace is left, be difficult to discern from similar viruses, and they can mutate within hosts to name a few. Lymphocytic choriomeningitis virus (LCMV) is a prime example of this, as it has many strains, however they segregate into acute and chronic viral variants based on a particular mutation. Described is a new methodology to identify LCMV infections in mice following viral clearance through differentiating antibody repertoire from serum on random peptide arrays. This technology was utilized to distinguish LCMV Arm and LCMV C-13 infections in mice, and also acute and chronic infections caused by low and high doses of LCMV C-13. Noonan syndrome is a hereditary disorder resulting in multiple physical impairments in afflicted patients as well as frequent neurological impairments. Multiple gene mutations can result in Noonan syndrome including the rapidly accelerated fibrosarcoma one (RAF1) gene, a gene critical in the rat sarcoma/mitogen activated protein kinase (RAS/MAPK) cell signaling pathway. The incidence of autoimmunity in patients with Noonan syndrome is estimated to be roughly 14% compared to 2-5% for an average population. As the RAS/MAPK is heavily involved with immune functions, characterizing the immune system in Noonan syndrome model mice could provide valuable insights. Mice expressing a Raf1L613V gain-of-function mutation were used to model Noonan syndrome in order to investigate the root cause of autoimmunity. Elevated numbers of splenocytes and thymocytes were found in the mutant mice compared to wild type mice. Also, higher rates of inflammatory cytokine production were found in cells from mutant mice infected with LCMV, particularly TNFa and IFNy, two hallmark cytokines in the pathogenesis of both SLE and Hashimoto thyroiditis, two commonly occurring autoimmune disorders in Noonan syndrome patients. This led to the hypothesis of autoreactive cells potentially escaping negative selection in the thymus which could be responsible for autoimmunity.