Influenza and Hydroxychloroquine Shaping of Self-Antigen Presentation in Systemic Lupus Erythematosus

About This Grant

PROJECT SUMMARY/ABSTRACT Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease caused by loss of tolerance to intracellular self-antigens. Altered antigen presentation by major histocompatibility complex class II (MHC II) is implicated in SLE pathogenesis, yet how self-antigens reach MHC II and the disease-relevant factors that influence antigen processing remain poorly understood. Two factors that converge on antigen processing pathways and exert opposing effects on SLE are of particular interest: influenza A virus (IAV), a trigger of SLE severe flares, and hydroxychloroquine (HCQ), an SLE treatment that protects against flares. Preliminary data demonstrate that IAV infection of murine antigen presenting cells increases MHC II presentation of self-peptides derived from SLE autoantigens such as ribosomes and ribonucleoproteins. IAV is known to utilize non-classical endogenous MHC II processing pathways and HCQ modulates the cellular compartments involved in these pathways, suggesting a common inflection point for autoantigen presentation. The central hypothesis in this proposal is that IAV manipulates endogenous processing pathways to alter the MHC II self-immunopeptidome and promote autoimmunity, while HCQ's therapeutic effects result from inhibiting these same pathways. Aim 1 will utilize detailed pathway mapping to identify the endogenous MHC II processing pathways required for IAV- induced self-peptide presentation and targeted by HCQ. Aim 2 will connect changes in autoantigen presentation to clinical disease by determining the impact of IAV infection and HCQ treatment on the self-immunopeptidome and autoimmune responses in lupus-prone B6.Sle123 mice. These studies will be the first to examine endogenous MHC II antigen processing pathways in autoimmune disease and will provide mechanistic insight into how viral infections trigger SLE flares and how HCQ achieves its therapeutic effects. This work builds on the candidate's training as a pediatric rheumatologist and viral immunologist. As the work proceeds, she will gain expertise in cellular biology and microscopy, lupus mouse models, and bioinformatics for immunopeptidomics analysis. The mentor, Dr. Laurence Eisenlohr, is an internationally recognized expert in MHC II antigen processing with a strong commitment to mentorship and an extensive NIH funding track record. Experiments will be conducted at the Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, a collegial, collaborative, and state-of-the-art institution with exceptional resources in antigen presentation biology, autoimmunity, and proteomics. This professional development and training plan will position the candidate to become an independent physician-scientist investigating viral-autoimmune interactions that can be leveraged to develop precision immunotherapies for antigen presentation pathways in SLE and other autoimmune diseases.