There is a fundamental gap in understanding how ultraviolet (UV) light precipitates and exacerbates the symptoms of the autoimmune disorder lupus erythematosus (LE). This lack of knowledge is an important problem because it signifies a need for more mechanistic insight into LE photosensitivity and represents a barrier to predicting the severity of patient disease outcomes. The long-term goal is to better understand how the repair of UV-induced DNA damage controls human disease pathogenesis. The objective of this particular exploratory proposal is to examine how the small, excised, damage-containing DNA oligonucleotide (sedDNA) products of nucleotide excision repair impact the aberrant inflammatory and immune response pathways that define LE and to determine whether cutaneous LE patients develop autoantibodies against the proteins and sedDNAs that are involved in these signaling processes. The central hypothesis is that the association of sedDNAs with specific pattern recognition receptor proteins (PRRs) leads to the overstimulation or amplification of the autoimmune response in the skin of LE patients. This hypothesis has been derived from preliminary data and reports that a number of DNA-binding PRRs are present at higher levels in the skin and/or blood of LE patients. The rationale for the proposed research is that once the roles of sedDNAs and PRRs in LE photosensitivity is known, new strategies for diagnosing and treating LE may be developed. The investigators will test a novel hypothesis by pursuing the following three specific aims: 1) Identify the DNA-sensing inflammatory and immune response signaling proteins (PRRs) that associate with sedDNA;2) Characterize the role of nucleotide excision repair and DNA-sensing PRR genes in UV-mediated inflammatory and immune response signaling;and 3) Characterize LE patient autoantibodies against sedDNAs and sedDNA-binding proteins. The investigators will use novel methods for detecting sedDNAs in cultured human cells and mouse skin to determine the specific inflammatory and immune signaling pathways that sense and respond to sedDNAs. Cutaneous LE patient sera will then be used to characterize autoantibody reactivity towards these proteins and DNAs. This approach is innovative because it provides a new and exciting paradigm for understanding inflammatory and immune responses in LE patients. The proposed research is significant because it is expected to vertically advance and expand understanding of how UV contributes to the cutaneous and systemic manifestation of LE. Ultimately, this knowledge has the potential to improve the understanding of LE patient photosensitivity and lead to the development of new tools for diagnosing, classifying, and treating specific LE patient subtypes.
The proposed research is relevant to public health because it will examine how small DNA oligonucleotides that are generated by the nucleotide excision repair system following environmental exposures to ultraviolet (UV) light contribute to the development of autoimmune disorders such as lupus erythematosus. Thus, this project is relevant to the NIH's mission to increase the understanding of life processes and lay the foundation for prevention and treatment of human autoimmune diseases.