059 HLA drives both autoimmune activation and protection in pemphigus

Abstract

Pemphigus vulgaris (PV) is tightly correlated with HLA types DRB1*0402 and DQB1*0503, but their full functional importance remains to be determined. Prior work by our group evaluated genome-wide expression profiles in patients and healthy controls by microarray. A distinct separation was observed by unsupervised hierarchical clustering between PV patients (both matched and unmatched for the PV-associated HLA risk allele) and HLA-matched controls based upon the most variable genes in the dataset, and a PV-associated “disease signature” of differentially expressed genes was determined. In a new analysis presented here, we further include transcriptional profiles from HLA-unmatched controls that do not carry the PV associated HLA risk alleles as compared to PV patients and HLA matched controls. Surprisingly, when all 3 sample types are examined together the HLA-matched healthy individuals group more closely with PV patients carrying DRB1*0402 or DQB1*0503, while PV patients negative for these risk alleles group together with HLA-unmatched controls. These data highlight HLA as a key driver of gene expression, overriding even disease status, leading us to define a PV-associated “HLA signature”. Ontology enrichment analysis of the “HLA signature” reveals a large overlap with the PV “disease signature” in pathways and processes related to immune/inflammatory response, cytoskeletal reorganization, MAPK signaling, cell adhesion and apoptosis, indicating that even among healthy individuals the presence of PV HLA risk alleles results in (at least partial) autoimmune activation. There are additional upregulated pathways and processes in the “disease signature” that are absent in the “HLA signature”, i.e. lacking in “at risk”, but healthy, individuals. We have previously reported that healthy individuals carrying PV-associated HLA alleles may be “protected” from progression to disease by the down-regulation of several “disease signature” associated genes/pathways. We propose that HLA status is central to both autoimmune activation and protection in PV.