Absence of ERAP1 in B Cells Increases Susceptibility to Central Nervous System Autoimmunity, Alters B Cell Biology, and Mechanistically Explains Genetic Associations between ERAP1 and Multiple Sclerosis.

Abstract

Hundreds of genes have been linked to multiple sclerosis (MS); yet, the underlying mechanisms behind these associations have only been investigated in a fraction of cases. Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an endoplasmic reticulum-localized aminopeptidase with important roles in trimming peptides destined for MHC class I and regulation of innate immune responses. As such, genetic polymorphisms in ERAP1 have been linked to multiple autoimmune diseases. In this study, we present, to our knowledge, the first mechanistic studies performed to uncover why polymorphisms in ERAP1 are associated with increased susceptibility to MS. Combining multiple mouse models of CNS autoimmunity with high-dimensional single-cell spectral cytometry, adoptive transfer studies, and integrative analysis of human single-cell RNA-sequencing datasets, we identify an intrinsic defect in B cells as being primarily responsible. Not only are mice lacking ERAP1 more susceptible to CNS autoimmunity, but adoptive transfer of B cells lacking ERAP1 into B cell-deficient mice recapitulates this susceptibility. We found B cells lacking ERAP1 display decreased proliferation in vivo and express higher levels of activation/costimulatory markers. Integrative analysis of single-cell RNA sequencing of B cells from 36 individuals revealed subset-conserved differences in gene expression and pathway activation in individuals harboring the MS-linked K528R ERAP1 single-nucleotide polymorphism. Finally, our studies also led us to create, to our knowledge, the first murine protein-level map of the CNS IL-10+ immune compartment at steady state and during neuroinflammation. These studies identify a role for ERAP1 in the modulation of B cells and highlight this as one reason why polymorphisms in this gene are linked to MS.