The novel multiple sclerosis susceptibility gene ATXN1 regulates B cell receptor signaling in B-1a cells

Qin Ma, Alessandro Didonna
Molecular Brain 2021 January 21, 14 (1): 19
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) caused by complex gene-environment interactions. ATXN1 maps to 6p22.3, within the 233 loci associated with an increased risk of developing MS. Toxic gain-of-function mutations in ATXN1 cause the neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1). Conversely, ATXN1 loss-of-function is involved in Alzheimer's disease (AD) and tumorigenesis. We have recently shown that ATXN1 exerts a protective immunomodulatory activity in the MS model experimental autoimmune encephalomyelitis (EAE). Specifically, we demonstrated that mice lacking Atxn1 experience aggravated EAE due to aberrant B cell functions. Atxn1-null mice exhibit increased B cell proliferation with the concomitant expansion of specific B cell subsets including B-1a cells. This population of B cells is responsible for the production of natural immunoglobulins and has been associated with the etiology of multiple autoimmune diseases. To understand the role played by Atxn1 in these cells, we performed comprehensive transcriptomic profiling of Atxn1-null B-1a cells before and after stimulation with an encephalitogenic antigen. Importantly, we show that in this sub-population Atxn1 regulates immunoglobulin gene transcription and signaling through the B cell receptor (BCR).

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