Peptidylarginine Deiminase 2 Autoantibodies Are Linked to Less Severe Disease in Multiple Sclerosis and Post-treatment Lyme Disease.

ABSTRACT

Background: Peptidylarginine deiminase 2 (PAD2) mediates the post-translational conversion of arginine residues in proteins to citrullines and is highly expressed in the central nervous system (CNS). Dysregulated PAD2 activity has been implicated in the pathogenesis of several neurologic diseases, including multiple sclerosis (MS). In this study, we sought to define the cellular and regional expression of the gene encoding for PAD2 (i.e. PADI2) in the human CNS using publicly available datasets and evaluate whether anti-PAD2 antibodies were present in patients with various neurologic diseases. Methods: A total of 491 study participants were included in this study 91 people with MS, 32 people with neuromyelitis optica (NMO), 281 people with post-treatment Lyme disease (PTLD), and 87 healthy controls. To measure PADI2 expression in the CNS from healthy individuals, publicly available tissue and single cell RNA sequencing data was analyzed. Anti-PAD2 antibodies were measured in the serum of study participants using anti-PAD2 ELISA. Clinical and demographic variables were compared according to anti-PAD2 antibody positivity for the MS and PTLD groups and correlations between anti-PAD2 levels and disease severity were examined. Results: PADI2 expression was highest in oligodendrocytes (mean ± SD; 6.4 ± 2.2), followed closely by astrocytes (5.5 ± 2.6), microglia/macrophages (4.5 ± 3.5), and oligodendrocyte precursor cells (3.2 ± 3.3). There was an increased proportion of anti-PAD2 positivity in the MS (19.8%; p = 0.007) and PTLD groups (13.9%; p = 0.057) relative to the healthy controls (5.7%), and these antibodies were not detected in NMO patients. There was a modest inverse correlation between anti-PAD2 levels and disease severity in people with MS (τ = -0.145, p = 0.02), with levels being the highest in those with relapsing-remitting disease. Similarly, there was a modest inverse correlation between anti-PAD2 levels and neurocognitive score (τ = -0.10, p = 0.027) in people with PTLD, with difficulty focusing, memory changes, fatigue, and difficulty finding words contributing most strongly to the effect. Conclusion: PADI2 expression was observed in diverse regions and cells of the CNS, and anti-PAD2 autoantibodies were associated with less severe symptoms in subsets of patients with MS and PTLD. These data suggest that anti-PAD2 antibodies may attenuate inflammation in diseases of different etiologies, which are united by high PADI2 expression in the target tissue.