Abstract
Natural antibodies, particularly natural IgM, are proved to play indispensable roles in the immune defenses against common infections. More recently, the protective roles of these natural IgM were also recognized in autoimmune diseases. They are mainly produced by B-1 and innate-like B cells (ILBs). Human CD19+CD27+IgD+ B cells, also termed as un-switched memory B cells, were proposed to be a kind of ILBs. However, functional features and characteristics of these cells in rheumatoid arthritis (RA) remained poorly understood. In this study, we found that human CD27+IgD+ B cells could produce natural antibody-like IgM. Under RA circumstance, the frequencies of these cells were significantly decreased. Moreover, the IgM-producing capacities of these cells were also dampened. Interestingly, the BCR repertoire of these cells was altered in RA, demonstrating decreased diversity with preferential usage alteration from VH3-23D to VH1-8. Single cell sequencing further revealed the proinflammatory biased features of these cells in RA. These CD27+IgD+ B cells were negatively correlated with RA patient disease activities and clinical manifestations. After effective therapy with disease remission in RA, these cells could be recovered. Taken together, these results have revealed that CD27+IgD+ B cells were impaired in RA with dysfunctional features, which might contribute to the disease perpetuation.
Highlights
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by hyperplasia of synovial fibroblasts and variable degrees of bone and cartilage erosion, leading to impairment of joint function [1]
The variable region of these IgM heavy (μ) chain (VH) showed preferential usage as shown below, yet with low level of somatic hypermutation (3.18 ± 1.58%). These results showed that human CD27+IgD+ B cells could produce natural antibody-like IgM without antigen encounter, demonstrating polyreactivity with low affinity and VH preferential usage with low mutation
Since CD27+IgD+ B cells were decreased in rheumatoid arthritis (RA) patients and negatively correlated with the disease activity, we further evaluated whether these cells would be recovered after effective therapy
Summary
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by hyperplasia of synovial fibroblasts and variable degrees of bone and cartilage erosion, leading to impairment of joint function [1]. Citrullination and anti-citrullinated protein antibodies (ACPAs) have been studied extensively [2]. These autoantibodies could be detected as long as 14 years before the onset of. The high-affinity IgG autoantibodies contribute directly to RA pathogenicity by multiple mechanisms. ACPAs were proved to induce osteoclastogenesis and bone-resorption directly via an IL-8-dependent mechanism, exacerbating the disease progression [4]. Some IgG autoantibodies are pathogenic, mounting evidence indicates that specialized classes of IgM natural antibodies exist, with properties that can oppose the development of RA
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