Crosstalk between B cells and neutrophils in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease without known cure that primarily affects synovial joints. RA has a prevalence of approximately 1% of the population worldwide. A vicious circle between two critical immune cell types, B cells and neutrophils, develops and promotes disease. Pathogenic anti‐citrullinated protein antibodies (ACPA) directed against a range of citrullinated epitopes are abundant in both plasma and synovial fluid of RA patients. In addition to stimulating numerous cell types, ACPA and other autoantibodies, notably rheumatoid factor, form immune complexes (ICs) that potently activate neutrophils. Attracted to the synovium by abundant chemokines, neutrophils are locally stimulated by ICs. They generate cytokines and release cytotoxic compounds including neutrophil extracellular traps (NETs), strands of decondensed chromatin decorated with citrullinated histones and granule‐derived neutrophil proteins, which are particularly abundant in the synovial fluid. In this way, neutrophils generate citrullinated epitopes and release peptidylarginine deiminase (PAD) enzymes capable of citrullinating extracellular proteins in the rheumatic joint, contributing to renewed ACPA generation. This review article focusses on the central function of citrullination, a post‐translational modification of arginine residues in RA. The discussion includes ACPA and related autoantibodies, somatic hypermutation‐mediated escape from negative selection by autoreactive B cells, promotion of the dominance of citrullinated antigens by genetic and lifestyle susceptibility factors and the vicious circle between ACPA‐producing pathogenic B cells and NET‐producing neutrophils in RA.

Neutrophils recruited to immunization sites initiating vaccine-induced antibody responses by locally expressing BAFF

“…Obviously, a positive feedback loop existed in the BAFF mediated B cell activation. Consequently, the neutrophil-derived BAFF activated the B cells to upregulate their CD40, enabling the B cells activate helper T cells to be more efficiently, and stimulated the B cells to differentiate into plasma cells, thus resulting in the enhanced antibody responses ( Karmakar and Vermeren, 2021 ). Hopefully, by focusing on the research of the role of the neutrophil-driving BAFF at the immunization sites and the B cell activation at an early stage after vaccination could help us in evaluating the efficacy of the vaccines on time, instead of traditionally assessing the induction of memory B cells (Bmem) for long-term vaccine-induced protection ( Ahmed and Slifka, 1998 , Bernasconi et al., 2003 , Mark et al., 2002 , Traggiai et al., 2003 , Yoshida et al., 2010 , Yuichi Aiba et al., 2010 ).…”

Restoring the Balance between Pro-Inflammatory and Anti-Inflammatory Cytokines in the Treatment of Rheumatoid Arthritis: New Insights from Animal Models

“…Lungs are constantly exposed to insults due to infections, injury, and inhalants, dust, silica, asbestos, and especially tobacco smoke [ 1 , 2 , 3 ]. In addition, bacterial infections in the oropharynx, leading to gingivitis or periodontal disease, are considered a possible key early factor (see reviews) [ 1 , 4 , 5 , 6 , 7 ]. The inflammatory responses that drive RA usually originate with autoimmune responses against normal, modified or immuno-mimetics of self-proteins that are often found within skeletal joints.…”

“…This molecule, the BCR, is important for activating B cells and also promotes the phagocytosis of its corresponding antigen. The internalized antigen is then processed, and its peptides become the dominant peptide on MHC II molecules that are presented to and activate CD4 T cells, which can ultimately amplify the immune response to the antigen [ 5 , 18 ].…”

“…Other cells, including macrophages and myeloid suppressor cells, can also produce these regulatory cytokines to control inappropriate or inflammatory responses. The tolerance that these cells impose can be overridden by infections and other challenges that disrupt the homeostatic balance and lead to the production of large amounts of acute phase cytokines (IL-1, IL-6, TNF-α), allowing responses to the microbial or modified antigens that mimic human antigens to initiate autoimmune responses [ 5 , 19 , 20 ].…”

Neutrophil Migratory Patterns: Implications for Cardiovascular Disease

“…However, with the persistence of the inflammatory process, neutrophils become necessary as parts of the resolution of inflammation, the initiation of wound healing, and the return of the system to homeostasis (Kolaczkowska and Kubes;Puhl and Steffens;Ma, 2021). Neutrophils have also been shown to modulate the effects of the adaptive immune system by manipulating cytokines necessary for both B-and T-cell survival and activation (Karmakar and Vermeren., 2021;Kvedaraite, 2021). Therefore, identifying the precise cellular mechanisms that regulate neutrophil trafficking and activation is of the utmost importance, especially when it comes to manipulating the immune response for a successful therapeutic benefit.…”