B Cells on the Stage of Inflammation in Juvenile Idiopathic Arthritis: Leading or Supporting Actors in Disease Pathogenesis?

Abstract

Juvenile idiopathic arthritis (JIA) is a term that collectively refers to a group of chronic childhood arthritides, which together constitute the most common rheumatic condition in children. The International League of Associations for Rheumatology (ILAR) criteria define seven categories of JIA: oligoarticular, polyarticular rheumatoid factor (RF) negative (RF-), polyarticular RF positive (RF+), systemic, enthesitis-related arthritis, psoriatic arthritis, and undifferentiated arthritis. The ILAR classification includes persistent and extended oligoarthritis as subcategories of oligoarticular JIA, but not as distinct categories. JIA is characterized by a chronic inflammatory process affecting the synovia that begins before the age of 16 and persists at least 6 weeks. If not treated, JIA can cause significant disability and loss of quality of life. Treatment of JIA is adjusted according to the severity of the disease as combinations of non-steroidal anti-inflammatory drugs (NSAIDs), synthetic and/ or biological disease modifying anti-rheumatic drugs (DMARDs). Although the disease etiology is unknown, disturbances in innate and adaptive immune responses have been implicated in JIA development. B cells may have important roles in JIA pathogenesis through autoantibody production, antigen presentation, cytokine release and/ or T cell activation. The study of B cells has not been extensively explored in JIA, but evidence from the literature suggests that B cells might have indeed a relevant role in JIA pathophysiology. The detection of autoantibodies such as antinuclear antibodies (ANA), RF and anti-citrullinated protein antibodies (ACPA) in JIA patients supports a breakdown in B cell tolerance. Furthermore, alterations in B cell subpopulations have been documented in peripheral blood and synovial fluid from JIA patients. In fact, altered B cell homeostasis, B cell differentiation and B cell hyperactivity have been described in JIA. Of note, B cell depletion therapy with rituximab has been shown to be an effective and well-tolerated treatment in children with JIA, which further supports B cell intervention in disease development.

The immune landscape of the inflamed joint defined by spectral flow cytometry

“…A restricted number of markers specific to B cells in inflammatory environments were included in this phenotyping panel, limiting comparisons to other studies in inflammatory disease (77). Nevertheless, we were able to confirm reduced B cell numbers in JIA SF (8), additionally displaying SF B cells to be highly activated, in agreement with the hyperactivity of B cells recently suggested as a possible pathogenesis factor of JIA (29, 78).…”

“…As we confirmed, B cell frequency in the inflamed joint is dramatically decreased compared to PB (Figure 3A)(8, 10). Despite this, it has been suggested that B cell hyperactivity might contribute to JIA pathogenesis (29). Indeed, B cell cluster 18, which was found almost exclusively in the joint (47.3±5.5% of SF B cells vs 3.1±1.4% of HC PB and 2.7±0.3% of JIA PB B cells, Figure 3D), were characterised by high CD71 expression (Figure 3B-D), a transferrin receptor upregulated on activated lymphocytes.…”

T lymphocytes-related cell network in the pathogenesis of juvenile idiopathic arthritis: a key point for personalized treatment

“…Indeed, although no specific autoantibodies have been described in JIA, a significant fraction of patients displays the presence of antinuclear antibodies (ANA), rheumatoid factor (RF) or anticitrullinated antibodies (ACPA). RF and ACPA are detected in patients with higher risk to develop severe disease and to progress to adult RA [27], while ANA are mainly detected in oligo- and poly-articular JIA, and target several cellular antigens commonly hidden but exposed during apoptotic processes. The pathogenic role of autoantibodies in JIA is still debated, although their presence has been related to the development of ectopic lymphoid structures in synovial tissue [28].…”

Synovial Monocytes Drive the Pathogenesis in Oligoarticular Juvenile Idiopathic Arthritis via IL-6/JAK/STAT Signalling and Cell-Cell Interactions

“…The affected joint is characterized by hyperplasia, inflammation, and presence of infiltrating immune cells from both the innate and adaptive immune system (4). T-and B-cells are thought to play a role, given the genetic relationship to MHC class II alleles and the presence of ANAs (4)(5)(6). Though, the contribution of members from the innate immune system, such as monocytes, is becoming increasingly recognized (7)(8)(9)(10).…”