Antibody-dependent and -independent mechanisms of inflammatory arthritis

Abstract

Inflammatory arthritis encompasses a set of common diseases characterized by immune-mediated attack on joint tissues. Most but not all affected patients manifest circulating autoantibodies. Decades of study in human and animal arthritis have identified key roles for autoantibodies in immune complexes and through direct modulation of articular biology. However, joint inflammation can arise because of pathogenic T cells and other pathways that are antibody-independent. Here we review the evidence for these parallel tracks, in animal models and in humans, to explore the range of mechanisms engaged in the pathophysiology of arthritis and to highlight opportunities for targeted therapeutic intervention.

Figure 1. Intersection of murine arthritis models with the pathogenic sequence of inflammatory arthritis.

Inflammation in murine arthritis can arise through immune dysfunction arising at a wide variety of levels, ranging from errant T and B cell–driven antigen targeting to overexpression of downstream inflammatory mediators. Autoimmunity can translate into arthritis via antibody-dependent pathways, typically through IgG and immune complexes (ICs), but also independent of autoantibodies through the action primarily of pathogenic T lymphocytes. Murine models (red-lined gray boxes) illustrating each respective mechanism are indicated. CAIA, collagen antibody–induced arthritis; FcR, Fcγ receptor; C′, complement; Cit, citrullinated peptide; OVA, ovalbumin; Nɸ, neutrophil; Mɸ, monocyte/macrophage; ILC, innate lymphocyte; mast, mast cell; hTNF-Tg, human TNF–transgenic. Modified from Monach et al. (184). Illustrated by Mao Miyamoto.

Figure 2. Antibody-mediated mechanisms of inflammatory arthritis.

Joint inflammation mediated by antibodies can proceed via distinct and not mutually exclusive pathways. ICs formed in circulation can precipitate in joint tissue and trigger enhanced vascular permeability that enables entry of pathogenic antibodies into the joint. ICs/antibody clusters can form within the joint through binding to joint-intrinsic antigens such as collagen, blood-borne antigen deposited on cartilage, or antigens formed de novo in the inflamed milieu such as citrullinated peptides and platelet microparticles, the latter generating microparticle-associated immune complexes (mpICs). Independent of IC formation, antibodies can mediate pathology via binding to specific targets. For example, antibodies promote citrullination by altering the activation threshold of PADs and stimulate the development or activation of osteoclasts. In addition to promotion of bone erosions and local osteopenia, osteoclasts may promote further osteoclastogenesis and contribute to neutrophil recruitment via IL-8 and other mediators. Illustrated by Mao Miyamoto.

Figure 3. Antibody-independent processes in the initiation and perpetuation of inflammatory arthritis.

Multiple cell lineages contribute to the pathogenesis of inflammatory arthritis independent of antibodies. Murine studies implicate multiple lymphocyte subtypes in specific contexts, including CD4⁺ T cells, exFoxP3-converted Tregs, entheseal-resident T cells, and γδ T cells. CD8⁺ T cells and B cells/plasma cells are abundant in synovium but their role is unclear. Evidence for the presence and function of synovial T_RM cells is preliminary. Fibroblasts within the synovium are heterogeneous and contribute via mediator production and direct attachment and invasion, including into cartilage. Myeloid cells of multiple types participate actively in disease. Neutrophils appear essential for the normal evolution of chronic inflammatory arthritis in most contexts. Local resident macrophages, recruited monocytes, and newly differentiated macrophages are implicated both in propagation and in resolution of synovitis. Mast cells can initiate arthritis and are abundant in chronic synovitis, but their role in established arthritis is not well defined. Osteoclasts mediate bone erosion and can potentially amplify or even initiate joint inflammation. Downstream effector pathways include cytokines (e.g., TNF, IL-1, IL-6, IL-8, IL-17), chemokines such as ligands for the chemokine receptors CCR1 and CXCR2, lipid mediators such as leukotriene B₄, proteases, and direct tissue injury. Illustrated by Mao Miyamoto.