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Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis
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Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis
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Journal Article
Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis
2017
Overview
Key Points
Anti-citrullinated protein antibodies (ACPAs) bind specifically to osteoclasts and osteoclast precursors in the normal bone and joint compartment; such binding promotes osteoclast differentiation and osteolytic function
in vitro
Osteoclast differentiation is dependent on the citrullination of proteins by protein-arginine deiminases
Both Fc-dependent and Fc-independent mechanisms are involved in ACPA-mediated osteoclast activation
Binding of ACPAs to osteoclasts induces the production of the chemokine IL-8
Infusion of ACPAs into mice causes IL-8-dependent bone loss and IL-8-mediated pain behaviour
The unique role of citrullination in osteoclast differentiation and ACPA-induced osteoclast activation might explain important features of the gradual development of rheumatoid arthritis, including why the joints are targeted
How and why systemic autoimmunity targets the joints in rheumatoid arthritis remains a major unanswered question. In this Review, Catrina
et al
. discuss the evidence for a driving role for osteoclasts in the homing of autoimmunity to the joints.
A key unanswered question in the pathophysiology of rheumatoid arthritis (RA) is how systemic autoimmunity progresses to joint-specific inflammation. In patients with seropositive RA (that is, characterized by the presence of autoantibodies) evidence is accumulating that immunity against post-translationally modified (such as citrullinated) autoantigens might be triggered in mucosal organs, such as the lung, long before the first signs of inflammation are seen in the joints. However, the mechanism by which systemic autoimmunity specifically homes to the joint and bone compartment, thereby triggering inflammation, remains elusive. This Review summarizes potential pathways involved in this joint-homing mechanism, focusing particularly on osteoclasts as the primary targets of anti-citrullinated protein antibodies (ACPAs) in the bone and joint compartment. Osteoclasts are dependent on citrullinating enzymes for their normal differentiation and are unique in displaying citrullinated antigens on their cell surface in a non-inflamed state. The binding of ACPAs to osteoclasts releases the chemokine IL-8, leading to bone erosion and pain. This process initiates a chain of events that could lead to attraction and activation of neutrophils, resulting in a complex series of proinflammatory processes in the synovium, eventually leading to RA.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
