Disease Association and Arthritogenic Potential of Circulating Antibodies against the a1,4-Polygalacturonic Acid Moiety

Much progress has been made in recent years on the diagnostic value, Ag specificity, and pathogenic roles of autoantibodies correlated to the development of rheumatoid arthritis (RA) in humans. However, carbohydrate Ag-specific autoantibodies that may also play important roles in RA have largely been ignored. In this article, we report that serum levels of Abs capable of recognizing a1,4-polygalacturonic acid [(PGA); major structural component of pectin] strongly correlate with RA in humans. The measurements of PGA-specific Abs (PGA-Abs) in sera are comparable to rheumatoid factors and anti–cyclic citrullinated peptide Abs as serological diagnostic markers for RA in terms of sensitivity and specificity. Immunohistochemical staining results indicate that the PGA-Abs selectively bound synovial membrane cells and chondrocytes in the joints of both humans and rabbits (but not rodents). Induction of PGA-Abs by s.c. immunization of rabbits with carrier protein–conjugated synthetic PGA led to severe inflammatory reactions (synovial hyperplasia, small vessel proliferation, and inflammatory cell infiltration) in the joints. Injection of affinity purified anti-PGA IgG into the synovial cavity of rabbits resulted in accumulation of proinflammatory cytokines such as TNF-a, IL-8, and IL-1b in synovial fluid, as well as local pathological damage. We conclude that the PGA–cross-reactive moiety represents a major autoantigen in the joints and can be targeted by autoantibodies capable of triggering arthritogenic responses in vivo. R heumatoid arthritis (RA) is a complex chronic inflam-matory autoimmune disease that affects ∼ 0.5% of the adult population worldwide (1, 2). It has long been known to be associated with autoantibodies, most notably rheu-matoid factors (RFs) and anti–cyclic citrullinated peptide Abs (CCP-Abs), both of which have been widely used as diagnostic markers for RA since their discovery (3–6). However, association of autoantibodies in RA is likely to extend well beyond RFs and CCP-Abs. Many RA patients have circulating Abs against heterogeneous nuclear ribonucleoprotein A2, type II collagen, or heat shock proteins (7–11). Furthermore, simultaneous assessment of Ab specificities using autoantigen microarrays has revealed multiple reactivities in patient sera (12–14). Monach and colleagues (15) have recently reported that IgG fractions purified from joint immune complexes bound a diverse subset of proteins and pep-tides from synovium and cartilage. Elevations of a variety of anti-glycan Abs, including IgG, IgA, IgE, and IgM classes, have been demonstrated in a number of inflammatory autoimmune diseases (16–19). However, of studies on the diagnostic value, Ag speci-ficity, and pathogenic potential of autoantibodies correlated to the development of RA in humans, …