Importance of intestinal mucosal immunity and luminal bacterial cell wall polymers in the aetiology of inflammatory joint diseases.
The distal intestine contains bacterial cell wall polymers capable of inducing acute and chronic polyarthritis if systemically distributed. Parenteral injection of peptidoglycan-polysaccharide (PG-PS) polymers from certain bacterial species produces spontaneously relapsing erosive synovitis in susceptible rat strains, and normally subarthropathic amounts of PG-PS and lipopolysaccharide (endotoxin) can reactivate arthritis initially induced by PG-PS. These experimental results illustrate the inflammatory potential of luminal bacterial products and the importance of genetically determined host susceptibility factors in the pathogenesis of arthritis. Normally, luminal complexing by secretory IgA and an intact epithelial barrier limits uptake of luminal antigen; however, intestinal inflammation enhances mucosal uptake and systemic distribution of potentially injurious macromolecules, including PG-PS and lipopolysaccharide. Occult intestinal inflammation, which may be related to non-steroidal anti-inflammatory drugs or may be disease-associated, occurs in approximately two thirds of patients with rheumatoid arthritis, idiopathic reactive arthritis and ankylosing spondylitis. Enhanced mucosal permeability to macromolecules occurs in rheumatoid arthritis, enteric infections and idiopathic inflammatory bowel disease. Intestinal inflammation is associated with increased mucosal IgG production and circulating immune complexes. Hyperactive IgA synthesis occurs in many types of inflammatory joint disease. Polyclonal IgA is increased in rheumatoid arthritis, Sjögren's syndrome, ankylosing spondylitis, Reiter's syndrome, and reactive arthritis following Yersinia infection. Anti-Klebsiella IgA cross-reacts with HLA-B27 antigen, and antibodies to enteric bacteria are able to lyse lymphocytes from HLA-B27 patients with ankylosing spondylitis. Anti-Yersinia IgA is produced at the mucosa in increased quantities in patients who develop arthritis following Yersinia enteritis, possibly as a consequence of defective cellular immunity. Serum concentrations of IgA correlate with activity of rheumatoid arthritis and ankylosing spondylitis, and serum IgA immune complexes are associated with rheumatoid vasculitis, suggesting that IgA contributes to the pathogenesis of arthritis. We speculate that intestinal injury may also induce or perpetuate arthritis by systemic distribution of inflammatory mediators produced by intestinal immune effector cells.