It has been proposed that the chronic inflammatory process of rheumatic diseases is the direct result of the persistence in tissue of toxic mucopeptide-C polysaccharide complexes from Group A streptococcal cell wails (1-3). In this concept, the tissue damage is produced by the direct toxicity of the mucopeptide moiety. This is supported by the observation that the isolated mucopeptide can induce a severe acute necrotic reaction, and the degree of acute toxicity is inversely related to the amount of residual polysaccharide (2). The polysaccharide, therefore, plays the dual role of protecting the mucopeptide from tissue lysozyme and masking the toxic property. Thus, the cell wall fragments can persist in tissue in a relatively innocuous state, and as the polysaccharide is gradually removed by tissue enzymes the mucopeptide is exposed to produce chronic irritation.One experimental model of this toxicity is a chronic, relapsing nodular lesion of the dermal connective tissue of rabbits which occurs over a period of at least 92 days following a single injection of a preparation of Group A streptococcal cell walls (3, 4). Chronic inflammatory lesions showing a comparable histologic process also have been produced in rabbit knee joints (1, 5), and mouse hearts (6). The joint lesions were produced by the intra-articular injection of sterile cell wall fragments and the active inflammation was demonstrable for at least 6 wk. Granulomatous lesions involving valves and myocardium were produced by intraperitoneal injection of much larger doses (about 10 rag) of the cell wall fragments.Heretofore, we have had only indirect evidence that the chronic lesions produced with streptococcal cell walls in these various models are directly related to persistence of cell wall material. This paper describes the relationship of the injected cell wall antigens to the various phases of the relapsing nodular lesion

Mice injected intraperitoneally with isolated cell wall fragments of Group A streptococci develop a carditis similar to that previously observed in mice injected with crude extracts of this organism. Neither the soluble cytoplasmic components of Group A streptococcal cells nor the nonfragmented cell walls produced carditis in this experimental model. Fluorescein and 125I-labeled antibodies specific for Group A streptococcal cell wall antigens were used to demonstrate that, for 5 wk after injection, cell wall material is localized around the sites of active lesions in the heart. In addition, the cell wall antigen accumulates in the liver, spleen, mediastinal lymph nodes, and the adjacent loose connective tissue, where it persists for at least 10 wk.

A single injection of isolated fragments of group A streptococcal cell walls into the joints of rabbits stimulated an initial acute reaction which was followed by a prolonged inflammatory process. The chronic process was characterized by hyperplasia of the synovial cells, diffuse infiltration of the villi by macrophages, and focal collections of lymphocytes in the stroma of the villi. These histological changes were similar to those seen in the early stages of rheumatoid arthritis. Antibodies specific for the mucopeptide and group-specific C polysaccharide antigens of group A streptococcal cell walls were labeled with either fluorescein or 125I, and were used to demonstrate antigen in the synovial tissues. The antigens persisted within macrophages for at least 5 weeks. Their presence correlated with the evolution of the chronic inflammatory process.

Specific chemical modification of group A polysaccharide antigen to the A-variant structure was demonstrated in the lymphoid organs of mice by autoradiography by use of radioantibodies specific for these structures. Both antigenic moieties persisted and were still' discerned 10 weeks after injection of the group A cell wall. In rabbit skin, the group A specificity was altered after a prolonged period. Unlike the situation for the mouse, polysaccharide A was not converted to A-variant structure, but another specificity common to both polysaccharides persisted at the site of injection. Mucopeptide, separated from the polysaccharide of group A cell walls, was eliminated from the site of injection in rabbit skin between 4 and 8 hr after injection. Group D streptococcal cell walls were also rapidly eliminated from tissue, and were no longer detectable 8 hr after injection into rabbit skin or 24 hr after injection into mice. The rapid degradation of these structures was correlated with their susceptibility to lysozyme in vitro and was in contrast to the prolonged persistence of group A cell walls, which were completely resistant to egg white lysozyme. This persistence in tissue correlated with the capacity of group A cell wall fragments to induce a chronic inflammatory process, whereas the isolated mucopeptide or group D cell walls produced only an acute necrotoxic reaction.

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