The causal link between Group A streptococcal infection and rheumatic fever is firmly established, but the underlying mechanisms of the disease remain a subject of debate. Moreover, the range of pathologic lesions induced by streptococci remains inadequately defined. One approach to the study of these issues is to inject Group A streptococcal components into experimental animals and observe their effects. The effects of injecting SCW fragments have been studied in several species. Injection of SCW into mice induces rheumatic fever-like cardiac lesions (Cromartie and Craddock, 1966). Transient arthritis (Koga et al., 1985) and hepatic granulomas (Chen et al., 1992) have also been observed. The development of pathology in mice is highly dependent upon both host and bacterial factors (Chen et al., 1992; Koga et al., 1985). Injection of strepto-coccal cell wall materials into rabbits occasionally induces chronic arthritis (Stein et al.,
1973). Rats, however, have been the experimental animal of choice for most investigations of the effects of SCW injections. This focus on rats was stimulated by the observations of Cromartie et al. (1977) whereby outbred Sprague-Dawley rats develop chronic erosive arthritis, resembling rheumatoid arthritis, when injected with a single intraperitoneal injection of an aqueous suspension of SCW fragments. Strep-tococcal cell wall arthritis in rats is widely regarded as an excellent experimental model for the investigation of many aspects of acute and chronic inflammation. The model exhibits numerous characteristics that resemble rheumatoid arthritis in humans, and, as a consequence, it is commonly listed in support of the hypothesis that rheumatoid arthritis may have a microbial etiology (Crofford and Wilder, 1992; Taylor et al., 1994). The model is particularly valuable, in comparison with other rat arthritis models such as adjuvant arthritis (unit 15.4) and collagen arthritis (unit 15.5), because the cell walls that are used to induce arthritis can be easily detected and measured in host tissues, and the resulting host response evaluated (Allen et al., 1985; Anderle et al., 1985; Fox et al., 1982). Detailed investigation of etiopathogenetic mechanisms are possible because the investigator can control the time of onset and kinetics of disease expression. These features make the model very valuable for studies of critical cell wall factors, host genetics, pathogenesis, and various therapies of acute and chronic erosive arthritis.
The SCW arthritis model is a prominent example of a group of bacterial cell wall-induced arthritides in rats. In addition to Group A SCW fragments, cell wall fragments from other types of streptococci (Abd et al, 1990), from lactobacilli (Lehman et al., 1983), and from a variety of enteric anaerobes also have arthritogenic potential (Severijnen et al., 1988, 1990; Stimpson et al., 1986). These observations have led to numerous studies attempting to define the characteristics of cell walls that render them arthritogenic.
Cell walls consist of two major components: peptidoglycan (PG) linked to a group-specific polysaccharide (PS). Peptidoglycan is a large biopolymer, made up of long amino sugar chains, cross-linked by oligopeptides. The amino sugar chains consist of alternating N-acetylmuramic acid and N-acetyl-D-glu-cosamine, coupled by P-1,4 bonds. The car-boxyl group of muramic acid is substituted by an oligopeptide, cross-linked directly or via an interpeptide bridge to adjacent peptide subunits. The peptide moiety contains alternating l- and D-amino acids. The group-specific polysaccharide is covalently coupled to the PG and protects it from degradation. In Group A SCW, the PS consists of polyrhamnose chains to which N-acetylglucosamine is attached. The PS component differs markedly among different bacterial species (Schleifer and Kandler, 1972).
Peptidoglycans have several potent biological activities, which have been reviewed by Dziarski (1986), including complement activation, macrophage activation, and polyclonal B cell stimulation. Group-specific PS functions as an antigenic moiety, but the maj or role of PS appears to be that of limiting enzymatic degradation of the attached PG component. Thus, PG-PS fragments from different bacteria may have markedly different properties.
The development of chronic arthritis, after systemic injection of an aqueous suspension of SCW PG-PS fragments, appears to depend upon the capacity of the fragments (1) to deposit in joint tissues; (2) to persist in tissues, including the joints, for prolonged periods of time; and (3) to stimulate macrophage and T cell-dependent proinflammatory mechanisms in thejoints (Abd et al., 1990; Allen et al., 1985; Anderle et al., 1985; Bristol et al., 1993; Case et al., 1989; Schwab and Smialowicz, 1975; Van Den Broek et al., 1992a,b; Wilder et al., 1987; Yocum et al., 1988; Yoshino et al., 1991). Arthritogencity of Group A SCW PG-PS fragments is also strongly affected by their size distribution. Very large fragments (>500 x 106 Da) do not deposit in joints, or do so extremely slowly after systemic injection; very small fragments (<5 x 106 Da) do not persist in joint tissues and are weak stimulators of macrophage cytokine production (Fox et al., 1982). Tissue persistence and arthritogenicity of Group A SCW PG-PS fragments may be facilitated by their relative resistance to lysozyme, in contrast to PG-PS fragments derived from Streptococcus mutans, which are highly lysozyme sensitive. PG-PS fragments from S. mutans induce only transient, acute arthritis. Investigators studying PG-PS fragments from other types of bacteria have questioned the importance of lysozyme resistance to arthritogencity (Severi-jnen et al., 1990). Most investigators, however, agree that tissue persistence of the PG-PS fragments is an important element in the induction of chronic inflammatory disease.
The development of SCW arthritis is strongly influenced by genetic factors (Wilder et al., 1982). For example, inbred Lewis rats (Table 15.10.1) are highly susceptible to acute and chronic arthritis, whereas WKY, F344, and BUF inbred rats are relatively resistant. These differences in susceptibility are under poly-genic control (R. Wilder, unpub. observ.). The extreme susceptibility to arthritis of Lewis rats, as compared to F344 rats, is related, in part, to their blunted secretion of corticosterone, which is secondary to a global defect in the hypotha-lamic-pituitary-adrenal axis (Sternberg et al., 1989a,b; Calogero et al., 1992). Inflammation in Lewis rats, which is similar to that observed in humans with rheumatoid arthritis, is easily suppressed with corticosteroid treatment. As in human disease, gender also plays a role in susceptibility to arthritis in some inbred strains (Wilder et al., 1982). For example, male Lewis rats typically develop milder disease than female Lewis rats. These gender effects appear to depend upon the protective effects of testosterone. Castrated Lewis male rats develop arthritis with severity usually equal to that in females
Animal Models for Autoimmune and
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