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Streptococcal cell wall (SCW)-induced arthritis is a chronic, erosive polyarthritis that can be induced in susceptible Lewis rats by one i.p. injection of an aqueous, slerile suspension of SCW. F344 rats are resistant to chronic joint inflammation. Our previous studies showed a correlation between susceptibility to SCW-induced arthritis and the ability to mount SCW-specific T cell responses, suggesting tolerance to SCW as a putative mechanism. Here we prevented the induction of tolerance lo bacterial epitopes in F344 rats by using them germ-free and analysed susceptibility to arthritis subsequently. In addition, we conventionalized germ-free F344 rats at different times before induction of arthritis. Our results show that germ-free F344 rats are susceptible to SCW-induced arthritis with a similar severity, chronicity. incidence and onset as Lewis rats. Moreover. T cells isolated from germ-free F344 rats were able to respond to SCW. Conventionalization dramatically moderates arthritis and makes T cells unresponsive to SCW again. Thus, in normal rats (F344) a stale of tolerance to arthritogenic epilopes is induced (neonatally) and maintained through life by the bacterial flora, resulting in resistance to bacterium-induced artritides. In arthritis-prone (Lewis) rats, this tolerance is deficient and/or easily broken. [ABSTRACT FROM AUTHOR]

One i.p. injection of a sterile suspension of streptococcal cell walls (SCW) induces chronic erosive polyarthritis in susceptible Lewis rats, but not in resistant F344 or nude Lewis rats. Because continuous exacerbations may be one possible mechanism underlying chronic disease, we studied the mechanism of these flare-up reactions in Lewis and F344 rats. Injection of SCW into the right knee joint of rats induced a transient monoarthritis in both strains. Reactivation of the subsided arthritis by i.v. administration of the same antigen could be evoked only in the Lewis rat. Even repeated i.v. challenges with SCW failed to induce a flare-up reaction in the F344 rat, while the Lewis rat went through an exacerbation after every challenge. Removal of T lymphocytes by monoclonal antibodies before induction of an exacerbation rendered Lewis rats refractory to flare-up reactions, thus indicating the T cell-dependence of this reaction. Furthermore, when cell walls from heterologous bacteria were tested for their capacity to induce exacerbations of SCW-induced monoarthritis and to induce proliferation of SCW-specific T lymphocytes in vitro, a strong correlation between both features was found, again pointing to a role for SCW-specific T cells in exacerbations. Together, these data support our hypothesis that chronic arthritis is the result from repeated reactivations of a waning arthritis which are dependent on antigen-specific T lymphocytes. [ABSTRACT FROM AUTHOR]

The presence of anti-heparan sulphate (HS) reactivity in serum is closely related to the occurrence of nephritis in patients with systemic lupus erythematosus (SLE). Since patients with lupus nephritis in general also have high titres of anti-DNA antibodies, we wanted to clarify the relationship between anti-HS and anti-DNA reactivity in serum. Therefore, we studied longitudinally six patients with lupus nephritis who experienced 12 exacerbations of their disease, and five SLE patients without nephritis experiencing 10 periods of non-renal disease exacerbations. In addition, we tested single serum samples of another 24 patients obtained during a renal disease exacerbation and 22 sera of patients without nephritis. The sera of all patients were tested for anti- DNA (Farr assay) and anti-HS reactivity (ELISA). We confirmed that SLE patients during renal exacerbations have a significantly higher anti-HS reactivity than patients without nephritis (P < 0.003), In addition, patients with nephritis also had higher titres of anti-DNA antibodies during renal exacerbations than during non-renal exacerbations (P < 0.01). A correlation between anti- DNA and anti-HS reactivity was observed (r = 0.40, P < 0.02), which in itself explains the correlation between nephritis and anti-HS reactivity. Comparing sera from nephritis and nonnephritis patients matched for anti-DNA titre, we found no difference in anti-HS reactivity, and therefore must conclude that the anti-HS reactivity is a direct reflection of anti-DNA reactivity. [ABSTRACT FROM AUTHOR]

Cross-reactive antibodies against heparan sulphate (HS) have been suggested to play a role in initiating renal disease in SLE. Recently, we found that HS-reactivity is mediated by anti-DNA antibodies complexed with DNA and histones. To evaluate the clinical significance of anti-HS reactivity, we studied prospectively a cohort of 72 consecutive SLE patients, of whom 22 experienced 40 exacerbations. In 20 of these exacerbations renal symptoms were present. In these 20 exacerbations significantly higher anti-DNA (median 1: 160) and anti-HS (median 1: 30) titres were detected compared with exacerbations without renal manifestations (median 1:60 for anti-DNA and negative for anti-HS). There were no correlations with other symptoms of SLE. Anti-HS titres showed a significant correlation with anti-DNA antibody titres (rs = 0.57, P < 0.05). Anti-HS without anti-DNA reactivity was never detected. Some SLE patients showed a high anti-DNA titre without anti-HS reactivity, suggesting that not all anti-DNA antibodies are able to bind to histone/DNA complexes and thus to exhibit anti-HS reactivity. Our findings indicate that anti-HS reactivity is correlated with renal disease in SLE. [ABSTRACT FROM AUTHOR]