We investigated the possibility that manifestations of Lyme disease in certain hosts, such as arthritis and carditis, may be autoimmunity mediated due to molecular mimicry between the bacterium Borrelia burgdorferi and self-components. We first compared amino acid sequences of Streptococcus pyogenes M protein, a known inducer of antibodies that are cross-reactive with myosin, and B. burgdorferi and found significant homologies with OspA protein. We found that S. pyogenes M5-specific antibodies and sera from B. burgdorferi-infected mice reacted with both myosin and B. burgdorferi proteins by Western blots and enzyme-linked immunosorbent assay. To investigate the relationship between self-reactivity and the response to B. burgdorferi, NZB mice, models of autoimmunity, were infected. NZB mice infected with B. burgdorferi developed higher degrees of joint swelling and higher anti-B. burgdorferi immunoglobulin M cross-reactive responses than other strains with identical major histocompatibility complex (DBA/2 and BALB/c). These studies reveal immunological crossreactivity and suggest that B. burgdorferi may share common epitopes which mimic self-proteins. These implications could be important for certain autoimmunity-susceptible individuals or animals who become infected with B. burgdorferi.

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Borrelia burgdorferi, the spirochetal bacterium that causes human Lyme disease, encodes numerous lipoproteins which have the capacity to trigger the release of proinflammatory cytokines from a variety of host cell types, and it is generally believed that these cytokines contribute to the disease process in vivo. We previously reported that low-passage-number infectious B. burgdorferi spirochetes express a novel lipidation-independent activity which induces secretion of the proinflammatory cytokine tumor necrosis factor alpha (TNF-␣) by the mouse MC/9 mast cell line. Using RNase protection assays, we determined that mast cells exposed in vitro to low-passage-number, but not high-passage-number, B. burgdorferi spirochetes show increased expression of additional mRNAs representing several chemokines, including macrophage-inflammatory protein 1␣ (MIP-1␣), MIP-1␤, and TCA3, as well as the proinflammatory cytokine interleukin-6. Furthermore, mast cell TNF-␣ secretion can be inhibited by the phosphatidylinositol 3-kinase inhibitor wortmannin and also by preincubation with purified mouse immunoglobulin G1 (IgG1) and IgG2a, but not mouse IgG3, and by a mouse Fc gamma receptor II and III (Fc␥RII/III)-specific rat monoclonal antibody, suggesting the likely involvement of host Fc␥RIII in B. burgdorferi-mediated signaling. A role for passively adsorbed rabbit or bovine IgG or serum components in B. burgdorferi-mediated Fc␥R signaling was excluded in control experiments. These studies confirm that low-passage-number B. burgdorferi spirochetes express a novel activity which upregulates the expression of a variety of host cell chemokine and cytokine genes, and they also establish a novel antibodyindependent role for Fc␥Rs in transduction of activation signals by bacterial products.Lyme disease, the most prevalent arthropod-borne disease in the United States, is a chronic inflammatory disorder caused by Borrelia burgdorferi sensu lato spirochetes (9). Early symptoms of infection include fatigue, joint and muscle pain, and, in approximately 60% of cases, characteristic erythema migrans lesions. If the patient is not treated, secondary pathological symptoms may manifest as arthritis, carditis, and neurologic disorders (48).Numerous in vitro studies have confirmed that B. burgdorferi spirochetes can directly activate a variety of host cell types, eliciting effects which include proliferation, cytokine or chemokine secretion, and adhesion molecule upregulation (14,15,29,30,32,34,43,44,61). It is generally believed that these events provoke heightened inflammatory responses and may contribute to the pathological manifestations seen in Lyme disease. Since activity is enriched in lipoprotein-containing subfractions (44) and studies with recombinant B. burgdorferi outer surface lipoproteins (Osps) indicate that lipidation is required (34,60,61), this activity appears to be mediated mainly by bacterial lipoproteins, although some investigators have detected activity in nonlipidated recombinant Osps (17). In a previous report (53), we des...

The development and course of normally lethal parasitemias in mice inoculated intraperitoneally with erythrocytic stages of Plasmodium yoelii or Plasmodium berghei were markedly affected by treatment with the antilymphoid drug cyclosporin A (CS-A). When the first offour daily subcutaneous 25-mg/kg doses of CS-A was given at the time of parasite inoculation, patent infections-failed to develop. If begun up to 5 days earlier, this same treatment regimen prolonged the prepatent period, attenuated parasitemia, and reduced mortality. In mice with patent infections, two consecutive daily 25-mg/kg doses of CS-A were sufficient to terminate parasitemias which, after several days, reappeared but were selflimiting. This pattern of apparent cure followed by transient recrudescence remained unaltered even when daily treatment with the same drug dose was continued for 3 weeks. Recrudescence was associated with the emergence of parasite populations that were relatively resistant to CS-A and, in the case of P. yoelii, of reduced virulence. In more limited experiments, CS-A was found to be active in vitro against erythrocytic stages of the human malarial parasite Plasmodiumfalciparum. Depending on the concentration of drug in the culture medium, parasite growth was either prevented or inhibited.

National death certificate data greatly overestimate deaths in which HZ is the underlying or contributing cause of death. The HZ vaccination program could prevent some HZ-related deaths, but the impact will be difficult to assess using national mortality data.