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Protective versus immunopathogenic responses

The potential for chlamydia to induce both protective and immunopathogenic immune responses calls for theories on the likely conditions leading to such outcomes in the framework of current immunologic paradigms. Recent finding from an IL-10KO (knock out) DC-based cellular vaccine [Igietseme et al., 2000] would suggest that a fast and vigorous Th1 response after an infection will rapidly arrest chlamydial replication, clear the infection, eliminate residual antigens and prevent the establishment of a latent infection. On the other hand, an inadequate or sub-optimal Th1 response delays clearance of the pathogen, leading to the establishment of a latent or persistent infection, which fuels a low-grade chronic immune response that causes tissue damage. This proposition is supported by recent findings in experimental pulmonary chlamydial infection in mice in which IL-10KO animals resolved the infection and exhibited potent Th1 and strong DTH responses without tissue damage [Yang et al., 1999]; however, IFN-g KO mice exhibited a poor DTH and Th1 response profile, and inability to clear the infection [Wang et al., 1999]. In addition, ICAM-1KO mice displayed a delayed Th1 response to chlamydial genital infection, severe acute cervical and ascending infection, and high rate of tubal complications such as hydrosalpinx, which was associated with a slow activation of specific Th1 cells by ICAM-1KO APCs [Igietseme et al., 1999]. A high incidence of hydrosalpinx was also observed in reinfected FcRKO mice that developed a relatively slow Th1 response (unpublished observation). The role of stress and host genetics in delayed or suboptimal Th1 response to chlamydial infection and development of complications in certain individuals, is unclear. Furthermore, an auxiliary mechanism of immunopathology could be engendered through certain immune evasive mechanisms of chlamydia (e.g., inhibition of cellular apoptosis [Fan et al., 1998], and down-regulation of MHC class I and II antigen expression [Zhong et al., 2000]). Such immunosuppressive mechanisms have the potential to modulate Th1 response and function, leading to inadequate effector function, chlamydial latency or persistence, chronic host reaction and tissue damage. Finally, the involvement of immunopathogenic chlamydial antigens in the pathogenesis of chlamydial disease is not ruled out [LaVerda et al., 1999]. Additional support for immunopathogenic antigens is that the highly immunogenic OMP2 of several C. trachomatis serovars, C. pneumoniae and C. psittaci harbors a sequence homologous to the pathogenic epitope of the human alpha-myosin heavy chain capable of inducing autoimmune myocarditis in mice [Bachmaier et al., 1999]. While its role in microbial pathogenesis is currently unknown, the involvement of such epitopes in the pathogenesis of chlamydia-associated inflammatory and autoimmune-like diseases cannot be ruled out. Thus, specific strategies for analyzing vaccine toxicity are additional requirements for evaluating any candidate subunit vaccine.

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