1 Division of Immunology and Infectious Diseases, Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, 515 East 71st St, New York 10021, USA and 2 Department of Gynecology, Hospital das Clinicas, University of Sao Paulo Medical School, Sao Paulo, Brazil
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Abstract |
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Key words: antibodies/Chlamydia trachomatis/endocervix/heat shock protein/tubal infertility
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Introduction |
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In this article we review evidence in favour of specific C. trachomatis antibody testing as a means of identifying women at greatest risk for harbouring this organism. Although attention is focused on female partners of infertile couples, we strongly emphasize that when the female partner is being treated for this infection it is mandatory to also treat the male partner.
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C. trachomatis persistence |
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There is evidence that an asymptomatic chlamydial genital tract infection can evade immune destruction and remain within the reproductive tract for long periods of time (months or years) (McCormack et al., 1979; Ruijs et al., 1990
; Golden et al., 2000
). This is undoubtedly due to the induction of persistence by the immune response to this organism. The reactivation of a chlamydial infection after its apparent clearance has also been demonstrated both in experimentally infected mice (Cotter et al., 1997
) and in humans (Ormsby et al., 1952
; Batteiger et al., 1989
). The problem for infertility practitioners, and especially for centres specializing in assisted reproduction, is how to assess patients who never knowingly had a chlamydial infection and therefore were never specifically treated with antibiotics, but who, nevertheless, have sequela consistent with possibly having had an asymptomatic chlamydial infection. Reactivation of a persistent and unexpected C. trachomatis infection could interfere with a successful pregnancy outcome, as outlined above.
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C. trachomatis antibody assays |
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Systemic versus local C. trachomatis antibodies |
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More recent studies have demonstrated that while the presence of cervical anti-chlamydial IgA antibodies is correlated with IVF failure (Witkin et al., 1994), circulating anti-chlamydial IgG antibodies are unrelated to IVF outcome (Spandorfer et al., 1999
). Although other mechanisms are possible, these observations are also consistent with a relationship between cervical IgA immunity and the continued presence of C. trachomatis in the female reproductive tract.
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Immunity to heat shock protein |
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Studies in man have established that humoral (Brunham et al., 1985; Toye et al., 1993
) and cell-mediated (Witkin et al., 1993
) immunity to chlamydial hsp60 can be demonstrated in women with recurrent pelvic inflammatory disease and tubal infertility. Most importantly, the detection of anti-chlamydial hsp60 immunity in the circulation was highly correlated with the presence of tubal occlusion (Brunham et al., 1985
; Toye et al., 1993
; Claman et al., 1997
; Ault et al., 1998
). Furthermore, the chlamydial hsp60 antibodies in women with tubal infertility appeared to be unrelated to a prior C. pneumoniae infection (Persson et al., 1999
). Antibodies to recombinant human hsp60 also correlated with tubal occlusion (Spandorfer et al., 1999
). Detection of immunity to specific epitopes of hsp60 that are present in both the chlamydial and human proteins (Arno et al., 1995
; Domeika et al., 1998
; Sziller et al., 1998
) may further increase the specificity of this analysis. It has been reported that analysing for antibodies to both the chlamydial hsp60 and a second protein, polypeptide encoded by open reading frame 3 of the plasmid (pgp3), increased sensitivity and specificity (Bas et al., 2001
). Cervical IgA antibodies to chlamydial hsp60 have also been detected in some women undergoing IVF and their presence was associated with adverse outcomes (Witkin et al., 1994
). Importantly, studies in monkeys have also demonstrated that detection of circulating antibodies to hsp60 correlated with the continued presence of this micro-organism in the upper genital tract (Peeling et al., 1999
).
The continued release of chlamydial hsp60 from persistently infected epithelial cells can eventually lead to development of autoimmunity to the homologous human hsp60 (Witkin et al., 1996). Hsp60 is one of the first proteins expressed by mammalian zygotes after fertilization and is present on both the early stage embryo and maternal decidua (Neuer et al., 2000
) (review paper). Therefore, in women with pre-existing immunity to chlamydial hsp60, exposure to human hsp60 in the early stages of pregnancy can lead to reactivation of hsp60-sensitized lymphocytes. The subsequent pro-inflammatory immune response can foster immune rejection of the developing embryo. Similarly, immunity to hsp60 has also been associated with spontaneous abortion (Kligman et al., 1998
), inhibition of in-vitro development of mouse embryos (Neuer et al., 1998
) and preterm birth (Ziegert et al., 1999
).
One small published study with a total of only 37 pregnancies (and a low 22% overall pregnancy rate) concluded that, among women who were seropositive for antibodies to C. trachomatis, those who also had anti-chlamydial hsp60 IgG in their sera had a higher pregnancy rate after IVF than those who were chlamydial hsp60 IgG seronegative (Claman et al., 1996). Until further investigations on a greater number of subjects corroborate this observation the putative positive effect of these antibodies on IVF success must remain highly questionable.
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Summary and recommendations |
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It will initially be more expensive to test women for chlamydial antibodies and to treat only the positive patients than to non-selectively prescribe antibiotics for every infertility patient. However, in our opinion the small increased cost is more than justified. Studies on cost-effectiveness must take into account the increasing problem to society of antibiotic resistance among micro-organisms as well as potential side-effects of antibiotic usage on other body systems.
While the presence of C. trachomatis in the genital tract is a clear risk for a successful pregnancy outcome, unfortunately there are no published trials to definitively determine whether antibiotic treatment of cervical IgA-positive or serum hsp60 IgG-positive women is indeed effective in improving pregnancy outcome. Such studies are urgently needed.
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Notes |
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References |
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