Host genetic factors and scarring disease.

C. trachomatis

In both trachoma and pelvic inflammatory disease the main damage is caused by tissue scarring following severe or prolonged infection. In endemic regions of the developing world, individuals are frequently exposed from an early age to ocular infection with C. trachomatis yet only a minority develop significant conjunctival scarring. Perhaps individual differences in the scarring response to trachoma and pelvic inflammatory disease relate to differences in the genotype [genetic constitution] of the person concerned. There is evidence for this from both genital tract infection and trachoma.

Pelvic inflammatory disease and tubal scarring

In the pig-tailed macaque model of pelvic inflammatory disease (PID) susceptibility or relative resistance to the rapid fromation of tubal adhesions is correlated with the expression of MHC Class 1 alleles [Lichtenwalner et al., 1997]. In humans, a study of 302 female sex workers in Kenya, 23 developed chlamydial upper genital tract infection (pelvic inflammatory disease; PID) and a further 21 had PID involving both chlamydiae and gonococci [the agent of gonorrhoea]. Those who developed PID were over 5 times more likely than those who didn't to have the HLA-A31 gene, a gene associated with the cell mediated immune response [Kimani et al., 1996]. [There was <1 in 20 chance that this result could have been due to chance; p=.043; OR5.6; 95% CI 1.1-29.4]. Cohen et al., 2000 demonstrated an association between C trachomatis microimmunofluorescence antibody and different histocompatability genes, HLA DQA*0101, DQA*0102, and DQB*0501, among Kenyan women with tubal infertility arising from PID. However, because of the large number of HLA alleles tested, there were concerns that this association might have arisen by chance, or because of a close linkage with another immunoregulatory or cytokine gene, such as DRB1, DRB5. Accordingly, Cohen et al., 2003 performed a further study to confirm the observed association. In particular they looked at human leukocyte antigen (HLA) class II DQ alleles, their linked DRB genes, and polymorphisms in selected cytokine genes (i.e. tumour necrosis factor alpha-308 promoter; transforming growth factor beta1-10 and -25 codons; interleukin 10-1082, -819, and -592 promoters; interleukin 6-174 promoter; and interferon gamma+874 codon 1). They failed to confirm their earlier observation of an association between DQA*0102 and decreased odds of C trachomatis microimmunofluorescence antibody in women with tubal infertility. This was probably due to linkage disequilibrium with DRB1*1503, as alleles linked to DQA*0102 at the DRB1 and B5 loci (DRB1*1503 and DRB5*0101) were less common among C trachomatis associated infertility cases. A further study is indicated to test whether the DRB1*1503/DRB5*0101 haplotype is associated with protection against _C trachomatis infection in a general Kenyan population. However they suggest that DRB1*1503 and DRB5*0101 either lead to an immunologically mediated mechanism of protection against C. trachomatis infection and associated tubal damage, or increase the risk for tubal scarring due to another unknown cause [Cohen et al., 2003].


In trachoma, severe disease also arises from scarring damage to tissue [see: Human_Infections/Ocular.TrachomaPathology]. T-helper 1 cell mediated responses are thought to be protective [see: Main.ArchiveDocsBiologyVaccdev2] and it has been suggested that the failure to mount such responses might result in chronic ocular chlamydial infection and conjunctival scarring. Comparison of the type of cell mediated immune response made by blood mononuclear cells from individuals in a Gambian village with endemic trachoma found that those with scarring trachoma tended to make mixed T-helper 1 / T-helper 2 responses [Holland et al., 1996]. Weak associations were also observed between certain HLA class II alleles [lay reader: human genes associated with the cell mediated immune response] and cellular immune responses to chlamydial antigens. A larger study by the same group compared 153 cases scarring trachoma with matched controls. One class I gene, HLA-A28 A*6802, was significantly more common among those with scarring disease [Statisticians: OR = 3.14, 95% confidence interval 1.32 - 7.44] [Conway et al., 1996]. The mechanism by which the A*6802 allele, or something segregating with it, might be associated with severe disease is unclear but might be related to cytotoxic T-cell responses [Lay reader: cytotoxic T lymphocytes attack infected cells expressing microbial components at the cell surface, their role in chlamydial infection is uncertain]. Cytotoxic T cell activity in the blood of a small number of patients with trachoma was observed only in children with active infection or in adults without conjunctival scarring [Holland et al., 1997]. The same group also found alterations in the human gene encoding tumour necrosis factor (TNFalpha) which resulted in elevated levels of the inflammatory cytokine TNFalpha in the tear fluid of individuals with scarring trachoma [Conway et al., 1997]. There were also indications that specific genotypes of the interleukin 10 promoter sequences might be correlated with an increased risk of trachomatous conjunctival scarring [Conway et al., 1996], although no such polymorphisms were observed in pelvic inflammatory disease in tubal scarring [Cohen et al., 2003]. Alterations in a gene encoding the subunit 1 of a transporter protein (TAP1) concerned with the processing of foreign, (eg chlamydial) proteins did not attain statistical significance [Felton et al., 1998]. Polymorphisms in the promoter region of NFkappaB were significantly less frequent among patients with trachoma compared to controls, [Mozato-Chamay et al., 2001].

It is important to gain an overall perspective of the importance of host genotype to chlamydial disease mechanisms and protection. Accordingly the ability of peripheral blood lymphocytes to respond to various substances likely to trigger a cell mediated immune response was assessed in 64 twin pairs aged 12 to 68 years, of whom 19 pairs were identical twins. The rationale here is that, if genetic factors are important, there should be a difference between identical and non-identical twins. The ability of the substances tested to cause the lymphocytes to divide and multiply (lymphocyte proliferation) was taken as an index of the ability to mount a cell mediated immune response. The substances tested included C. trachomatis elementary bodies (relevant to trachoma), tuberculosis antigen and plant phytohemagglutinin (common substances used to test cell mediated immunity). Comparison of the responses of the identical and non-identical twins by a statistical technique known as analysis of variance, gave an estimate of 39% at p=0.07 for the contribution of genetic factors [researchers: excluding T-cell receptor repertoire] for the observed variation in cell mediated immunity [Bailey et al., 1998]. This is the first study to provide an overall estimate of the role of host genetic factors in cell mediated immune responses to chlamydial infection.

C. pneumoniae

Possible host genotypic factors involved in chronic C. pneumoniae infection have been little studied. It is known however that IL-1 is important in the host response to chlamydial infection [see: Immunopathogenesis.CytokineInduction]. Momiyama et al., 2001 looked for gene polymorphisms in IL-1 beta and in IL-1 receptor antagonist in 259 patients undergoing cardiac angiography. The percentage of patients having IL-1 beta (-511) C/C genotype and/or IL-1Ra (intron 2) 2- or 3-repeat allele was higher in patients with coronary artery disease than without coronary artery disease (29 vs. 16%, p < 0.025). When these results were analysed in terms of any associated antibody to C. pneumoniae, it was found that the odds ratios for coronary artery disease were 1.4 in the seropositive group, 1.7 for the group with gene polymorphisms alone, and 3.8 for the two combined. Myocardial infarction was confined to the group who were both C. pneumoniae seropositive and who had IL-1 polymorphisms. It was concluded that IL-1 gene polymorphisms played a role in the development of coronary artery disease, and particularly myocardial infarction, in patients with serological evidence of C. pneumoniae infection [Momiyama et al., 2001].

[PICK Comment: It is difficult to study the contribution of host genotype to the scarring sequelae of chlamydial infection. The trachoma studies presented here have all been performed by one enterprising collaborative group based on the London School of Hygiene and the UK Medical Research Council Tropical Disease research unit in the Gambia. Similarly studies of infertility and pelvic inflammatory disease have been focussed in Kenya. Studies are needed in different geographic settings before any reliable picture emerges. It seems likely that human genetic factors regulating the immune and other responses must significantly influence the development of the severe scarring sequelae of chlamydial infection. But, by how much? In the case of C. pneumoniae , research in this area is only just beginning].

Main.MeWard August 2003

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Bailey, R., Fowler, A., Peeling, R. et al., (1998). Lymphoproliferative responses to C. trachomatis EBs in a Gambian twin population: estimating the role of host genetic factors. Pages 474-477. In: (Stephens R. S. et al., eds). Chlamydial Infections. Proceedings of the ninth international symposium on human chlamydial infection. International Chlamydia Symposium, San Francisco, USA. ISBN 0-9664383-0-2.

Cohen, C. R., Sinei, S., Bukusi, E., Bwayo, J., Holmes, K. & Brunham, R. (2000). Human leukocyte antigen class II DQ alleles associated with Chlamydia trachomatis tubal infertility. Obstetrics and Gynecology 95, 72 - 77. Full article

Cohen, C. R., Gichui, J., Rukaria, R., Sinei, S. S., Gaur, L. K. & Brunham, R. C. (2003). Immunogenetic correlates for Chlamydia trachomatis-associated tubal infertility. Obstetrics and Gynecology 101, 438 - 444. Full article

Conway, D.J., Holland, M.J., Campbell, A.E., Bailey, R.L. et al., (1996). HLA Class I and HLA Class II polymorphisms and trachomatous scarring in a Chlamydia trachomatis endemic population. Journal of Infectious Diseases 174, 643 - 646.

Conway, D. J., Holland, M. J., Bailey, R. L. et al., (1997). Scarring trachoma is associated with polymorphism in the tumor necrosis factor alpha (TNF-alpha) gene promoter and with elevated TNF-alpha levels in tear fluid. Infection and Immunity 65, 1003 - 1006. Full article

Felton, M., Hsia, R. C., Mabey, D. & Bailey, R. (1998). The effects of TAP1 polymorphisms in scarring trachoma. Pages 415-418. In: (Stephens R. S. et al., eds). Chlamydial Infections. Proceedings of the ninth international symposium on human chlamydial infection. International Chlamydia Symposium, San Francisco, USA. ISBN 0-9664383-0-2.

Holland, M. J., Bailey, R. L., Conway, D. J. et al., (1996). T-helper th1/th2 profiles of peripheral-blood mononuclear- cells (PBMC): responses to antigens of C. trachomatis in subjects with severe trachomatous scarring. Clinical and Experimental Immunology 105, 429 - 435.

Holland, M. J., Conway, D. J., Blanchard, T. J. et al., (1997). Synthetic peptides based on C. trachomatis antigens identify cytotoxic T lymphocyte responses in subjects from a trachoma endemic population. Clinical and Experimental Immunology 107, 44 - 49.

Kimani, J., Maclean, I.W., Bwayo, J.J. et al. (1996). Risk factors for Chlamydia trachomatis pelvic inflammatory disease among sex workers in Nairobi, Kenya. Journal of Infectious Diseases 173, 1437 - 1444.

Lichtenwalner, A. B., Patton, D. L., Cosgrove Sweeney, Y. T., Gaur, L. K. & Stamm, W. E. (1997). Evidence of genetic susceptibility to Chlamydia trachomatis-induced pelvic inflammatory disease in the pig-tailed macaque. Infection and Immunity 65, 2250 - 2253. Full article

Momiyama, Y., Hirano, R., Taniguchi, H., Nakamura, H. & Ohsuzu, F. (2001). Effects of interleukin-1 gene polymorphisms on the development of coronary artery disease associated with Chlamydia pneumoniae infection. Journal of the American College of Cardiology 38, 712 - 717.

Mozzato-Chamay, N., Corbett, E. L., Bailey, R. L., Mabey, D. C., Raynes, J. & Conway, D. J. (2001). Polymorphisms in the IkappaB-alpha promoter region and risk of diseases involving inflammation and fibrosis. Genes and Immunity 2, 153 - 155.

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