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Kei Kawana,
Junko Matsumoto,
Shiho Miura,
Li Shen,
Yukiko Kawana,
Takeshi Nagamatsu,
Toshiharu Yasugi,
Tomoyuki Fujii, Huixia Yang,
Alison J Quayle,
Yuji Taketani,
Danny J Schust
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ABSTRACT: Mucosal epithelia of the human lower reproductive tract (vagina, cervix, and penile urethra) are exposed to sexually transmitted microbes, including Chlamydia trachomatis. The in vivo susceptibility of each tissue type to infection with C. trachomatis is quite distinct. CD1d is expressed on the surface of antigen-presenting cells, including mucosal epithelial cells, and interacts specifically with invariant NKT cells. Invariant NKT cells play a role in both innate and adaptive immune responses to microbes. Here we assessed CD1d expression in normal reproductive tissues by using immunohistochemistry. Immortalized epithelial cell lines from the human lower reproductive tract (vagina, endocervix, and penile urethra) were examined for CD1d expression and for ligand-induced cytokine production induced by CD1d cross-linking. CD1d expression in normal tissue was strong in the vagina but weak in the endocervix and penile urethra. Gamma interferon exposure induced CD1d transcription in all of the cell types studied, with the strongest induction in vaginal cells. Flow cytometry revealed cell surface expression of CD1d in vaginal and penile urethral epithelial cells but not in endocervical cells. Ligation of surface-expressed CD1d by monoclonal antibody cross-linking promoted interleukin-12 (IL-12) and IL-15, but not IL-10, production in vaginal and penile urethral cells. No induction was demonstrated in endocervical cells. CD1d-mediated cytokine production in penile urethral cells was abrogated by C. trachomatis infection. Basal deficiency in CD1d-mediated immune responsiveness may result in susceptibility to sexually transmitted agents. Decreased CD1d-mediated signaling may help C. trachomatis evade detection by innate immune cells.
Infection and immunity 08/2008; 76(7):3011-8. · 4.21 Impact Factor
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Kei Kawana,
Alison J Quayle,
Mercedes Ficarra,
Joyce A Ibana,
Li Shen,
Yukiko Kawana, Huixia Yang,
Luis Marrero,
Sujata Yavagal,
Sheila J Greene,
You-Xun Zhang,
Richard B Pyles,
Richard S Blumberg,
Danny J Schust
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ABSTRACT: Chlamydia trachomatis is an obligate intracellular pathogen that can persist in the urogenital tract. Mechanisms by which C. trachomatis evades clearance by host innate immune responses are poorly described. CD1d is MHC-like, is expressed by epithelial cells, and can signal innate immune responses by NK and NKT cells. Here we demonstrate that C. trachomatis infection down-regulates surface-expressed CD1d in human penile urethral epithelial cells through proteasomal degradation. A chlamydial proteasome-like activity factor (CPAF) interacts with the CD1d heavy chain, and CPAF-associated CD1d heavy chain is then ubiquitinated and directed along two distinct proteolytic pathways. The degradation of immature glycosylated CD1d was blocked by the proteasome inhibitor lactacystin but not by MG132, indicating that degradation was not via the conventional proteasome. In contrast, the degradation of non-glycosylated CD1d was blocked by lactacystin and MG132, consistent with conventional cellular cytosolic degradation of N-linked glycoproteins. Immunofluorescent microscopy confirmed the interruption of CD1d trafficking to the cell surface, and the dislocation of CD1d heavy chains into both the cellular cytosol and the chlamydial inclusion along with cytosolic CPAF. C. trachomatis targeted CD1d toward two distinct proteolytic pathways. Decreased CD1d surface expression may help C. trachomatis evade detection by innate immune cells and may promote C. trachomatis persistence.
Journal of Biological Chemistry 04/2007; 282(10):7368-75. · 4.77 Impact Factor
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ABSTRACT: The mucosal lymphocyte population is the largest in the body, and the gastrointestinal compartment has been well characterized in HIV infection. Much less is known about the effects of HIV on the genital tract.
: To examine the T-lymphocyte phenotype and receptor repertoire as well as total and virus-specific immunoglobulin concentrations in the endocervix of HIV-infected women at different stages of infection as compared with uninfected women.
Participants were 12 seronegative women, 10 HIV-infected "slow progressors" not taking antiretroviral therapy, and 9 HIV-infected women whose antiretroviral therapy was failing. We used multiparameter flow cytometry to enumerate T-cell populations on cytobrush-obtained cervical specimens, the immunoscope technique to determine the T-cell receptor (TCR) repertoire, and quantitative enzyme-linked immunosorbent assays for antibody determinations on cervical secretions absorbed onto ophthalmic sponges. Nonparametric statistical analyses were performed.
We found marked depletion of leukocytes and CD4 T lymphocytes in the endocervix of HIV-infected women as compared with uninfected women; this was significant at more advanced disease stages. Naive T cells were rare in the endocervix of all groups. Activation marker expression was higher in endocervical T lymphocytes than in peripheral blood among control and slow-progressing HIV-infected women but not in women failing therapy. Endocervical T lymphocytes showed highly restricted utilization of Vbeta TCR families. Unlike other mucosal sites, the cervix contained IgG as the predominant immunoglobulin isotype. HIV-IgG was detected in the cervix of most HIV-infected women and in blood of all infected women.
HIV infection induces substantial changes in the immune profile of the female genital tract. Further study of the implications of these findings for HIV acquisition and transmission is needed.
JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2007; 44(3):292-8. · 4.43 Impact Factor
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Edith Porter, Huixia Yang,
Sujata Yavagal,
Gloria C Preza,
Omar Murillo,
Heriberto Lima,
Sheila Greene,
Laily Mahoozi,
Marcia Klein-Patel,
Gill Diamond,
Sunita Gulati,
Tomas Ganz,
Peter A Rice,
Alison J Quayle
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ABSTRACT: Defensins are key participants in mucosal innate defense. The varied antimicrobial activity and differential distribution of defensins at mucosal sites indicate that peptide repertoires are tailored to site-specific innate defense requirements. Nonetheless, few studies have investigated changes in peptide profiles and function after in vivo pathogen challenge. Here, we determined defensin profiles in urethral secretions of healthy men and men with Chlamydia trachomatis- and Neisseria gonorrhoeae-mediated urethritis by immunoblotting for the epithelial defensins HBD1, HBD2, and HD5 and the neutrophil defensins HNP1 to -3 (HNP1-3). HBD1 was not detectable in secretions, and HBD2 was only induced in a small proportion of the urethritis patients; however, HD5 and HNP1-3 were increased in C. trachomatis infection and significantly elevated in N. gonorrhoeae infection. When HNP1-3 levels were low, HD5 appeared mostly as the propeptide; however, when HNP1-3 levels were >10 microg/ml, HD5 was proteolytically processed, suggesting neutrophil proteases might contribute to HD5 processing. HD5 and HNP1-3 were bactericidal against C. trachomatis and N. gonorrhoeae, but HD5 activity was dependent upon N-terminal processing of the peptide. In vitro proteolysis of proHD5 by neutrophil proteases and analysis of urethral secretions by surface-enhanced laser desorption ionization substantiated that neutrophils contribute the key convertases for proHD5 in the urethra during these infections. This contrasts with the small intestine, where Paneth cells secrete both proHD5 and its processing enzyme, trypsin. In conclusion, we describe a unique defensin expression repertoire in response to inflammatory sexually transmitted infections and a novel host defense mechanism wherein epithelial cells collaborate with neutrophils to establish an antimicrobial barrier during infection.
Infection and Immunity 08/2005; 73(8):4823-33. · 4.16 Impact Factor
