Mucosal immunology in pictures

Mucosal immunology of the Genital tract and Chlamydial infection

[The following illustrations are from a presentation on the mucosal immunology of the genital tract, written by Drs Nils Lycke and Tina Johansson and given as a plenary session of the IUSTI - Europe meeting in Vienna, 2002. The legends to the figures have been added by MEW. Double click on the thumbnails to view the illustrations].

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Fig 1. All figures Johansson & Lycke 2002.
Diagram showing the circulation of IgA producing cells in the mucosal system via the mesenteric lymph node (MLN) and through the mucosal associated lymphoid tissue (MALT) of the gut including the Peyer's patches. Dimeric IgA joined by the J chain is transcytosed across the gut epithelia in association with secretory piece to become sIgA. IgA producing cells migrate to other mucosal or secretory sites including the genital and respiratory tracts, the salivary glands and the lactating breast. In contrast, the humoral immune system involves the separate circulation of IgG at the enteric surface. producing cells.
Fig 2. Diagram showing how lymphocytes from one region of the gut circulate via the mesenteric lymph nodes and are redestined for another mucosal site, in this case the gut again. PP are the Peyer's Patches, immunocompetent lymphoid nodules with T and B lymphocytes, suppressor cells and specialised antigen processing cells, M cells, which transcytose antigen to T cells. The PP is an important site for the induction of the primary mucosal immune response in the gut. Fig 3. Mucosal tissues belonging to the 'common mucosal immune system' include the gut associated lymphoid tissue (GALT), the broncho associated lymphoid tissue (BALT) and the nasal associated lymphoid tissue (NALT). The GALT is best understood. Unlike the gut, the genital tract lacks organised lymphoid follicles analogous to the PP. It is also influenced dramatically by hormonal changes and hosts both sterile (upper genital tract) and non sterile environments. In the female genital tract, IgG is efficiently transported from the circulation into genital tract secretion. Thus there is more IgG than IgA. There are approximately equal amounts of IgA1 and IgA2.
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Fig 4. In the female genital tract there is a fine balance between the necessity for tolerance of foreign antigen in sperm / foetus and the need for local immunity against infection, including C. trachomatis. This balance is effected by reproductive hormones of the menstrual cycle. Some of the factors affected are shown. Fig 5. A photomicrograph of a transverse section of a small region of the uterine mucosa. Part of the uterine lumen is shown, with a lining layer of epithelial cells, where C. trachomatis can multiply. In humans the epithelium is shed monthly due to the menstrual cycle but chlamydial infection persists in gland cells. Fig 6. The balance between immune protection and tolerance is analogous to the Th1 and Th2 arms of the cellular immune system. Th1 responses, upregulated by IL12 and characterised by an * IFNγ* response, is protective against chlamydial and other infections. Th2 responses, upregulated by IL10, are associated with more immune tolerance but less immunity to infection.
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Fig 7. Some key questions about mucosal immunity in the genital tract for immunologists. It is particularly impotant to understand whether and how immune responses can be induced in the genital tract itself. Figs 8 - 14 are a sequence showing how this might occur in practice. Fig 8. T cells are the key to initiating (priming) the cellular immune response. Foreign antigenic protein is broken down to peptide by antigen processing cells such as Immunopathogenesis.AntigenProcessing (DC). Antigen may also enter the underlying genital stroma directly or via epithelial cells (EC). Antigenic peptide, when presented to T cells in the folds of histocompatability antigen (MHC) with associated Main.ArchiveDocsBiologyImunolProtectCostim, initiates the cellular immune response. Immunopathogenesis.HostGenotype may influence the ability to mount appropriate cellular responses against chlamydial infection. Fig 9. Dendritic cells endocytose chlamydiae, and either transport them unchanged, or process them to peptides. Within the draining para-aortic lymph node (PALN) and other lymph nodes, the dendritic cell comes into contact with an uncommitted T cell (Th0).
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Fig 10. Antigen presentation to T cells occurs in the PALN in the stroma. Fig 11. Priming results in the induction of both Th1 and Th2 responses, the balance of which will be determined by the cytokine environment and hormonal factors. The result is a mixture of effector, regulatory and memory cells. Fig 12. Various regulatory and effector cytokines and chemokines are produced by the primed T cells. Some of these stimulate B cells to produce antibody. There are both diffusion and active transport mechanisms to get large molecules to the mucosal surface. Active transport is particularly important in getting IgG and sIgA across the genital epithelial barrier.
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Fig 13. The induction of cytokines and chemokines in situ attracts polymorphs and macrophages to the site. These are phagocytic cells endowed with a variety of mechanisms for killing bacteria. They also attract cytotoxic T lymphocytes, capable of killing epithelial cells expressing microbial antigens at their surface. Fig 14. T cells primed in mucosal tissue carry the adhesins α4β7 and α4β1 which enable them to home into mucosal tissue carrying VCAM-1 or MadCAM-1 receptors. This is the basis of the circulation of mucosal lymphocytes from mucosa through the lymph and blood to other mucosa. Fig 15. Enhanced resistance to infection, particularly to intracellular bacteria like chlamydiae, requires an upgraded Th1 response [Johansson et al., 1997a; 1997b] but is independent of B cells [Johansson et al., 1997c]. Long term immunological memory of prior chlamydial infection is dependent on CD4+ T lymphocytes and not persistng antigen antibody complexes or chronic infection, Johansson & Lycke 2001.
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Fig 16. Distribution of CD3+ T cells (denoted by dark brown staining) in the uninfected uterus. In the absence of infection there are relatively small numbers of T cells. Fig 17. There are almost no CD8+ T cytotoxic and suppressor cells in the uninfected uterus. Fig 18. In the chlamydial infected uterus there is a marked increase in CD8+ T cells.
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Fig 19. In the chlamydial infected uterus, there are even more CD4+ T helper cells. Fig 20. The CD3+ marker gives an impression of the massive T cell response in the chlamydial infected uterus. Compare this with the uninfected uterus shown in Fig 16. Fig 21. IgA synthesising plasma cells in the stroma of the chlamydial infected uterus. Much of this IgA will be transported to the mucosal surface
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Fig 22. Unique immunocompetent cells of the genital tract include the CD56+ uterine NK cells thought to be important in the establishment of pregnancy, NK cells and CD25+ regulatory cells. Fig 23. Vaccination strategies for inducing local immunity. Fig 24. Topical application of vaccine elicits local immune responses [Wassen et al., 1994].
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Fig 25. Cholera toxin is a well known enhancer (an adjuvant ) of mucosal immune responses, binding to cellular GM1 ganglioside receptor. This figure, derived from *X-ray crystallographic data, shows that cholera toxin consists of 5 binding subunits (CTB) that latch onto the ganglioside receptor and one toxin subunit (CTA). The latter, after entry into the cell and cleavage, elevates cAMP , a cellular second messenger , deranging the electrolyte pumps. Depending on circumstances, cholera toxin can stimulate either immune tolerance or protective immunity. Fig 26. The adjuvant and tolerance producing activity of cholera toxin can be exploited 1) by targeting CTA1 to surface immunoglobulin on B cells with B cell binding moiety D derived from S. aureus Protein A [Agren et al., 2000; Mowatt et al., 2001]. CTA1-DD upregulates costimulatory molecules and germinal centre formation and decreases apoptosis. Or 2) by using the natural ability of CTB to bind to ubiquitous cell GM1 ganglioside receptors. Fig 27. The adjuvant activity of cholera toxin & CTA1-DD is dependent on the ability to stimulate cellular ADP ribosylation . The adjuvant is mixed with the vaccine to which an enhanced response is required, or chemically coupled directly to it.
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Fig 28. Figure showing the ability of the CTA1-DD adjuvant to enhance the local IgA antibody response to ovalbumin or to C. trachomatis in bronchial or genital secretions. Fig 29. Digitally processed electron micrograph of iscoms ( immune stimulating complexes). These lipophilic molecular cage structures, used to encapsulate vaccine preparations, are made from detergent like quil A molecules derived from quillaia bark . Fig 30. Diagram showing how iscoms can enhance cell mediated immunity to ovalbumin in the presence of modified cholera toxin adjuvant. Stimulation of T lymphocytes is shown by increasing radioactive counts per minute (cpm) on the vertical axis. See: Lycke, 2001; Mowatt et al., 2001.

[Presentation: MJ & NL; Text: MeWard; November 2002]

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Agren, L., Sverremark, E., Ekman, L., Schon, K., Lowenadler, B., Fernandez, C. & Lycke, N. (2000). The ADP-ribosylating CTA1-DD adjuvant enhances T cell-dependent and independent responses by direct action on B cells involving anti-apoptotic Bcl-2- and germinal center-promoting effects. Journal of Immunology 164, 6276 - 6286.

Johansson, M., Schon, K., Ward, M. and Lycke, N. (1997a) Genital tract infection with Chlamydia trachomatis fails to induce protective immunity in gamma interferon receptor-deficient mice despite a strong local immunoglobulin A response. Infect. Immun, 65, 1032-1044. Full article

Johansson, M., Schon, K., Ward, M. and Lycke, N. (1997b). Front Line: Studies in knockout mice reveal that anti-chlamydial protection requires TH1 cells producing IFN-gamma: is this true for humans?. Scand J Immunol, 46, 546 - 552.

Johansson M, Ward M, Lycke N. (1997c). B-cell-deficient mice develop complete immune protection against genital tract infection with Chlamydia trachomatis. Immunology 92, 422 - 428.

Johansson, M. & Lycke, N. (2001). Immunological memory in B-cell-deficient mice conveys long-lasting protection against genital tract infection with Chlamydia trachomatis by rapid recruitment of T cells. Immunology 102, 199 - 208.

Lycke, N. (2001). The B-cell targeted CTA1-DD vaccine adjuvant is highly effective at enhancing antibody as well as CTL responses. Current Opinion in Molecular Therapeutics 3, 37 - 44. Review.

Mowat, A. M., Donachie, A. M., Jagewall, S., Schon, K., Lowenadler, B., Dalsgaard, K., Kaastrup, P. & Lycke, N. (2001). CTA1-DD-immune stimulating complexes: a novel, rationally designed combined mucosal vaccine adjuvant effective with nanogram doses of antigen. Journal of Immunology 167, 3398 - 3405. Full article

Wassen, L., Schon, K., Holmgren, J., Jertborn, M. & Lycke, N. (1994). Local intravaginal vaccination of the female genital tract. Scandinavian Journal of Immunology 44, 408 - 414.

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