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Review
. 2004 Jul;53(7):1035-43.
doi: 10.1136/gut.2003.026278.

The CD40/CD40L costimulatory pathway in inflammatory bowel disease

S Danese  1 , M Sans, C Fiocchi
Affiliations
Review

The CD40/CD40L costimulatory pathway in inflammatory bowel disease

S Danese et al. Gut. 2004 Jul.
No abstract available

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Figures

Figure 1
Figure 1
Major molecular receptor-ligand pairs involved in T cell activation, downregulation, costimulation, and amplification of immune responses. Ag, antigen; APC, antigen presenting cell; CTLA, cytolytic T lymphocyte associated antigen; ICAM, intercellular adhesion molecule; ICOS, inducible costimulator; IL-1…n, interleukin 1 to n; IL-R, interleukin receptor; LFA, lymphocyte function associated antigen; MHC, major histocompatibility complex; TCR, T cell receptor.
Figure 2
Figure 2
Pleiotropic effects resulting from the interaction of activated CD40L+ T cells, activated CD40L+ platelets, or soluble CD40L with immune and non-immune cells. Engagement of CD40 on B cells leads to antibody production whereas a much wider range of effects are induced in monocytes, macrophages, and dendritic cells activated through the CD40 pathway. Some of these include production of cytokines, chemokines, cyclooxygenases (COX), prostaglandins (PGs), metalloproteinases (MMPs), and nitric oxide (NO), upregulation of cell adhesion molecules (CAMs), and modulation of apoptosis. Activation of non-immune cells through the CD40 pathway induces a spectrum of effects similar to those observed in monocytic cells.
Figure 3
Figure 3
Proposed framework for continuous recruitment of T cells into the gut mucosa through CD40/CD40L dependent mechanisms. In the early stages of mucosal inflammation, local T cells become activated and express CD40L, binding to and activating CD40+ mesenchymal (HIF) and endothelial (HIMEC) cells. HIF and HIMEC start secreting chemokines that attract more T cells that transmigrate into the interstitial space, become activated, and express CD40L, initiating a new cycle of chemokine secretion by non-immune cells which results in additional T cell recruitment. Activated T cells and platelets in the circulation of inflammatory bowel disease (IBD) patients contribute to this process through expression of CD40L on their surface. This framework supports the notion of a non-immune, cell mediated, antigen independent mechanism perpetuating IBD.
Figure 4
Figure 4
Proposed framework for recruitment of T cells into the gut mucosa by activated CD40L+ platelets. CD40L+ platelets and soluble CD40L bind to CD40+ endothelial cells (HIMEC) that start producing chemokines such as interleukin (IL)-8. On contact with HIMEC, activated platelets release massive amounts of RANTES (regulated on activation normal T expressed and secreted) stored in their granules which is retained on the surface and HIMEC and mediates binding of T cell to the microvascular cells through the receptors CCR1, 3, and 5. In addition, CD40L+ platelets bind to HIMEC where they induce upregulation of intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1, both of which contribute to recruitment of additional T cells.
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References

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