Serotonin and delayedtype hypersensitivity

Thus far, substantial evidence has been obtained indicating that some type of antigen-specific T cell factor is capable of activating mast cells to release mediators, especially vasoactive amines in the early and late phases of DTH responses. The molecular nature of such factors remains to be fully defined. Activation of the mast cell may, conceivably, be achieved through specific receptors for the T cell factors. The events that take place during DTH responses can be summarized as follows. Early after immunization, antigen-specific T cell factors are produced and released by T cells in the lymphoid organs. These factors are transported in the circulation and leave the circulation to sensitize the peripheral extra-vascular tissues, i.e. bind to the mast cells that possess putative specialized receptors for these factors. Upon local antigen challenge the sensitized mast cells, and perhaps other serotonin-containing cells, release serotonin. This acts on serotonin receptors of postcapillary venules causing activation and the formation of gaps between endothelial cells, which results in increased vascular permeability. This allows circulating T cells, some of which are antigen specific, to leave the circulation and enter the site ot the reaction where interaction with antigen rakes place, probably in the context of major histocompatibility complex (MHC) class II antigens on local antigen-presenting cells such as I.angerhans cells. Activation of these T cells by antigen-MHC complexes, and also by serotonin through 5-HT, receptors on their membranes, leads to local production of non antigen-specific lymphokincs, which ultimately attract circulating bone marrow-derived leukocytes, such as monocytes, to also enter through the gaps between endothelial cells and constitute the classical perivascular infiltrate of DTH reactions.

There are several lines of evidence that favor a role of serotonin released from mast cells or platelets in

DTH-associated cellular immune responses in the mouse. First, these responses are elicited preferentially at those cutaneous sites that are enriched in mast cells, such as ears and footpads. In contact-sensitivity to trinitrochlorobenzene, as well as in hema-toporphyrin derivative-induced phototoxicity, evidence of release of mediators by mast cells was obtained; in these studies histologic signs of hypo-granulation of mast cells were noted. Secondly, pre-treatment of cutaneous sites with serotonin causes tachyphylaxis, i.e. specific desensitization of vascular serotonin receptors on the endothelial cells, and this inhibits subsequent elicitation of DTH by local antigen challenge. Thirdly, treatment with the cromo-glycate-like drug proxicromil, which prevents release of mediators including serotonin, or treatment with serotonin antagonists, like methysergide or ketan-serin, suppresses contact sensitivity and also T cell-mediated inflammatory responses due to infection with Trichinella spiralis. Fourthly, studies employing the drug reserpine, which depletes serotonin from mast cells, platelets and neurons, showed suppression of DTH responses, contact photosensitivity, T cell-dependent immune responses to tumor cells, and the development of allergic encephalomyelitis. Finally, defective DTH responses have been observed in two strains of mast cell-deficient mice. This pertains to contact sensitivity to picryl chloride, delayed-type hypersensitivity to sheep red blood cells and to allogeneic tumor cells, and in mice sensitized to 3,3',4',5-tetrachlorosalicyIanilide.

A potential role for mast cells and serotonin in contact sensitivity has been challenged. In contrast to defective DTH responses in mast cell-deficient mice, normal and even greater than normal responses were noted in other studies. Local reconstitution of mast cell-deficient ears with mast cells did not increase the responsiveness of such ears with respect to contact sensitivity. It can be concluded from these conflicting results that DTH can be elicited in mast cell-deficient mice, but that it is sometimes diminished. Crucial in this respect is how serotonin-dependent DTH responses are elicited in mast cell-deficient mice. The skin of these mice is not serotonin deficient. The source of serotonin is undoubtedly platelets, which could thus play a role in DTH. Therefore, recent findings concerning the role of platelets in IgE-depen-dent hypersensitivity responses could be extended to indicate an important role for platelets in DTH responses. It is noteworthy thar active systemic ana-phylatic responses were shown to occur in mast cell-deficient mice. Since such immediate-type IgE-depen-dent hypersensitivity reactions are shown to involve mast cells, these data can lead to two types of conclusions: 1) It may be that the relative low number of mast cells (less than 1 % of mast cells of normal litter mates) provides sufficient amounts of mediators, including serotonin, for systemic anaphylactic reactions and also can support DTH responses. Thus, mast cell-deficient mice may be a poor model to study the role of mast cells in such responses. 2) It is possible that other nonmast cell sources of serotonin are available for the elicitation of responses. In the skin this could be the rich supply of serotonin in platelets in the vessels and in systemic anaphylaxis this could be the extensive enterochromaffin tissue of the gut.

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