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Histamine receptor H1 (H1R) is a susceptibility gene in both experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune orchitis (EAO), 2 classical T cell mediated models of organ-specific autoimmune disease. Here we showed that expression of H1R in naive CD4+ T cells was required for maximal IFN-γ production but was dispensable for proliferation. Moreover, H1R signaling at the time of TCR ligation was required for activation of p38 MAPK, a known regulator of IFN-γ expression. Importantly, selective reexpression of H1R in CD4+ T cells fully complemented both the IFN-γ production and the EAE susceptibility of H1R-deficient mice. These data suggest that the presence of H1R in CD4+ T cells and its interaction with histamine regulates early TCR signals that lead to Th1 differentiation and autoimmune disease.

The ovarian steroid hormone estrogen (E2) elicits a multiplicity of both systemic and uterotropic responses in vivo. For example, the administration of E2 to ovariectomized (Ovx) and sexually immature rodents leads to uterine-specific inflammatory infiltrates. In this study, we quantitated the number of eosinophils and BM8+, Ia+, and CD4+ cells in uteri obtained from adult Ovx control and E2-treated C57BL/6J, C3H/HeJ, and (C57BL/6J x C3H/HeJ) (B6C3) F1 hybrid mice. All three strains exhibited a significant increase in the number of uterine eosinophils and BM8+ macrophages after E2 treatment. However, C57BL/6J and B6C3 F1 hybrid mice responded with a greater number of infiltrating eosinophils and macrophages as compared with C3H/HeJ. A similar analysis of Ia+ and CD4+ cells showed that E2 treatment either down-regulates or does not affect the number of such cells in all three strains. Genome exclusion mapping using a (C57BL/6J x C3H/HeJ) x C3H/HeJ backcross population localized Est1, the major locus controlling the number of eosinophils infiltrating the uterus after E2 treatment, to chromosome 4. In addition, suggestive linkage to marker loci on chromosomes 10 and 16 was detected and evidence for locus interaction is presented. Our results conclusively demonstrate that E2-regulated/ dependent responses can be genetically controlled, indicating that the phenotypic variation observed in both the normal and pathological effects of E2 may, in part, be due to a genetic component.

To study the steroid regulation of estradiol-induced uterine eosinophil chemotactic factor activity (ECF-U) in the rat, we injected immature female rats with combinations of estradiol, dexamethasone, progesterone, and the antihormones RU-486 and ketoconazole. An in vitro chemotactic system using blind well chambers and employing eosinophil-differentiated HL-60 promyelocytic cells was used as a bioassay for ECF-U activity. Dexamethasone and progesterone both antagonized the effects of estradiol on stimulation of ECF-U activity; neither hormone induced ECF-U activity when given alone. RU-486 and ketoconazole were able to block the inhibitory effects of dexamethasone and progesterone. The effects of dexamethasone and progesterone appear to be mediated through their specific nuclear receptors and are not due to direct effects on the chemotactic cell. Comparison of the steroid regulation of ECF-U activity with the estradiol-induced synthesis and secretion of complement component C3 showed that progesterone antagonized the effects of estradiol in both systems, whereas dexamethasone was antagonistic on ECF-U, but not on the secretion of C3. Taken together these results suggest that estradiol's effects in the rat uterus may be modulated by other steroids in at least two systems, bringing into question the common practice of studying uterine steroid actions by evaluation of a single protein or mRNA.