Oral, perioral and systemic pathosis in HgCl2-induced autoimmunity in the BN rat.

Male BN rats were repeatedly skin-injected with HgCl2 solution and sacrificed after 6, 9, 14, 21, 28 or 24 days. Mononuclear cell infiltrates were observed in the oral mucosa and in lacrimal, salivary and thyroid glands from 6-9 days onwards, with a peak at 14-21 days. Immunohistochemistry identified these cells as predominantly T cells with some NK cells but very few B cells. Reversible parenchymal changes were observed but there was no obvious persistent tissue destruction. Serum titers of IgE, IgG1, anti-laminin and anti-DNP, but not IgG2a antibodies, were raised and peaked at 14-21 days. However, there was no correlation, within animals, between these titers and the extent of mononuclear cell infiltration. Mercury was histochemically detected within dendritic cells/macrophages in the connective tissue stroma of the glands and in the oral mucosa, but no correlation was found between the distribution of mercury and the degree of inflammation. We conclude that the accumulation of mononuclear cells in oral and perioral tissues of HgCl2-treated BN rats does not represent a local immune response to tissue-retained Hg. Instead, we propose that the extravasation represents an epiphenomenon that is not necessarily deleterious to the infiltrated organ.

Experimental graft versus host disease in the (BN x LEW) F1 rat hybrid: an immunohistochemical study of early disease in oral mucosa.

OBJECTIVE: To study the initial cellular events in oral mucosa (tongue) of experimental hyperplastic GVHD, in order to increase our understanding of the possible pathogenic mechanisms that may be shared with eg mercury (and other drug)-induced immunological reactions. MATERIALS AND METHODS: GVHD was induced by one i.v. injection of 0.5-1 x 10(8) BN spleen cells into (BNxLEW)F1 hybrid rats. The pre-onset stages of the developing semiallogeneic GVHD were investigated in tongue mucosa by immunohistochemistry and monoclonal antibodies. RESULTS: No detectable tissue infiltrates were found 24 h post induction. The pioneer cells appeared at day 3 and were RTIB+/CD2+ and RTIB1-/CD45 (240 kD)-/ EDI-/CD45RC-. At day 3, there was also a visible increase in spleen and lymph node size. Between day 3 and 7, there was a statistically significant increase of CD2+, RTIB+, TCR-alpha beta+, CD4+ and CD8+ cells, but no increase of NKR-PI+ cells. At day 10 there were focal accumulations of CD8+ and NKR-PI+ cells in subepithelial c.t. and in the basal parts of the adjacent epithelium. Animals not sacrificed earlier, showed signs of disease onset at day 11-14. CONCLUSIONS: The early inflammatory infiltrate in this GVHD model consists of activated T cells of donor origin. We suggest, that these originally 'naive' cells migrate initially into lymphoid tissue and following an activation (day 3) enter host's peripheral tissue. Here, (allo-) antigen in constitutively RTIB1 (and EDI) expressing connective tissue dendritic cells may be immune targets of the primed T cells. Such interaction may lead to focal inflammation (increase of CD2+, RTIB+, TCR-alpha beta+, CD4+ and CD8+ cells) and to secondary epithelial damage executed by CD8+ and NKR-PI+ lymphocytes.

Experimental graft versus host disease in the (BN x LEW) F1 rat hybrid as a model for autoimmune disease. Study of early adenitis in lacrimal and salivary glands.

We analysed inflammatory changes at selected time intervals, of salivary and lacrimal glands in the developing immunostimulatory [BN-->(BN x LEW)F1] model of graft-versus-host (GVH) reaction. A focal mononuclear adenitis in lacrimal and salivary glands developed at day 7 and increased clearly in "onset"-rats. Inflammatory responses in submandibular and parotid glands were less consistent and weaker than in lacrimal glands. There was no significant focus score difference between males and females. The lacrimal infiltrates were characterised immunohistochemically with monoclonal antibodies. Our findings indicate that CD4+ cells of donor origin dominated infiltrates, whereas a moderate number of B cells appeared only in large (late) foci. At stages corresponding to the onset of GVH disease (GVHD) in skin/labial mucosa, numerous CD8+ lymphocytes and NK cells were found in lacrimal glands, adjacent to ductal/ vascular plexa, sometimes forming small foci and with evidence of epithelial damage. We conclude that GVHD-associated T cell migration into rat exocrine glands occurs as a result of the semi-alloantigen-activated phenotype properties of the T cells. This activation occurs initially in lymphoid tissue and migration into glands is secondary to this and unrelated to antigen specificity. We also found evidence of amplification and tissue damage, interpreted as due to local reactivation of the T cells.

Mononuclear cell thyroiditis in rats with graft-versus-host disease.

Rats with graft-versus-host disease (GVHD), induced by injecting spleen cells of parental strain rats (Brown Norway) into non-irradiated (Brown Norway x Lewis) F1 hybrid rats, develop thyroiditis. This is characterized by mononuclear cell infiltration with destruction of the epithelium and a significant reduction in serum thyroid hormone levels. Immunohistochemically, the mononuclear cells consisted mainly of CD8-positive cells and macrophages. These findings provide evidence that the thyroid gland can now be enumerated as one of the target organs during GVHD. The CD8-positive cells may serve as important effector cells in lesion development, either by direct cytotoxicity or by supporting the cytotoxic potential of macrophages.

Allergic and irritant contact responses to DNFB in BN and LEW rat strains with different TH1/TH2 profiles.

BN and LEW rats possess different and extreme profiles of TH1/TH2 cells. The main objective of this study was to determine if this constitutively expressed property may influence the propensity to develop contact allergy to a potent contact sensitizer, 2,4-dinitro-1-fluorobenzene (DNFB). In order to avoid overlapping reactions due to toxicity, we defined non-irritant threshold levels of DNFB histologically in ear skin, dorsal skin and oral mucosa prior to the sensitization experiments. Evaluation of the elicitation response was carried out by an invasive method (biopsy). LEW rats proved to express a more extensive challenge response to DNFB than rats of the BN strain. Further, epicutaneous sensitization with DNFB gave a better challenge response than the subcutaneous route regardless of rat strain. In ear skin, but not in oral mucosa, the response was more vigorous after five than after two exposures. Our results are discussed with respect to the possibility that the TH1 type cells may play a significant role in the development of experimental contact allergy.

HgCl2-induced glandular pathosis in the brown Norway rat.

Low doses of HgCl2 induce a genetically restricted autoimmune syndrome in Brown Norway (BN) rats (BN(Hg)). Part of the syndrome includes spontaneously developing mononuclear cell foci in salivary and lacrimal glands, morphologically similar to focal sialoadenitis in Sjögren's syndrome in man. In this study, we have shown that Hg-induced focal adenitis in BN rat is not female predominant and not solely dependent on Hg uptake in the glands. In BN(Hg), focal adenitis was found to develop in several different glands (parotid, submandibular, lacrimal, thyroid) as a specific manifestation of immunopathosis induced by Hg in the RT1n-haplotype-carrying BN. Such manifestations were absent in another strain, the Hg-resistant Lewis (RT1l). Also a potent contact sensitizer, DNFB, induced focal adenitis in isolated glands, provided that strong sensitization had occurred. Immunohistochemical characterization of focal adenitis in BN(Hg) with monoclonal antibodies showed that T cells and dendritic cells dominate the early infiltrates, whereas B cells were absent.

Extraosseous and intraosseous oral traumatic neuromas and their association with tooth extraction.

Tooth extraction has been suggested as the most common etiologic factor in the development of oral traumatic neuroma, but intraosseous lesions are stated to be rare. The clinicopathologic features of 45 oral traumatic neuromas are reviewed. Fifteen cases were painful. Inflammatory infiltrate was present in 53% of the painful cases in contrast to only 17% of asymptomatic neuromas, and was the only light microscopic feature significantly related to the incidence of pain. Eleven of 45 cases were found in an intraosseous location. Four of 45 reviewed neuromas were associated with extractions. All 4 cases were painful and 2 of them were in an intraosseous location. Only 3 of the 15 painful cases and 2 of the remaining asymptomatic 30 cases had a tentative clinical diagnosis of traumatic neuroma before removal.

Irritant and sensitizing potential of copper, mercury and tin salts in experimental contact stomatitis of rat oral mucosa.

HgCl2, CuSO4, SnCl2, SnCl4 or sodium lauryl sulphate (SLS) were openly applied to rat oral mucosa for 1 min, followed 6 h later by histologic examination of the tissue response. Granulocytes were the predominant inflammatory cells and no lymphocytic infiltration could be seen with any of the substances tested. Irritant threshold levels were defined histologically for each of the substances. CuSO4 was found to be non-irritant at all concentrations. The addition of non-irritant concentrations of SLS lowered the threshold levels for HgCl2 and SnCl2, but CuSO4/SLS was non-irritant at all concentrations tested. Preapplication to the mucosa of SLS at non-irritant concentrations gave results with HgCl2, SnCl2 and CuSO4 similar to those with SLS added to the metal salt solutions. Lesions of allergic contact type could not be induced in the oral mucosa to any of the metal salt preparations.