Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease in which the colonic mucosa is infiltrated with plasma cells producing IgG autoantibodies. It is not known whether this represents a local mucosal response which has switched to IgG or a peripheral response which may have been initiated by peripheral antigen which homed to the colonic mucosa. The clonal distribution of IgG secreting cells and isotype switched variants in UC is not known. Aims: To investigate the clonal distribution of mucosal IgG in UC and to search for related IgG and IgA secreting cells in normal and diseased mucosa and blood in UC. To investigate characteristics which may discriminate between the mucosal and peripheral repertoire in the normal mucosa and in UC.Patients: Blood and normal and diseased mucosa from two patients with UC were studied. Methods: Immunoglobulin gene analysis and clone specific polymerase chain reaction were used to study the clonal distribution and characteristics of IgG and related IgA in the mucosa and blood of patients with UC. Results: The IgG response in the mucosa of UC patients included widespread clones of cells that were present in both the diseased mucosa and blood but that were scarce in normal mucosa. Clonally related IgA class switch variants, all IgA1, were detected but also only in the diseased mucosa and blood. This suggests that these clones home preferentially to the diseased mucosa. We showed that J H 1 usage was characteristic of the peripheral repertoire, and that examples of J H 1 usage were observed in mucosal IgG in UC. Conclusions: Overall, these data are consistent with a model of UC in which a peripheral response is expressed and expanded in the colonic mucosa.
It has been known for decades that solid malignancies in humans are associated with an infiltrate of inflammatory cells. A number of studies have found a clear positive correlation between the density of the lymphoid infiltrate and the prognosis of the patient [1][2][3][4]. This, together with the partial oligoclonality of carcinoma-infiltrating T cells [5], indicates that local immune responses to the tumours are likely to be occurring, although the precise nature of the response, and the reason for the survival of the tumours despite the anti-tumour response, are not known. It has been shown that in vitro, CD8 + T-IEL are able to spontaneously lyse colon carcinoma cell lines [6]. Around 20% of the stromal, but almost none of the intraepithelial CD8 + T cells express perforin in Dukes' A carcinomas, decreasing to just 3% in the stroma in Dukes' C cases [7]. Carcinoma-infiltrating Vd1 + T cells also lyse colon carcinoma cell lines [8], recognizing MICA and MICB on the tumour cells [9], and it has been shown in mice that Va14 + NK T cells lyse tumour cells [10]. As CD1, the target for human Va24 + NK T cells, is expressed on the intestinal epithelium [11], these cells may also respond to colorectal carcinoma cells.The phenotypes of the infiltrating lymphocytes have been investigated, and the proportions of CD4 + , CD8 + , TCRab + and TCRgd + cells reported vary considerably in different studies [12][13][14][15][16][17][18][19]. However, overall, it appears that CD8 + T cells localize to the epithelium, as in the normal gut. It has also been shown that the numbers of CD56 + and CD57 + NK T cells are increased within colorectal carcinomas compared with the normal gut [20,21].To increase understanding of the anti-tumour immune response, we have asked which subsets of tumour-infiltrating T cells are stimulated to proliferate in the T-IEL compartment, where T cells are in direct contact with the tumour, and in the stroma. We have also compared the proliferation frequencies observed for each T-cell subset with that observed in areas of maximal T cell stimulation in tonsils and Peyer's patches. In addition, T cells within intact cultured explants of colorectal carcinomas were studied to determine whether the T cell response is supported by factors in the tumour microenvironment. The explant model described here will also enable future studies of the functional relationship between the stromal and lymphoid elements of the tumour microenvironment. MATERIALS AND METHODS Tissues SUMMARYWe have investigated the proliferation rates of T-cell subsets in colorectal carcinomas using immunohistochemistry. It was found that the tumour-infiltrating T cells in contact with the tumour cells have a significantly higher frequency of proliferation than those in the stroma. In particular, the CD8 + intraepithelial lymphocytes (T-IEL) within the tumours have a significantly higher frequency of proliferation in comparison with CD8 + T cells in the stromal compartment or in any normal mucosal lymphoid tissues. It is possible that the proli...
Germinal center (GC) T cells are a poorly investigated population with a unique helper-inducer memory phenotype. Murine GC T cells have been demonstrated to be oligoclonal and antigen specific. The aim of this study was to investigate the diversity of human tonsillar GC T cells. Immunohistochemistry with a panel of different TCRVbeta family antibodies and sequencing of TCRgamma gene rearrangements obtained from individual microdissected GC demonstrated local diversity of human tonsillar GC T cells. No evidence of local clonal dominance or of a local migratory pathway from the T cell zone to adjacent GC was seen. Primers specific to the junctional region of the TCRgamma gene of individual GC T cell clones were designed, and used to trace the dissemination of the clones. One was found to be concentrated locally. Both clones studied were present in both of the patient's tonsils, suggesting widespread dissemination. In addition, no evidence of somatic hypermutation was found in the TCRgamma gene sequences, or in expressed TCRalpha and beta gene sequences obtained by reverse transcriptase-PCR from isolated tonsillar GC.
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