Asunto(s)
Inmunoglobulina A Secretora , Cambio de Clase de Inmunoglobulina , Mucosa Intestinal/inmunología , Células Plasmáticas/metabolismo , Animales , Formación de Anticuerpos , Quimiocinas CC/inmunología , Citidina Desaminasa/genética , Humanos , Inmunoglobulina M , Ratones , Ratones Noqueados , Modelos AnimalesRESUMEN
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.
Asunto(s)
Células Productoras de Anticuerpos/inmunología , Colitis Ulcerosa/inmunología , Colon/inmunología , Inmunoglobulina A Secretora/biosíntesis , Inmunoglobulina G/biosíntesis , Mucosa Intestinal/inmunología , Secuencia de Bases , Células Clonales , Colitis Ulcerosa/sangre , Colitis Ulcerosa/patología , Colon/patología , Femenino , Humanos , Inmunoglobulina A Secretora/genética , Inmunoglobulina G/genética , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Alineación de SecuenciaRESUMEN
We 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 proliferation of the CD8+ T-IEL may be driven by self-antigens expressed on the tumour cells. The proportion of CD3+ CD7- T cells is increased within carcinomas compared with the normal colon, and a population of CD57+ T cells was observed which is absent from the normal colon. It is possible that these phenotypes are acquired in situ due to repeated stimulation of the T cells by tumour antigens. Intact colorectal carcinoma explants were cultured, and the presence of tumour-infiltrating T cells analysed after 3 days of culture in isolation from the systemic compartments. CD3+ T cells were proliferating (at a low rate) within the explants after 3 days of culture, indicating that they may be sustained by factors present in the tumour microenvironment.
