Related IgA1 and IgG producing cells in blood and diseased mucosa in ulcerative colitis.

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.

Proliferation of T-cell subsets that contact tumour cells in colorectal cancer.

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.

Role of innate immunity in cancer.

Recently, much progress has been made in the field of tumor immunology. Much of this work has focused on understanding and exploiting the innate immune response to tumor cells. A novel human receptor-ligand system that mediates natural killer (NK) and gammadelta T-cell killing of carcinoma cells has been identified, and the functions of an equivalent system in mice are beginning to be explored. The mechanisms of action of an innate tumoricidal cytokine, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and of tumor cell resistance to it, are emerging, as are the ways in which tumor cells evade the damaging effects of IFN-gamma and of complement. Overcoming tumor cell resistance to innate immune attack could prove to be a fruitful approach to cancer immunotherapy in the clinic.

Human tonsillar germinal center T cells are a diverse and widely disseminated population.

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.