T lymphocytes in Wegener’s granulomatosis

Sammanfattning: Wegener's granulomatosis (WG) is a systemic necrotizing vasculitis that affects small and medium size blood vessels. The respiratory tract and lungs are usually compromised with necrotizing granulomatous formations. The aetiology is unknown and untreated the prognosis of generalised WG is very poor. There are several indications that the T cells are involved and might play an important role in the pathology of the disease. T lymphocytes are the principal initiators and regulators of immune reactions. The specificity of the T lymphocytes resides in the T cell receptor (TCR) molecule. In this thesis we investigated the T cell repertoire by using MoAb and flow cytometry. PCR amplifications of the TCRBV gene segments and analyses of the CDR3 fragments for length and sequencing were performed. The CTLA-4 and IL- 10 genes were amplified and the polymorphisms analysed. We reported a bias in the usage of the TCR, with sustained dramatic expansions and higher frequencies of expanded CD4+ and /or CD8+ T cells than in normal controls. The expanded T cells expressed the activation markers CD25 and HLA-DR, and secreted IL-2, IL-4, and IFN-[gamma]. The expanded populations were mono/oligoclonal. Functionally, the cells were more difficult to stimulate with Con A or anti-CD3 when compared to the non-expanded T cells, indicating a state of anergy. The peripheral blood mononuclear cells from the patients had a significant higher spontaneous uptake of 3[H] Thymidine than cells from healthy controls. A recurrent motif in TCRBV8+CD4+ T cells of HLA-DRB1'0401 positive patients was observed in four unrelated patients suggesting a conventional antigen eliciting the immune response. There was a higher prevalence of the long alleles in the (AT)n in the untranslated region of the CTLA-4 gene in the patients than controls. Polymorphism in the promoter region of the CTLA-4 gene were also different between patients and controls. IL-10 is a growth and differentiation factor for activated B cells and is critical for Ig production. We observed a significant number of ANCA positive patients to be heterozygous for a certain allele in the IL-10 gene. These studies demonstrate that the T lymphocytes are expanded, the monoclonality of the expansions and the correlation with a certain HLA type for some of the T cell expansions suggest that WG patients are exposed to a conventional antigen. The activated status indicates their involvement in the pathogenesis of the disease. There are genetic variations in the patients that favour an exaggerated immune response. A therapeutic blockade of markers that regulate activation on the T cells might prove to be beneficial in the treatment of WG.

  Denna avhandling är EVENTUELLT nedladdningsbar som PDF. Kolla denna länk för att se om den går att ladda ner.