The immunopathogenesis of BD is unknown. Various micro-organisms such as streptococci and herpes simplex virus have been implicated in the pathogenesis in genetically susceptible HLA-B51+ individuals [12
There is evidence of immunological dysregulation, including neutrophil hyperfunction [14
], autoimmune manifestations [16
] and several phenotypic and functional lymphocyte abnormalities, most of the immunological studies suggesting a central role for T cells in the pathogenesis of this disease [17
]. Cytotoxic T cells are considered to play a role in the development of disease. Recent studies [18
] and our own [6
] point also for a role of activated Vγ9/Vδ2 T lymphocytes in the progression and probably in the pathogenesis of the disease.
The treatment of BD comprises mainly systemic corticosteroids for most manifestations of BD. Supplemental therapy with other immunomodulatory agents is often necessary to control serious manifestations such as uveitis and meningoencephalitis and to reduce the incidence of long-term steroid toxicity. Drugs usually used in BD such as glucocorticoids, pentoxifylline and cyclosporine have been demonstrated to modulate peripheral blood gamma delta T lymphocytes [20
The role of TNF-blocking agents on gamma delta T lymphocyte functions has not yet been investigated. In BD, increased serum levels of TNF-α and soluble TNF-RII has been observed during the active stage of disease suggesting a role for TNF-α in the pathogenesis [23
]. In addition, TNF-α, that has been reported also to be produced by γδ T cells, might stimulate the TNF receptor bearing γδ T cells, in an autocrine or paracrine manner or both, to proliferate [26
In this study we investigated the functional changes of Vγ9/Vδ2 T lymphocytes in both active and inactive Behçet's disease and the effect of Infliximab on Vγ9/Vδ2 T cell expansion, activation and cytotoxicity.
Infliximab is a high affinity monoclonal anti TNF-α antibody that has been introduced for Crohn's disease and rheumatoid arthritis treatment in patients who are resistant to standard therapy. Our previous studies demonstrated a complete remission of all disease manifestations in BD patients with ocular involvement and cerebral vasculitis [1
Infliximab interferes with Vγ9/Vδ2 T cell functions. In particular, in vitro and in vivo studies demonstrated that this drug was able to suppress the Vγ9/Vδ2 T cell expansion and activation (TNF-RII expression and IFN-γ production) induced by DMAPP. Infliximab interferes also with the potential cytotoxic activity of these cells that we evaluated through the expression of the cytoplasmic granule-associated molecules perforin and the GrA release in the medium of cultures.
In this paper we did not study the phenotype of circulating Vγ9/Vδ2 T lymphocytes being our cytofluorimetric analysis not sensitive enough to measure membrane antigens in a relatively low number of cells. Although these preliminary observations have to be properly defined, after phosphoantigen stimulation, however, we observed frequently that the Vγ9/Vδ2 subpopulation was mainly composed by effector cells in active patients and by memory cells in inactive patients and controls. After in vitro exposure to Infliximab, there was a lack of effector cells, suggesting that this drug might block the lineage pattern of differentiation (naive → memory → effector → terminally differentiated cells), as a consequence of expansion and activation inhibition.