Research & Publications
The T-cell receptor is encoded by a gamma-delta and an alpha-beta gene complex. As the T-cell matures, the first rearrangement occurs in the gamma-delta gene complex. If this initial rearrangement is successful in producing a non-host reactive protein, such cells develop into mature CD3+, gamma-delta+, CD4-, CD8-, lymphocytes. Some of these cells migrate to the skin and others circulate within the peripheral blood. When this primary rearrangement is unproductive, the alpha-beta T-cell receptor gene complexes then undergo rearrangement, to produce CD3+, alpha-beta+, CD4+, CD8+ cells. Such cells circulate in the blood in a ratio of approximately 2-3:1, and constitute approximately 70% of all lymphocytes. After exit from the thymus to the circulation, T-cells undergo further maturation; skin is one site where maturation occurs in the presence of a variety of cytokines and skin-specific cell adhesion molecules. Not all T-cells migrate to and differentiate in the skin, as only those with homing receptors for cutaneous vascular adressins will do so.
Several theories have been proposed to explain the pathogenesis of the disorder known as cutaneous T-cell lymphoma (CTCL), or mycosis fungoides (MF). The first of two leading hypothesis proposes that MF is a disorder of malignant helper CD4+ T-cells, with a single neoplastic clone present at the very start of the disease process. The second hypothesis postulates a two stage process: a phase of chronic antigenic stimulation which results in a benign polyclonal proliferation of T lymphocytes, in which one clone is mutated (by polymerase errors, exposure to endogenous oxygenating agents, or an exogenous mutagen) and dominates the T-cell infiltrate. Cells are stimulated to develop "malignant potential," and to proliferate freely in the skin subsequently producing lesions clinically consistent with CTCL.
Weiss et. al. clearly demonstrated that cutaneous T-cell lymphoma (Mycosis Fungoides) is a disorder resulting from an expansion of a neoplastic clone of T-cells with characteristic rearrangements in T-cell receptor genes. Therefore, it should be possible to determine whether a "clinical recurrence" derives from the original neoplastic clone or represents a different neoplastic clonal T-cell expansion (which would reveal a second primary) by comparing the T-cell receptors (and/or the genes which have been rearranged to produce the receptor) in the primary lesion and the recurrence. This is an example of one area of research which our group has pursued.
Girardi M, Heald P.W., Wilson L.D.: The Pathogenesis of Mycosis Fungoides. New England Journal of Medicine 350:1978, 2004)
Specialized Terms: Cutaneous Lymphoma; Lung Cancer; Total Skin Electron Beam Therapy
Dermatology; Lung Neoplasms; Mycosis Fungoides; Lymphoma, T-Cell, Cutaneous; Radiation Oncology