Drugs, sun and T cells in lupus

Abstract

That T cells are central in the expression of systemic autoimmunity as it relates to systemic lupus erythematosus (SLE) is well established [1,2]; treatment of lupus-prone mice with anti-T cell antibodies limits systemic disease [3,4] and, in humans, T cells are also central in the development of disease [2]. SLE T cells display a number of biochemical aberrations [5] that underwrite a T cell receptor (TCR) overexcitable phenotype [6,7] and lower excitation threshold to antigen [8,9] and presumably to autoantigen.Various T cell subsets are involved including TCR ab positive [10] and TCR gd positive [11] subsets. Both can help B cells to produce autoantibody but their role in effecting organ injury is not well understood. It appears that certain T cell clonotypes are involved in this process [12], suggesting strongly that limited autoantigens are responsible for the initiation of the autoimmune process. The ability of expanded T helper cells able to provide help to B cells has been exploited in clinical trials where the CD40-CD40 ligand cognate B-T cell interaction is disrupted with appropriate biologics [13].There is an important unanswered question: if autoantibodies and immune complexes are not responsible for all end organ damage then to what extent are T cells directly involved?TCR a -/ -MRL mice develop disease characterized by increased mortality, overt renal disease and skin lesions. While delayed in onset and/or reduced in severity, compared with TCR a +/+ MRL/ lpr animals, renal and skin lesions in TCR ab T cell-deficient animals are clearly increased in severity compared with agematched control non-autoimmune mice. The TCR a -deficient MRL/lpr mice displayed a predominantly IgG1 immune complex deposition, with poor complement fixation [14]. Therefore, systemic autoimmunity can be dissociated at least partially from skin and possibly renal disease and, therefore, the factors that are involved deserve special study. A study published in this issue [15] indicates that lack of TCR ab in a non-autoimmune murine background can facilitate fluorouracil and ultraviolet light-instigated skin lesions. The study is preliminary in many ways, as it is not indicated whether the lack of TCR a cells or the inadvertent expansion of other subsets is responsible for the skin disease. Transfer of gd T cells did not alter the appearance skin lesions, but the cell transfer experiment was not designed to address the role of these cells. Fluorouracil and ultraviolet light can damage skin cells and redistribute the localization of cellular antigens to surface blebs and henceforth stimulate a local and systemic immune response [16].Evidence suggests that the regulation of systemic autoimmune disease does not depend solely on the initial activation of autoreactive cells in lymphoid organs but also on factors related to the target organ. A recent study reported an interesting dissociation of target organ disease in b 2-microglobulin-deficient MRL/lpr mice: lupus skin lesions were accelerated, whereas nephritis was ameliorated [17]...