The information outlined above can be used to generate a model of the immunopathogenesis of SSc (Fig. 3). This model includes a susceptible host, with age greater than 25 and female gender being risk factors. The model also includes exposure to exogenous agents, which could be different in different individuals and may include inhaled or ingested chemicals or infectious agents. An early event is T-cell activation, with infiltration in the skin and internal organs. Activation of the T cells is a selective process that appears to be influenced by antigen in SSc patients. The importance of a particular T-cell subpopulation may depend upon the organ involved and the stage of the disease. CD4+ T cells predominate in the skin. In contrast, CD8+ T cells are increased in the lungs of patients with alveolitis, where they are oligoclonal, showing evidence of antigen-driven selection. V delta 1+ gamma/delta T cells are increased in both the blood and lungs of SSc patients and also show evidence of selection by antigen. B cells are activated early, with polyclonal activation leading to hypergammaglobulinemia. SSc-specific autoantibodies target DNA topoisomerase I, centromeric proteins, and RNA polymerases I and III. Characteristics of autoantibodies in SSc suggest that the target antigens are presented to the immune system as native molecules or even part of a multiunit complex. There is some homology between viruses and autoantibody targets in SSc, which suggests that molecular mimicry may play a role in initiating the antibody response. Many nonspecific inflammatory cells infiltrate the tissues and show evidence of activation. These include macrophages and monocytes, mast cells, eosinophils, basophils, and natural killer cells. Soluble mediators made by these T cells, B cells, and nonspecific inflammatory cells can activate and damage fibroblasts, endothelial cells, and other vascular cells. The relative importance of the various candidate cytokines, the temporal sequence of their production, and their cellular sources remain largely to be defined. There may be some contribution of direct T-cell cytotoxicity or antibody-dependent cellular cytoxicity to the tissue damage that occurs.