Figure 1

Proposed role of CLA-positive T cells in lupus pathogenesis. In response to a range of noxious stimuli, keratinocytes undergo apoptosis and promote the formation of a cutaneous inflammatory infiltrate via the release of pro-inflammatory cytokines (PC) (acute phase). In susceptible individuals, apoptotic material taken up by DCs is transported to draining lymph nodes and is presented to autoreactive T cells (T). Once activated, these T cells stimulate production of ANA by specific B cells (B). CLA-positive T cells are activated and migrate back to the site of injury. IFN-γ produced by these activated cells triggers further basal cell apoptosis by facilitating a productive interaction between keratinocyte Fas and FasL on infiltrating immunocytes. The T-cell infiltrate hence triggers production of its own stimulating antigen and the process becomes self-perpetuating (chronic phase) and self-amplifying. With chronic exposure to antigen, the immune response undergoes affinity maturation. Apoptotic material taken up by DCs further stimulates both infiltrating and lymph node (LN) resident T cells. IFN-γ also induces ICAM and MHC expression in basal keratinocytes. Presentation of apoptotic material taken up by these cells is tolerogenic to T cells (see text), providing a possible safety valve to switch the process off [29]. In this model, genetic defects leading to excessive keratinocyte apoptosis or alterations in the balance of uptake, and processing of apoptotic material by professional and non-professional APCs could determine an individual's susceptibility to SLE.