5.1The Role of T Cells in SjS

Three observations have weakened the dogma that T cells are central to SjS:

1. The process may occur when interferon (IFN) induces an excessive production of BAFF [15] by dendritic cells (DCs).

2. Antibody responses may develop outside the germinal centers [16].

3. Germinal centers can develop in the total absence of T cells [7]. By the same token, T lymphocytes do not appear to be mandatory for Ig class-switching to occur in SjS.

Germinal center evolution is initiated by immature [17] or mature transitional [18] B lymphocytes that have just migrated from the bone marrow to the peripheral blood. Once in the periphery, transitional B cells are engaged by their B-cell antigen receptor (BCRs) and promoted by follicular T helper (Th) cells and interdigitating dendritic cells upstream from the germinal centers [19] (Table 5.2). The requirement for T cells in this process that once seemed indisputable is now challenged by recent findings. For example, TNF deficiency fails to protect predisposed mice against SjS [20]. This experimental discovery is reminiscent of the clinical observation that a proportion of SjS patients develop ectopic germinal centers independent of T-cell-mediated inflammation [21].

T lymphocytes might also be advantageous for differentiation of naïve B lymphocytes into cytokine-producing B lymphocytes. According to the CD4+ T lymphocyte paradigm, Th1 cells secrete a specific array of cytokines, such as IFN-g and interleukin (IL)-2. Both of these cytokines favor the T-cell-mediated arm of the response, and Th-2 cells secrete a different array of cytokines, such as IL-4 and IL-6, which prefer its B-cell-mediated arm. The production of IFN-g and IL-2 by B effector (Be)-1 cells on one side and the elaboration of IL-4 and IL-6 by Be-2 cells on the other are regulated by Th-1 and Th-2 cells, respectively [22]. The beauty of such a model is that Be-1 and Be-2 polarize naïve CD4+ T cells toward Th-1 and Th-2 responses, respectively (Fig. 5.1). The Be-1 cells of the salivary glands of patients with SjS [23] may hence have been imprinted by Th-1 cells, but inversely this latter phenotype, which predominates over the Th2 at that site [24], might have been promoted by Be-1 cells [25].

It has been proposed that the Th-1/Th-2 balance changes with the progress of the immunopathological lesions in primary SjS and, concomitantly, with the cytotoxic T cell and antibody-producing B-cell involvement [26].