Salivary gland tissue expression of interleukin-23 and interleukin-17 in Sjögren's syndrome: findings in humans and mice.

The various subsets of CD4+ Th cells regulating development of adaptive immunity possess the ability to differentiate into functionally distinct effector cells often defined by their cytokine profiles (1-3). Currently, Th cells are divided into 3 major subsets: Th1 cells (secreting interferon-γ [IFNγ]), Th2 cells (secreting interleukin-4 [IL-4], IL-5, and/or IL-13), and the recently defined Th17 cells (secreting IL-17 and/or IL-22) (4). The unique interactions and cross-talk between these 3 different CD4+ T cell lineages result in both the development and regulation of specialized immune responses against invading pathogens and other environmental antigens. However, regulation of the immune response can be circumvented, leading to states of hypersensitivity and autoimmunity resulting in tissue and organ pathology. Recently, much attention has focused on the relationship between innate responses and subsequent activation of specific adaptive immunity in an attempt to understand subsequent immune dysregulation. With the identification of the CD4+ Th17 cell population (5), which initially challenged the long-standing Th1/Th2 cell paradigm, several of these important relationships between innate and adaptive immunity are now being uncovered. The IL-17–producing Th17 cells are developmentally and functionally divergent from the classic Th1 and Th2 cells (5,6). Upon stimulation by IL-6 and transforming growth factor β, a subset of naive CD4+ T cells can be activated to differentiate into Th17 cells (5). As mature memory cells, Th17 cell survival and maintenance appear to be dependent on IL-23, a heterodimeric cytokine comprising the p40 subunit expressed in IL-12 and a distinct p19 subunit (7). Activated Th17 cells secrete IL-17, a family of cytokines consisting of 6 members: IL-17A (IL-17), IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F (4). These are potent inflammatory cytokines that are actively involved in tissue inflammation by inducing expression of numerous proinflammatory cytokines and chemokines, such as IL-6, tumor necrosis factor (TNF), macrophage inflammatory protein 2, granulocyte colony-stimulating factor, CXCL1, CXCL2, CXCL5, matrix metalloproteinase 3 (MMP-3), and MMP-13, in other cell types (8). In addition, as part of the local inflammatory response, IL-17 is involved in the proliferation, maturation, and migration of neutrophils (9). Recently, CD4+ Th17 cells have been shown to be tissue seeking and intimately involved in autoimmune diseases (e.g., Crohn’s disease [CD] [10,11], experimental autoimmune encephalomyelitis [EAE] [12], and collagen-induced arthritis [CIA] [13]) in which tissue destruction appears to result, in part, from the up-regulation of MMPs. In the present study, we asked whether the Th17/IL-23 system, involving both of the cytokines IL-23 and IL-17, is important in the development of Sjogren’s syndrome (SS), an autoimmune disease characterized primarily by destruction of acinar tissue within the salivary and lacrimal glands (14-23). Using an animal model of SS, we were able to investigate the temporal appearance of both IL-17– and IL-23–positive cells in the targeted glandular tissues, as well as the correlation between these cell populations and the presence of lymphocytic foci. In addition, we investigated whether similar results are present in specimens from SS patients.