Abundant expression of chemokines in malignant and infective human lymphadenopathies.

Lymph nodes can be the primary target of infection or malignant transformation and may exhibit characteristic patterns of leukocyte infiltration analogous to those seen in inflammation of other tissues. Leukocyte migration to lymph nodes in vivo is a highly regulated, multi-step process that depends upon adhesion molecules and as yet, uncharacterized chemotactic signals. Chemokines are a key part of the orchestrated code of signals that directs leukocyte subsets to sites of inflammation or immune response. The potential role of these chemoattractants in selective trafficking of leukocyte subsets into lymph nodes was assessed by determining the expression of chemokines on a range of pathological and normal human lymph nodes and by evaluating the cellular composition of each lymph node. In situ hybridization using chemokine riboprobes and immunohistochemistry using specific antibodies were performed in order to correlate the mRNA and protein expression of the chemokines. The cellular source(s) of each chemokine was assessed by immunohistochemical staining of adjacent sections using antibodies directed against distinctive cellular markers. Substantial, but varied, expression of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, RANTES, macrophage chemotactic protein (MCP)-1, eotaxin, and interleukin 8 (IL-8) were detected in the pathological lymph nodes by diverse cell types. Control lymph nodes showed expression only of RANTES, mainly by high endothelial venules. In all lymph nodes, except the nodes infiltrated with breast cancer, chemokine mRNA expression was highly concordant with the corresponding protein. In contrast with in vitro studies that have suggested discrete target cell specificity of chemokines, this study showed that with the possible exception of the neutrophil chemoattractant, IL-8, no chemokine appeared to be uniquely associated with the accumulation of a specific leukocyte subset. These data implicate chemokines in the recruitment of leukocytes to lymph nodes affected by diverse disease states.

Chemokine expression and leucocyte infiltration in Sjögren's syndrome.

OBJECTIVE: To investigate the expression and source of chemokines in minor salivary gland biopsies (MSGs) in patients with Sjögren's syndrome (SS). METHODS: Immunohistochemical analysis was used to determine the pattern of chemokine expression in MSGs from patients with (n=6) and without (n=5) SS, as well as to examine the phenotype of both resident and infiltrating cells expressing chemokines. RESULTS: Significant differences in the number of infiltrating mononuclear (MN) cells in patients with and without SS were noted. Ductal epithelial cells of SS biopsies expressed significantly increased levels of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, interleukin-8 (IL-8) and RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted). Biopsies from patients with SS showed that MIP-1beta was expressed by 51% of infiltrating cells, while 41% expressed MIP-1alpha, whereas 22 and 7% expressed RANTES and IL-8, respectively. CONCLUSION: Chemokines expressed by ductal epithelial cells may attract circulating leucocytes, in particular CD4+ T cells, towards the site of inflammation, thereby orchestrating the influx of MN cells characteristically seen in MSGs in SS. Chemokines may be induced directly by a putative triggering agent for SS, or secondary to the release of pro-inflammatory cytokines produced by epithelial cells. These findings further implicate epithelial cells as playing a major role in the pathogenesis of SS and implicate chemokines in the leucocyte recruitment in this setting.

Distribution of lymphocytes and cell adhesion molecules in iris biopsy specimens from patients with uveitis.

To investigate the mechanisms responsible for lymphocyte accumulation in the eye in uveitis, we examined iris biopsy specimens that were obtained from 10 patients with uveitis and from 12 patients with cataract for the presence of adhesion molecules on vascular endothelium, uveal cells, and infiltrating inflammatory cells. Immunoperoxidase staining of iris biopsy specimens that were obtained from patients with uveitis revealed an increased expression of intercellular adhesion molecule 1 (CD54) on endothelial cells, lymphocytes, fibroblasts, and iris epithelial cells. Seven of the 10 iris biopsy specimens that were obtained from patients with uveitis had a significant inflammatory cell infiltrate. Lymphocytes (CD2 positive) that infiltrated the iris were predominantly helper T cells (70%) and strongly expressed the lymphocyte function-associated antigen 1 (CD11a, CD18) molecule, the ligand for intercellular adhesion molecule 1, in four of the seven biopsy specimens. In contrast, small numbers of lymphocytes were evident in only three (25%) of the iris biopsy specimens that were obtained from patients with cataract. Vascular endothelium from the latter group did not express intercellular adhesion molecule 1 or endothelial leukocyte adhesion molecule 1. The results of this study revealed the enhanced expression of vascular endothelial cell and lymphocyte adhesion molecules in the iris biopsy specimens that were obtained from patients with uveitis. The presence of these receptors and their presumed ligands may have important implications for the role of these molecules in the pathogenesis of uveitis.