Objective. In ϳ25% of synovial tissues from rheumatoid arthritis (RA) patients, infiltrates of T cells, B cells, and follicular dendritic cells (FDCs) are spatially organized into structures resembling lymph nodes with germinal centers. The remainder of the tissues lack FDCs and show either a diffuse or an aggregated T cell and B cell infiltrate. To gain more insight into this specific disease process, we sought to identify the genes expressed in RA tissues with ectopic lymphoid structures.Methods. Gene expression profiling of RA synovial tissues was determined by complementary DNA microarray analysis and quantitative real-time polymerase chain reaction. The presence of lymphoid follicles and localization of interleukin-7 (IL-7) in synovial tissue sections was determined by immunofluorescence staining using specific antibodies.Results. Findings of gene expression analysis confirmed previous reports that tissues with lymphoid structures showed elevated expression of CXCL13, CCL21, CCR7, and lymphotoxin ␣ and ␤ messenger RNA. In addition, the tissues also showed enhanced expression of the chemokines CXCL12 and CCL19 and the associated receptors CXCR4 and CXCR5, which are important for the attraction of T cells, B cells, and dendritic cells. Pathway analysis revealed increased expression of genes involved in JAK/STAT signaling, T cell-and B cell-specific pathways, Fc receptor type I signaling in mast cells, and IL-7 signal transduction in the tissues with ectopic lymphoid follicles, accompanied by increased expression of IL-7 receptor ␣ (IL-7R␣)/IL-2R␥ chains and IL-7. Protein expression of IL-7 in RA tissues was localized within fibroblast-like synoviocytes, macrophages, and blood vessels and was colocalized with extracellular matrix structures around the B cell follicles.Conclusion. Activation of the IL-7 pathway may play an important role in lymphoid neogenesis, analogous to its role in the development of normal lymphoid tissue.

Objective. Given the heterogeneity of gene expression patterns and cellular distribution between rheumatoid arthritis (RA) synovial tissues, we sought to determine whether this variability was also reflected at the level of the fibroblast-like synoviocyte (FLS) cultured from RA synovial tissues.Methods. Gene expression profiles in FLS cultured from synovial tissues obtained from 19 RA patients were analyzed using complementary DNA microarrays and hierarchical cluster analysis. To validate the subclassification, we performed prediction analysis and principal components analysis. Genes that differed significantly in their expression between FLS cultures were selected using Statistical Analysis of Microarrays software. Real-time quantitative polymerase chain reaction was performed to validate the microarray data. Immunocytochemistry was applied to study the expression of the genes of interest in FLS and synovial tissues.Results. Hierarchical clustering identified 2 main groups of FLS characterized by distinctive gene expression profiles. FLS from high-inflammation synovial tissues revealed increased expression of a transforming growth factor ␤/activin A-inducible gene profile that is characteristic of myofibroblasts, a cell type considered to be involved in wound healing, whereas increased production of growth factor (insulin-like growth factor 2/insulin-like growth factor binding protein 5) appeared to constitute a characteristic feature of FLS derived from low-inflammation synovial tissues. The molecular feature that defines the myofibroblast-like phenotype was reflected as an increased proportion of myofibroblast-like cells in the heterogeneous FLS population. Myofibroblast-like cells were also found upon immunohistochemical analysis of synovial tissue.Conclusion. Our findings support the notion that heterogeneity between synovial tissues is reflected in FLS as a stable trait, and provide evidence of a possible link between the behavior of FLS and the inflammation status of RA synovium.Rheumatoid arthritis (RA) is a chronic inflammatory joint disease of unknown etiology that affects the

IntroductionEosinophils play an important role in immunity against helminth infection. Parasite infection results in enhanced eosinophil numbers and in migration toward and degranulation at the site of parasite invasion. In vitro studies demonstrated that eosinophils are capable of adhering to parasites in the presence of different antibody isotypes (immunoglobulin E [IgE], IgG, IgA) 1,2 and complement components (C3b). 3 At the site of contact, eosinophils degranulate, resulting in damage to the tegumental membranes and eventually in the death of parasites. 4 The toxic effect of eosinophilic granule proteins, such as eosinophilic cationic protein (ECP), is complemented by the generation of toxic oxygen metabolites. 5 Besides their role in immunity against parasitic infection, eosinophils are thought to play an important role in the pathogenesis of allergic diseases, among them asthma and dermatitis. Eosinophils are recruited to the site of allergic inflammation by chemoattractants, such as C5a and platelet activating factor (PAF). 6,7 Release of granular contents at the inflammatory locus can result in long-term tissue damage. For example, airway epithelium can be damaged during airway inflammation. 8,9 Eosinophils are derived from pluripotent hematopoietic stem cells (HSCs) in the bone marrow. These progenitors are defined as precursors for all lineages of mature blood cells, and they are capable of self-renewal. Such cells can be divided into long-term repopulating hematopoietic stem cells (LT-HSCs) and short-term repopulating hematopoietic stem cells (ST-HSCs). ST-HSCs can differentiate to multipotent progenitor cells, which are capable of differentiation toward a subset of the hematopoietic lineage. These multipotent stem cells include the common lymphoid precursor 10 and the common myeloid precursor. 11 Common myeloid progenitor cells, known as the granulocyte/erythrocyte/macrophage/ megakaryocyte colony-forming unit (CFU-GEMM), can differentiate toward the erythroid, megakaryocytic, and myelomonocytic lineage. It has been demonstrated that genes specific for erythroid, myeloid, or megakaryocytic lineages are transcribed in the common myeloid progenitors before commitment to a single lineage. Genes specific for differentiation toward other lineages are downregulated on commitment to a single lineage. 12 Myeloid differentiation is regulated by a variety of cytokines, including erythropoietin (EPO), granulocyte-colony-stimulating factor (G-CSF), thrombopoietin (TPO), interleukin-3 (IL-3), granulocyte macrophagecolony-stimulating factor (GM-CSF), macrophage-colony-stimulating factor (M-CSF), and IL-5. IL-3 and GM-CSF are cytokines that regulate proliferation and survival during myeloid differentiation of various lineages, whereas EPO, TPO, G-CSF, M-CSF, and IL-5 are required for the final maturation of erythrocytes, 13 megakaryocytes, platelets, 14,15 neutrophils, monocytes, 16 and eosinophils, 17,18 respectively.Hematopoietic cytokines can activate several signal transduction pathways, including the Ras/Raf/...

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