Rheumatoid arthritis is the most common inflammatory arthritis and is a major cause of disability. It existed in early Native American populations several thousand years ago but might not have appeared in Europe until the 17th century. Early theories on the pathogenesis of rheumatoid arthritis focused on autoantibodies and immune complexes. T-cell-mediated antigen-specific responses, T-cell-independent cytokine networks, and aggressive tumour-like behaviour of rheumatoid synovium have also been implicated. More recently, the contribution of autoantibodies has returned to the forefront. Based on the pathogenic mechanisms, specific therapeutic interventions can be designed to suppress synovial inflammation and joint destruction in rheumatoid arthritis.

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Evolving concepts of rheumatoid arthritis

MSCs are nonhematopoietic stromal cells that are capable of differentiating into, and contribute to the regeneration of, mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, and adipose. MSCs are rare in bone marrow, representing approximately 1 in 10,000 nucleated cells. Although not immortal, they have the ability to expand manyfold in culture while retaining their growth and multilineage potential. MSCs are identified by the expression of many molecules including CD105 (SH2) and CD73 (SH3/4) and are negative for the hematopoietic markers CD34, CD45, and CD14. The properties of MSCs make these cells potentially ideal candidates for tissue engineering. It has been shown that MSCs, when transplanted systemically, are able to migrate to sites of injury in animals, suggesting that MSCs possess migratory capacity. However, the mechanisms underlying the migration of these cells remain unclear. Chemokine receptors and their ligands and adhesion molecules play an important role in tissue-specific homing of leukocytes and have also been implicated in trafficking of hematopoietic precursors into and through tissue. Several studies have reported the functional expression of various chemokine receptors and adhesion molecules on human MSCs. Harnessing the migratory potential of MSCs by modulating their chemokine-chemokine receptor interactions may be a powerful way to increase their ability to correct inherited disorders of mesenchymal tissues or facilitate tissue repair in vivo. The current review describes what is known about MSCs and their capacity to home to tissues together with the associated molecular mechanisms involving chemokine receptors and adhesion molecules.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/epdf/10.1634/stemcells.2007-0197

Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing.

Chemokine receptors comprise a large family of seven transmembrane domain G protein-coupled receptors differentially expressed in diverse cell types. Biological activities have been most clearly defined in leukocytes, where chemokines coordinate development, differentiation, anatomic distribution, trafficking, and effector functions and thereby regulate innate and adaptive immune responses. Pharmacological analysis of chemokine receptors is at an early stage of development. Disease indications have been established in human immunodeficiency virus/acquired immune deficiency syndrome and in Plasmodium vivax malaria, due to exploitation of CCR5 and Duffy, respectively, by the pathogen for cell entry. Additional indications are emerging among inflammatory and immunologically mediated diseases, but selection of targets in this area still remains somewhat speculative. Small molecule antagonists with nanomolar affinity have been reported for 7 of the 18 known chemokine receptors but have not yet been studied in clinical trials. Virally encoded chemokine receptors, as well as chemokine agonists and antagonists, and chemokine scavengers have been identified in medically important poxviruses and herpesviruses, again underscoring the importance of the chemokine system in microbial pathogenesis and possibly identifying specific strategies for modulating chemokine action therapeutically. The purpose of this review is to update current concepts of the biology and pharmacology of the chemokine system, to summarize key information about each chemokine receptor, and to describe a widely accepted receptor nomenclature system, ratified by the International Union of Pharmacology, that is facilitating clear communication in this area.

https://pharmrev.aspetjournals.org/content/pharmrev/52/1/145.full.pdf

International Union of Pharmacology. XXII. Nomenclature for Chemokine Receptors

Chemokines and their receptors are important elements for the selective attraction of various subsets of leukocytes. To better understand the selective migration of functional subsets of T cells, chemokine receptor expression was analyzed using monoclonal antibodies, RNase protection assays, and the response to distinct chemokines. Naive T cells expressed only CXC chemokine receptor (CXCR)4, whereas the majority of memory/activated T cells expressed CXCR3, and a small proportion expressed CC chemokine receptor (CCR)3 and CCR5. When polarized T cell lines were analyzed, CXCR3 was found to be expressed at high levels on T helper cell (Th)0s and Th1s and at low levels on Th2s. In contrast, CCR3 and CCR4 were found on Th2s. This was confirmed by functional responses: only Th2s responded with an increase in [Ca2+]i to the CCR3 and CCR4 agonists eotaxin and thymus and activation regulated chemokine (TARC), whereas only Th0s and Th1s responded to low concentrations of the CXCR3 agonists IFN-γ–inducible protein 10 (IP-10) and monokine induced by IFN-γ (Mig). Although CCR5 was expressed on both Th1 and Th2 lines, it was absent in several Th2 clones and its expression was markedly influenced by interleukin 2. Chemokine receptor expression and association with Th1 and Th2 phenotypes was affected by other cytokines present during polarization. Transforming growth factor β inhibited CCR3, but enhanced CCR4 and CCR7 expression, whereas interferon α inhibited CCR3 but upregulated CXCR3 and CCR1. These results demonstrate that chemokine receptors are markers of naive and polarized T cell subsets and suggest that flexible programs of chemokine receptor gene expression may control tissue-specific migration of effector T cells.

https://rupress.org/jem/article-pdf/187/6/875/1115420/97-1974.pdf

Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes.

Since the pioneering work of Gowans and colleagues in the 1960s,1,2 much progress has been made in understanding the pivotal role of cell migration in immunity. We now have considerable knowledge of the way in which specialized leukocytes are channeled to distinct target tissues in immune responses and inflammation (Figure 1). This review will concentrate on the migration of T cells, which are at the heart of most adaptive immune responses. Since T cells respond to pathogens only on direct contact with pathogen-derived antigen, they must migrate to sites where antigen is found. The T-cell receptor recognizes a peptide . . .

T-cell function and migration. Two sides of the same coin.

T cells infiltrating inflammatory sites are usually of the activated/memory type. The precise mechanism for the positioning of these cells within tissues is unclear. Adhesion molecules certainly play a role; however, the intricate control of cell migration appears to be mediated by numerous chemokines and their receptors. Particularly important chemokines for activated/memory T cells are the CXCR3 ligands IP-10 and Mig and the CCR5 ligands RANTES, macrophage inflammatory protein-1alpha, and macrophage inflammatory protein-1beta. We raised anti-CXCR3 mAbs and were able to detect high levels of CXCR3 expression on activated T cells. Surprisingly, a proportion of circulating blood T cells, B cells, and natural killer cells also expressed CXCR3. CCR5 showed a similar expression pattern as CXCR3, but was expressed on fewer circulating T cells. Blood T cells expressing CXCR3 (and CCR5) were mostly CD45RO+, and generally expressed high levels of beta1 integrins. This phenotype resembled that of T cells infiltrating inflammatory lesions. Immunostaining of T cells in rheumatoid arthritis synovial fluid confirmed that virtually all such T cells expressed CXCR3 and approximately 80% expressed CCR5, representing high enrichment over levels of CXCR3+ and CCR5+ T cells in blood, 35 and 15%, respectively. Analysis by immunohistochemistry of various inflamed tissues gave comparable findings in that virtually all T cells within the lesions expressed CXCR3, particularly in perivascular regions, whereas far fewer T cells within normal lymph nodes expressed CXCR3 or CCR5. These results demonstrate that the chemokine receptor CXCR3 and CCR5 are markers for T cells associated with certain inflammatory reactions, particularly TH-1 type reactions. Moreover, CXCR3 and CCR5 appear to identify subsets of T cells in blood with a predilection for homing to these sites.

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Paul Myers

Papers

The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions.