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Do Chemokines Spark Autoimmunity in Juvenile and Adult Rheumatic Disease?
Immunobiol. (2002) 206, pp. 459 – 471 © 2002 Urban & Fischer Verlag http://www.urbanfischer.de/journals/immunobiol
Review 1
Department of Laboratory Medicine and Department of Pediatrics – Immunology/Rheumatology Unit, University of Graz, Austria, 2 Pediatric Clinic, University Hospital Nis, Serbia, Yugoslavia, and 3 Department of Pathophysiology University of Graz, Austria
Do Chemokines Spark Autoimmunity in Juvenile and Adult Rheumatic Disease? HARALD MANGGE 1, JELENA VOJINOVIC 2, and KONRAD SCHAUENSTEIN 3 Received January 16, 2002 · Accepted in revised form May 28, 2002
Abstract The recent increase in knowledge on chemokines contributes substantially to the understanding of autoimmune inflammatory diseases, as cell migration is an essential prerequisite for the local immune reaction. The purpose of this review is to summarize the essential functions of chemokines in immune activation and to examine their role(s) in the initiation and perpetuation of autoimmunity in juvenile idiopathic arthritis and adult rheumatic disease. The possible relevance of chemokines as therapeutical targets will be discussed.
Introduction In recent years it became clear that chemokines and their receptors, which are expressed by a wide variety of hematopoetic and nonhematopoetic cells, play widespread and important roles extending far beyond their functions on leukocytes (1). By genomic Abbrevations: BLC = B-cell attracting chemokine; ELC (synonym: MIP-3b) = Epstein Barr virus induced-1 ligand chemokine; ELR-chemokines = chemokines sharing the short sequence motif Glu-Leu-Arg (=ELR) preceding the first cysteine required for receptor triggering; ENA-78 = epithelial cell derived neutrophil activating peptide-78; Fkn = Fractalkine; GCP-2 = granulocyte chemotactic protein-2; GRO-a = growth related oncogene-a; G-CSF = granulocyte colony stimulating factor; ICAM-1 = intercellular adhesion molecule-1; IL = interleukin; IP-10 = interferon-g inducible protein of 10 kd; I-TAC = interferon-g inducible T cell alpha chemoattractant; JIA = juvenile idiopathic arthritis; LARC (synonym: MIP-3a) = liver and activation-regulated chemokine; LPS = Lipopolysaccharid; Ltn = Lymphotactin; MAPK = mitogen activated protein kinase; MCP = monocyte chemotactic protein; MDC = macrophage derived chemokine; MIG = monokine induced by interferon-g; MIP = macrophage inflammatory protein; NAP-2 = neutrophil activating protein-2; MAPK/JNK = mitogen-activated protein kinase/c-Jun N-terminal protein kinase; PI-3K = phosphatidylinositol-3 kinase; RANTES = regulated on activation, normally T-cell expressed and secreted; SDF-1 = stromal cell derived factor-1; TARC = thymus and activation-regulated chemokine; TECK = Thymus expressed chemokine; TGF-b = Transforming growth factor beta 0171-2985/02/206/04-459 $ 15.00/0
460 · H. MANGGE, J. VOJINOVIC and K. SCHAUENSTEIN efforts about 50 or more human chemokines could be identified so far. They form a large family of small proteins with four conserved cysteins. Based on the configuration of the cystein residues near the NH2-terminus, two major groups are distinguished: CC, and CXC (Table 1). In the CC group two cysteins are adjacent, while in the CXC group the two cysteins are separated by one amino acid other than cystein. By virtue of the detection of Lymphotactin (Ltn) and Fractalkine (Fkn), two additional chemokine groups, i.e. “C” and “CX3C” were defined. Ltn shows similarity to CC chemokines, but has lost the first and third cysteine residues (“C”) (2, 3). Fkn is another chemokine with a structure, in which two cysteins are separated by three aminoacids other than cystein (“CX3C”) (4). The knowledge about chemokine functions is still fragmentary, not the least because the dose responses for given effects in vitro are not relevant in vivo. Nevertheless, we will summarize recent data, and discuss implications in pathogenesis of juvenile and adult rheumatic disease. Chemokine function Chemokines are diverse proteins mediating inflammatory responses, cell trafficking, activation (e.g. intracellular Ca2+ influx) and homing (1, 5). They can trigger signal transduction cascades, such as mitogen-activated protein kinase/c-Jun N-terminal protein kinase (MAPK/JNK) and phosphatidylinositol-3 kinase (PI-3K) pathways (6–9). Furthermore, chemokines were identified as potent cofactors for T-cell activation (10–12). Taken together, four major biological functions of chemokines can be distinguished (13): 1. Leukocyte chemotaxis. Migrating cells are transformed resulting in a redistribution of chemoattractant receptors, integrins, cytoskeletal and regulatory intracellular proteins (e.g.: tyrosine-, lipid-kinases, second messengers, members of Rho family of small GTPases). CXC chemokines attract neutrophils, monocytes and lymphocytes (5), CC chemokines act on T lymphocytes, dendritic cells, NK cells and all leukocyte types but neutrophils. Ltn and Fkn both act on T lymphocytes, and Fkn is also particularly active on monocytes (14, 15). The exclusive action of Ltn on lymphocytes makes it unique among chemokines (2). 2. Steering leukocyte-endothelial interactions by signaling of integrin activation. 3. Leukocyte degranulation, stimulation of respiratory burst and release of inflammatory mediators. Examples are IL-8, which induces neutrophil granule exocytosis (16), and monocyte chemotactic protein-1 (MCP-1), which stimulates histamine release by basophils (17). 4. Stimulation of angiogenesis (eg. ELR*-positive CXC chemokines, Fkn) (18, 19) or angiostasis [e.g. the CXC receptor 3 ligands interferon-g inducible protein of 10 kd (IP-10) and monokine induced by interferon-g (MIG)] (20).
* Chemokines sharing a short sequence motif “Glu-Leu-Arg”, which precedes the first cysteine amino acid residue
Chemokines and onset of rheumatic disease · 461 Table 1. Chemokine receptors and corresponding chemokines CXC receptors
CXC chemokines
CXCR 1 CXCR 2 CXCR 3 CXCR 4 CXCR 5
IL-8, GCP-2 IL-8, GRO-a,b,g, NAP-2, ENA-78, GCP-2 IP-10, MIG, I-TAC SDF-1 BLC
CC receptors
CC chemokines
CCR 1 CCR 2 CCR 3 CCR 4 CCR 5 CCR 6 CCR 7 CCR 8 CCR 9
MIP-1a, RANTES, MCP-2, MCP-3 MCP-1, MCP-2, MCP-3, MCP-4, MCP-5 Eotaxin, RANTES, MCP-2, MCP-3, MCP-4 MIP-1a, RANTES, MCP-1, TARC MIP-1a, MIP-1b, RANTES LARC (MIP-3a) ELC (MIP-3b) I-309 TECK
C receptors
C chemokines
XCR1
Ltn
CX3C receptors
CX3C chemokines
CX3CR1
Ftn
Chemokine receptors The so far identified chemokine receptors are transmembrane domain proteins coupled to heterotrimeric GTP-binding proteins with homology to the family of chemotactic receptors. Five receptors for CXC chemokines (CXCR 1–5), nine for CC chemokines (CCR 1–9), one for C chemokines (XCR1), and one for CX3C chemokines (CX3CR1) have been identified so far (Table 1). These receptors show different ligand specificities and are differentially expressed in leukocytes (1) (Table 2). Certain chemokine receptors are mainly expressed by specific leucocyte subtypes, such as e.g. CXCR1 on neutrophils, CCR3 on eosinophil and basophil granulocytes, CCR9 on intestinal T lymphocytes (21), and XCR1 on neutrophils and T and B cells (3), whereas other receptors, like CCR1 and CCR2, are expressed more ubiquitously. The differential expression of chemokine receptors and the interaction with their ligands controls substantially the level and specificity of leukocyte migration. This could be shown in vivo by intradermal injection of macrophage inflammatory protein-1a (MIP-1a) to human probands, leading to endothelial cell mediated (E-selectin) ingression of monocytes, T-lymphocytes, eosinophils and neutrophils to the injection site, which was paralleled by an increased expression of CCR1 on peripheral blood neutrophils (22). Notably, such a CCR1–MIP-1a activation of neu-
462 · H. MANGGE, J. VOJINOVIC and K. SCHAUENSTEIN Table 2. Chemokine receptor expression on leukocytes Receptor
Main cellular expression
CXCR 1 CXCR 2 CXCR 3 CXCR 4 CXCR 5 CCR 1 CCR 2 CCR 3 CCR 4 CCR 5 CCR 6 CCR 7 CCR 8 CCR 9 XCR1 CX3CR1
neutrophils neutrophils activated T-lymphocytes T and B lymphocytes, monocytes, macrophages, granulocytes B lymphocytes, T lymphocyte subpopulation monocytes, basophils, activated T lymphocytes monocytes, basophils, activated T lymphocytes eosinophils, basophils, activated T lymphocytes CD4+ T lymphocytes Activated monocytes, activated T lymphocytes, dentritic cells Activated T lymphocytes, B lymphocytes EBV-B cell lines, T cell lines NK cell lines, activated T lymphocytes intestinal T lymphocytes neutrophils, B lymphocytes, T lymphocytes monocytes/macrophages
trophils could not be observed by in vitro experiments, indicating the importance of in vivo studies for an understanding of chemokine functions (22). Furthermore, chemokine receptors play an important role in T- and B-lymphocyte development, regulation and homing. Th1 lymphocytes selectively express CXCR3 and CCR5, while CCR3 and CCR4 are preferentially expressed by Th2 lymphocytes (23). CCR8 and its ligand I-309 was shown to be involved in the recruitment of skin-homing regulatory CD4+ T cells (23), whereas CCR9 and Thymus-expressed chemokine (TECK) attract T cells (CD4+ and CD8+) selectively to the small intestine (21). Finally, CXCR5, the receptor for B cell attracting chemokine (BLC or CXCL13), which is mainly expressed by B-lymphocytes and only on a minor fraction of T lymphocytes, directs the migration of activated B cells into germinal centers (24). Chemokines and receptors – involvement in immune regulation Chemokines control cytokine profiles, influence isotype switching (25), and the balance between Th1 and Th2 cells (23, 26). CC chemokines, such as MIP-1a, were shown to direct the chemoattraction of mononuclear inflammatory cells in T cell-mediated autoimmune diseases, like experimental autoimmune encephalitis (EAE) (27). The presence of MIP-1a promoted naive Th0 cells to differentiate to Th1 cells, whereas MCP-1, another CC chemokine, stimulated Th2 cell development (27, 28), and inhibited the adoptive transfer of EAE (27). MCP-1 is also involved in oral tolerance induction in EAE by inhibition of Th1 cell-related cytokines (29). These observations suggest a differential role for CC chemokines in the development and activation of T cells during autoimmune activation. RANTES (regulated on activation, normal T cell expressed and secreted), another chemokine, is involved in an antigen-independent activation of T lymphocyte chem-
Chemokines and onset of rheumatic disease · 463
otaxis and proliferation by inducing a biphasic intracellular Ca2+ influx (30). The initial cytosolic Ca2+ peak is associated with chemotaxis (G-protein mediated), whereas a second peak (tyrosine kinase mediated) is dominated by an upregulation of surface IL-2 receptor expression, cytokine release, and T cell receptor activation (30). From this point of view, chemokines and their receptors can be devided into two functionally distinct categories: i) inflammatory chemokines upregulated by recruitment signals of local inflammatory reactions. ii) constitutive chemokines produced in bone marrow, thymus and secondary lymphoid organs controlling leukocyte traffic and driving the encounter of cells that need to interact for the generation of a local immune response. Chemokines and receptors – involvement in adult and juvenile rheumatoid arthritis In rheumatoid arthritis (RA) the major site of joint destruction is the pannus, a tissue predominated by macrophages and aggressive fibroblast-like synoviocytes (FLS) (31). Lymphocytes, dendritic cells, and polymorphonuclear leukocytes are found in the synovial sublining layers of the pannus, whereas the interface between pannus and cartilage is dominated again by activated macrophages and synoviocytes secreting abundantly destructive proteases (32). During inflammation, the pannus migrates over the underlying cartilage and to the subchondral bone, a process which causes tissue erosion (33, 34). Pannus lymphocytes are mainly CD4+CD45RO+ T cells and cytokines, such as IL-2, IL-7, IL-10 and IL-12 seem to sustain survival and function of such chronically activated T cells (35). The majority was identified as members of the Th1-subtype, with production of IL-2 and IFN-g (36), and it is well established now that a sustained Th1-cell activation plays an important role in the pathophysiology of RA (37–38). Proinflammatory, immunoregulatory and chemotactic cytokines [e.g.: IL-1, TNF-a, transforming growth factor-b (TGF-b), fibroblast grow factor (FGF) ] are increased as well (39, 40). Cell recruitment is crucial in the establishment of synovitis, pannus activity, and inflammatory perpetuation in rheumatoid disease. Chemokines and their receptors are centrally involved in the recruitment of inflammatory cells (41). Synovial infiltrating activated/memory T cells express the Th1 cell associated chemokine receptors CXCR3 and CCR5 (Fig. 1). Chemokines reacting with CXCR3 (IP-10, MIG) and CCR5 (MIP-1a, MIP-1b) seem to induce and perpetuate the recruitment of such CXCR3+ and CCR5+ T cells (Fig. 1) (42). The CXCR3+ phenotype prevails especially in synovial perivascular regions of RA patients, whereas only a low percentage of T cells express CXCR3 or CCR5 within normal lymph nodes (43). Furthermore, CXCR4 and its ligand stromal-derived factor-1 (SDF-1) mediate synovial accumulation of T cells (44) (Fig. 1), whereby the CXCR4 expression on synovial T cells seems to be induced by TGF-b (44) and IL-15 (45). SDF-1 positive pannus endothelial cells induce a strong integrin-mediated adhesion of synovial T cells to fibronectin and intercellular adhesion molecule-1 (ICAM-1) (44) (Fig. 1), and inhibit activation-induced apoptosis of T cells (45). Comparable to the pannus site, virtually all T cells in SF of RA patients (RA SF) show CXCR3+ (≈100%) and/or CCR5+ (≈ 80%) phenotypes, representing a high enrichment
464 · H. MANGGE, J. VOJINOVIC and K. SCHAUENSTEIN
Figure 1. Chemokines and receptors within the affected rheumatic joint.
over levels of CXCR3+ (35%) and CCR5+ (15%) T cells in peripheral blood (PB) (43). Furthermore, the specific ligands for CCR5, MIP-1a, MIP-1b and RANTES, are increased in SF (46) (Fig. 1), and SF CCR5+CD4+ T cells produce IFN-g, but not IL-4, in response to anti-CD3 stimulation in vitro (45). These results indicate that the chemokine receptors CXCR3 and CCR5 are importantly involved in homing of activated/memory T cells to chronically inflamed articular sites, and that they are associated with a Th-1 weigthed immune activation. The CX3C chemokine Fkn plays an important role in monocyte chemoattraction. As shown by CHAPMAN et al., Fkn acts as adhesion molecule tethering monocytes to endothelial cells by binding with its receptor CX3CR1 (47) (Fig. 1). Soluble fractalkine (sFkn) levels were observed to be elevated in RA SF, as compared to osteoarthritis and other forms of arthritis (Fig. 1). sFkn-depleted RA SF showed significantly decreased chemotactic activity for monocytes compared with sham-depleted RA SF (48). Furthermore, differential expression of CC chemokine receptors was observed to be crucial for monocyte recruitment from circulation and retention in affected joints of RA patients (49). Neoangiogenesis, another hallmark of pannus activity, is essentially stimulated by the ELR-containig CXC chemokines, IL-8, epithelial neutrophil activating peptide 78 (ENA-78) (50, 51), and Fkn was observed recently to mediate angiogenesis in RA (19) (Fig. 1).
Chemokines and onset of rheumatic disease · 465
Chemokines are also involved in cartilage pathophysiology. Chondrocytes produce CXC chemokines (IL-8, GRO-a) and CC chemokines (MCP-1, MIP-1a, RANTES) after stimulation with IL-1b or TNF-a (Fig. 1) (52). The production of these chemokines in chondrocytes is modulated by antinflammatory mediators, like TGF-b and IL-10, which may play a role in the perpetuation of rheumatic joint disease (53, 44). Bone resorptive osteoclasts from patients with RA express mRNA for IL-8, and this expression is potentiated after stimulation with IL-1b, IL-6 or TNF-a (Fig. 1) (54). Although, as compared to adult RA, the available data are scarce, evidence exists that chemokines and their receptors are also involved in the pathophysiology of juvenile idiopathic arthritis (JIA). JIA represents a heterogenous syndromatology consisting of different subtypes (Systemic onset JIA, polyarticular seronogative-, polyarticular seropositive JIA, pauciarticular JIA, psoriatric arthritis) differing markedly in clinical appearance and prognosis (55, 40). Furthermore, with the exception of seropositive polyarticular JIA, the JIA subtypes are clinically markedly different from adult RA. On the other hand, a potentially destructive chronic synovitis is shared by both RA and JIA. DE BENEDETTI et al. (56) found that in patients with active systemic JIA serum levels of IL-8 and MCP-1 were higher as compared to active polyarticular, pauciarticular JIA and healthy controls. Furthermore, in systemic JIA IL-8 and MCP-1 levels correlated with clinical disease activity. RA patients showed similarly elevated SF levels of IL-8 and MCP-1 as compared to patients with systemic, polyarticular and pauciarticular JIA, suggesting comparable local production of these two chemokines (56). By virtue of a very recent study investigating a caucasian population, a single nucleotide polymorphism of the macrophage migration inhibitory factor (MIF) gene (position 173: G-to-C transition = MIF-173*C allele) was shown to be associated with a significantly increased risk to develop systemic JIA as compared to a caucasian control group not bearing this allele (57). Finally, circulating immune complexes (CICs) purified from JIA patient sera were found to trigger IL-8 mRNA and protein production in normal human synoviocytes (58). Concerning Th1/Th2 activation, the data are contradictory. WEDDERBURN et al. observed in patients with pauciarticular and polyarticular JIA an increased production of Th1 cytokines by CXCR3+CCR5+CD45RO+ synovial T cells as compared to peripheral blood T cells, suggesting JIA, like RA, to be an autoimmune disease with a Th1 polarization of synovial T cells (59). Conversely, in a study by THOMPSON et al., a synovial accumulation of CCR4+ T cells was found to be associated with very early stages of JIA. Such CD4+CCR4+ synovial T lymphocytes produced more IL-4 and less IFN-g and were supposed to act anti-inflammatory by virtue of IL-4 release (60). Macrophage derived chemokine levels did not differ between JIA and adult RA (60). It can be speculated from these data that, as compared to RA, the significantly better prognosis in many cases of JIA may be due to an initially less disturbed Th1–Th2 balance with an increased Th2 activity serving as a “brake” in early stages of disease (60). Besides this, the findings support the view that JIA and RA are in fact comparable diseases with chemokines and their receptors centrally involved in chronic inflammation of the target organs. Animal experiments In rat adjuvant-induced arthritis (AIA), a model of human RA, SF levels of TNFa, IL-1b and MIP-1a correlated with clinical symptoms of arthritis and blood neutrophil
466 · H. MANGGE, J. VOJINOVIC and K. SCHAUENSTEIN counts (61). Fractalkine and its receptor CX3CR1 were identified in synovial tissue macrophages, fibroblasts, endothelial cells, and dendritic cells, with weaker expression of CX3CR1 in endothelial cells (48). As was measured by RT-PCR, Fkn expression levels correlated with rat joint inflammation (48). These data indicate that Fkn and its receptor are involved in monocyte chemotaxis in AIA (48). In collagen induced arthritis (CIA), paws of collagen-treated mice exhibited increased mRNA levels of IL-1b, IL-2, MIP-1a, MIP-2, IL-6, IL-1 receptor antagonist, RANTES, TNF-a, TNF-b, IL-11, and TGF-b as compared to paws of unimmunized animals (62). Even clinically uninvolved paws of immunized mice showed increased mRNA levels of certain cytokines (IL-11, TNF-a, TNF-b) and chemokines (RANTES, MIP-1a) as compared to paws of unimmunized controls (62). This observation was confirmed by KRAAN et al., who detected in serial synovial tissue biopsies of CIA in rhesus monkeys by virtue of serial synovial tissue biopsies an influx of macrophages well before the occurence of arthritis (63). Taken together, animal models affirm the central role of chemokines and receptors in rheumatic inflammation. Based on these observations in humans and animal models of RA, chemokines can be considered as a future target for pharmacologic modulation of angiogenesis, chemotaxis, lymphocyte homing, T cell activation, Th1-Th2 switch and proinflammatory cytokine release in rheumatoid disease (50, 64, 65). Findings with a DNA-polymorphism of CCR5 seem to support such a concept. A 32bp deletion (CCR5 delta 32 allele) leads to a completely abolished (homozygotes) or diminished (heterozygotes) expression of CCR5 on Th1 cells and monocyte/macrophages. RA patients carrying the CCR5 delta 32 allele showed indeed a significantly less severe course of RA as compared to other patients not bearing this allele (66). Research activities developing and critically evaluating new chemokine antagonists in modifying disease symptoms will help to elucidate the potency of antichemokine therapy in future. Towards this, a first step may be the study by NAYA et al., who discovered a new substance (xanthene-9-carboxamide 1a) acting as a highly effective antagonist of murine and human CCR1 receptors (67). Chemokines and receptors – are they the initiators? Synovial accumulation of macrophages occurs very early in RA (65). MIP-1a and MCP-1 may initiate synovial invasion with macrophages, because they were found to be increased in earliest phases of RA (65). During RA prolongation CD68+ expression of infiltrating macrophages correlated with elevated MIP-1a, but not with MCP-1 expression (65). The question remains, if these chemokines are initiators or effectors. IL-15, which has been shown to act pivotally by inducing MCP-1 and IL-8 secretion in monocytes, but inhibiting the production of these chemokines in human colonic epithelial cells (68), may be involved (69). However, no data concerning IL-15 in very early phases of RA are available. In a study by KRAAN et al. it could be shown that asymptomatic synovitis precedes clinically manifest arthritis, both in RA and in an animal arthritis model (rhesus monkey) (63). This earliest, clinically asymptomatic phase was characterised by synovial macrophage infiltration and expression of macrophage-derived cytokines (63). More in depth investigation of such preclinically alterated synovial tissues may help to clarify the question about a causal role of chemokines in rheumatic pathophysiology. Furthermore, chemokine gene polymorphisms should be considered.
Chemokines and onset of rheumatic disease · 467
On the other hand, T lymphocytes are important in striking the rheumatic fire. The chemokine receptors CXCR3 (ligands IP-10, MIG) (10), and CCR5 (ligands: RANTES, MIP-1a, MIP-1b) (12) are involved in attraction of activated/memory T cells into inflamed rheumatic joints (43). As increased IL-2, IL-12 and IFN-g levels have been observed to be associated with early stages of RA (70, 71) animal models of RA (e.g.: CIA) (62) and other Th1-driven autoimmune diseases like multiple sclerosis (72), a selective T cell recruitment by virtue of specific chemokine/chemokine receptor activation may represent a further very early event in the immune dysregulation leading to chronic arthritis (43, 60) Taken together, the so far available data strongly suggest that the chemokine receptors CXCR3, CCR5 and their speficic ligands play a central role in early Th1 cell recruitment, and may indeed be critical in triggering an autoimmune activation loop in RA.
Therapeutic significance of anti-chemokine therapy? Experiences with anti-cytokine therapy (anti-TNF, anti-IL1 etc.) showed that, albeit blocking one cytokine, like TNF-a, can lead to transient clinical improvement, the disturbance of the cytokine network in rheumatic diseases is too complex that a sustained, complete remission can be achieved with such an approach (73, 74). The same may be very probably true for chemokines. The given diversity of chemokines with binding of a single chemokine to many chemokine receptors makes any therapy directed towards a single chemokine doubtful, because other chemokines with related receptor specificities and cellular effects would readily compensate for its inactivation (1). Ways to go could be antibodies either specifically reacting with common epitopes of different chemokines, or reagents that block chemokine receptors. Towards the latter, the afore mentioned findings with the CCR5 delta 32 allele seem to strongly suggest an important pathophysiological relevance of CCR5 activation in RA. GARRED et al. reported that HIV patients carrying this CCR5 deletion allele not only had less pronounced symptoms of AIDS but also showed a lower incidence of RA, and were unable to produce rheumatoid factor IgM antibodies (75). References 1. ROLLINS, JR. 1997. Chemokines. Blood 90: 909. 2. KENNEDY, J., G. KELNER, S. KLEYENSTEUBER, T. SCHALL, M.WEISS, H. YSSEL, P.SCHNEIDER, B.COCKS, K. BACON, and A. ZLOTNIK. 1995. Molecular cloning and functional characterization of human lymphotactin. J. Immunol. 155: 203. 3. HUANG, H., F. LI, C. M. CAIRNS, J. R. GORDON, and J. XIANG. 2001. Neutrophils and B cells express XCR1 receptor and chemotactically respond to lymphotactin. Biochem. Biophys. Res. Commun. 281: 378. 4. BAZAN, J. F., K. B. BACON, G. HARDIMAN, W. WANG, K. SOO, D. ROSSI, D. R. GREAVES, A. ZLOTNIK, and T. J. SCHALL. 1997. A new class of membrane-bound chemokine with a CX3C motif. Nature 385: 640. 5. GUNN, M. D., V. N. NGO, K. M. ANSEL, E. H. EKLAND, J. G. CYSTER, and L. T. WILLIAMS. 1998. A B-cell-homing chemokine made in lymphoid follicles activates Burkitt’s lymphoma receptor-1. Nature 391: 799.
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Review 1
Department of Laboratory Medicine and Department of Pediatrics – Immunology/Rheumatology Unit, University of Graz, Austria, 2 Pediatric Clinic, University Hospital Nis, Serbia, Yugoslavia, and 3 Department of Pathophysiology University of Graz, Austria
Do Chemokines Spark Autoimmunity in Juvenile and Adult Rheumatic Disease? HARALD MANGGE 1, JELENA VOJINOVIC 2, and KONRAD SCHAUENSTEIN 3 Received January 16, 2002 · Accepted in revised form May 28, 2002
Abstract The recent increase in knowledge on chemokines contributes substantially to the understanding of autoimmune inflammatory diseases, as cell migration is an essential prerequisite for the local immune reaction. The purpose of this review is to summarize the essential functions of chemokines in immune activation and to examine their role(s) in the initiation and perpetuation of autoimmunity in juvenile idiopathic arthritis and adult rheumatic disease. The possible relevance of chemokines as therapeutical targets will be discussed.
Introduction In recent years it became clear that chemokines and their receptors, which are expressed by a wide variety of hematopoetic and nonhematopoetic cells, play widespread and important roles extending far beyond their functions on leukocytes (1). By genomic Abbrevations: BLC = B-cell attracting chemokine; ELC (synonym: MIP-3b) = Epstein Barr virus induced-1 ligand chemokine; ELR-chemokines = chemokines sharing the short sequence motif Glu-Leu-Arg (=ELR) preceding the first cysteine required for receptor triggering; ENA-78 = epithelial cell derived neutrophil activating peptide-78; Fkn = Fractalkine; GCP-2 = granulocyte chemotactic protein-2; GRO-a = growth related oncogene-a; G-CSF = granulocyte colony stimulating factor; ICAM-1 = intercellular adhesion molecule-1; IL = interleukin; IP-10 = interferon-g inducible protein of 10 kd; I-TAC = interferon-g inducible T cell alpha chemoattractant; JIA = juvenile idiopathic arthritis; LARC (synonym: MIP-3a) = liver and activation-regulated chemokine; LPS = Lipopolysaccharid; Ltn = Lymphotactin; MAPK = mitogen activated protein kinase; MCP = monocyte chemotactic protein; MDC = macrophage derived chemokine; MIG = monokine induced by interferon-g; MIP = macrophage inflammatory protein; NAP-2 = neutrophil activating protein-2; MAPK/JNK = mitogen-activated protein kinase/c-Jun N-terminal protein kinase; PI-3K = phosphatidylinositol-3 kinase; RANTES = regulated on activation, normally T-cell expressed and secreted; SDF-1 = stromal cell derived factor-1; TARC = thymus and activation-regulated chemokine; TECK = Thymus expressed chemokine; TGF-b = Transforming growth factor beta 0171-2985/02/206/04-459 $ 15.00/0
460 · H. MANGGE, J. VOJINOVIC and K. SCHAUENSTEIN efforts about 50 or more human chemokines could be identified so far. They form a large family of small proteins with four conserved cysteins. Based on the configuration of the cystein residues near the NH2-terminus, two major groups are distinguished: CC, and CXC (Table 1). In the CC group two cysteins are adjacent, while in the CXC group the two cysteins are separated by one amino acid other than cystein. By virtue of the detection of Lymphotactin (Ltn) and Fractalkine (Fkn), two additional chemokine groups, i.e. “C” and “CX3C” were defined. Ltn shows similarity to CC chemokines, but has lost the first and third cysteine residues (“C”) (2, 3). Fkn is another chemokine with a structure, in which two cysteins are separated by three aminoacids other than cystein (“CX3C”) (4). The knowledge about chemokine functions is still fragmentary, not the least because the dose responses for given effects in vitro are not relevant in vivo. Nevertheless, we will summarize recent data, and discuss implications in pathogenesis of juvenile and adult rheumatic disease. Chemokine function Chemokines are diverse proteins mediating inflammatory responses, cell trafficking, activation (e.g. intracellular Ca2+ influx) and homing (1, 5). They can trigger signal transduction cascades, such as mitogen-activated protein kinase/c-Jun N-terminal protein kinase (MAPK/JNK) and phosphatidylinositol-3 kinase (PI-3K) pathways (6–9). Furthermore, chemokines were identified as potent cofactors for T-cell activation (10–12). Taken together, four major biological functions of chemokines can be distinguished (13): 1. Leukocyte chemotaxis. Migrating cells are transformed resulting in a redistribution of chemoattractant receptors, integrins, cytoskeletal and regulatory intracellular proteins (e.g.: tyrosine-, lipid-kinases, second messengers, members of Rho family of small GTPases). CXC chemokines attract neutrophils, monocytes and lymphocytes (5), CC chemokines act on T lymphocytes, dendritic cells, NK cells and all leukocyte types but neutrophils. Ltn and Fkn both act on T lymphocytes, and Fkn is also particularly active on monocytes (14, 15). The exclusive action of Ltn on lymphocytes makes it unique among chemokines (2). 2. Steering leukocyte-endothelial interactions by signaling of integrin activation. 3. Leukocyte degranulation, stimulation of respiratory burst and release of inflammatory mediators. Examples are IL-8, which induces neutrophil granule exocytosis (16), and monocyte chemotactic protein-1 (MCP-1), which stimulates histamine release by basophils (17). 4. Stimulation of angiogenesis (eg. ELR*-positive CXC chemokines, Fkn) (18, 19) or angiostasis [e.g. the CXC receptor 3 ligands interferon-g inducible protein of 10 kd (IP-10) and monokine induced by interferon-g (MIG)] (20).
* Chemokines sharing a short sequence motif “Glu-Leu-Arg”, which precedes the first cysteine amino acid residue
Chemokines and onset of rheumatic disease · 461 Table 1. Chemokine receptors and corresponding chemokines CXC receptors
CXC chemokines
CXCR 1 CXCR 2 CXCR 3 CXCR 4 CXCR 5
IL-8, GCP-2 IL-8, GRO-a,b,g, NAP-2, ENA-78, GCP-2 IP-10, MIG, I-TAC SDF-1 BLC
CC receptors
CC chemokines
CCR 1 CCR 2 CCR 3 CCR 4 CCR 5 CCR 6 CCR 7 CCR 8 CCR 9
MIP-1a, RANTES, MCP-2, MCP-3 MCP-1, MCP-2, MCP-3, MCP-4, MCP-5 Eotaxin, RANTES, MCP-2, MCP-3, MCP-4 MIP-1a, RANTES, MCP-1, TARC MIP-1a, MIP-1b, RANTES LARC (MIP-3a) ELC (MIP-3b) I-309 TECK
C receptors
C chemokines
XCR1
Ltn
CX3C receptors
CX3C chemokines
CX3CR1
Ftn
Chemokine receptors The so far identified chemokine receptors are transmembrane domain proteins coupled to heterotrimeric GTP-binding proteins with homology to the family of chemotactic receptors. Five receptors for CXC chemokines (CXCR 1–5), nine for CC chemokines (CCR 1–9), one for C chemokines (XCR1), and one for CX3C chemokines (CX3CR1) have been identified so far (Table 1). These receptors show different ligand specificities and are differentially expressed in leukocytes (1) (Table 2). Certain chemokine receptors are mainly expressed by specific leucocyte subtypes, such as e.g. CXCR1 on neutrophils, CCR3 on eosinophil and basophil granulocytes, CCR9 on intestinal T lymphocytes (21), and XCR1 on neutrophils and T and B cells (3), whereas other receptors, like CCR1 and CCR2, are expressed more ubiquitously. The differential expression of chemokine receptors and the interaction with their ligands controls substantially the level and specificity of leukocyte migration. This could be shown in vivo by intradermal injection of macrophage inflammatory protein-1a (MIP-1a) to human probands, leading to endothelial cell mediated (E-selectin) ingression of monocytes, T-lymphocytes, eosinophils and neutrophils to the injection site, which was paralleled by an increased expression of CCR1 on peripheral blood neutrophils (22). Notably, such a CCR1–MIP-1a activation of neu-
462 · H. MANGGE, J. VOJINOVIC and K. SCHAUENSTEIN Table 2. Chemokine receptor expression on leukocytes Receptor
Main cellular expression
CXCR 1 CXCR 2 CXCR 3 CXCR 4 CXCR 5 CCR 1 CCR 2 CCR 3 CCR 4 CCR 5 CCR 6 CCR 7 CCR 8 CCR 9 XCR1 CX3CR1
neutrophils neutrophils activated T-lymphocytes T and B lymphocytes, monocytes, macrophages, granulocytes B lymphocytes, T lymphocyte subpopulation monocytes, basophils, activated T lymphocytes monocytes, basophils, activated T lymphocytes eosinophils, basophils, activated T lymphocytes CD4+ T lymphocytes Activated monocytes, activated T lymphocytes, dentritic cells Activated T lymphocytes, B lymphocytes EBV-B cell lines, T cell lines NK cell lines, activated T lymphocytes intestinal T lymphocytes neutrophils, B lymphocytes, T lymphocytes monocytes/macrophages
trophils could not be observed by in vitro experiments, indicating the importance of in vivo studies for an understanding of chemokine functions (22). Furthermore, chemokine receptors play an important role in T- and B-lymphocyte development, regulation and homing. Th1 lymphocytes selectively express CXCR3 and CCR5, while CCR3 and CCR4 are preferentially expressed by Th2 lymphocytes (23). CCR8 and its ligand I-309 was shown to be involved in the recruitment of skin-homing regulatory CD4+ T cells (23), whereas CCR9 and Thymus-expressed chemokine (TECK) attract T cells (CD4+ and CD8+) selectively to the small intestine (21). Finally, CXCR5, the receptor for B cell attracting chemokine (BLC or CXCL13), which is mainly expressed by B-lymphocytes and only on a minor fraction of T lymphocytes, directs the migration of activated B cells into germinal centers (24). Chemokines and receptors – involvement in immune regulation Chemokines control cytokine profiles, influence isotype switching (25), and the balance between Th1 and Th2 cells (23, 26). CC chemokines, such as MIP-1a, were shown to direct the chemoattraction of mononuclear inflammatory cells in T cell-mediated autoimmune diseases, like experimental autoimmune encephalitis (EAE) (27). The presence of MIP-1a promoted naive Th0 cells to differentiate to Th1 cells, whereas MCP-1, another CC chemokine, stimulated Th2 cell development (27, 28), and inhibited the adoptive transfer of EAE (27). MCP-1 is also involved in oral tolerance induction in EAE by inhibition of Th1 cell-related cytokines (29). These observations suggest a differential role for CC chemokines in the development and activation of T cells during autoimmune activation. RANTES (regulated on activation, normal T cell expressed and secreted), another chemokine, is involved in an antigen-independent activation of T lymphocyte chem-
Chemokines and onset of rheumatic disease · 463
otaxis and proliferation by inducing a biphasic intracellular Ca2+ influx (30). The initial cytosolic Ca2+ peak is associated with chemotaxis (G-protein mediated), whereas a second peak (tyrosine kinase mediated) is dominated by an upregulation of surface IL-2 receptor expression, cytokine release, and T cell receptor activation (30). From this point of view, chemokines and their receptors can be devided into two functionally distinct categories: i) inflammatory chemokines upregulated by recruitment signals of local inflammatory reactions. ii) constitutive chemokines produced in bone marrow, thymus and secondary lymphoid organs controlling leukocyte traffic and driving the encounter of cells that need to interact for the generation of a local immune response. Chemokines and receptors – involvement in adult and juvenile rheumatoid arthritis In rheumatoid arthritis (RA) the major site of joint destruction is the pannus, a tissue predominated by macrophages and aggressive fibroblast-like synoviocytes (FLS) (31). Lymphocytes, dendritic cells, and polymorphonuclear leukocytes are found in the synovial sublining layers of the pannus, whereas the interface between pannus and cartilage is dominated again by activated macrophages and synoviocytes secreting abundantly destructive proteases (32). During inflammation, the pannus migrates over the underlying cartilage and to the subchondral bone, a process which causes tissue erosion (33, 34). Pannus lymphocytes are mainly CD4+CD45RO+ T cells and cytokines, such as IL-2, IL-7, IL-10 and IL-12 seem to sustain survival and function of such chronically activated T cells (35). The majority was identified as members of the Th1-subtype, with production of IL-2 and IFN-g (36), and it is well established now that a sustained Th1-cell activation plays an important role in the pathophysiology of RA (37–38). Proinflammatory, immunoregulatory and chemotactic cytokines [e.g.: IL-1, TNF-a, transforming growth factor-b (TGF-b), fibroblast grow factor (FGF) ] are increased as well (39, 40). Cell recruitment is crucial in the establishment of synovitis, pannus activity, and inflammatory perpetuation in rheumatoid disease. Chemokines and their receptors are centrally involved in the recruitment of inflammatory cells (41). Synovial infiltrating activated/memory T cells express the Th1 cell associated chemokine receptors CXCR3 and CCR5 (Fig. 1). Chemokines reacting with CXCR3 (IP-10, MIG) and CCR5 (MIP-1a, MIP-1b) seem to induce and perpetuate the recruitment of such CXCR3+ and CCR5+ T cells (Fig. 1) (42). The CXCR3+ phenotype prevails especially in synovial perivascular regions of RA patients, whereas only a low percentage of T cells express CXCR3 or CCR5 within normal lymph nodes (43). Furthermore, CXCR4 and its ligand stromal-derived factor-1 (SDF-1) mediate synovial accumulation of T cells (44) (Fig. 1), whereby the CXCR4 expression on synovial T cells seems to be induced by TGF-b (44) and IL-15 (45). SDF-1 positive pannus endothelial cells induce a strong integrin-mediated adhesion of synovial T cells to fibronectin and intercellular adhesion molecule-1 (ICAM-1) (44) (Fig. 1), and inhibit activation-induced apoptosis of T cells (45). Comparable to the pannus site, virtually all T cells in SF of RA patients (RA SF) show CXCR3+ (≈100%) and/or CCR5+ (≈ 80%) phenotypes, representing a high enrichment
464 · H. MANGGE, J. VOJINOVIC and K. SCHAUENSTEIN
Figure 1. Chemokines and receptors within the affected rheumatic joint.
over levels of CXCR3+ (35%) and CCR5+ (15%) T cells in peripheral blood (PB) (43). Furthermore, the specific ligands for CCR5, MIP-1a, MIP-1b and RANTES, are increased in SF (46) (Fig. 1), and SF CCR5+CD4+ T cells produce IFN-g, but not IL-4, in response to anti-CD3 stimulation in vitro (45). These results indicate that the chemokine receptors CXCR3 and CCR5 are importantly involved in homing of activated/memory T cells to chronically inflamed articular sites, and that they are associated with a Th-1 weigthed immune activation. The CX3C chemokine Fkn plays an important role in monocyte chemoattraction. As shown by CHAPMAN et al., Fkn acts as adhesion molecule tethering monocytes to endothelial cells by binding with its receptor CX3CR1 (47) (Fig. 1). Soluble fractalkine (sFkn) levels were observed to be elevated in RA SF, as compared to osteoarthritis and other forms of arthritis (Fig. 1). sFkn-depleted RA SF showed significantly decreased chemotactic activity for monocytes compared with sham-depleted RA SF (48). Furthermore, differential expression of CC chemokine receptors was observed to be crucial for monocyte recruitment from circulation and retention in affected joints of RA patients (49). Neoangiogenesis, another hallmark of pannus activity, is essentially stimulated by the ELR-containig CXC chemokines, IL-8, epithelial neutrophil activating peptide 78 (ENA-78) (50, 51), and Fkn was observed recently to mediate angiogenesis in RA (19) (Fig. 1).
Chemokines and onset of rheumatic disease · 465
Chemokines are also involved in cartilage pathophysiology. Chondrocytes produce CXC chemokines (IL-8, GRO-a) and CC chemokines (MCP-1, MIP-1a, RANTES) after stimulation with IL-1b or TNF-a (Fig. 1) (52). The production of these chemokines in chondrocytes is modulated by antinflammatory mediators, like TGF-b and IL-10, which may play a role in the perpetuation of rheumatic joint disease (53, 44). Bone resorptive osteoclasts from patients with RA express mRNA for IL-8, and this expression is potentiated after stimulation with IL-1b, IL-6 or TNF-a (Fig. 1) (54). Although, as compared to adult RA, the available data are scarce, evidence exists that chemokines and their receptors are also involved in the pathophysiology of juvenile idiopathic arthritis (JIA). JIA represents a heterogenous syndromatology consisting of different subtypes (Systemic onset JIA, polyarticular seronogative-, polyarticular seropositive JIA, pauciarticular JIA, psoriatric arthritis) differing markedly in clinical appearance and prognosis (55, 40). Furthermore, with the exception of seropositive polyarticular JIA, the JIA subtypes are clinically markedly different from adult RA. On the other hand, a potentially destructive chronic synovitis is shared by both RA and JIA. DE BENEDETTI et al. (56) found that in patients with active systemic JIA serum levels of IL-8 and MCP-1 were higher as compared to active polyarticular, pauciarticular JIA and healthy controls. Furthermore, in systemic JIA IL-8 and MCP-1 levels correlated with clinical disease activity. RA patients showed similarly elevated SF levels of IL-8 and MCP-1 as compared to patients with systemic, polyarticular and pauciarticular JIA, suggesting comparable local production of these two chemokines (56). By virtue of a very recent study investigating a caucasian population, a single nucleotide polymorphism of the macrophage migration inhibitory factor (MIF) gene (position 173: G-to-C transition = MIF-173*C allele) was shown to be associated with a significantly increased risk to develop systemic JIA as compared to a caucasian control group not bearing this allele (57). Finally, circulating immune complexes (CICs) purified from JIA patient sera were found to trigger IL-8 mRNA and protein production in normal human synoviocytes (58). Concerning Th1/Th2 activation, the data are contradictory. WEDDERBURN et al. observed in patients with pauciarticular and polyarticular JIA an increased production of Th1 cytokines by CXCR3+CCR5+CD45RO+ synovial T cells as compared to peripheral blood T cells, suggesting JIA, like RA, to be an autoimmune disease with a Th1 polarization of synovial T cells (59). Conversely, in a study by THOMPSON et al., a synovial accumulation of CCR4+ T cells was found to be associated with very early stages of JIA. Such CD4+CCR4+ synovial T lymphocytes produced more IL-4 and less IFN-g and were supposed to act anti-inflammatory by virtue of IL-4 release (60). Macrophage derived chemokine levels did not differ between JIA and adult RA (60). It can be speculated from these data that, as compared to RA, the significantly better prognosis in many cases of JIA may be due to an initially less disturbed Th1–Th2 balance with an increased Th2 activity serving as a “brake” in early stages of disease (60). Besides this, the findings support the view that JIA and RA are in fact comparable diseases with chemokines and their receptors centrally involved in chronic inflammation of the target organs. Animal experiments In rat adjuvant-induced arthritis (AIA), a model of human RA, SF levels of TNFa, IL-1b and MIP-1a correlated with clinical symptoms of arthritis and blood neutrophil
466 · H. MANGGE, J. VOJINOVIC and K. SCHAUENSTEIN counts (61). Fractalkine and its receptor CX3CR1 were identified in synovial tissue macrophages, fibroblasts, endothelial cells, and dendritic cells, with weaker expression of CX3CR1 in endothelial cells (48). As was measured by RT-PCR, Fkn expression levels correlated with rat joint inflammation (48). These data indicate that Fkn and its receptor are involved in monocyte chemotaxis in AIA (48). In collagen induced arthritis (CIA), paws of collagen-treated mice exhibited increased mRNA levels of IL-1b, IL-2, MIP-1a, MIP-2, IL-6, IL-1 receptor antagonist, RANTES, TNF-a, TNF-b, IL-11, and TGF-b as compared to paws of unimmunized animals (62). Even clinically uninvolved paws of immunized mice showed increased mRNA levels of certain cytokines (IL-11, TNF-a, TNF-b) and chemokines (RANTES, MIP-1a) as compared to paws of unimmunized controls (62). This observation was confirmed by KRAAN et al., who detected in serial synovial tissue biopsies of CIA in rhesus monkeys by virtue of serial synovial tissue biopsies an influx of macrophages well before the occurence of arthritis (63). Taken together, animal models affirm the central role of chemokines and receptors in rheumatic inflammation. Based on these observations in humans and animal models of RA, chemokines can be considered as a future target for pharmacologic modulation of angiogenesis, chemotaxis, lymphocyte homing, T cell activation, Th1-Th2 switch and proinflammatory cytokine release in rheumatoid disease (50, 64, 65). Findings with a DNA-polymorphism of CCR5 seem to support such a concept. A 32bp deletion (CCR5 delta 32 allele) leads to a completely abolished (homozygotes) or diminished (heterozygotes) expression of CCR5 on Th1 cells and monocyte/macrophages. RA patients carrying the CCR5 delta 32 allele showed indeed a significantly less severe course of RA as compared to other patients not bearing this allele (66). Research activities developing and critically evaluating new chemokine antagonists in modifying disease symptoms will help to elucidate the potency of antichemokine therapy in future. Towards this, a first step may be the study by NAYA et al., who discovered a new substance (xanthene-9-carboxamide 1a) acting as a highly effective antagonist of murine and human CCR1 receptors (67). Chemokines and receptors – are they the initiators? Synovial accumulation of macrophages occurs very early in RA (65). MIP-1a and MCP-1 may initiate synovial invasion with macrophages, because they were found to be increased in earliest phases of RA (65). During RA prolongation CD68+ expression of infiltrating macrophages correlated with elevated MIP-1a, but not with MCP-1 expression (65). The question remains, if these chemokines are initiators or effectors. IL-15, which has been shown to act pivotally by inducing MCP-1 and IL-8 secretion in monocytes, but inhibiting the production of these chemokines in human colonic epithelial cells (68), may be involved (69). However, no data concerning IL-15 in very early phases of RA are available. In a study by KRAAN et al. it could be shown that asymptomatic synovitis precedes clinically manifest arthritis, both in RA and in an animal arthritis model (rhesus monkey) (63). This earliest, clinically asymptomatic phase was characterised by synovial macrophage infiltration and expression of macrophage-derived cytokines (63). More in depth investigation of such preclinically alterated synovial tissues may help to clarify the question about a causal role of chemokines in rheumatic pathophysiology. Furthermore, chemokine gene polymorphisms should be considered.
Chemokines and onset of rheumatic disease · 467
On the other hand, T lymphocytes are important in striking the rheumatic fire. The chemokine receptors CXCR3 (ligands IP-10, MIG) (10), and CCR5 (ligands: RANTES, MIP-1a, MIP-1b) (12) are involved in attraction of activated/memory T cells into inflamed rheumatic joints (43). As increased IL-2, IL-12 and IFN-g levels have been observed to be associated with early stages of RA (70, 71) animal models of RA (e.g.: CIA) (62) and other Th1-driven autoimmune diseases like multiple sclerosis (72), a selective T cell recruitment by virtue of specific chemokine/chemokine receptor activation may represent a further very early event in the immune dysregulation leading to chronic arthritis (43, 60) Taken together, the so far available data strongly suggest that the chemokine receptors CXCR3, CCR5 and their speficic ligands play a central role in early Th1 cell recruitment, and may indeed be critical in triggering an autoimmune activation loop in RA.
Therapeutic significance of anti-chemokine therapy? Experiences with anti-cytokine therapy (anti-TNF, anti-IL1 etc.) showed that, albeit blocking one cytokine, like TNF-a, can lead to transient clinical improvement, the disturbance of the cytokine network in rheumatic diseases is too complex that a sustained, complete remission can be achieved with such an approach (73, 74). The same may be very probably true for chemokines. The given diversity of chemokines with binding of a single chemokine to many chemokine receptors makes any therapy directed towards a single chemokine doubtful, because other chemokines with related receptor specificities and cellular effects would readily compensate for its inactivation (1). Ways to go could be antibodies either specifically reacting with common epitopes of different chemokines, or reagents that block chemokine receptors. Towards the latter, the afore mentioned findings with the CCR5 delta 32 allele seem to strongly suggest an important pathophysiological relevance of CCR5 activation in RA. GARRED et al. reported that HIV patients carrying this CCR5 deletion allele not only had less pronounced symptoms of AIDS but also showed a lower incidence of RA, and were unable to produce rheumatoid factor IgM antibodies (75). References 1. ROLLINS, JR. 1997. Chemokines. Blood 90: 909. 2. KENNEDY, J., G. KELNER, S. KLEYENSTEUBER, T. SCHALL, M.WEISS, H. YSSEL, P.SCHNEIDER, B.COCKS, K. BACON, and A. ZLOTNIK. 1995. Molecular cloning and functional characterization of human lymphotactin. J. Immunol. 155: 203. 3. HUANG, H., F. LI, C. M. CAIRNS, J. R. GORDON, and J. XIANG. 2001. Neutrophils and B cells express XCR1 receptor and chemotactically respond to lymphotactin. Biochem. Biophys. Res. Commun. 281: 378. 4. BAZAN, J. F., K. B. BACON, G. HARDIMAN, W. WANG, K. SOO, D. ROSSI, D. R. GREAVES, A. ZLOTNIK, and T. J. SCHALL. 1997. A new class of membrane-bound chemokine with a CX3C motif. Nature 385: 640. 5. GUNN, M. D., V. N. NGO, K. M. ANSEL, E. H. EKLAND, J. G. CYSTER, and L. T. WILLIAMS. 1998. A B-cell-homing chemokine made in lymphoid follicles activates Burkitt’s lymphoma receptor-1. Nature 391: 799.
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