We will also present novel insights into the function of Th cells

We will also present novel insights into the function of Th cells in tissues. We will especially focus on Th-cell subsets in the skin as a model organ to investigate the full spectra of functional Th-cell diversity. The first approach to define distinct Th-cell subsets relates to the pioneering work of Mosmann and Coffman, who observed that Th cells could be distinguished according their secreted signature cytokines (reviewed in [1]). They defined two distinct subsets, Th1 cells and Th2 cells, selleck kinase inhibitor that differed in that Th1 cells produced IFN-γ and Th2 cells produced IL-4

(Fig. 1). This dichotomous paradigm of Th1 and Th2 subsets persisted for more than 20 years, until about 7 years ago when the emergence of Th17 cells challenged

this simplistic dualism of only two Th-cell subsets [2]. The definition of Th17 cells also sparked the concept of a broader heterogeneity in the Th-cell immune compartment (reviewed in [2, 3]). Following the discovery of Th17 cells, which secrete their name-giving cytokine IL-17, other Th-cell subsets emerged on the scene, including Th22 [4-6] and Th9 cells [7], which express the signature cytokines IL-22 and IL-9, respectively. This system of categorization is well-appreciated and immunology textbooks use these terms to distinguish between Th-cell subsets. However, reality is a bit more complex and immunologists are puzzled by the fact that some Th cells are not restricted to these firm lineage boundaries and co-express signature cytokines of distinct subsets in parallel. Th1 or Th2 cells co-secreting IL-17 are two examples of AZD2281 mw Th-cell subsets that do not fit into the original concept of Th-cell classification. This observation has been attributed to the plasticity of Th-cell subsets.

It is still debated how the phenotype of these “plastic” cells is regulated, and if they indeed have to be regarded as distinct subsets [8-10]. This is especially important with respect to the fact that these “hybrid” T cells change their function upon acquisition of additional cytokine secretion properties. That is, IL-17- CYTH4 and IFN-γ-co-expressing cells are considered to be pathogenic in settings of autoimmunity [11], while IL-17+IFN-γ− cells have even been assigned anti-inflammatory functions [12]. In the future, the original Th classification concept will be further challenged by new detection techniques that allow deciphering the full secretome of cells. This overwhelming information will ultimately lead to the question if categorization according to secreted factors is still reasonable. Another widely used possibility to classify Th cells is the assignment of lineage-specific transcription factors, which are responsible for the initiation of subset-specific differentiation programs and maintenance of the phenotype (Fig. 1). Tbet, GATA3, and RORC are well-established transcriptional regulators of Th1, Th2, and Th17 cells, respectively.

Evidence from both animal models and human studies suggest that t

Evidence from both animal models and human studies suggest that the elevated female sex hormone levels and a Th2-biased immunological state in pregnancy play a major role in promoting the expansion of autoreactive B cells. In mouse models of human SLE, both oestrogen and prolactin can exacerbate and accelerate autoimmune conditions by exerting a positive influence on the survival, proliferation, maturation and autoantibody production of the mature B cell population [28, 67-70]. Such findings from animal models strongly reflect

the evidence in human clinical studies where Acalabrutinib female populations have a significantly higher ratio of autoantibody-mediated autoimmune conditions (including SLE, APS, Grave’s disease, myasthenia gravis, scleroderma GDC-973 and Sjögren’s syndrome) than males, and these conditions are often exacerbated during pregnancy, where elevated levels of the female sex hormones occur [70]. The Th2-biased state of pregnancy, which is influenced positively by

high levels of oestrogen during pregnancy, is also well known to promote B cell proliferation, activation and antibody production in experimental animal models [70]. Evidence from animal studies and human B cell models show that the expansion and activation of autoreactive B cells can be amplified by mutual positive regulatory feedback loops between the oestrogen-receptor alpha (ER-α) pathway and other autoimmune-promoting cytokines such as interferon (IFN)-α and B cell-activating factor (BAFF) to promote survival, maturation and expansion of autoreactive B cells [71, 72]. Data from animal models, in conjunction with evidence from human studies, suggest that these co-operative signalling pathways can also promote the antibody class-switching of polyreactive natural antibody IgM to a more pathogenic IgG autoantibody production by B1 cells [13, Amino acid 70-74]. The positive feedback loop and the production

of IFN-α and BAFF may be activated and amplified through the innate pathways mediated by endogenous ligands and Toll-like receptors (TLRs) on B cells, monocytes and dendritic cells. Such endogenous ligands may consist of self-antigens, including lipoproteins, glycoprotein, single-stranded RNA (ssRNA) and dsDNA materials that are generated as a by-product from placental tissue-shedding during pregnancy. These endogenous ligands also provide a readily available source of autoantigens for the positive selection and activation of autoreactive B cell clones through BCR signals as well as the activation of TLR-mediated innate responses that contribute further to the exacerbation of the maternal autoimmunity and expansion of pathogenic autoantibody production. Evidence from epidemiological, clinical and experimental studies has established that autoantibodies produced by maternal B cells contribute directly to adverse pregnancy outcomes [9, 10].

5) In summary, we conclude that both, CD28 and CTLA-4 (at least

5). In summary, we conclude that both, CD28 and CTLA-4 (at least through its regulation of CD28 at C646 mw the IS), are required for the different efficiencies of CD80 and CD86 costimulation. The increased Ca2+ signals observed after sc CD86/anti-CD33 costimulation compared with sc CD80/anti-CD33 costimulation can, in principle, be a result

of two general mechanisms: increased Ca2+ release or increased net Ca2+ influx. To test this, we separated Ca2+ release and Ca2+ influx. The Ca2+ release was not different when induced by dscFv anti-CD33/anti-CD3 in combination with sc CD86/anti-CD33 compared with dscFv anti-CD33/anti-CD3 in combination with sc CD80/anti-CD33 (Fig. 6a). The figure also shows that Ca2+ release between different donors was extremely homogeneous (Fig. 6b), which was also the case for the influx (data not shown). Both, costimulation with CD80 and CD86 emptied the Ca2+ stores equally well. To analyse Ca2+ influx independently of Ca2+ release, we compared Paclitaxel Ca2+ influx after the full depletion of Ca2+ stores. The TG was used to fully deplete Ca2+ stores after the initial stimulation with the different bi-specific antibodies. Because Ca2+ release by costimulation does not occur simultaneously in the cells (in Fig. 6 all cells were aligned to the initiation of the Ca2+ release), only a slight but inhomogeneous Ca2+ signal during the release phase

could be observed. In cells with a clear Ca2+ release after costimulation, no further Ca2+ release by TG was detected indicating that TG-sensitive BCKDHA stores were already fully depleted by the costimulation (Fig. 7). While the Ca2+ release was not influenced by costimulation, the Ca2+ influx was clearly different, as was evident after Ca2+ re-addition. The dscFv anti-CD33/anti-CD3 in combination with sc CD86/anti-CD33 induced a larger Ca2+ entry in comparison with dscFv anti-CD33/anti-CD3 in combination with sc CD80/anti-CD33. This indicates that costimulation increases Ca2+ influx independent of Ca2+ release. Export rates of Ca2+ were not

different for both costimulation methods (data not shown). We conclude that the different amplitudes of Ca2+ signals following dscFv anti-CD33/anti-CD3 in combination with sc CD86/anti-CD33 when compared with dscFv anti-CD33/anti-CD3 in combination with sc CD80/anti-CD33 can only be explained by differences in net Ca2+ entry but are independent of Ca2+ release. Soboloff et al.19 and Parvez et al.21 discovered that STIM2 can inhibit CRAC channel activity. In addition, Parvez et al. showed that STIM2 can also activate a store-independent mode of CRAC/ORAI channels. The store-independent mode of CRAC activation was also observed following the application of low concentrations of 2-aminoethyldiphenyl borate (2-APB) in STIM2/ORAI1 over-expressing HEK-293 cells and in ORAI3 over-expressing HEK-293 cells.

To further understand the delayed inducing effects of simvastatin

To further understand the delayed inducing effects of simvastatin, we added simvastatin at different time-points after the initiation of TCR stimulation with TGF-β or added simvastatin at culture initiation and then blocked its action at different time-points by the addition of mevalonate. All cultures were analysed for the expression of Foxp3+ cells after 72 hr of stimulation (Fig. 4b). The maximal inducing

effects of simvastatin could be observed even when it was added as late as 24 hr after the initiation of the cultures, but its synergistic activity was completely abolished when it was added after 48 hr (Fig. 4b). Similarly, the neutralization of the effects Alvelestat clinical trial of simvastatin with mevalonate was only observed when mevalonate was added during the first 24–32 hr of the culture.

This study suggested that simvastatin mediated its activity between 24 and 48 hr after T-cell activation. We confirmed this result by adding simvastatin at 24 hr and neutralizing its effects with mevalonate at 48 hr (Fig. 4c). The magnitude of the enhancement of the induction of Foxp3-expressing cells was similar in cells pulse-exposed to simvastatin only between 24 and 48 hr after activation to that in cells that had been exposed for the entire 72-hr culture period. To address whether synergistic action of simvastatin on TGF-β-mediated induction is controlled at the transcriptional level, we assayed the Foxp3 messenger RNA (mRNA) levels in cells treated with TGF-β alone or with the combination of TGF-β and simvastatin (Fig. 5a). Up-regulation of Foxp3 mRNA was observed after 24 hr of culture in the TGFβ only treated group compared to cells find more cultured with vehicle alone and no enhancement of Foxp3 mRNA was seen in cultures with simvastatin. In contrast, marked enhancement of Foxp3 mRNA levels were seen after 48 and 72 hr in cultures containing both TGF-β and simvastatin, whereas levels of Foxp3 mRNA in cultures with TGF-β alone were slightly diminished. This result together with the results of the time–course study strongly suggest that

the effects of simvastatin are not related to enhancement of the initial Cyclooxygenase (COX) signals induced by TGF-β and raise the possibility that simvastatin might regulate epigenetic control of Foxp3 transcription. Recent studies6,15 have identified two or three CpG islands within the promoter and enhancer regions of the Foxp3 gene that regulate the induction of Foxp3 transcription and the stabilization of Foxp3 expression. We focused on one site in the Foxp3 promoter that contains six CpGs within a 173-base-pair sequence of the mouse Foxp3 promoter that are located close to the proximal transcription start site. To verify if this candidate site is specific for Foxp3 promoter activity, Foxp3− and Foxp3+ CD4+ cells were isolated from Foxp3gfp male mice, and methylation profiles of both were analysed by bisulphite-modified sequence reading.

The loss of DN thymocytes was accompanied by a decrease in the pr

The loss of DN thymocytes was accompanied by a decrease in the proportion and absolute number of cells expressing IL-7Rα in the lineage negative and DN populations. This was also associated with decreased proliferation and increased apoptosis of the immature DN2 and DN3 populations. Interleukin-7 signalling has been shown to be essential for DN thymocyte proliferation and survival,[18]

and previous Inhibitor Library studies have shown that lack of IL-7 or IL-7Rα results in an overall decrease in thymic cellularity.[17, 42] Therefore, diminished IL-7Rα expression and/or IL-7 signalling may be causing proliferative and survival defects in the DN thymocyte populations and contributing to Ts65Dn thymic hypocellularity. The loss of IL-7Rα expression, however, was selective for T-cell progenitors rather than cells committed to the T-cell lineage. Cells that had already undergone β-selection had similar cell surface expression levels of IL-7Rα comparing Ts65Dn with euploid controls. This

is also reflected in the periphery, where there were small decreases in IL-7Rα expression in the spleens of Ts65Dn mice. The IL-7 signalling pathway plays an essential role in peripheral T-cell homeostasis[43, 44] as well as the generation and maintenance of memory T cells.[45] Previous reports indicated increased plasma IL-7 in individuals with DS,[13] but although assay sensitivity precluded measuring IL-7 protein in Ts65Dn mice, IL-7 mRNA levels were not changed. Therefore, Acalabrutinib purchase the modest changes in IL-7Rα in the periphery may result in the observed changes in naive and central memory T cells. It is unclear why there is decreased IL-7Rα expression selectively in immature lymphoid progenitors, but the current results have identified potential regulators of IL-7Rα expression. One potential mechanism for regulation of IL-7Rα expression may be increases in oxidative stress. Previous data suggested that exposure of IL-7Rα+ cells to pro-oxidants in vitro decreased the percentage of IL-7Rα+ cells.[6] Existing[10, 41] and current

data suggest the presence of increased oxidative stress in Ts65Dn thymus, and the results suggest that decreased antioxidant defences, including glutathione and antioxidant Exoribonuclease enzymes, promote pro-oxidant conditions in Ts65Dn mice. Inefficient induction of antioxidant enzyme defences may also contribute to increased oxidative stress in Ts65Dn thymus. Decreased NQO1 expression reflects diminished signalling through Nrf2-antioxidant response element-dependent gene expression.[34] Nrf2-antioxidant response element-induced expression of cytoprotective enzymes is a major mechanism for cellular defence against xenobiotics and oxidative stress. A possible mechanism for decreased NQO1 expression is the triplication of BACH1 on mouse chromosome 16 in the Ts65Dn mouse.

E H holds a CIHR Doctoral

E. H. holds a CIHR Doctoral Panobinostat purchase award, a MSFHR Junior Trainee Award, and a MSFHR/CIHR Transplant Trainee award; S. Q. C. holds a MSFHR Senior Graduate Studentship award and a CIHR/SRTC Strategic Training Program in Skin Research award. M. K. L. is a Canada Research Chair in Transplantation. Core support for flow cytometry sorting and lentiviral production provided by Lixin Xu and Rupinder Dhesi respectively, and was funded by the Immunity and Infection Research Centre MSFHR Research Unit. Conflict of interest: The authors declare no financial or commercial conflict of interest. Detailed facts of importance to specialist readers

are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. “
“Myeloid FcαRI, a receptor for immunoglobulin (Ig)A, mediates cell activation or inhibition depending on the type of ligand interaction, which can be either multivalent or monovalent.

Anti-inflammatory signalling is triggered by monomeric targeting using anti-FcαRI Fab or IgA ligand binding, which inhibits immune and non-immune-mediated renal inflammation. The participation of Toll-like receptors (TLRs) in kidney pathology in experimental models and various forms of human glomerular nephritis has been discussed. However, little is known about negative regulation of innate-immune activation. In the present study, we generated new transgenic mice that express FcαRIR209L/FcRγ chimeric protein and Selleck Kinase Inhibitor Library showed that the monovalent targeting of FcαRI exhibited inhibitory effects in an in vivo model of TLR-9 signalling-accelerated 3-oxoacyl-(acyl-carrier-protein) reductase nephritis. Mouse monoclonal anti-FcαRI MIP8a Fab improved urinary protein levels and reduced the number of macrophages and immunoglobulin deposition in the glomeruli. Monovalent targeting using MIP8a Fab attenuates the TLR-9 signalling pathway

and is associated with phosphorylation of extracellular signal-related protein kinases [extracellular signal-regulated kinase (ERK), P38, c-Jun N-terminal kinase (JNK)] and the activation of nuclear factor (NF)-κB. The inhibitory mechanism involves recruitment of tyrosine phosphatase Src homology 2 domain-containing phosphatase-1 (SHP-1) to FcαRI. Furthermore, cell transfer studies with macrophages pretreated with MIP8a Fab showed that blockade of FcαRI signalling in macrophages prevents the development of TLR-9 signalling-accelerated nephritis. These results suggest a role of anti-FcαRI Fab as a negative regulator in controlling the magnitude of the innate immune response and a new type of anti-inflammatory drug for treatment of kidney disease. Chronic inflammatory disease results from continuous injuries or errors in regulatory control mechanisms [1,2].

These extraordinary

gene possession

These extraordinary

gene possession signaling pathway differences can only arise via HGT mechanisms. HGT is defined in contrast to vertical gene transfer, which is the standard mechanism by which a mother cell replicates her entire complement of DNA and then passes along identical (or nearly so) copies of each chromosome and plasmid to each of her daughter cells during cell division. Genes and chromosomes that are acquired solely though vertical transmission can be used to construct phylogenetic relationships among bacterial strains, species, and higher taxa; however, genes that are acquired through HGT mechanisms produce mosaic chromosomes in which each part of the chromosome that was acquired horizontally has a different ancestry from every other part of the chromosome (unless there are two or more

simultaneous transformative events arising from the uptake of DNA from a single donor/competence event), which therefore makes phylogenetics at the whole chromosome level very difficult. In other words, for any set of strains containing mosaic chromosomes, each individual gene that has been horizontally transferred and then used to build a phylogenetic HM781-36B tree will produce a different tree structure from the same set of strains (Fig. 1) (Shen et al. 2005; Hall et al., 2010). Extensive HGT does not always completely obliterate the average chromosomal phylogenetic signal as has been demonstrated recently for S. pneumoniae (Donati et al., submitted); however, because of extensive HGT, strains that are phylogenetically related may have profoundly different Non-specific serine/threonine protein kinase genic compositions and thus produce very different disease phenotypes (Buchinsky et al., 2007). HGT is accomplished largely through three fundamentally different mechanisms: competence and transformation, mating or conjugation, and viral transduction. Some species of bacteria use only one of these mechanisms, whereas

others utilize two or even all three. Transformation and mating are active processes and require significant energetic expenditures by the recipient and the donor bacteria, respectively, as well as the maintenance of entire genetic regulons that encode the necessary machinery for the uptake and transfer of DNA, respectively (Mann et al., 2009). Thus, the bacteria that possess and maintain these systems must receive an evolutionary advantage in order for them to persist, particularly in the face of strong genomic deletatory mechanisms present in bacteria that are designed to minimize the genomic burden and eliminate unwanted foreign DNA – particularly that of bacteriophages (Brussow et al., 2004). Viral transduction, on the other hand, is a passive process engendered by temperate phage. The widespread possession of HGT mechanisms among pathogenic bacterial species, regardless of phylogeny and gram status, was one of the chief observational points on which the DGH was built (Ehrlich, 2001; Shen et al.

In contrast, CSF IL-6 levels were slightly elevated in patients w

In contrast, CSF IL-6 levels were slightly elevated in patients with NBD and significantly elevated in patients with AM and MS compared with healthy controls. Patients with NBD were subdivided into two groups according to their clinical course (eight patients with a slowly progressive course presenting with psychosis and dementia and 10 patients with an acute course including aseptic meningitis, brainstem involvement and myelopathy). BAFF levels

were significantly increased in those with a slowly progressive course compared with those with an acute course. CSF BAFF levels did not correlate with serum BAFF levels, CSF cell counts or CSF IL-6 levels in patients with NBD. These data suggested that BAFF was produced within the central nervous system and may be associated with the development of NBD, particularly with a progressive course. “
“Patients carrying activating killer

cell immunoglobulin-like LY2109761 purchase receptor (KIR) genes are significantly protected from CMV-associated complications after solid FDA approved Drug Library datasheet organ or hematopoietic stem cell transplantation. Whether previous infection with CMV affects NK-cell function in healthy donors is unknown. We studied the KIR repertoire and alterations of KIR expression after in vitro exposure to CMV in 54 healthy donors. The expression of neither activating nor inhibitory KIRs was different at baseline between 23 seropositive and 31 seronegative donors. However, after co-culture of NK cells with CMV-infected fibroblast cells, expression of the inhibitory Gefitinib price receptors KIR2DL1 and KIR2DL3 and the activating receptor KIR3DS1 significantly increased in CMV-seropositive donors. In CMV-seronegative donors, changes were subtle and restricted to the subset of NK cells expressing NK-cell group antigen 2C (NKG2C). Expansion of inhibitory KIRs occurred exclusively in donors carrying the cognate HLA class I ligands, whereas the presence of the putative ligand HLA-Bw4 was not necessary for the expansion of KIR3DS1-expressing NK cells. Our data show that previous infection with CMV does not alter the resting NK-cell

receptor repertoire, but appears to modify how NK cells respond to re-exposure to CMV in vitro. NK cells are an important component of the immune system in the control of viral infection [1]. Unlike B and T cells, NK cells do not display rearranged receptors but instead are regulated by the integration of signaling from germline encoded activating and inhibitory receptors. One important and incompletely characterized family of receptors are the killer cell immunoglobulin-like receptors (KIRs) [2]. KIRs are almost exclusively expressed on NK cells and encoded by 15 different gene loci, nine inhibitory iKIRs, and six activating aKIRs. The KIR genes cluster in chromosome 19, forming haplotypes composed of 7–11 individual KIR genes. The most common haplotype in Caucasians contains mostly iKIRs accompanied by a single or no aKIR gene and is called “A” haplotype [3].

(Level 2b) MMF dose during induction therapy should be 1 5–2 g/da

(Level 2b) MMF dose during induction therapy should be 1.5–2 g/day. Duration of MMF treatment (i.e. before its discontinuation or replacement with AZA) should be at least 24 months when MMF used as induction immunosuppression. (Level 2b) Calcineurin inhibitors (in particular tacrolimus, see more on which there is more data) to be considered: a.  as induction therapy, in combination with corticosteroids, in patients who do not tolerate standard therapy such as MMF or CYC (Level 2b) Immunosuppressive treatment recommended for (pure) Class V LN when proteinuria ≥2 g/day. (Level 4) Monitoring of patients with active

disease should be no less frequent than every 2–4 weeks, until the patient shows a definite trend towards improvement. (Level 5) This category refers to patients with Class II (mesangial proliferative) LN. Most of these patients BVD-523 datasheet present with non-nephrotic proteinuria without deterioration of renal function. Similar to the recommendations in the KDIGO guidelines, treatment is to include corticosteroid at a moderate dose with or without a well-tolerated immunosuppressive agent, the latter mainly for its steroid-sparing effect. The treatment response and progress of these patients should be closely monitored, as limited sampling from renal biopsy may miss more serious renal histology.

This refers to patients with Class III or Class IV LN (alone or in combination with Class V membranous features), or Class V LN with heavy proteinuria. These patients present with active urinary sediment (in the case of Class

III or IV LN), variable degree of proteinuria, with or without renal function impairment. Even if the serum creatinine is within the normal range, MycoClean Mycoplasma Removal Kit a decrease or deterioration in estimated glomerular filtration rate should alert the clinician to the possibility of severe nephritis. When there is practical difficulty in obtaining a renal biopsy, patients with microscopic haematuria and dysmorphic red cells, with or without red cell casts, an active lupus serology profile with high anti-dsDNA titres and evidence of complement activation such as low level of complement components, variable levels of proteinuria and renal function, should be considered to have severe nephritis and treated accordingly. In patients with renal biopsy prior to starting treatment, features indicating a need for more aggressive treatment include the presence of crescents, fibrinoid necrosis affecting the glomerular capillaries, and thrombotic microangiopathy. Reporting of renal biopsy findings according to the 2003 International Society of Nephrology / Renal Pathology Society (ISN/RPS) Classification of LN is standard practice.[69] Inter-observer variation remains a limitation of activity and chronicity indices,[70] and the inclusion of these indices in the renal biopsy report is variable but recommended. The severity of tubulo-interstitial fibrosis and tubular atrophy is a well-established prognostic indictor for renal survival.

Combined treatment with D8 and MTX caused additional protection

Combined treatment with D8 and MTX caused additional protection. Significant reduction of inflammation in D8-treated animals was also demonstrated in pathological and X-ray examinations. Inhibition of eotaxin-2 by monoclonal antibodies has a significant protective effect in adjuvant arthritis. These results may introduce a novel therapeutic target in rheumatoid arthritis and additional inflammatory joint disorders. Rheumatoid

arthritis (RA) is a common, chronic inflammatory disease, characterized by intense, destructive infiltration selleck chemicals llc of synovial tissue by a broad spectrum of inflammatory cells [1]. Multiple cytokines, derived from macrophages and fibroblasts, are responsible for induction of secretion of both cytokines and chemokines in RA [2]. The accumulation of leucocytes in the joint space leads to secretion of tissue degrading factors, including cytokines and matrix-degrading enzymes. Chemokines are small cytokines which act as chemoattractants for leucocytes, coordinating both homeostatic trafficking of these cells as well as recruiting Buparlisib datasheet specific cell populations to sites of inflammation. Chemokine dysregulation is considered to play a part in a wide spectrum of human disease involving the immune system, including human

immunodeficiency virus (HIV) infection [3], malignancy [4] and autoimmunity [5]. The CC chemokine eotaxin-2/CCL11 binds to the eosinophil receptor CCR3, acting as a strong chemoattractant for eosinophils [6], basophils [7] and T helper type 2 (Th2) lymphocytes [8]. However, eotaxin-2 is not the sole ligand for CCR3, which can also be activated by regulated upon activation normal T cell expressed and secreted (RANTES) (CCL5) [9], monocyte

chemoattractant protein-3 (MCP-3) (CCL7) and MCP-4 (CCL13) [10]. CCR3, the eotaxin receptor, is a 7-transmembrane G protein-coupled receptor which is expressed by eosinophils, as well as by a wide array of cell types including macrophages and endothelial cells [11]. This chemokine is also expressed on human T helper cells [12]. CCR3 expression was originally studied extensively in the pathogenesis Branched chain aminotransferase of asthma and allergy, where it continues to pose a therapeutic target [13]. More recently, however, a role for this pathway has emerged in the study of additional inflammatory and autoimmune disorders including inflammatory bowel disease [14], multiple sclerosis [15] and RA. Thus, CCR3 has been shown to play a role in recruitment of leucocytes to synovial tissue in adjuvant-induced arthritis (AIA), a commonly used animal model of RA [16]. In early AIA, CCR3 has been detected in synovial tissue macrophages and lining cells, with a subsequent trend towards declining expression [16]. This has been interpreted as reflecting a role for the eotaxin/CCR3 system in the initial trafficking of leucocytes into the synovial joint.