Expression Patterns Of Chemokine Receptors Research Articles

#1511 The immune cell ‘signature’ of incident hypertension

Abstract Background and Aims Hypertension results from complex genetic and environmental interactions, mediated by cardiac, vascular, endocrine, and renal systems. The immune system may modulate all of these, though the exact mechanisms linking immune activation with hypertension and organ damage remain poorly defined. We aimed to identify the immune cell ‘signature’ in patients with newly diagnosed, untreated hypertension (HTN; n=76) compared to normotensive controls (NTN; n=67), as well as in relation to nocturnal dipping status. Method Flow cytometry of peripheral blood mononuclear cells (Attune, Thermo Fisher) characterising B cell, T cell, monocyte and dendritic cells (DC) subsets, including activation signature with intracellular staining, in an exploratory comparative analysis. Results The proportion of CD4+ naïve T cells (CD45RA+CCR7+) was lower in hypertension, with CD45RO+CD62L+ cells attaining nominal statistical significance between NTN and HTN groups (1.3 ± 1.1 vs 1.2 ± 1.0, p=0.039). CD4+ T central memory cells were expanded (TCM, 23.1 ± 7.2 vs 27.7 ± 10.0, p=0.002, Figure) in HTN along with T effector memory (TEM) cells lacking CD62 in an adjusted model, (TEM, CD4+CD45RA-CCR7-CD62l-; 31.4 ± 7.5 vs 33.7 ± 10.3, p0.035; CD8+CD45RA-CCR7-CD45RO+CD62l− 48.9 ± 10.5 vs 52.2 ± 13.3, p=0.011). Hypertensive group had proportionally fewer CD4+CD28+ cells (95.1 ± 9.8 vs 92.0 ± 13.5, p=0.034) and CD8+CD28+ (68.0 ± 19.7 vs 62.0 ± 21.0, p=0.011), as well as CD8+ TEMRA cells (Figure). In a fully adjusted model, the CCR7-CD45RO-CD62L+ (52.2 ± 14.5 vs 50.2 ± 16.1, p=0.036), and CD8+CD28+CD45RA+CCR7- significantly differed between groups (23.1 ± 14.7 vs 25.0 ± 17.8, p=0.008). On the molecular level, T cells were polarised in HTN towards a Th1/Tc1 and Th17.1/Tc17.1 pro-inflammatory milieu (Figure). No differences were detected in B cell subsets. The innate immune ‘signature’ was characterised by intermediate monocytes with a differing pattern of CCR2 and CCR5 chemokine receptor expression (Table 1), and alterations in STAT1 and STAT6 phosphorylation cascades. NK cell CD56+Dim expression and fewer CD122-expressing NKT (0.13 ± 0.0 vs 0.08 ± 0.1, p=0.046) and CD122+ T lymphocytes (1.3 ± 3.4 vs 0.6 ± 0.4, p=0.019) further supported pro-inflammatory milieu in hypertension. Finally, in an exploratory nominal statistical analysis, nocturnal non-dipping was associated with particular changes in immune cell signature, including expanded CD4+TCM (CD4+CD45RO+CD62L-, 9.4 ± 4.3 vs 8.0 ± 3.3, p=0.04) and reduced CD4+TEM and TEMRA compartments; polarisation towards Th17 and Tc1; and altered Monocyte CCR2 and CCR5 expression. Additionally, non-dipping was linked to dendritic cell mannose receptor downregulation e.g. mDC non-dipper 10.9 ± 5.8 vs dipper 13.6 ± 9.7, p=0.03. Conclusion These exploratory data support alterations of circulating innate (monocytes) and adaptive (T cells) immune compartments in newly diagnosed untreated, and uncomplicated hypertension.

"Evaluation of the Effect of α-L-Guluronic Acid (G2013), as a New Member of NSAID Family, on Expression Pattern of Chemokine Receptors in Systemic Lupus Erythematosus"

"Evaluation of the Effect of α-L-Guluronic Acid (G2013), as a New Member of NSAID Family, on Expression Pattern of Chemokine Receptors in Systemic Lupus Erythematosus"

Accumulation of tissue-resident natural killer cells, innate lymphoid cells, and CD8+ T cells towards the center of human lung tumors

ABSTRACT Lung cancer is a leading cause of cancer-related death worldwide. Despite recent advances in tissue immunology, little is known about the spatial distribution of tissue-resident lymphocyte subsets in lung tumors. Using high-parameter flow cytometry, we identified an accumulation of tissue-resident lymphocytes including tissue-resident NK (trNK) cells and CD8+ tissue-resident memory T (TRM) cells toward the center of human non-small cell lung carcinomas (NSCLC). Chemokine receptor expression patterns indicated different modes of tumor-infiltration and/or residency between trNK cells and CD8+ TRM cells. In contrast to CD8+ TRM cells, trNK cells and ILCs generally expressed low levels of immune checkpoint receptors independent of location in the tumor. Additionally, granzyme expression in trNK cells and CD8+ TRM cells was highest in the tumor center, and intratumoral CD49a+CD16− NK cells were functional and responded stronger to target cell stimulation than their CD49a− counterparts, indicating functional relevance of trNK cells in lung tumors. In summary, the present spatial mapping of lymphocyte subsets in human NSCLC provides novel insights into the composition and functionality of tissue-resident immune cells, suggesting a role for trNK cells and CD8+ TRM cells in lung tumors and their potential relevance for future therapeutic approaches.

Population rearrangement of B-lymphocytes expressing chemokine receptors in patients with chronic obstructive pulmonary disease

To date, there are no drugs that can prevent progressive destruction of lung tissue and small airway fibrosis in patients with chronic obstructive pulmonary disease (COPD). Therefore, molecular mechanisms of this disease are being studied. The aim of this study was to determine the chemokine receptor expression pattern of B-lymphocytes from peripheral blood and airways of patients with COPD. Peripheral blood was collected from 51 smokers with COPD, 21 healthy smokers, and 20 healthy non-smokers. Seven smokers with COPD and 7 healthy smokers were recruited to undergo bronchoscopy with bronchoalveolar lavage (BAL). The expression of chemokine receptors CCR5, CCR6, CCR7, CXCR3, CXCR4, and CXCR5 on the surface of blood and BAL B-lymphocytes was determined by flow cytometry. It was found that the percentage of blood B-lymphocytes expressing chemokine receptors CCR5 and CXCR3 was higher in smokers with COPD compared with healthy smokers and healthy non-smokers. The percentage of CD27⁺ B-cells expressing CCR5 and CXCR3 receptors exceeded the proportion of CD27⁻ B-lymphocytes expressing these receptors in peripheral blood of patients with COPD and healthy controls. In smoking patients with COPD, the percentage of BAL B-cells expressing receptors CCR5 and CXCR3 was also increased compared with healthy smokers. There were no differences in the percentage of B-lymphocytes expressing receptors CXCR4, CXCR5, CCR6, and CCR7 in both peripheral blood and BAL between smokers with COPD and healthy smokers. A greater percentage of CD27⁻ B-lymphocytes than CD27⁺ B-cells expressed receptors CXCR4, CXCR5, CCR6, and CCR7 in the peripheral blood of smokers with COPD and healthy controls. The results of this study indicate a modification in the chemokine receptor profile of B-lymphocytes in COPD.

Imperfect storm: is interleukin-33 the Achilles heel of COVID-19?

The unique cytokine signature of COVID-19 might provide clues to disease mechanisms and possible future therapies. Here, we propose a pathogenic model in which the alarmin cytokine, interleukin (IL)-33, is a key player in driving all stages of COVID-19 disease (ie, asymptomatic, mild–moderate, severe–critical, and chronic–fibrotic). In susceptible individuals, IL-33 release by damaged lower respiratory cells might induce dysregulated GATA-binding factor 3-expressing regulatory T cells, thereby breaking immune tolerance and eliciting severe acute respiratory syndrome coronavirus 2-induced autoinflammatory lung disease. Such disease might be initially sustained by IL-33-differentiated type-2 innate lymphoid cells and locally expanded γδ T cells. In severe COVID-19 cases, the IL-33–ST2 axis might act to expand the number of pathogenic granulocyte–macrophage colony-stimulating factor-expressing T cells, dampen antiviral interferon responses, elicit hyperinflammation, and favour thromboses. In patients who survive severe COVID-19, IL-33 might drive pulmonary fibrosis by inducing myofibroblasts and epithelial–mesenchymal transition. We discuss the therapeutic implications of these hypothetical pathways, including use of therapies that target IL-33 (eg, anti-ST2), T helper 17-like γδ T cells, immune cell homing, and cytokine balance.

The Complexity of Targeting Chemokines to Promote a Tumor Immune Response.

Immunotherapeutic treatment strategies greatly extend patient survival following malignant disease across a wide range of tumor types, including even those with metastatic disease. While diverse in approach, adoptive cell therapy, introduction of T cells that express chimeric antigen receptors, and checkpoint inhibitors all aim to re-invigorate the immune system to promote tumor cell identification and elimination. This review will focus on immune cell infiltration into tumors as well as a cellular organization within the tumor microenvironment as directed by the cell-specific expression patterns of chemokines and chemokine receptors. Through better understanding the chemokine network within tumors, we can uncover mechanisms to promote beneficial immune cell infiltration that can be combined with checkpoint inhibition. Conversely, chemokine expression is not limited to cells of the immune system, and it is understood that tumor cells also express chemokines and chemokine receptors. Tumor cells can hijack the chemokine networks to promote immune suppression and metastatic tumor cell trafficking. We will discuss the ways in which the chemokine network lies at the crossroad of immune evasion and tumor regression. Overall, this review will summarize key publications in the field of immune cell recruitment to tumors, highlight the dichotomous nature of chemokine interventions into cancer, and aims to identify therapeutic pathways forward.

Treatment failure in neovascular age-related macular degeneration is associated with a complex chemokine receptor profile

ObjectiveTo investigate if chemokine expression patterns on leucocyte subsets influence the short-term anatomical treatment response of intravitreal antivascular endothelial growth factor therapy against neovascular age-related macular degeneration (AMD).Methods and analysisThis...

E-protein-regulated expression of CXCR4 adheres preselection thymocytes to the thymic cortex.

Preselection thymocytes are normally retained in the thymic cortex, but the mechanisms responsible remain incompletely understood. We now report that deletion of genes encoding the E-protein transcription factors E2A and HEB disorders chemokine receptor expression on developing thymocytes to allow escape of preselection TCR-CD8+ thymocytes into the periphery. We document that CXCR4 expression normally anchors preselection thymocytes to the thymic cortex via interaction with its ligand CXCL12 on cortical thymic epithelial cells, and that disruption of CXCR4-CXCL12 engagements release preselection thymocytes from the thymic cortex. We further document that CXCR4 expression must be extinguished by TCR-mediated positive selection signals to allow migration of TCR-signaled thymocytes out of the thymic cortex into the medulla. Thus, E-protein transcription factors regulate the ordered expression pattern of chemokine receptors on developing thymocytes, and the interaction of the chemokine receptor CXCR4 with its ligand adheres TCR-unsignaled preselection thymocytes to the thymic cortex.

Chemokine receptor expression on peripheral blood T-helper cells in Helicobacter pylori-associated diseases: chronic gastroduodenitis and peptic ulcer disease

Helicobacter pylori represents a pathogen causing chronic infection in around a half of the global human population, which manifestations vary from asymptomatic infection to developing gastritis and peptic ulcer. The data accumulated suggest that overt clinical types of this infection are associated with lost immunoregulation and increased pro-inflammatory cell-mediated immune response triggered by H. pylori-specific T helper cells. Here, we examined the degree of peripheral blood CD4+ T cell maturity and related expression of chemokine receptors involved in migration to gastrointestinal tract (CCR9 and CCR6), as well as Тand B-cell zones of lymphoid organs (CCR7 and CXCR5). It was shown that overt H. pylori-infection was coupled to changes in expression pattern of chemokine receptors on T helper cells. In particular, percentage of mature CD4+CD45RO+ T cells bearing CCR9 and immature CD4+CD45RO– Т cells expressing CXCR5 was increased in peripheral blood of patients with chronic gastroduodenitis. However, increased amount of activated mature CD4+CD45RO+ICOS+ T cells was observed in patients with chronic gastroduodenitis comorbid with peptic ulcer that was also associated with elevated amount of mature CCR6+ T helpers (mainly CD4+CD45RO+CCR7– CCR6+ cells) and follicular T helper cells as well as emerging minor CD4+CD45RO+CXCR5+CCR6+.T cell subset, not affecting CD4+CCR9+ Т cells. Thus, the data obtained evidence that tissue-specific T-helper cell migration is controlled separately in of H. pylori-associated diseases.

Long-Term Engraftment of ESC-Derived B-1 Progenitor Cells Supports HSC-Independent Lymphopoiesis.

SummaryIt is generally considered that mouse embryonic stem cell (ESC) differentiation into blood cells in vitro recapitulates yolk sac (YS) hematopoiesis. As such, similar to YS-derived B-progenitors, we demonstrate here that ESC-derived B-progenitors differentiate into B-1 and marginal zone B cells, but not B-2 cells in immunodeficient mice after transplantation. ESC-derived B-1 cells were maintained in the recipients for more than 6 months, secreting natural IgM antibodies in vivo. Gene expression profiling displayed a close relationship between ESC- and YS-derived B-1 progenitors. Because there are no hematopoietic stem cells (HSCs) detectable in our ESC differentiation culture, successful long-term engraftment of ESC-derived functional B-1 cells supports the presence of HSC-independent B-1 cell development.

The immune microenvironment in malignant lymphoma

Recent advances in immunotherapy have highlighted the importance of the tumor microenvironment. Lymphomas are a heterogeneous group of malignancies that arise from lymphocytes and typically develop in lymphoid tissues. It has been recognized that the elements of the lymphoma microenvironment are not mere bystanders to a host antitumor inflammatory response but are important components of the tumor that support proliferation, survival, and chemoresistance of lymphoma cells. Lymphoma cells have individual expression patterns of chemokine receptors and adhesion molecules, according to their histological subtypes, and the patterns of surface molecules determine the sites of tumor involvement. Lymphoma cells often depend on the signals provided by non-tumor cells, such as stromal cells and macrophages, through direct cell contact and paracrine factors. On the other hand, there are genetic and non-genetic mechanisms allowing lymphoma cells to escape from anti-tumor immunity, such as downregulation of HLA molecules, B2M, CD58, CD70, and/or upregulation of PD-L1 and PD-L2. Further understanding of the interactions of lymphoma cells and the tumor microenvironment gives an insight into the pathogenesis of lymphomas and supports new approaches to their treatment.

Association of Chemokines and Chemokine Receptor Expression with Monocytic-Myeloid-Derived Suppressor Cells during Tumor Progression.

Myeloid-derived suppressor cells (MDSCs) are highly immunosuppressive myeloid cells that show increased expression in cancer patients; however, the molecular mechanisms underlying their generation and function are unclear. Whereas granulocytic-MDSCs correlate with poor overall survival in breast cancer (BC), the presence and relevance of monocytic (Mo)-MDSCs are unknown. Here, we report for the first time increased chemokine and chemokine receptor production by Mo-MDSCs in BC patients. A clear population of Mo-MDSCs with the typical cell surface phenotype (human leukocyte antigen-antigen D related [HLA-DR]low/− CD11b+ CD33+ CD14+) increased significantly during disease progression. In addition, the chemokine receptor expression level on Mo-MDSCs in patients with invasive BC was the highest. Furthermore, different chemokine receptor expression patterns were noted in Mo-MDSCs between healthy controls (HC) and BC patients. Additionally, CD4 T cells proliferations were significantly decreased in the invasive BC groups compared with the HC group. However, the ductal carcinoma in situ (DCIS) group had no significantly compared with the HC group. Our data suggest that monitoring chemokine and chemokine receptor production by Mo-MDSCs may represent a novel and simple biomarker for assessing disease progression in BC patients.

Targeting CXCR4 (CXC Chemokine Receptor Type 4) for Molecular Imaging of Aldosterone-Producing Adenoma.

Primary aldosteronism is the most frequent cause of secondary hypertension and is associated with increased morbidity and mortality compared with hypertensive controls. The central diagnostic challenge is the differentiation between bilateral and unilateral disease, which determines treatment options. Bilateral adrenal venous sampling, currently recommended for differential diagnosis, is an invasive procedure with several drawbacks, making it desirable to develop novel noninvasive diagnostic tools. When investigating the expression pattern of chemokine receptors by quantitative real-time polymerase chain reaction and immunohistochemistry, we observed high expression of CXCR4 (CXC chemokine receptor type 4) in aldosterone-producing tissue in normal adrenals, adjacent adrenal cortex from adrenocortical adenomas, and in aldosterone-producing adenomas (APA), correlating strongly with the expression of CYP11B2 (aldosterone synthase). In contrast, CXCR4 was not detected in the majority of nonfunctioning adenomas that are frequently found coincidently. The specific CXCR4 ligand 68Ga-pentixafor has recently been established as radiotracer for molecular imaging of CXCR4 expression and showed strong and specific binding to cryosections of APAs in our study. We further investigated 9 patients with primary aldosteronism because of APA by 68Ga-pentixafor-positron emission tomography. The tracer uptake was significantly higher on the side of increased adrenocortical aldosterone secretion in patients with APAs compared with patients investigated by 68Ga-pentixafor-positron emission tomography for other causes. Molecular imaging of aldosterone-producing tissue by a CXCR4-specific ligand may, therefore, be a highly promising tool for noninvasive characterization of patients with APAs.

Chemokine receptor co-expression reveals aberrantly distributed TH effector memory cells in GPA patients

BackgroundPersistent expansion of circulating CD4+ effector memory T cells (TEM) in patients with granulomatosis with polyangiitis (GPA) suggests their fundamental role in disease pathogenesis. Recent studies have shown that distinct functional CD4+ TEM cell subsets can be identified based on expression patterns of chemokine receptors. The current study aimed to determine different CD4+ TEM cell subsets based on chemokine receptor expression in peripheral blood of GPA patients. Identification of particular circulating CD4+ TEM cells subsets may reveal distinct contributions of specific CD4+ TEM subsets to the disease pathogenesis in GPA.MethodPeripheral blood of 63 GPA patients in remission and 42 age- and sex-matched healthy controls was stained immediately after blood withdrawal with fluorochrome-conjugated antibodies for cell surface markers (CD3, CD4, CD45RO) and chemokine receptors (CCR4, CCR6, CCR7, CRTh2, CXCR3) followed by flow cytometry analysis. CD4+ TEM memory cells (CD3+CD4+CD45RO+CCR7-) were gated, and the expression patterns of chemokine receptors CXCR3+CCR4-CCR6-CRTh2-, CXCR3-CCR4+CCR6-CRTh2+, CXCR3-CCR4+CCR6+CRTh2-, and CXCR3+CCR4-CCR6+CRTh2- were used to distinguish TEM1, TEM2, TEM17, and TEM17.1 cells, respectively.ResultsThe percentage of CD4+ TEM cells was significantly increased in GPA patients in remission compared to HCs. Chemokine receptor co-expression analysis within the CD4+ TEM cell population demonstrated a significant increase in the proportion of TEM17 cells with a concomitant significant decrease in the TEM1 cells in GPA patients compared to HC. The percentage of TEM17 cells correlated negatively with TEM1 cells in GPA patients. Moreover, the circulating proportion of TEM17 cells showed a positive correlation with the number of organs involved and an association with the tendency to relapse in GPA patients. Interestingly, the aberrant distribution of TEM1 and TEM17 cells is modulated in CMV- seropositive GPA patients.ConclusionsOur data demonstrates the identification of different CD4+ TEM cell subsets in peripheral blood of GPA patients based on chemokine receptor co-expression analysis. The aberrant balance between TEM1 and TEM17 cells in remission GPA patients, showed to be associated with disease pathogenesis in relation to organ involvement, and tendency to relapse.

Neoplastic plasma cells generate an inflammatory environment within bone marrow and markedly alter the distribution of T cells between lymphoid compartments.

Monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) are characterised by the accumulation of malignant plasma cells within bone marrow and lead to a range of abnormalities in the peripheral blood T cell repertoire. We investigated the level of inflammatory chemokines within the bone marrow and blood of patients with MGUS and MM and related this to the pattern of chemokine receptor expression on T cells in both compartments.The expression of a wide range of chemokine ligands for CXCR3 and CCR4 was markedly increased within the bone marrow of patients with MGUS and MM compared to healthy donors. The most marked effects were seen for CCL4 and CXCL9 which were increased by 4 and 6 fold respectively in the bone marrow of patients with myeloma. The expression of CXCR3 and CCR4, the major TH1 and TH2-associated chemokine receptors, was increased substantially on T cells within the bone marrow of patients whereas the percentage of CXCR3-expressing T cells within blood was correspondingly decreased. The presence of even small numbers of neoplastic plasma cells or associated stroma can therefore generate an inflammatory chemokine tumour microenvironment. This leads to the selective recruitment or retention of specific T cell subsets which is likely to underlie many of the features regarding the peripheral T cell repertoire in myeloma and may also contribute to the immune suppression associated with this disease. This local inflammatory reaction may represent a tumour-specific immune response or may itself play an important role in tumour progression and as such may offers a potential novel target for therapeutic intervention.

Modulation of Neuroinflammation in the Central Nervous System: Role of Chemokines and Sphingolipids

Neuroinflammation is a process involved in the pathogenesis of different disorders, both autoimmune, such as neuropsychiatric systemic lupus erythematosus, and degenerative, such as Alzheimer's and Parkinson's disease. In the central nervous system, the local milieu is tightly regulated by different mediators, among which are chemoattractant cytokines, also known as chemokines. These small molecules are able to modulate trafficking of immune cells in the course of nervous system development or in response to tissue damage, and different patterns of chemokine molecule and receptor expression have been described in several neuroinflammatory disorders. In recent years, a number of studies have highlighted a pivotal role of sphingolipids in regulating neuroinflammation. Sphingolipids have different functions, among which are the control of leukocyte egress from lymphonodes into inflamed tissues, the expression of various mediators of inflammation and a direct effect on the cells of the central nervous system as regulators of neuroinflammation. In the future, a better knowledge of these two groups of mediators could provide insight into the pathogenesis of neuroinflammatory disorders and could help develop novel diagnostic tools and therapeutic strategies.

A role for CCR5+CD4 T cells in cutaneous psoriasis and for CD103+ CCR4+ CD8 Teff cells in the associated systemic inflammation

Recent results have identified critical components of the T cell response involved in the initiation and amplification phases of psoriasis. However the link between T cell responses arising in the skin and the systemic inflammation associated with severe psoriasis is largely unknown. We hypothesized that specific subsets of memory T cells recirculating from the skin could play a role. We therefore dissected the circulating memory T cell compartment in patients by analyzing the TCM, TEM and Teff phenotype, the pattern of CCR4 and CCR5 chemokine receptor expression and the expression of the tissue homing molecule CD103. For each subset we calculated the correlation with the Psoriasis Area and Severity Index (PASI) and with the extent of systemic inflammation measured as serum level of the prototypic short pentraxin, C reactive protein (CRP). Validation was performed by comparison with gene expression data in psoriatic plaques. We found that circulating CD103+CCR4+CCR5+ and CCR4+CCR6- CD8+ Teff cells, were highly correlated with CRP levels as well as with the validated index PASI, reflecting a link between skin involvement and systemic inflammation in patients with severe psoriasis. In addition we observed a contraction of circulating CCR5+ T cells in psoriasis patients, with a highly significant inverse correlation between CCR5+CD4 T cells and the PASI score. Increased expression of CCR5 and CCL5 genes in psoriatic skin lesions was consistent with an accumulation of CCR5+ cells in psoriatic plaques indicating a role for CCR5/CCL5 axis in disease pathogenesis.

Chemokine receptors expression on CD3+ blood cells in bronchial asthma

PurposeChemokines and their receptors participate in pathomechanism of bronchial asthma.The aim of the study was to analyze the pattern of chemokine receptor expression on T cells in severe asthmatics and to compare to mild-to-moderate patients and controls. Material/methodsFlow cytometric analysis of CXCR1, CXCR2, CXCR3, CCR3, CCR4, CCR5, CCR7, CCR8 expression on CD3+CD8− and CD3+CD8+ cells was performed in patients with different severity of chronic asthma and in controls. ResultsPercentages of CD3+CD8+ cells expressing CXCR1 were significantly lower in severe asthmatic than in mild-to-moderate asthmatics and in controls. Percentages of CD3+CD8+ cells expressing CCR7 were significantly lower in the severe asthma group than in control group. Percentages of CD3+CD8− cells expressing CXCR1, CXCR2 and CCR8 were significantly lower in the severe asthma group than in mild-to-moderate asthmatics and in controls. The number of cells CD3+CD8− and CD3+CD8+ expressing of CXCR1 was significantly lower in the group of patients using more than 800μg of budesonide daily than in the group of patients using less than 400μg of budesonide. Percentages of CD3+CD8− cells expressing CXCR3, CCR4 and CCR5 were visibly higher (not significantly) in chronic mild-to-moderate asthma than in healthy controls and severe asthmatics. ConclusionsThese results may indicate impairment of some chemokine expression on T cells in severe asthma patients. Moreover participation of both chemokine receptors related to Th1 and Th2 responses in mild-to-moderate asthma and attenuation of these responses in severe asthma has been suggested.

Abnormal expression of chemokine receptor on B cells in patients with SLE

SLE is a systemic autoimmune disease characterized by overactivation of autoreactive memory B cells. However, little is known about the mechanism of qualitative abnormality of B cells. The subset classification of T cells by expression pattern of master transcription factors and chemokine receptors has been established. The biology of T cells is useful information to assess qualitative abnormality of B cells. Therefore, we focused on the expression of chemokine receptors such as CXCR5 and CXCR3 on B cells in order to define the B cell subset classification in patients with SLE. Our results revealed that pathological B cells, which lose CXCR5 and express CXCR3, might be involved in autoantibody production through the interaction with Tfh cells, and in acquisition of effector function of memory B cells during the pathological process in SLE. In addition, the results revealed that those effector B cells still remained after improvement of disease activity by immunosuppressive therapy, indicating that the quantitative abnormality, which is not improved by current therapy, may underlie in this disease.

Chemokines and skin diseases.

Chemokines are small molecules that induce chemotaxis and activation of certain subsets of leukocytes. The expression patterns of chemokines and chemokine receptors are specific to certain organs and cells. Therefore, chemokines are important to elucidate the mechanism of organ-specific human diseases. CCL17 expressed by Langerhans cells, blood endothelial cells, and fibroblasts plays a key role in attracting Th2 cells and tumor cells of adult T-cell leukemia/lymphoma and mycosis fungoides/Sézary syndrome into the skin, developing various Th2-type inflammatory skin diseases as well as cutaneous lymphoma. CCL11 and CCL26 expressed by skin-resident cells, such as fibroblasts, blood endothelial cells, and keratinocytes, induce infiltration of CCR3-expressing cells such as Th2 cells and eosinophils. CCL11 may also serve as an autocrine as well as a paracrine in anaplastic large cell lymphoma. CX3CL1 expressed on blood endothelial cells leads to infiltration of CX3CR1(+) immune cells, such as mast cells, neutrophils, and macrophages, playing important roles in wound healing, tumor immunity, and vasculitis. Biologics targeting chemokines and their receptors are promising strategies for various skin diseases that are resistant to the current therapy.