Skip to main content
Erschienen in: Journal of Clinical Immunology 5/2013

01.07.2013 | Original Research

Characterization of Th1- and Th2-associated Chemokine Receptor Expression in Spleens of Patients with Immune Thrombocytopenia

Erschienen in: Journal of Clinical Immunology | Ausgabe 5/2013

Einloggen, um Zugang zu erhalten

Abstract

Purpose

In view of the numerous clinical observations and laboratory studies that suggest a critical role for the spleen in immune thrombocytopenia (ITP) pathophysiology, we aimed to characterize Th1-associated chemokine receptors CXCR3 and CCR5 and Th2-associated chemokine receptor CCR3 in spleens of ITP patients and assess the significance of their differential expression in the clinical setting.

Methods

The histopathology of spleens was observed using hematoxylin-eosin staining (HE), and the positive rate of CXCR3, CCR5 and CCR3 expression in spleens of 24 ITP patients and 12 patients with traumatic splenic rupture as normal controls was detected by immunohistochemistry using the SP method. CXCR3, CCR5 and CCR3 protein expression was analyzed by Western blot and mRNA levels were investigated by real-time polymerase chain reaction (RT-PCR).

Results

Reactive hyperplasia could be seen in follicles of the white pulp, the germinal central zone was enlarged and the marginal zone was thickened, the central arteries were thickened and fibrotic, and the density of the capillary vessel was increased in ITP patients. ITP group displayed a higher rate of expression of Th1-associated chemokine receptors CXCR3 and CCR5 (83.3 % vs. 75 %, 100 % vs. 83.3 %) but lower rate of expression of Th2-associated chemokine receptor CCR3 (50 % vs. 66.7 %) compared with the controls (P < 0.05, respectively). Western blot analysis revealed that CXCR3 and CCR5 protein expression was significantly increased in ITP patients while CCR3 was significantly reduced (P < 0.05, respectively). Meanwhile, ITP patients displayed increased mRNA levels of CXCR3 and CCR5 but decreased gene expression of CCR3 (P < 0.05, respectively).

Conclusion

The data suggested that the abnormal expression of Th1/Th2 chemokine receptors may participate in splenic immune disorder in patients with ITP. Using corresponding inhibitors may inhibit Th1-dominant expression and mitigate the progress of the disease.
Literatur
1.
Zurück zum Zitat Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JB, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115:168–86.PubMedCrossRef Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JB, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115:168–86.PubMedCrossRef
2.
Zurück zum Zitat Guo C, Chu X, Shi Y, He W, Li L, Wang L, et al. Correction of Th1-dominant cytokine profiles by high-dose dexamethasone in patients with chronic idiopathic thrombocytopenic purpura. J Clin Immunol. 2007;27:557–62.PubMedCrossRef Guo C, Chu X, Shi Y, He W, Li L, Wang L, et al. Correction of Th1-dominant cytokine profiles by high-dose dexamethasone in patients with chronic idiopathic thrombocytopenic purpura. J Clin Immunol. 2007;27:557–62.PubMedCrossRef
3.
4.
Zurück zum Zitat Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood. 2004;104:2623–34.PubMedCrossRef Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood. 2004;104:2623–34.PubMedCrossRef
5.
Zurück zum Zitat Stasi R, Del Poeta G, Stipa E, Evangelista ML, Trawinska MM, Cooper N, et al. Response to B-cell depleting therapy with rituximab reverts the abnormalities of T cell subsets in patients with idiopathic thrombocytopenic purpura. Blood. 2007;110:2924–30.PubMedCrossRef Stasi R, Del Poeta G, Stipa E, Evangelista ML, Trawinska MM, Cooper N, et al. Response to B-cell depleting therapy with rituximab reverts the abnormalities of T cell subsets in patients with idiopathic thrombocytopenic purpura. Blood. 2007;110:2924–30.PubMedCrossRef
6.
Zurück zum Zitat Lichtman AH, Abbas AK. T-cell subsets: recruiting the right kind of help. Curr Biol. 1997;7:242–4.CrossRef Lichtman AH, Abbas AK. T-cell subsets: recruiting the right kind of help. Curr Biol. 1997;7:242–4.CrossRef
7.
Zurück zum Zitat Austrup F, Vestweber D, Borges E, Löhning M, Bräuer R, Herz U, et al. P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflamed tissues. Nature. 1997;385:81–3.PubMedCrossRef Austrup F, Vestweber D, Borges E, Löhning M, Bräuer R, Herz U, et al. P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflamed tissues. Nature. 1997;385:81–3.PubMedCrossRef
8.
Zurück zum Zitat Zlotnik A, Yoshle O. Chemokines: a new classification system and their role in immunity. Immunity. 2000;12:121–7.PubMedCrossRef Zlotnik A, Yoshle O. Chemokines: a new classification system and their role in immunity. Immunity. 2000;12:121–7.PubMedCrossRef
9.
Zurück zum Zitat Antonelli A, Rotondi M, Fallahi P, Ferrari SM, Paolicchi A, Romagnani P, et al. Increase of CXC chemokine CXCL10 and CC chemokine CCL2 serum levels in normal ageing. Cytokine. 2006;34:32–8.PubMedCrossRef Antonelli A, Rotondi M, Fallahi P, Ferrari SM, Paolicchi A, Romagnani P, et al. Increase of CXC chemokine CXCL10 and CC chemokine CCL2 serum levels in normal ageing. Cytokine. 2006;34:32–8.PubMedCrossRef
10.
Zurück zum Zitat Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C, et al. CCR5 is characteristic of Th1 lymphocytes. Nature. 1998;391:344–5.PubMedCrossRef Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C, et al. CCR5 is characteristic of Th1 lymphocytes. Nature. 1998;391:344–5.PubMedCrossRef
11.
Zurück zum Zitat Imai T, Nagira M, Takagi S, Kakizaki M, Nishimura M, Wang J, et al. Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine. Int Immunol. 1999;11:81–8.PubMedCrossRef Imai T, Nagira M, Takagi S, Kakizaki M, Nishimura M, Wang J, et al. Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine. Int Immunol. 1999;11:81–8.PubMedCrossRef
12.
Zurück zum Zitat Sallusto F, Lenig D, Mackay CR, Lanzavecchia A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med. 1998;187:875–83.PubMedCrossRef Sallusto F, Lenig D, Mackay CR, Lanzavecchia A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med. 1998;187:875–83.PubMedCrossRef
13.
Zurück zum Zitat Bonecchi R, Bianchi G, Bordignon PP, D’Ambrosio D, Lang R, Borsatti A, et al. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med. 1998;187:129–34.PubMedCrossRef Bonecchi R, Bianchi G, Bordignon PP, D’Ambrosio D, Lang R, Borsatti A, et al. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med. 1998;187:129–34.PubMedCrossRef
14.
Zurück zum Zitat Sallusto F, Mackay CR, Lanzavecchia A. Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells. Science. 1997;277:2005–7.PubMedCrossRef Sallusto F, Mackay CR, Lanzavecchia A. Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells. Science. 1997;277:2005–7.PubMedCrossRef
15.
Zurück zum Zitat Aggarwal A, Agarwal S, Misra R. Chemokine and chemokine receptor analysis reveals elevated interferon-inducible protein- 10 (IP)- 10/CXCL 10 levels and increased number of CCR5+ and CXCR 3+ CD 4 T cells in synovial fluid of patients with enthesitis-related arthritis (ERA). Clin Exp Immunol. 2007;148:515–9.PubMedCrossRef Aggarwal A, Agarwal S, Misra R. Chemokine and chemokine receptor analysis reveals elevated interferon-inducible protein- 10 (IP)- 10/CXCL 10 levels and increased number of CCR5+ and CXCR 3+ CD 4 T cells in synovial fluid of patients with enthesitis-related arthritis (ERA). Clin Exp Immunol. 2007;148:515–9.PubMedCrossRef
17.
Zurück zum Zitat Luster AD. Chemokines-chemotactic cytokines that mediate inflammation. N Engl J Med. 1998;338:436–45.PubMedCrossRef Luster AD. Chemokines-chemotactic cytokines that mediate inflammation. N Engl J Med. 1998;338:436–45.PubMedCrossRef
18.
Zurück zum Zitat Kemp EH, Metcalfe RA, Smith KA, Woodroofe MN, Watson PF, Weetman AP. Detection and localization of chemokine gene expression in autoimmune thyroid disease. Clin Endocrinol (Oxf). 2003;59:207–13.CrossRef Kemp EH, Metcalfe RA, Smith KA, Woodroofe MN, Watson PF, Weetman AP. Detection and localization of chemokine gene expression in autoimmune thyroid disease. Clin Endocrinol (Oxf). 2003;59:207–13.CrossRef
19.
Zurück zum Zitat Gu D, Chen Z, Zhao H, Du W, Xue F, Ge J, et al. Th1 (CXCL10) and Th2 (CCL2) chemokine expression in patients with immune thrombocytopenia. Hum Immunol. 2010;71:586–91.PubMedCrossRef Gu D, Chen Z, Zhao H, Du W, Xue F, Ge J, et al. Th1 (CXCL10) and Th2 (CCL2) chemokine expression in patients with immune thrombocytopenia. Hum Immunol. 2010;71:586–91.PubMedCrossRef
20.
Zurück zum Zitat Hanaoka R, Kasama T, Muramatsu M, Yajima N, Shiozawa F, Miwa Y, et al. A novel mechanism for the regulation of IFN-gamma inducible protein-10 expression in rheumatoid arthritis. Arthritis Res Ther. 2003;5:R74–81.PubMedCrossRef Hanaoka R, Kasama T, Muramatsu M, Yajima N, Shiozawa F, Miwa Y, et al. A novel mechanism for the regulation of IFN-gamma inducible protein-10 expression in rheumatoid arthritis. Arthritis Res Ther. 2003;5:R74–81.PubMedCrossRef
21.
Zurück zum Zitat Narumi S, Takeuchi T, Kobayashi Y, Konishi K. Serum levels of ifn-inducible PROTEIN-10 relating to the activity of systemic lupus erythematosus. Cytokine. 2000;12:1561–5.PubMedCrossRef Narumi S, Takeuchi T, Kobayashi Y, Konishi K. Serum levels of ifn-inducible PROTEIN-10 relating to the activity of systemic lupus erythematosus. Cytokine. 2000;12:1561–5.PubMedCrossRef
22.
Zurück zum Zitat Antonelli A, Ferri C, Fallahi P, Ferrari SM, Giuggioli D, Colaci M, et al. CXCL10 (alpha) and CCL2 (beta) chemokines in systemic sclerosis – a longitudinal study. Rheumatology (Oxford). 2008;47:45–9.CrossRef Antonelli A, Ferri C, Fallahi P, Ferrari SM, Giuggioli D, Colaci M, et al. CXCL10 (alpha) and CCL2 (beta) chemokines in systemic sclerosis – a longitudinal study. Rheumatology (Oxford). 2008;47:45–9.CrossRef
23.
Zurück zum Zitat Sorensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA, et al. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest. 1999;103:807–15.PubMedCrossRef Sorensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA, et al. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest. 1999;103:807–15.PubMedCrossRef
24.
Zurück zum Zitat Shimada A, Morimoto J, Kodama K, Suzuki R, Oikawa Y, Funae O, et al. Elevated serum IP-10 levels observed in type 1 diabetes. Diabetes Care. 2001;24:510–5.PubMedCrossRef Shimada A, Morimoto J, Kodama K, Suzuki R, Oikawa Y, Funae O, et al. Elevated serum IP-10 levels observed in type 1 diabetes. Diabetes Care. 2001;24:510–5.PubMedCrossRef
25.
Zurück zum Zitat Antonelli A, Fallahi P, Rotondi M, Ferrari SM, Romagnani P, Grosso M, et al. Increased serum CXCL10 in Graves’ disease or autoimmune thyroiditis is not associated with hyper- or hypothyroidism per se, but is specifically sustained by the autoimmune, inflammatory process. Eur J Endocrinol. 2006;154:651–8.PubMedCrossRef Antonelli A, Fallahi P, Rotondi M, Ferrari SM, Romagnani P, Grosso M, et al. Increased serum CXCL10 in Graves’ disease or autoimmune thyroiditis is not associated with hyper- or hypothyroidism per se, but is specifically sustained by the autoimmune, inflammatory process. Eur J Endocrinol. 2006;154:651–8.PubMedCrossRef
26.
Zurück zum Zitat Panitsas FP, Theodoropoulou M, Kouraklis A, Karakantza M, Theodorou GL, Zoumbos NC, et al. Adult chronic idiopathic thrombocytopenic purpura (ITP) is the manifestation of a type-1 polarized immune response. Blood. 2004;103:2645–7.PubMedCrossRef Panitsas FP, Theodoropoulou M, Kouraklis A, Karakantza M, Theodorou GL, Zoumbos NC, et al. Adult chronic idiopathic thrombocytopenic purpura (ITP) is the manifestation of a type-1 polarized immune response. Blood. 2004;103:2645–7.PubMedCrossRef
27.
Zurück zum Zitat Lanzavecchia A, Sallusto F. Dynamics of T lymphocyte responses: intermediates, effectors and memory cells. Science. 2000;290:92–7.PubMedCrossRef Lanzavecchia A, Sallusto F. Dynamics of T lymphocyte responses: intermediates, effectors and memory cells. Science. 2000;290:92–7.PubMedCrossRef
28.
Zurück zum Zitat D’Ambrosio D, Iellem A, Bonecchi R, Mazzeo D, Sozzani S, Mantovani A, et al. Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. J Immunol. 1998;161:5111–5.PubMed D’Ambrosio D, Iellem A, Bonecchi R, Mazzeo D, Sozzani S, Mantovani A, et al. Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. J Immunol. 1998;161:5111–5.PubMed
29.
Zurück zum Zitat Langenkamp A, Nagata K, Murphy K, Wu L, Lanzavecchia A, Sallusto F. Kinetics and expression patterns of chemokine receptors in human CD4+ T lymphocytes primed by myeloid or plasmacytoid dendritic cells. Eur J Immunol. 2003;33:474–82.PubMedCrossRef Langenkamp A, Nagata K, Murphy K, Wu L, Lanzavecchia A, Sallusto F. Kinetics and expression patterns of chemokine receptors in human CD4+ T lymphocytes primed by myeloid or plasmacytoid dendritic cells. Eur J Immunol. 2003;33:474–82.PubMedCrossRef
30.
Zurück zum Zitat Kim CH, Rott L, Kunkel EJ, Genovese MC, Andrew DP, Wu L, et al. Rules of chemokine receptor association with T cell polarization in vivo. J Clin Invest. 2001;108:1331–9.PubMed Kim CH, Rott L, Kunkel EJ, Genovese MC, Andrew DP, Wu L, et al. Rules of chemokine receptor association with T cell polarization in vivo. J Clin Invest. 2001;108:1331–9.PubMed
31.
Zurück zum Zitat Yoshimura C, Nomura S, Nagahama M, Ozaki Y, Kagawa H, Fukuhara S. Plasma-soluble Fas (APO-1, CD95) and soluble Fas ligand in immune thrombocytopenic purpura. Eur J Haematol. 2000;64:219–24.PubMedCrossRef Yoshimura C, Nomura S, Nagahama M, Ozaki Y, Kagawa H, Fukuhara S. Plasma-soluble Fas (APO-1, CD95) and soluble Fas ligand in immune thrombocytopenic purpura. Eur J Haematol. 2000;64:219–24.PubMedCrossRef
32.
Zurück zum Zitat Turner JE, Steinmetz OM, Stahl RA, Panzer U. Targeting of Th1-associated chemokine receptors CXCR3 and CCR5 as therapeutic strategy for inflammatory diseases. Mini Rev Med Chem. 2007;7:1089–96.PubMedCrossRef Turner JE, Steinmetz OM, Stahl RA, Panzer U. Targeting of Th1-associated chemokine receptors CXCR3 and CCR5 as therapeutic strategy for inflammatory diseases. Mini Rev Med Chem. 2007;7:1089–96.PubMedCrossRef
33.
Zurück zum Zitat Patel DD, Zachariah JP, Whichard LP. CXCR3 and CCR5 ligands in rheumatoid arthritis synovium. Clin Immunol. 2001;98:39–45.PubMedCrossRef Patel DD, Zachariah JP, Whichard LP. CXCR3 and CCR5 ligands in rheumatoid arthritis synovium. Clin Immunol. 2001;98:39–45.PubMedCrossRef
34.
Zurück zum Zitat Koch AE, Kunkel SL, Harlow LA, Mazarakis DD, Haines GK, Burdick MD, et al. Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. J Clin Invest. 1994;93:921–8.PubMedCrossRef Koch AE, Kunkel SL, Harlow LA, Mazarakis DD, Haines GK, Burdick MD, et al. Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. J Clin Invest. 1994;93:921–8.PubMedCrossRef
35.
Zurück zum Zitat Volin MV, Shah MR, Tokuhira M, Haines GK, Woods JM, Koch AE. RANTES expression and contribution to monocyte chemotaxis in arthritis. Clin Immunol Immunopathol. 1998;89:44–53.PubMedCrossRef Volin MV, Shah MR, Tokuhira M, Haines GK, Woods JM, Koch AE. RANTES expression and contribution to monocyte chemotaxis in arthritis. Clin Immunol Immunopathol. 1998;89:44–53.PubMedCrossRef
36.
Zurück zum Zitat Jiang PJ, Lin QD, Bao SM, Zhao AM, Xiao SJ. Relationship between expression of chemokine receptors CCR3, CCR5 and CXCR3 on CD4+ T cells and spontaneous abortion in mice. Chin Med J. 2009;122:390–5.PubMed Jiang PJ, Lin QD, Bao SM, Zhao AM, Xiao SJ. Relationship between expression of chemokine receptors CCR3, CCR5 and CXCR3 on CD4+ T cells and spontaneous abortion in mice. Chin Med J. 2009;122:390–5.PubMed
37.
Zurück zum Zitat Panitsas FP, Mouzaki A. Effect of splenectomy on type-1/type-2 cytokine gene expression in a patient with adult idiopathic thrombocytopenic purpura (ITP). BMC Blood Disord. 2004;4:4–8.PubMedCrossRef Panitsas FP, Mouzaki A. Effect of splenectomy on type-1/type-2 cytokine gene expression in a patient with adult idiopathic thrombocytopenic purpura (ITP). BMC Blood Disord. 2004;4:4–8.PubMedCrossRef
Metadaten
Titel
Characterization of Th1- and Th2-associated Chemokine Receptor Expression in Spleens of Patients with Immune Thrombocytopenia
Publikationsdatum
01.07.2013
Erschienen in
Journal of Clinical Immunology / Ausgabe 5/2013
Print ISSN: 0271-9142
Elektronische ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-013-9883-4

Weitere Artikel der Ausgabe 5/2013

Journal of Clinical Immunology 5/2013 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.