CD72在免疫性血小板减少症中的基因表达
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摘要
目的:研究免疫性血小板减少症(ITP)患者信号素Sema4D和其免疫受体CD72的基因表达情况、血浆Sema4D.血浆Th细胞因子IL-2, IL-4, IL-6和INF-γ水平及二者的相关性,探讨其在ITP发病机制中的作用。
     方法:采用放射免疫法(RIA)测定血浆细胞因子IL-2,IL-4,IL-6.水平,ELISA检测血浆sSema4D和INF-γ水平,实时荧光定量PCR法(RQ-PCR)检测Sema4D.cD72.IL-4和INF-γmRNA表达水平。
     结果:共检测39例ITP患者和23名正常对照,血浆工L-2水平未治疗ITP组(1.435±0.617ng/mL)显著低于完全缓解组为(3.100±2.410ng/mL,P<0.01)和正常对照组(2.272±1.385ng/mL,P<0.05),在缓解组和对照组间无统计学差异(P>0.05)。血浆IL-4水平未治疗ITP组(0.856±0.183ng/mL)和完全缓解组为(0.898±0.218ng/mL)显著高于正常对照组(0.714±0.170ng/mL,P<0.01),在缓解组和未治疗组间无统计学差异(P>0.05).IFN-γ/JL-4(Thl/Th2)mRNA水平在活动期ITP患者(中位数1.957,0.181-9.292)和缓解期患者(中位数2.499,0.186-29.32)是明显高于对照组(中位数0.819,0.018-4.88,P(0.01,P=0.01)。在缓解期和活动期患者之间无统计学差异(P>0.05)。活动期ITP患者CD72 mRNA(中位数1.664,0.184-9.659)的表达水平与正常对照组(中位数3.251,0.289-19.15,P<0.05.有明显差异,与完全缓解期患者相比(中位数3.491,0.266-47.38,P<0.05也有显著差异,但是缓解期患者与正常对照组的CD72mRNA的表达水平无统计学差异。未治疗组患者CD72 mRNA表达水平与血浆IL-2水平(P=0.036)及Sema4DmRNA表达水平(p=0.024)呈正相关。
     结论:CD72在ITP发病中可能起着一种负性调节的作用,ITP患者存在Thl/Th2细胞的失衡,CD72与Sema4D与IL-2存在一定相关性。
     目的:为探讨老年ITP患者的临床特征,合并症,治疗反应以及预后情况,我们对在我院1980-2009年间就诊的大于60岁的患者的临床资料进行了回顾性分析。
     研究对象和方法:我们共回顾性分析了525例(325例女性,200例男性)患者,中位年龄66岁(60-91岁)。
     结果:在最初诊断时,461例(87.8%)患者有出血症状,62.5%的患者合并有其他疾病,其中合并高血压为112例(22.1%),冠心病77例(14.7%)。144例患者(27.4%)没有接受任何治疗,299例患者(57%)仅接受一线治疗。14例患者行脾切除术,仅占患者总数的2.7%。90例长期随访患者,中位随访时间51个月(12-128月),总的治疗反应率68.8%(CR+PR)。31.2%患者未到CR或R,但是血小板中位数随访时为48.5×109/L(5-95×109/L)。直接或间接因治疗ITP相关死亡率为8%。
     结论:在60-69岁年龄段女性发病多于男性,出血症状更多,由于药物治疗近期和远期反应率较好,在老年患者中较少实施脾切除。尽管老年ITP因血小板减少死亡率较高,但是和其他死亡原因并无显著性差异。由此可认为老年ITP仍旧为一种良性疾病。
Objectives:To explore the role of CD72 in the pathogenesis of immune thrombocytopenia (ITP), we detected CD72, Sema4D, IL-4 and IFN-γmRNA expression and the levels of plasma Sema4D, IL-2, IL-4, IL-6 and INF-γin ITP patients(n=39) and controls (n=23).
     Methods:The levels of plasma IL-2, IL-4 and IL-6 were assayed by radioimmunoassay (RIA), The levels of plasma INF-γand sSema4D were analyzed by enzyme-linked immunosorbent assay(ELISA). Sema4D, CD72, IFN-γand IL-4MRNA expression by real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR).
     Results:The expression of CD72 mRNA in ITP patients (n=23) with active disease was significantly lower than that in patients in remission (P<0.05) (n=16) and controls (P<0.05) (n=23). The IFN-γ/IL-4 mRNA (Th1/Th2) expression in ITP patients with active disease and in remission was significantly higher than that in controls (P<0.01, P<0.05). The level of plasma IL-2 in ITP patients with active disease was significantly lower than that in patients in remission (P<0.05) and controls (P<0.05). The levels of plasma IL-4 in ITP patients with active disease and in remission were significantly higher than that of controls (P<0.01). The CD72 mRNA expression level correlated with Sema4DmRNA expression in peripheral blood mononuclear cells and level of plasma IL-2 in active ITP patients (P=0.024 and P=0.036).
     Conclusions:Our findings suggest that CD72 plays a negative role and correlate with Sema4D mRNA expression in peripheral blood mononuclear cells and level of plasma IL-2 in the active ITP patients.
     In this retrospective study, we evaluated the clinical features and the effects of various treatment modalities on the clinical course in elderly patients (i. e., age≥60 yr) diagnosed with immune thrombocytopenia (ITP) at our center from 1980 to 2009. We retrospectively examined the medical records of 525 (325 females,200 males) ITP patients. The median age of the patients at presentation was 66 years (range:60-91yr). At initial diagnosis,461 (87.8%) patients had signs of bleeding, we find 62.5% patients had co-existing diseases, the most prevalent of which were hypertension (n=112,22.1%) and coronary heart disease (n=77,14.7%). One hundred-and-Forty-four patients (27.4%) received no treatment, and 299 (57%) received first line treatment only. Fourteen patients (2.7%) underwent splenectomy. Ninety patients who have follow-up≥12months, (median51months, range,12-128months) the total rate of response was 68.8%(CR+PR).31.2%patients had not achieved CR or R, but the median platelets was 48.5×109/L (range,5-95×109/L). The death rate from causes directly related to ITP or its treatment was 8.0%with at last follow up in 113patients. In conclusion, there are more female aged patients during 60-69 years old. The splenectomy was rarely performed in patients more than 60 years old because of a good reponse to therapy. Even though the mortality was higher attributed to ITP or complications, this incidence was not significantly different from other death cause (p>0.05). This retrospective review represents the largest collection of elderly patients with ITP in China in a single center.
引文
[1]Nugent D, McMillan R, Nichol JL, Slichter SJ:Pathogenesis of chronic immune thrombocytopenia:increased platelet destruction and/or decreased platelet production. Br J Haematol 2009;146:585.
    [2]Cines DB, Blanchette VS:Immune thrombocytopenic purpura. N Engl J Med 2002:346:995.
    [3]Wang T, Zhao H, Ren H, Guo J, Xu M, Yang Ret al.:Type 1 and type 2 T-cell profiles in idiopathic thrombocytopenic purpura. Haematologica 2005;90:914.
    [4]Zhou B, Zhao H, Yang RC, Han ZC:Multi-dysfunctional pathophysiology in ITP. Crit Rev Oncol Hematol 2005:54:107.
    [5]Semple JW, Milev Y, Cosgrave D, Mody M, Hornstein A, Blanchette Vet al.:Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura:relationship to platelet phenotype and antiplatelet T-cell reactivity. Blood 1996:87:4245.
    [6]Yu J, Heck S, Patel V, Levan J, Yu Y, Bussel JBet al.:Defective circulating CD25 regulatory T cells in patients with chronic immune thrombocytopenic purpura. Blood 2008:112:1325.
    [7]Olsson B, Andersson PO, Jernas M, Jacobsson S, Carlsson B, Carlsson LMet al.:T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat Med 2003:9:1123.
    [8]Kalwak K, Gorczynska E, Wojcik D, Toporski J, Turkiewicz D, Slociak Met al.:Late-onset idiopathic thrombocytopenic purpura correlates with rapid B-cell recovery after allogeneic T-cell-depleted peripheral blood progenitor cell transplantation in children. Transplant Proc 2002:34:3374.
    [9]Stasi R, Del Poeta G, Stipa E, Evangelista ML, Trawinska MM, Cooper Net 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.
    [10]Liu B, Zhao H, Poon MC, Han Z, Gu D, Xu Met al.:Abnormality of CD4(+)CD25(+) regulatory T cells in idiopathic thrombocytopenic purpura. Eur J Haematol 2007:78:139.
    [11]周虎,杨仁池。第二代促血小板生成剂治疗特发性血小板减少性紫癜的研究进展.中华血液学杂志2010;31:4.208-211.
    [12]Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JBet al.:International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010;115:168.
    [13]Wu HJ, Bondada S:CD72, a coreceptor with both positive and negative effects on B lymphocyte development and function. J Clin Immunol 2009:29:12.
    [14]Kumanogoh A, Shikina T, Watanabe C, Takegahara N, Suzuki K, Yamamoto Met al.:Requirement for CD100-CD72 interactions in fine-tuning of B-cell antigen receptor signaling and homeostatic maintenance of the B-cell compartment. Int Immunol 2005;17:1277.
    [15]Kumanogoh A, Watanabe C, Lee I, Wang X, Shi W, Araki Het al. Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100:a novel mechanism for regulating B cell signaling. Immunity 2000:13:621.
    [16]Delaire S, Elhabazi A, Bensussan A, Boumsell L:CD100 is a leukocyte semaphorin. Cell Mol Life Sci 1998;54:1265.
    [17]Bougeret C, Mansur IG, Dastot H, Schmid M, Mahouy G, Bensussan Aet al.:Increased surface expression of a newly identified 150-kDa dimer early after human T lymphocyte activation. J Immunol 1992;148:318.
    [18]Pan C, Baumgarth N, Parnes JR:CD72-deficient mice reveal nonredundant roles of CD72 in B cell development and activation. Immunity 1999:11:495.
    [19]Shi W, Kumanogoh A, Watanabe C, Uchida J, Wang X, Yasui Tet al.:The class IV semaphorin CD100 plays nonredundant roles in the immune system:defective B and T cell activation in CD1OO-deficient mice. Immunity 2000;13:633.
    [20]Kaneko U, Toyabe S, Hara M, Uchiyama M:Increased mutations of CD72 transcript in B-lymphocytes from adolescent patients with systemic lupus erythematosus. Pediatr Allergy Immunol 2006:17:565.
    [21]Nakano S, Morimoto S, Suzuki J, Mitsuo A, Nakiri Y, Katagiri Aet al. Down-regulation of CD72 and increased surface IgG on B cells in patients with lupus nephritis. Autoimmunity 2007;40:9.
    [22]Smith AJ, Gordon TP, Macardle PJ:Increased expression of the B-cell-regulatory molecule CD72 in primary Sjogren's syndrome. Tissue Antigens 2004:63:255.
    [23]Xu J, Lu S, Tao J, Zhou Z, Chen Z, Huang Yet al.:CD72 polymorphism associated with child-onset of idiopathic thrombocytopenic purpura in Chinese patients. J Clin Immunol 2008;28:214.
    [24]Venkataraman C, Muthusamy N, Muthukkumar S, Bondada S:Activation of lyn, blk, and btk but not syk in CD72-stimulated B lymphocytes. J Immunol 1998:160:3322.
    [25]Venkataraman C, Lu PJ, Buhl AM, Chen CS, Cambier JC, Bondada S: CD72-mediated B cell activation involves recruitment of CD19 and activation of phosphatidylinositol 3-kinase. Eur J Immunol 1998:28:3003.
    [26]Subbarao B, Mosier DE:Induction of B lymphocyte proliferation by monoclonal anti-Lyb 2 antibody. J Immunol 1983:130:2033.
    [27]Subbarao B, Mosier DE:Activation of B lymphocytes by monovalent anti-Lyb-2 antibodies. J Exp Med 1984:159:1796.
    [28]Kumanogoh A, Kikutani H:The CD100-CD72 interaction:a novel mechanism of immune regulation. Trends Immunol 2001:22:670.
    [29]Hall KT, Boumsell L, Schultze JL, Boussiotis VA, Dorfman DM, Cardoso AAet al.:Human CD100, a novel leukocyte semaphorin that promotes B-cell aggregation and differentiation. Proc Natl Acad Sci USA 1996:93:11780.
    [30]Ishida I, Kumanogoh A, Suzuki K, Akahani S, Noda K, Kikutani H: Involvement of CD100, a lymphocyte semaphorin, in the activation of the human immune system via CD72:implications for the regulation of immune and inflammatory responses. Int Immunol 2003;15:1027.
    [31]Kumanogoh A, Suzuki K, Ch'ng E, Watanabe C, Marukawa S, Takegahara Net al.:Requirement for the lymphocyte semaphorin, CD100, in the induction of antigen-specific T cells and the maturation of dendritic cells. J Immunol 2002:169:1175.
    [32]Webber NP, Mascarenhas JO, Crow MK, Bussel J, Schattner EJ:Functional properties of lymphocytes in idiopathic thrombocytopenic purpura. Hum Immunol 2001:62:1346.
    [33]Andersson PO, Stockelberg D, Jacobsson S, Wadenvik H:A transforming growth factor-beta1-mediated bystander immune suppression could be associated with remission of chronic idiopathic thrombocytopenic purpura. Ann Hematol 2000;79:507.
    [34]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.
    [35]Panitsas FP, Theodoropoulou M, Kouraklis A, Karakantza M, Theodorou GL, Zoumbos NCet al.:Adult chronic idiopathic thrombocytopenic purpura (ITP) is the manifestation of a type-1 polarized immune response. Blood 2004;103:2645.
    [36]Kuwana M, Okazaki Y, Kaburaki J, Kawakami Y, Ikeda Y:Spleen is a primary site for activation of platelet-reactive T and B cells in patients with immune thrombocytopenic purpura. J Immunol 2002;168:3675.
    [37]Xiao C, Rajewsky K:MicroRNA control in the immune system:basic principles. Cell 2009;136:26.
    [38]Dai Y, Huang YS, Tang M, Lv TY, Hu CX, Tan YHet al.:Microarray analysis of microRNA expression in peripheral blood cells of systemic lupus erythematosus patients. Lupus 2007;16:939.
    [39]Wu KH, Peng CT, Li TC, Wan L, Tsai CH, Lan SJet al.:Interleukin 4, interleukin 6 and interleukin 10 polymorphisms in children with acute and chronic immune thrombocytopenic purpura. Br J Haematol 2005:128:849.
    [40]Zhao H, Du W, Wang D, Gu D, Xue F, Ge Jet al.:The expression of IFN-gamma, IL-4, Foxp3 and perforin genes are not correlated with DNA methylation status in patients with immune thrombocytopenic purpura. Platelets 2010;21:137.
    [41]Ogawara H, Handa H, Morita K, Hayakawa M, Kojima J, Amagai Het al. High Th1/Th2 ratio in patients with chronic idiopathic thrombocytopenic purpura. Eur J Haematol 2003:71:283.
    [42]Parnes JR, Pan C:CD72, a negative regulator of B-cell responsiveness. Immunol Rev 2000;176:75.
    [43]Alcon VL, Luther C, Balce D, Takei F:B-cell co-receptor CD72 is expressed on NK cells and inhibits IFN-gamma production but not cytotoxicity. Eur J Immunol 2009;39:826.
    [1]Nugent D, McMillan R, Nichol JL, Slichter SJ:Pathogenesis of chronic immune thrombocytopenia:increased platelet destruction and/or decreased platelet production. Br J Haematol 2009;146:585.
    [2]Neylon AJ, Saunders PW, Howard MR, Proctor SJ, Taylor PR:Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults:a prospective study of a population-based cohort of 245 patients. Br J Haematol 2003;122:966.
    [3]Segal JB, Powe NR:Prevalence of immune thrombocytopenia:analyses of administrative data. J Thromb Haemost 2006;4:2377.
    [4]Stasi R, Evangelista ML, Stipa E, Buccisano F, Venditti A, Amadori S:Idiopathic thrombocytopenic purpura:current concepts in pathophysiology and management. Thromb Haemost 2008;99:4.
    [5]Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A:Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood 2001:97:2549.
    [6]Vianelli N, Valdre L, Fiacchini M, de Vivo A, Gugliotta L, Catani Let al.:Long-term follow-up of idiopathic thrombocytopenic purpura in 310 patients. Haematologica 2001;86:504.
    [7]Cortelazzo S, Finazzi G, Buelli M, Molteni A, Viero P, Barbui T:High risk of severe bleeding in aged patients with chronic idiopathic thrombocytopenic purpura. Blood 1991;77:31.
    [8]Linares M, Cervero A, Colomina P, Pastor E, Lopez A, Perez Aet al. Chronic idiopathic thrombocytopenic purpura in the elderly. Acta Haematol 1995;93:80.
    [9]Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JBet al.:International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010;115:168.
    [10]Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DMet al.:Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 2009;113:2386.
    [11]George JN, el-Harake MA, Raskob GE:Chronic idiopathic thrombocytopenic purpura. N Engl J Med 1994;331:1207.
    [12]Karpatkin S:Autoimmune (idiopathic) thrombocytopenic purpura. Lancet 1997:349:1531.
    [13]Pamuk GE, Pamuk ON, Baslar Z, Ongoren S, Soysal T, Ferhanoglu Bet al. Overview of 321 patients with idiopathic thrombocytopenic purpura. Retrospective analysis of the clinical features and response to therapy. Ann Hematol 2002;81:436.
    [14]Pizzuto J, Ambriz R:Therapeutic experience on 934 adults with idiopathic thrombocytopenic purpura:Multicentric Trial of the Cooperative Latin American group on Hemostasis and Thrombosis. Blood 1984:64:1179.
    [15]Godeau B, Chevret S, Varet B, Lefrere F, Zini JM, Bassompierre Fet al.:Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura:a randomised, multicentre trial. Lancet 2002:359:23.
    [16]Kaufman DW, Kelly JP, Johannes CB, Sandler A, Harmon D, Stolley PDet al.:Acute thrombocytopenic purpura in relation to the use of drugs. Blood 1993:82:2714.
    [17]McMillan R, Durette C:Long-term outcomes in adults with chronic ITP after splenectomy failure. Blood 2004:104:956.
    [18]Feudjo-Tepie MA, Le Roux G, Beach KJ, Bennett D, Robinson NJ: Comorbidities of idiopathic thrombocytopenic purpura:a population-based study. Adv Hematol 2009;2009:963506.
    [19]Rodeghiero F, Besalduch J, Michel M, Provan D, Grotzinger K, Thompson G:Treatment practices in adults with chronic immune thrombocytopenia a European perspective. Eur J Haematol 2010;84:160.
    [20]Pang W, Li Z, Sun Z, Zheng L, Zhang X, Xu Cet al.:Prevalence of hypertension and associated factors among older rural adults:results from Liaoning Province, China. Med Princ Pract 2010;19:22.
    [21]Wang Y, Mi J, Shan XY, Wang QJ, Ge KY:Is China facing an obesity epidemic and the consequences? The trends in obesity and chronic disease in China. Int J Obes (Lond) 2007;31:177.
    [22]George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJet al.:Idiopathic thrombocytopenic purpura:a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996:88:3.
    [23]Watson-Williams EJ, Macpherson AI, Davidson S:The treatment of idiopathic thrombocytopenic purpura; a review of ninety-three cases. Lancet 1958;2:221.
    [24]Jiji RM, Firozvi T, Spurling CL:Chronic idiopathic thrombocytopenic purpura. Treatment with steroids and splenectomy. Arch Intern Med 1973:132:380.
    [1]Yu HH, Kolodkin AL:Semaphorin signaling:a little less per-plexin. Neuron 1999;22:11.
    [2]Pasterkamp RJ, Kolodkin AL:Semaphorin junction:making tracks toward neural connectivity. Curr Opin Neurobiol 2003;13:79.
    [3]Unified nomenclature for the semaphorins/collapsins. Semaphorin Nomenclature Committee. Cell 1999;97:551.
    [4]Tessier-Lavigne M, Goodman CS:The molecular biology of axon guidance. Science 1996;274:1123.
    [5]Kitsukawa T, Shimono A, Kawakami A, Kondoh H, Fujisawa H: Overexpression of a membrane protein, neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs. Development 1995:121:4309.
    [6]Behar 0, Golden JA, Mashimo H, Schoen FJ, Fishman MC:Semaphorin III is needed for normal patterning and growth of nerves, bones and heart. Nature 1996:383:525.
    [7]Sekido Y, Bader S, Latif F, Chen JY, Duh FM, Wei MHet al.:Human semaphorins A(V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns. Proc Natl Acad Sci U S A 1996:93:4120.
    [8]Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M:Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998:92:735.
    [9]Kumanogoh A, Kikutani H:Immune semaphorins:a new area of semaphorin research. J Cell Sci 2003:116:3463.
    [10]Kumanogoh A, Kikutani H:Roles of the semaphorin family in immune regulation. Adv Immunol 2003;81:173.
    [11]Delaire S, Elhabazi A, Bensussan A, Boumsell L:CD100 is a leukocyte semaphorin. Cell Mol Life Sci 1998;54:1265.
    [12]Kumanogoh A, Kikutani H:The CD100-CD72 interaction:a novel mechanism of immune regulation. Trends Immunol 2001;22:670.
    [13]Kikutani H, Kumanogoh A:Semaphorins in interactions between T cells and antigen-presenting cells. Nat Rev Immunol 2003;3:159.
    [14]Bougeret C, Mansur IG, Dastot H, Schmid M, Mahouy G, Bensussan Aet al.:Increased surface expression of a newly identified 150-kDa dimer early after human T lymphocyte activation. J Immunol 1992;148:318.
    [15]Furuyama T, Inagaki S, Kosugi A, Noda S, Saitoh S, Ogata Met al. Identification of a novel transmembrane semaphorin expressed on lymphocytes. J Biol Chem 1996;271:33376.
    [16]Hall KT, Boumsell L, Schultze JL, Boussiotis VA, Dorfman DM, Cardoso AAet al.:Human CD100, a novel leukocyte semaphorin that promotes B-cell aggregation and differentiation. Proc Natl Acad Sci USA 1996:93:11780.
    [17]Love CA, Harlos K, Mavaddat N, Davis SJ, Stuart DI, Jones EYet al. The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D. Nat Struct Biol 2003:10:843.
    [18]Esnouf RM, Love CA, Harlos K, Stuart DI, Jones EY:Structure determination of human semaphorin 4D as an example of the use of MAD in non-optimal cases. Acta Crystallogr D Biol Crystallogr 2006:62:108.
    [19]Chapoval SP, Smith E, Beasley K, DeTolla LJ, AD K:Semaphorin 4A downregulates allergic airway inflammation. Int Immunol 2010;22:v17.
    [20]Elhabazi A, Delaire S, Bensussan A, Boumsell L, Bismuth G:Biological activity of soluble CD100. I. The extracellular region of CD100 is released from the surface of T lymphocytes by regulated proteolysis. J Immunol 2001:166:4341.
    [21]Delaire S, Billard C, Tordjman R, Chedotal A, Elhabazi A, Bensussan Aet al.:Biological activity of soluble CD100. II. Soluble CD100, similarly to H-SemaIII, inhibits immune cell migration. J Immunol 2001:166:4348.
    [22]Wang X, Kumanogoh A, Watanabe C, Shi W, Yoshida K, Kikutani H: Functional soluble CD100/Sema4D released from activated lymphocytes: possible role in normal and pathologic immune responses. Blood 2001:97:3498.
    [23]Kumanogoh A, Kikutani H:Semaphorins and their receptors:novel features of neural guidance molecules. Proc Jpn Acad Ser B Phys Biol Sci 2010:86:611.
    [24]Suzuki K, Kumanogoh A, Kikutani H:Semaphorins and their receptors in immune cell interactions. Nat Immunol 2008;9:17.
    [25]Kumanogoh A, Suzuki K, Ch'ng E, Watanabe C, Marukawa S, Takegahara Net al.:Requirement for the lymphocyte semaphorin, CD100, in the induction of antigen-specific T cells and the maturation of dendritic cells. J Immunol 2002;169:1175.
    [26]Chabbert-de Ponnat I, Marie-Cardine A, Pasterkamp RJ, Schiavon V, Tamagnone L, Thomasset Net al.:Soluble CD100 functions on human monocytes and immature dendritic cells require plexin Cl and plexin B1, respectively. Int Immunol 2005;17:439.
    [27]He Z, Tessier-Lavigne M:Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell 1997;90:739.
    [28]Kolodkin AL, Levengood DV, Rowe EG, Tai YT, Giger RJ, Ginty DD: Neuropilin is a semaphorin III receptor. Cell 1997;90:753.
    [29]Winberg ML, Noordermeer JN, Tamagnone L, Comoglio PM, Spriggs MK, Tessier-Lavigne Met al.:Plexin A is a neuronal semaphorin receptor that controls axon guidance. Cell 1998;95:903.
    [30]Takahashi T, Fournier A, Nakamura F, Wang LH, Murakami Y, Kalb RGet al.:Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors. Cell 1999;99:59.
    [31]Tamagnone L, Artigiani S, Chen H, He Z, Ming GI, Song Het al.:Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 1999;99:71.
    [32]Maestrini E, Tamagnone L, Longati P, Cremona 0, Gulisano M, Bione Set al.:A family of transmembrane proteins with homology to the MET-hepatocyte growth factor receptor. Proc Natl Acad Sci USA 1996:93:674.
    [33]Moreau-Fauvarque C, Kumanogoh A, Camand E, Jaillard C, Barbin G, Boquet let al.:The transmembrane semaphorin Sema4D/CD100, an inhibitor of axonal growth, is expressed on oligodendrocytes and upregulated after CNS lesion. J Neurosci 2003;23:9229.
    [34]Kane LP:TIM family proteins and autoimmunity. Autoimmunity 2007;40:405.
    [35]Artigiani S, Barberis D, Fazzari P, Longati P, Angelini P, van de Loo JWet al.:Functional regulation of semaphorin receptors by proprotein convertases. J Biol Chem 2003;278:10094.
    [36]Nkyimbeng-Takwi E, Chapoval SP:Biology and function of neuroimmune semaphorins 4A and 4D. Immunol Res 2011;50:10.
    [37]Fazzari P, Penachioni J, Gianola S, Rossi F, Eickholt BJ, Maina Fet al.:Plexin-Bl plays a redundant role during mouse development and in tumour angiogenesis. BMC Dev Biol 2007;7:55.
    [38]Basile JR, Barac A, Zhu T, Guan KL, Gutkind JS:Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res 2004;64:5212.
    [39]Granziero L, Circosta P, Scielzo C, Frisaldi E, Stella S, Geuna Met al.:CD1OO/Plexin-Bl interactions sustain proliferation and survival of normal and leukemic CD5+B lymphocytes. Blood 2003;101:1962.
    [40]Parnes JR, Pan C:CD72, a negative regulator of B-cell responsiveness. Immunol Rev 2000;176:75.
    [41]Adachi T, Wakabayashi C, Nakayama T, Yakura H, Tsubata T:CD72 negatively regulates signaling through the antigen receptor of B cells. J Immunol 2000;164:1223.
    [42]Kumanogoh A, Watanabe C, Lee I, Wang X, Shi W, Araki Het al. Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100:a novel mechanism for regulating B cell signaling. Immunity 2000;13:621.
    [43]Robinson WH, Landolfi MM, Schafer H, Parnes JR:Biochemical identity of the mouse Ly-19.2 and Ly-32.2 alloantigens with the B cell differentiation antigen Lyb-2/CD72. J Immunol 1993:151:4764.
    [44]Ishida I, Kumanogoh A, Suzuki K, Akahani S, Noda K, Kikutani H: Involvement of CD100, a lymphocyte semaphorin, in the activation of the human immune system via CD72:implications for the regulation of immune and inflammatory responses. Int Immunol 2003;15:1027.
    [45]Wu HJ, Venkataraman C, Estus S, Dong C, Davis RJ, Flavell RAet al. Positive signaling through CD72 induces mitogen-activated protein kinase activation and synergizes with B cell receptor signals to induce X-linked immunodeficiency B cell proliferation. J Immunol 2001:167:1263.
    [46]Ogimoto M, Ichinowatari G, Watanabe N, Tada N, Mizuno K, Yakura H: Impairment of B cell receptor-mediated Ca2+influx, activation of mitogen-activated protein kinases and growth inhibition in CD72-deficient BAL-17 cells. Int Immunol 2004:16:971.
    [47]Fusaki N, Tomita S, Wu Y, Okamoto N, Goitsuka R, Kitamura Det al. BLNK is associated with the CD72/SHP-1/Grb2 complex in the WEHI231 cell line after membrane IgM cross-linking. Eur J Immunol 2000:30:1326.
    [48]Kumanogoh A, Marukawa S, Suzuki K, Takegahara N, Watanabe C, Ch'ng Eet al.:Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature 2002:419:629.
    [49]Puschel AW, Adams RH, Betz H:Murine semaphorin D/collapsin is a member of a diverse gene family and creates domains inhibitory for axonal extension. Neuron 1995:14:941.
    [50]Toyofuku T, Yabuki M, Kamei J, Kamei M, Makino N, Kumanogoh Aet al. Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via Plexin-Dl. EMBO J 2007:26:1373.
    [51]Chakravarti S, Sabatos CA, Xiao S, Illes Z, Cha EK, Sobel RAet al. Tim-2 regulates T helper type 2 responses and autoimmunity. J Exp Med 2005:202:437.
    [52]Knickelbein JE, de Souza AJ, Tosti R, Narayan P, Kane LP:Cutting edge: inhibition of T cell activation by TIM-2. J Immunol 2006:177:4966.
    [53]van der Zwaag B, Hellemons AJ, Leenders WP, Burbach JP, Brunner HG, Padberg GWet al.:PLEXIN-D1, a novel plexin family member, is expressed in vascular endothelium and the central nervous system during mouse embryogenesis. Dev Dyn 2002;225:336.
    [54]Yukawa K, Tanaka T, Yoshida K, Takeuchi N, Ito T, Takamatsu Het al. Sema4A induces cell morphological changes through B-type plexin-mediated signaling. Int J Mol Med 2010:25:225.
    [55]Roodink I, Verrijp K, Raats J, Leenders WP:Plexin Dl is ubiquitously-expressed on tumor vessels and tumor cells in solid malignancies. BMC Cancer 2009;9:297.
    [56]Tong Y, Hota PK, Penachioni JY, Hamaneh MB, Kim S, Alviani RSet al. Structure and function of the intracellular region of the plexin-b1 transmembrane receptor. J Biol Chem 2009;284:35962.
    [57]Santiago C, Ballesteros A, Tami C, Martinez-Munoz L, Kaplan GG, Casasnovas JM:Structures of T Cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family. Immunity 2007;26:299.
    [58]Kuchroo VK, Dardalhon V, Xiao S, Anderson AC:New roles for TIM family members in immune regulation. Nat Rev Immunol 2008;8:577.
    [59]Chen TT, Li L, Chung DH, Allen CD, Torti SV, Torti FMet al.:TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis. J Exp Med 2005;202:955.
    [60]Bismuth G, Boumsell L:Controlling the immune system through semaphorins. Sci STKE 2002;2002:re4.
    [61]Shi W, Kumanogoh A, Watanabe C, Uchida J, Wang X, Yasui Tet al.:The class IV semaphorin CD100 plays nonredundant roles in the immune system:defective B and T cell activation in CD1OO-deficient mice. Immunity 2000;13:633.
    [62]Herold C, Elhabazi A, Bismuth G, Bensussan A, Boumsell L:CD100 is associated with CD45 at the surface of human T lymphocytes. Role in T cell homotypic adhesion. J Immunol 1996;157:5262.
    [63]Yu HH, Araj HH, Ralls SA, Kolodkin AL:The transmembrane Semaphorin Sema I is required in Drosophila for embryonic motor and CNS axon guidance. Neuron 1998;20:207.
    [64]Conrotto P, Valdembri D, Corso S, Serini G, Tamagnone L, Comoglio PMet al.:Sema4D induces angiogenesis through Met recruitment by Plexin Bl. Blood 2005:105:4321.
    [65]Gu C, YoshidaY, Livet J, Reimert DV, Mann F, Merte Jet al.:Semaphorin 3E and plexin-Dl control vascular pattern independently of neuropilins. Science 2005;307:265.
    [66]Elhabazi A, Lang V, Herold C, Freeman GJ, Bensussan A, Boumsell Let al.:The human semaphorin-like leukocyte cell surface molecule CD1OO associates with a serine kinase activity. J Biol Chem 1997:272:23515.
    [67]Chapoval SP, David CS:Identification of antigenic epitopes on human allergens:studies with HLA transgenic mice. Environ Health Perspect 2003:111:245.
    [68]Horny HP, Sotlar K, Valent P:Mastocytosis:state of the art. Pathobiology 2007:74:121.
    [69]Li L, Yao Z:Mast cell and immune inhibitory receptors. Cell Mol Immunol 2004;1:408.
    [70]Unkeless JC, Jin J:Inhibitory receptors, ITIM sequences and phosphatases. Curr Opin Immunol 1997:9:338.
    [71]Kataoka TR, Kumanogoh A, Bandara G, Metcalfe DD, Gilfillan AM:CD72 negatively regulates KIT-mediated responses in human mast cells. J Immunol 2010:184:2468.
    [72]Sierra JR, Corso S, Caione L, Cepero V, Conrotto P, Cignetti Aet al. Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. J Exp Med 2008:205:1673.
    [73]Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G, Barberis Det al.:The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat Cell Biol 2002;4:720.
    [74]Basile JR, Castilho RM, Williams VP, Gutkind JS:Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis. Proc Natl Acad Sci U S A 2006:103:9017.
    [75]Dorfman DM, Shahsafaei A, Nadler LM, Freeman GJ:The leukocyte semaphorin CD100 is expressed in most T-cell, but few B-cell, non-Hodgkin's lymphomas. Am J Pathol 1998:153:255.
    [76]Okuno T, Nakatsuji Y, Moriya M, Takamatsu H, Nojima S, Takegahara Net al.:Roles of Sema4D-plexin-Bl interactions in the central nervous system for pathogenesis of experimental autoimmune encephalomyelitis. J Immunol 2010:184:1499.
    [77]Blauwet LA, Cooper LT:Myocarditis. Prog Cardiovasc Dis 2010:52:274.
    [78]Makino N, Toyofuku T, Takegahara N, Takamatsu H, Okuno T, Nakagawa Yet al.:Involvement of Sema4A in the progression of experimental autoimmune myocarditis. FEBS Lett 2008;582:3935.
    [79]Moreno PR, Purushothaman KR, Sirol M, Levy AP, Fuster V: Neovascularization in human atherosclerosis. Circulation 2006:113:2245.
    [80]Yukawa K, Tanaka T, Kishino M, Yoshida K, Takeuchi N, Ito Tet al. Deletion of Sema4D gene reduces intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Int J Mol Med 2010:26:39.
    [81]Celletti FL, Waugh JM, Amabile PG, Brendolan A, Hilfiker PR, Dake MD: Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med 2001:7:425.
    [82]Zhu L, Bergmeier W, Wu J, Jiang H, Stalker TJ, Cieslak Met al. Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury. Proc Natl Acad Sci U S A 2007;104:1621.
    [83]Zhu L, Stalker TJ, Fong KP, Jiang H, Tran A, Crichton let al. Disruption of SEMA4D ameliorates platelet hypersensitivity in dyslipidemia and confers protection against the development of atherosclerosis. Arterioscler Thromb Vasc Biol 2009:29:1039.
    [84]Li M, O'Sullivan KM, Jones LK, Lo C, Semple T, Kumanogoh Aet al. Endogenous CD100 promotes glomerular injury and macrophage recruitment in experimental crescentic glomerulonephritis. Immunology 2009;128:114.
    [85]Li M, O'Sullivan KM, Jones LK, Semple T, Kumanogoh A, Kikutani Het al.:CD100 enhances dendritic cell and CD4+ cell activation leading to pathogenetic humoral responses and immune complex glomerulonephritis. J Immunol 2006;177:3406.
    [86]Reinhardt RL, Bullard DC, Weaver CT, Jenkins MK:Preferential accumulation of antigen-specific effector CD4 T cells at an antigen injection site involves CD62E-dependent migration but not local proliferation. J Exp Med 2003;197:751.
    [87]Kumanogoh A, Shikina T, Suzuki K, Uematsu S, Yukawa K, Kashiwamura Set al.:Nonredundant roles of Sema4A in the immune system:defective T cell priming and Thl/Th2 regulation in Sema4A-deficient mice. Immunity 2005;22:305.
    [88]Izmailova E, Bertley FM, Huang Q, Makori N, Miller CJ, Young RAet al. HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages. Nat Med 2003;9:191.