甲状腺细胞因子.doc

细胞因子，Graves氏病以及甲状腺相关性眼病G氏病是与甲状腺功能失调相关的一种自动免疫相关过程，也可视为正常结缔组织的改变。病变组织产生免疫反应表现为机体细胞及骨髓来源细胞其细胞因子的产生释放及其细胞因子表面受体的表达。细胞因子是一种小分子，产生于多种细胞，也包括那些特殊免疫系统。异常细胞因子的表达在许多人类疾病病理过程中有重要作用，这也包括甲状腺自身免疫病。在甲状腺中细胞因子失衡的表达模式，辅助性T细胞的偏差，为凋亡信号创造条件，决定自身免疫反应的特征。再者，具有趋化性质的细胞因子，包括IL16，RANES，和CXCL10,在甲状腺和眼眶组织细胞编码，可能引起单核细胞过滤。其他因子可促细胞活化和组织改变。因此，细胞因子及其激活的信号通路呈现了可观的信号靶点。这些干预可能改变细胞G氏病的自然病程和它的眼部表现。引文G氏病是甲亢最常见原因，是一种受体介导的自身免疫病。它是一种在眼眶部的炎性过程，称为甲状腺相关性眼病。在G病中，甲状腺和眼眶组织中被证明有几种常见的细胞因子量异常。细胞因子是小分子，由多种细胞合成，在集体健康和疾病中发挥重要作用。部分细胞因子表达为膜结合蛋白，其他的为可溶性分子经释放捕获邻近细胞表面高亲和力受体。他们如同精细的网络般发挥作用，许多不同分子介质的作用总和表现了组织对疾病反应最终达到平衡的结果。这些细胞因子的集合看起来界定了特殊器官免疫反应的性质。细胞因子在炎性反应中的核心作用表明，细胞因子，细胞因子受体和他们使用的信号转导途径，都是甲状腺自身免疫性疾病可观的潜在作用靶点。G氏病中，甲状腺组织增生肥大并且伴有B和T淋巴细胞的浸润。CD4细胞为主，伴有未成熟B细胞生发中心的形成。甲状腺内淋巴细胞分泌细胞因子如白介素4，5，10，13，都辅助抗体介导的免疫反应。这种细胞因子环境可能成因于组织细胞和腺体招募的细胞包括T细胞，这些组织细胞有甲状腺细胞，内皮细胞，成纤维细胞。我们假定上皮组织和其他甲状腺组织在G氏病中对于炎性应的类型和组织重塑发挥重要的作用。组织重塑关键的一方面是凋亡的过程。G氏病人的甲状腺细胞表达Fas和FasL。桥本氏甲状腺炎和其他破坏程序中发现，甲状腺组织中的细胞因子可能有助于增强调亡的敏感性。相反，G氏病中相关的凋亡抵抗可能通过表达另一种的不同的细胞模式进行调节。桥本氏甲状腺炎中Th1细胞分泌的细胞因子占主导，如干扰素，IL2和肿瘤坏死因子，辅助细胞性免疫。这些因子通过引入一种称为caspase的酶来推进Fas介导的凋亡。相反，在甲状腺免疫性疾病中，浸润的淋巴细胞表达Fas,甲状腺，甲状腺内巨噬细胞和树突状细胞通过表达FasL促进凋亡。（图1细胞因子介导的细胞见相互作用：体细胞是通过产生释放具有趋化作用的细胞因子来招募这些专职的免疫系统。这些细胞浸润靶组织组成细胞因子环境。细胞因子的概况取决于招募的T细胞亚型。细胞因子的活动主要受结合同源受体调节。自身抗体也能通过结合细胞表面受体包括TSHR和IGF-1R来捕获激活细胞。PGE2和透明质酸的产生由炎性细胞因子激活。）Th2细胞型细胞因子通过上调抗凋亡蛋白保护甲状腺。因此，虽然细胞因子在凋亡中的作用复杂不能完全了解，是我在G氏病和桥本氏甲状腺炎中，细胞因子的分布可以解释这两种不同临床表现的原因。我们怀疑甲状腺通过产生细胞因子和发生相应反应来参与免疫反应。这和ANTES代表具有T淋巴细胞趋化效力的分子，它们由甲状腺产生可能是甲状腺疾病中淋巴细胞非正常运输的重要基础。甲状腺，眼眶成纤维细胞，脂肪细胞在INF的作用下，分泌CXCL10。CXCR3的同源受体在淋巴细胞和内皮细胞上高表达，表明另一种机制关于在G氏病中，可能通过CXCL10招募淋巴细胞到甲状腺和眼眶的发生机制。血清CXCL10的水平在病人中上升。在近来的G氏病中这尤为高。甲状腺和浸润淋巴细胞的交叉可能通过许多信号途径发生。起主导作用的是CD40和它的同源配体CD154。CD40是干扰素受体超家族的成员，最初发现于B细胞，作用于淋巴细胞的激活。G氏病中，甲状腺细胞内CD40水平的升高，而且参与细胞发育中表现为引导IL6的产生。CD40基因的但核苷酸多态性与G氏病的敏感性相关。这种SNP提升了CD40mRNA的转入效率，适度增加了B细胞表面蛋白的表达。细胞的激活阈值可能因此下降。细胞因子可能调节甲状腺上皮细胞的生产和功能。IL1，TNF表现为依赖碘125摄取的促甲状腺激素和甲状腺素在人为培养的甲状腺细胞中的释放。这些细胞因子的效应是可协同和可逆的。杰拉德等人证明了这样的甲状腺治疗，辅助性T细胞1的细胞因子联合IL1和INF可以导致甲状腺过氧化物的蛋白和mRNA的表达。TPO是一种重要的甲状腺酶负责碘的有机化，这是甲状腺形成的第一步。细胞因子的效应还在其他甲状腺的重要功能上表现，例如钠钾转运体的表达，甲状腺球蛋白的产生，cAMP的产生都有报道。另外，IL1通过甲状腺上皮细胞和成纤维细胞，诱发透明质酸的产生，这个过程可能有助于G氏病中的甲状腺肿。这可能是甲状腺分子介质的内环境，细胞因子和抗甲状腺抗体调节甲状腺功能和甲状腺肿的形成。再者，干扰素提高了一类和二类组织相容性抗原的在甲状腺细胞的表达，潜在地增强了抗原的提呈。另外，HLA-DR3，二类分子阻止了高亲和力结合TSH受体的多肽。HLA-DR3和TSH受体的结合，可以改变TSH受体的表达，和其表位在免疫系统的呈递。细胞因子的全身性施用会导致甲状腺功能失调。干扰素，用于肝炎的治疗中能导致甲状腺功能低下。然而，它也可引发甲状腺功能亢进和刺激甲状腺产生免疫球蛋白。患者在干扰素治疗下开展探测性TSI极少显示有临床性甲状腺相关性眼病。甲状腺功能失调容易发生在先前有抗甲状腺过氧化物抗体的患者上，而且通常不可逆。IL2的施用也可能导致甲状腺功能低下，可能是通过淋巴细胞的激活和细胞因子的二次释放。可能令人惊讶的是，干扰素治疗在甲状腺子身性免疫疾病中不能达到最好的疗效。全身性的细胞因子扰乱甲状腺功能的这个机制还未被证明清楚，但它可能跟直接作用于碘有机化有关。或者，它们可能增加自身抗体的生成。细胞因子在甲状腺相关性眼病的病理过程中的作用 甲状腺相关性眼病中，眼眶结缔组织的的改变成因于细胞因子依赖的成纤维细胞的激活。发现甲状腺相关性眼病的病理组织学中一个重要的特征是糖胺聚糖的积累，包括透明质酸。免疫细胞如TB淋巴细胞和肥大细胞，浸润的结缔组织和外周肌肉迫使组织改变。T细胞表型主导反应时相仍存争议。受累组织中细胞因子丰富尚未成为充分的特征，但干扰素，IL1,肿瘤坏死因子可被检测是其特征。mRNA编码的肿瘤坏死因子，IL1，INF，IL4,IL6,IL10也能在肌肉和眶脂肪中被检测。在疾病过程中，这些相关的细胞因子被表明有增多，但不能令人信服的证明。来自眶组织的成纤维细胞对几种细胞因子有反应。成纤维细胞于眶解剖位置上有选择性的参与炎性反应，是基于至少部分基于眶成纤维细胞对炎性分子的敏感性。在IL1或白细胞介素，T细胞起源的细胞因子作用下，眼眶的成纤维细胞上调表达前列腺素过氧化物H合酶，而后导致前列腺素的产生增加。然而细胞因子调节提高PGHS2基因的转录，它们实际上更增强了PGHS2mRNA的稳定性。IL1诱发PGE2产生被干扰素和IL4阻止。这些令人惊讶的结果表明在甲状腺肿相关性眼病的发展过程中，尽管从活动期到慢性期由TH1到TH2主导，但均受细胞因子对其的调节。PGE2在免疫中的影响目前尚在讨论，但是总的偏向于前列腺素使未成熟的T细胞向TH2表型方向发展而非TH1型。这些可能使得细胞因子的合成从受干扰素调节到受IL4，5，13调节。PGE2也影响B细胞和肥大细胞的发育。TH1来源的细胞因子引导TAO的活动期，而TH2可能引导其慢性期或后期。更有甚者，夏等人发现了TH1的主导作用与临床活动期评分的关联。象甲状腺细胞一样，眼眶成纤维细胞高表达CD40。这种受体表达在细胞表面，靠干扰素调节其水平。当CD40与同源配体结合是，信号转导通路被激活，导致下游专属基因的上调，包括IL6,IL8.PGHS2和透明质酸的合成。依赖于CD40-CD154的信号G氏病人的眼眶成纤维细胞增殖。CD40-CD154成为治疗许多疾病的核心。对它们的干预可能呈递了对一些慢性疾病的治疗靶点如类风湿性关节炎。最近发现，成纤维细胞如甲状腺细胞一样，在细胞因子象IL1的激活下，表达高水平的具有T细胞趋化作用的IL16和RANTES在随后的研究中，G氏病人分离的IgG尤为诱导成纤维细胞高水平表达IL6和RANTES。基于这些研究结果。成纤维细胞可能是T细胞来源的细胞因子表达的关键点，而GD-IgG可能作用于成纤维细胞引发T细胞非正常运送到受累组织。最近的观察表明自身抗原可以被GD-IgG识别。Pritchard和他的同事发现这些IgG结合一种胰岛素样生长因子受体，导致成纤维细胞的激活。因此，这表明第二种自身抗原IGF-1R可能与GD的病理过程有关。细胞因子作为一种潜在的治疗靶点GD中细胞因子在甲状腺和眼眶组织中含量提供了一条理论上的治疗探索途径，那就是干扰相关的途径可能有利。然而尽管几种细胞因子的干扰原件有效，几乎没有控制良好的充分有力的试验在进行。一种潜在的促炎因子产于巨噬细胞，肥大细胞和T淋巴细胞，可能用于阻断干扰素途径。甲状腺相关性眼病中，干扰素蛋白和mRNA在眼眶结缔组织中过表达。这种细胞因子可诱导眶成纤维细胞上细胞间黏附分子的表达。再者，尽管GD甲亢患者恢复甲状腺正常功能状态后其血清中水平然增高。干扰素基因启动子的的多样性与GD事件的增加有关。因此，捕获干扰素信号可能对GD有临床意义，尤其是对有甲状腺相关性眼病患者。三种食品和 药品监督管理局批准的肿瘤坏死因子- A抑制剂，随着治疗机制的明确，目前已经上市。这些改革了类风湿性关节炎和炎症性肠病的治疗。Paridaen等人在一个未控制的进展性试验中，检测了依那谱西在GD病人中的疗效。这种TNF抑制剂施用于十个活动期TAO的病人身上。治疗前，实验组的CAS是4，12周的抗细胞因子治疗后CAS到1.6。大部分的临床进展涉及到软组织，突眼度并无影响。总体而言，60 报告的研究对象中度至明显的改善。Durrani报道了个例接受英利昔单抗治疗出现TAO症状。没有试验中检测到干扰IL1途径带来潜在治疗益处的报道，尽管这些在TAO的发病中有重要作用。这些细胞因子在眼眶成纤维细胞和甲状腺细胞中诱发了很多反应。再者，在TAO病人的自身免疫性甲状腺和眶组织中能检测到这些细胞因子。陈等在95项GD病人与163个健康受试者的对照实验中发现IL1的基因启动子多态性与GD有关。Anakinra表示用重组IL1受体拮抗剂能成功地用于治疗类风湿关节炎的病人。因此，尽管没有现行的令人信服的证据支他们的使用，然而，捕获TNF和IL1原件将成为治疗TAO的良好考虑。小结在GD和TAO几种细胞因子的异常已被报道。尽管几乎没有现行的令人信服的证据存在证明它们在这些疾病的发生中的特殊作用。除了研究这些细胞因子间的相互作用外，还应通过在GD组织细胞和和专职免疫细胞被征集到甲状腺和眼眶中找寻到这些分子如何引发和维持疾病的答案。细胞因子及其受体仍然提供其对TAO的加剧和失明的干预治疗靶点。感谢我们感谢Debbie Hanaya协助编写手稿，这项工作受the National Institutes of Health grants RR017304, EY008976,EY011708, and DK063121的支持。参考文献1. Kim CH 2004 Chemokine-chemokine receptor network inimmune cell trafficking. Curr Drug Targets Immune EndocrMetabol Disord 4:343361.2. Gianoukakis AG, Smith TJ 2004 The role of cytokines inthe pathogenesis of endocrine disease. Canadian DiabetesJournal 28:2029.3. Tezuka H, Eguchi K, Fukuda T, Otsubo T, Kawabe Y, UekiY, Matsunaga M, Shimomura C, Nakao H, Ishikawa N, et al.1988 Natural killer and natural killer-like cell activity ofperipheral blood and intrathyroidal mononuclear cells frompatients with Graves disease. J Clin Endocrinol Metab 66:702707.4. Totterman TH, Andersson LC, Hayry P 1979 Evidence forthyroid antigen-reactive T lymphocytes infiltrating the thyroidgland in Graves disease. Clin Endocrinol (Oxf ) 11:5968.5. Stassi G, Di Liberto D, Todaro M, Zeuner A, Ricci-Vitiani L,Stoppacciaro A, Ruco L, Farina F, Zummo G, De Maria R2000 Control of target cell survival in thyroid autoimmunityby T helper cytokines via regulation of apoptotic proteins.Nat Immunol 1:483488.6. Mitsiades N, Poulaki V, Mitsiades CS, Koutras DA, ChrousosGP 2001 Apoptosis induced by FasL and TRAIL=Apo2Lin the pathogenesis of thyroid diseases. Trends EndocrinolMetab 12:384390.7. Nakamura Y, Watanabe M, Matsuzuka F, Maruoka H,Miyauchi A, Iwatani Y 2004 Intrathyroidal CD4t T lymphocytesexpress high levels of Fas and CD4t CD8t macrophages=dendritic cells express Fas ligand in autoimmunethyroid disease. Thyroid 14:819824.8. Chen S, Fazle Akbar SM, Zhen Z, Luo Y, Deng L, Huang H,Chen L, Li W 2004 Analysis of the expression of Fas, FasLand Bcl-2 in the pathogenesis of autoimmune thyroid disorders.Cell Mol Immunol 1:224228.9. Aust G, Scherbaum WA 1996 Expression of cytokines in thethyroid: thyrocytes as potential cytokine producers. Exp ClinEndocrinol Diabetes 104(Suppl 4):6467.10. Gianoukakis AG, Martino LJ, Horst N, Cruikshank WW,Smith TJ 2003 Cytokine-induced lymphocyte chemoattractionfrom cultured human thyrocytes: evidence for interleukin-16 and regulated upon activation, normal T cell expressed,and secreted expression. Endocrinology 144:28562864.11. Gianoukakis AG, Douglas RS, King CS, Cruikshank WW,Smith TJ 2006 Immunoglobulin G from patients withGraves disease induces interleukin-16 and RANTES expressionin cultured human thyrocytes: a putative mechanismfor T-cell infiltration of the thyroid in autoimmunedisease. Endocrinology 147:19411949.12. Weetman AP 2004 Cellular immune responses in autoimmunethyroid disease. Clin Endocrinol (Oxf ) 61:405413.13. Laberge S, Cruikshank WW, Kornfeld H, Center DM 1995Histamine-induced secretion of lymphocyte chemoattractantfactor from CD8t T cells is independent of transcription andtranslation. Evidence for constitutive protein synthesis andstorage. J Immunol 155:29022910.14. Schall TJ, Bacon K, Toy KJ, Goeddel DV 1990 Selectiveattraction of monocytes and T lymphocytes of the memoryphenotype by cytokine RANTES. Nature 347:669671.15. Antonelli A, Rotondi M, Ferrari SM, Fallahi P, RomagnaniP, Franceschini SS, Serio M, Ferrannini E 2006 INFgamma-inducible alpha-chemokine CXCL10 involvementin Graves ophthalmopathy: modulation by peroxisomeproliferator-activated receptor-gamma agonists. J Clin EndocrinolMetab 91:614620.16. Garcia-Lopez MA, Sancho D, Sanchez-Madrid F, MarazuelaM 2001 Thyrocytes from autoimmune thyroid disordersproduce the chemokines IP-10 and Mig and attract CXCR3tlymphocytes. J Clin Endocrinol Metab 86:50085016.17. Romagnani P, Annunziato F, Lasagni L, Lazzeri E, BeltrameC, Francalanci M, Uguccioni M, Galli G, Cosmi L, MaurenzigL, Baggiolini M, Maggi E, Romagnani S, Serio M 2001Cell cyReferences1. Kim CH 2004 Chemokine-chemokine receptor network inimmune cell trafficking. Curr Drug Targets Immune EndocrMetabol Disord 4:343361.2. Gianoukakis AG, Smith TJ 2004 The role of cytokines inthe pathogenesis of endocrine disease. Canadian DiabetesJournal 28:2029.3. Tezuka H, Eguchi K, Fukuda T, Otsubo T, Kawabe Y, UekiY, Matsunaga M, Shimomura C, Nakao H, Ishikawa N, et al.1988 Natural killer and natural killer-like cell activity ofperipheral blood and intrathyroidal mononuclear cells frompatients with Graves disease. J Clin Endocrinol Metab 66:702707.4. Totterman TH, Andersson LC, Hayry P 1979 Evidence forthyroid antigen-reactive T lymphocytes infiltrating the thyroidgland in Graves disease. Clin Endocrinol (Oxf ) 11:5968.5. Stassi G, Di Liberto D, Todaro M, Zeuner A, Ricci-Vitiani L,Stoppacciaro A, Ruco L, Farina F, Zummo G, De Maria R2000 Control of target cell survival in thyroid autoimmunityby T helper cytokines via regulation of apoptotic proteins.Nat Immunol 1:483488.6. Mitsiades N, Poulaki V, Mitsiades CS, Koutras DA, ChrousosGP 2001 Apoptosis induced by FasL and TRAIL=Apo2Lin the pathogenesis of thyroid diseases. Trends EndocrinolMetab 12:384390.7. Nakamura Y, Watanabe M, Matsuzuka F, Maruoka H,Miyauchi A, Iwatani Y 2004 Intrathyroidal CD4t T lymphocytesexpress high levels of Fas and CD4t CD8t macrophages=dendritic cells express Fas ligand in autoimmunethyroid disease. Thyroid 14:819824.8. Chen S, Fazle Akbar SM, Zhen Z, Luo Y, Deng L, Huang H,Chen L, Li W 2004 Analysis of the expression of Fas, FasLand Bcl-2 in the pathogenesis of autoimmune thyroid disorders.Cell Mol Immunol 1:224228.9. Aust G, Scherbaum WA 1996 Expression of cytokines in thethyroid: thyrocytes as potential cytokine producers. Exp ClinEndocrinol Diabetes 104(Suppl 4):6467.10. Gianoukakis AG, Martino LJ, Horst N, Cruikshank WW,Smith TJ 2003 Cytokine-induced lymphocyte chemoattractionfrom cultured human thyrocytes: evidence for interleukin-16 and regulated upon activation, normal T cell expressed,and secreted expression. Endocrinology 144:28562864.11. Gianoukakis AG, Douglas RS, King CS, Cruikshank WW,Smith TJ 2006 Immunoglobulin G from patients withGraves disease induces interleukin-16 and RANTES expressionin cultured human thyrocytes: a putative mechanismfor T-cell infiltration of the thyroid in autoimmunedisease. Endocrinology 147:19411949.12. Weetman AP 2004 Cellular immune responses in autoimmunethyroid disease. Clin Endocrinol (Oxf ) 61:405413.13. Laberge S, Cruikshank WW, Kornfeld H, Center DM 1995Histamine-induced secretion of lymphocyte chemoattractantfactor from CD8t T cells is independent of transcription andtranslation. Evidence for constitutive protein synthesis andstorage. J Immunol 155:29022910.14. Schall TJ, Bacon K, Toy KJ, Goeddel DV 1990 Selectiveattraction of monocytes and T lymphocytes of the memoryphenotype by cytokine RANTES. Nature 347:669671.15. Antonelli A, Rotondi M, Ferrari SM, Fallahi P, RomagnaniP, Franceschini SS, Serio M, Ferrannini E 2006 INFgamma-inducible alpha-chemokine CXCL10 involvementin Graves ophthalmopathy: modulation by peroxisomeproliferator-activated receptor-gamma agonists. J Clin EndocrinolMetab 91:614620.16. Garcia-Lopez MA, Sancho D, Sanchez-Madrid F, MarazuelaM 2001 Thyrocytes from autoimmune thyroid disordersproduce the chemokines IP-10 and Mig and attract CXCR3tlymphocytes. J Clin Endocrinol Metab 86:50085016.17. Romagnani P, Annunziato F, Lasagni L, Lazzeri E, BeltrameC, Francalanci M, Uguccioni M, Galli G, Cosmi L, MaurenzigL, Baggiolini M, Maggi E, Romagnani S, Serio M 2001Cell cycle-dependent expression of CXC chemokine receptor3 by endothelial cells mediates angiostatic activity. J ClinInvest 107:5363.18. Romagnani P, Rotondi M, Lazzeri E, Lasagni L, FrancalanciM, Buonamano A, Milani S, Vitti P, Chiovato L, TonaccheraM, Bellastella A, Serio M 2002 Expression of IP-10=CXCL10and MIG=CXCL9 in the thyroid and increased levels ofIP-10=CXCL10 in the serum of patients with recent-onsetGraves disease. Am J Pathol 161:195206.19. Antonelli A, Fallahi P, Rotondi M, Ferrari SM, Romagnani P,Grosso M, Ferrannini E, Serio M 2006 Increased serumCXCL10 in Graves disease or autoimmune thyroiditis is notassociated with hyper- or hypothyroidism per se, but isspecifically sustained by the autoimmune, inflammatoryprocess. Eur J Endocrinol 154:651658.20. Smith TJ, Sciaky D, Phipps RP, Jennings TA 1999 CD40 expressionin human thyroid tissue: evidence for involvementcle-dependent expression of CXC chemokine receptor3 by endothelial cells mediates angiostatic activity. J ClinInvest 107:5363.18. Romagnani P, Rotondi M, Lazzeri E, Lasagni L, FrancalanciM, Buonamano A, Milani S, Vitti P, Chiovato L, TonaccheraM, Bellastella A, Serio M 2002 Expression of IP-10=CXCL10and MIG=CXCL9 in the thyroid and increased levels ofIP-10=CXCL10 in the serum of patients with recent-onsetGraves disease. Am J Pathol 161:195206.19. Antonelli A, Fallahi P, Rotondi M, Ferrari SM, Romagnani P,Grosso M, Ferrannini E, Serio M 2006 Increased serumCXCL10 in Graves disease or autoimmune thyroiditis is notassociated with hyper- or hypothyroidism per se, but isspecifically sustained by the autoimmune, inflammatoryprocess. Eur J Endocrinol 154:651658.20. Smith TJ, Sciaky D, Phipps RP, Jennings TA 1999 CD40 expressionin humanCytokines, Graves Disease,and Thyroid-Associated OphthalmopathyAndrew G. Gianoukakis, M.D.,1,2 Nicole Khadavi, B.S.,2 and Terry J. Smith, M.D.1,2,3Graves disease, an autoimmune process associated with thyroid dysfunction, can also manifest as remodeling oforbital connective tissue. Affected tissues exhibit immune responses that appear to be orchestrated by residentcells and those recruited from the bone marrow through their expression and release of cytokines and surfacedisplay of cytokine receptors. Cytokines are small molecules produced by many types of cells, including thoseof the professional immune system. Aberrant cytokine expression appears to play an important role inthe pathogenesis of many human diseases, including thyroid autoimmunity. The skewed pattern of cytokineexpression in the thyroid, including the T helper cell bias, may condition the response to apoptotic signals anddetermine the characteristics of an autoimmune reaction. Furthermore, chemoattractant cytokines, includingIL16, RANTES, and CXCL10, elaborated by resident cells in the thyroid and orbit may provoke mononuclear cellinfiltration. Other cytokines may drive cell activation and tissue remodeling. Thus cytokines and the signalingpathways they activate represent attractive therapeutic targets. Interruption of these might alter the naturalcourse of Graves disease and its orbital manifestations.IntroductionGraves disease (GD) represents both the most commoncause of hyperthyroidism and an archetypical exampleof antibody-mediated autoimmunity. It is associatedwith an inflammatory process in the orbit known as thyroidassociatedophthalmopathy (TAO). Abnormalities in the levelsof several abundant cytokines have been documented inthyroid and orbital tissues in GD. Cytokines are small moleculessynthesized by many different cell types and playingimportant roles in health and disease (1,2). Some are expressedas membrane-bound proteins while others are releasedas soluble molecules targeting high-affinity receptorson the surfaces of adjacent cells. They function as elaboratenetworks and therefore the aggregate contribution of manydifferent molecular mediators represents the basis for thepattern of tissue reactivity found in disease (Fig. 1). Theprofile of cytokines appears to define the nature of organspecificimmune responses. Their central roles in inflammationsuggest that they, their receptors, and the signalingpathways they utilize are potentially attractive therapeutictargets for autoimmune diseases of the thyroid.GD and the ThyroidThyroid tissue becomes hyperplastic, hypertrophied, andinfiltrated with B and T lymphocytes in GD. CD4t cellspredominate and these are accompanied by moderate B cellgerminal center formation (3,4). GD is generally characterizedby a Th2 pattern of cytokine production. Intrathyroidal lymphocytessecrete cytokines such as interleukin (IL)-4, IL-5,IL-10, and IL-13, all of which tend to support antibodymediatedimmune responses. This cytokine milieu may resultfrom the contributions of both residential cells such as thyrocytes,endothelium, and fibroblasts and by cells recruited tothe gland, including T cells. We postulate that epithelium andthe other residential elements of the thyroid play importantroles in defining the pattern of inflammation and tissue remodelingfound in GD.A key aspect of tissue remodeling concerns the process ofapoptosis. Thyrocytes from individuals with GD expressboth Fas and FasL (5,6). The cytokine profile found in thyroidtissue in autoimmunity may contribute to the exaggeratedsusceptibility to apoptosis seen in Hashimotos thyroiditisand in other destructive processes. Conversely, the relativeresistance to apoptosis found in GD may be conditioned by adifferent pattern of cytokine expression. Th1