臺灣博碩士論文加值系統

葛瑞夫茲氏眼病變(Graves’ ophthalmopathy, GO)，或稱為甲狀腺眼病變(thyroid eye diease, TED)。 病人會有凸眼(proptosis)、眼瞼內縮(lid retraction)、眼瞼水腫(lid edema)，眼外肌(extraocular muscles)病變引起複視(diplopia)等影響美觀、視力的症狀。凸眼的原因包括眼外肌及眼窩脂肪組織的肥大。 而脂肪組織的病變，在最近10年對於脂肪組織有完全改觀的認知之後，更顯得有進一步研究的必要。 由於凸眼的治療目前僅有外科手術一途，我們也希望研究凸眼患者眼窩脂肪組織肥大的分子機轉能幫助找出內科治療或者預防發生的可能性。 相對於葛瑞夫茲氏病中甲狀腺功能亢進的致病機轉的了解，葛瑞夫茲氏眼病變的致病機轉較不是那麼清楚。 由於葛瑞夫茲氏病是一種自體免疫疾病，相關的發炎反應引起很多cytokines (或稱chemokines)的釋放，早期的研究偏重此方面的研究，而且是偏重淋巴球及纖維母細胞釋放cytokines的研究。 近幾年，發現了脂肪細胞也會分泌adipokines，除了影響代謝，也與發炎反應有關。脂肪組織中也發現形態上類似纖維母細胞，但是行為上是偏向於脂肪細胞的脂肪前驅細胞(preadipocyte)。 在受到刺激後脂肪前驅細胞可以分化成脂肪細胞，這樣的過程稱之為adipogenesis。 前幾年的眼窩脂肪組織研究重心在adipogenesis，主要使用isolated orbital fibroblasts來做細胞培養分化的研究。 我們認為脂肪組織包含不只脂肪細胞，必須要有全組織的研究才能有全面的了解。 運用cDNA微陣列(cDNA microarray)建立疾病假說是不錯的選擇。但是由於基因為數過大，而且個人的差異又很大，再加上人體組織的檢體通常數量很少，以致於難以區分分析結果到底是真的有不同還是干擾。 所以，我們使用基因群組增強分析(gene sets enrichment analysis, GSEA)，它是依生理途徑(biological pathway)作為分群的依據，所得結果較具生理的意義。 最後，進一步用定量即時聚合酵素連鎖反應(quantitative real-time PCR, QPCR)來做單一基因的測試，以證實基因的參與。結果發現，溶酶體相關基因群組與眼窩脂肪組織肥大有關。 其中，ceroid-lipofuscinosis, neuronal 2, late infantile (CLN2)，ceroid-lipofuscinosis, neuronal 3, juvenile (CLN3)以及β subunit of hexosaminidase A (HEXB) mRNA表現的減少與眼窩脂肪組織肥大有關。 此外，我們注意到代表巨噬細胞標誌的CD68基因也在溶酶體相關基因群組中，所以我們也針對巨噬細胞的浸潤情形及原因，做了相關的研究。 研究發現巨噬細胞在葛瑞夫茲氏眼病變病人眼窩脂肪組織的浸潤增加，而這種現象與肥胖個體脂肪組織的巨噬細胞的浸潤一樣與C-C motif chemokine family ligand 2 (CCL2)，也稱之為monocyte chemoattractant protein-1 (MCP-1)基因有關。 雖然，我們目前的研究結果尚不足以找出治療或預防眼窩脂肪組織肥大的方式，卻提供了整體可行的研究方向。

Graves’ ophthalmopathy (GO) or thyroid eye disease (TED) is associated with manifestations of proptosis, lid retraction, lid edema and extraocular muscles restriction related diplopia, which may influence patients’ cosmetics and visual acuity. Causes of proptosis included hypertrophy of extraocular muscle and orbital fat。 We are interested in orbital fat pathology as we know more about the new conepts of adipose tissue in its role in encocrine and inflammatory physiology as well as adipogensis in the recent 10 years. The only treatment for proptosis now is surgery. We hope the study about the molecular mechanism of Graves’ ophthalmoapthy will help to find out the possible medical treatment or the way to prevent it. In contrast to the understanding of the patholgenesis of hyperthyroidism in Graves’ disease, the pathogeneis of Graves’ ophthalmopathy is not so clear. Since Graves’ disease is an autoimmune disease, earlier studies focused in the release of cytokines (or chemokines) from lymphocytes and fibroblasts. However, in recent 10 years, we know that adipocytes could secret adipokines which will influence metabolism and inflammatory process and the preadipocytes which reside in adipose tissue have the ability to differentiate to adipocyte. After knowing that, studies began with adipogenesis in orbital fat using isolated orbital fibroblasts. We know that adipose tissue is a heterogenous tissue with multiple cell types, the studies using isolate orbital fibroblast would see only part of the mecahnism. For us to understand the whole tissue pathology, we need cDNA microassay to generate the hypothesis about the molecular mechanism of orbital fat hypertrophy. However, the large number of genes tested, the high variability between individuals, and the limited samples sizes in human studies have made it difficult to distinguish true differences from noise. The Gene Sets Enrichment Analysis (GSEA) is a powerful method to avoid the noise. By using the GSEA method, we found the expressions of specific gene sets related to lytic vacuoles, lysosomes and vacuoles, which we termed lysosome-related genes, were substantially different between orbital adipose tissues obtained from patients with and without Graves’ ophthalmopathy. We also use real-time quantitative PCR (QPCR) to validate single gene under those gene sets, which revealed the expression of CLN2, CLN3, and HEXB were down-regulated in orbital fat of patients with Graves’ ophthalmopathy. We also noticed that the macrophage marker, CD68, is a member of the lysosome-related gene set. We tried to elucidate the infiltration macrophage in orbital fat and its associated mechanism. We demonstrated macrophage infiltration is increased in orbital fat of patients with Graves’ ophthalmopathy and the mechanism is similar to the mechanism of macrophage infiltration in adipose tissue of obese subjects, to be associated with C-C motif chemokine family 2 (CCL2), or monocyte chemoattratant protein-1 (MCP-1). We understood that what we have done is not sufficient for generating medical treatment or way to prevent Graves’ ophthalmopathy, but our work provided a workable way to it.

口試委員會審定書……………………………………………………………………...i
誌謝………………………………………………………………………………..…….ii
中文摘要………………………………………………………………………………..iii
英文摘要………………………………………………………………………………..v
目錄……………………………………………………………………………………viii
圖目錄…………………………………………………………………………………xiii
表目錄…………………………………………………………………………………xiv
第一章 緒論………………………………………………………………………….....1
1.01葛瑞夫茲氏病(Graves’ disease)的臨床表現…………………………………1
1.011甲狀腺功能亢進的臨床症狀……………………………………………1
1.012甲狀腺及甲狀腺外的表徵………………………………………………1
1.02葛瑞夫茲氏病中甲狀腺功能亢進的致病機轉………………………………2
1.03葛瑞夫茲氏病引起甲狀腺功能亢進的治療………………………………..3
1.031藥物治療………………………………………………………………..3
1.032放射線治療……………………………………………………………..4
1.033外科手術治療…………………………………………………………..4
1.04葛瑞夫茲氏眼病變(Graves’ ophthalmopathy)的臨床表現…………………5
1.05 影像學上所觀察到的眼病變型態…………………………………………6
1.06葛瑞夫茲氏眼病變的組織病理…………………………………………….6
1.061眼外肌(extraocular muscles)………………………………………….7
1.062眼窩脂肪組織(orbital adipose tissue)………………………………...7
1.063苗勒氏肌(Müller''s muscle)…………………………………………...8
1.07 葛瑞夫茲氏眼病變與Adiposity……………………………………………8
1.08葛瑞夫茲氏眼病變的治療…………………………………………………..9
1.081腎上腺皮質類固醇(adrenal corticosteroids)…………………………..9
1.082 Octreotide………………………………………………………………9
1.083放射治療.……………………………………………………………….10
1.084外科手術.……………………………………………………………….10
1.09葛瑞夫茲氏眼病變的致病機轉研究近況………….……………………….11
1.091自體抗原(autoantigen)及動物模式……………………………………12
1.092眼窩纖維母細胞(orbital fibroblast)及脂肪增生(adipogenesis)……….12
1.093 黏多醣(glycosaminoglycan)堆積……………………………………..14
1.094遺傳及環境的影響…………………………………………………….15
1.095 細胞激素(cytokines)…………………………………………………..15
1.10眼窩脂肪組織肥大病因研究之重要性、研究假說及研究的目的………..16
1.101眼窩脂肪組織的異質性(heterogenesity)……………………………..17
1.102基因群組增強分析(gene sets enrichment analysis)…………………..18
1.103假說的建立及研究目的………………………………………………19
第二章 研究方法與材料……………………………………………………………...20
2.1 人類眼窩脂肪組織的取得…………………………………………………..20
2.2 RNA的分離………………………………………………………………...20
2.3 基因微陣列檢體(microarray)的準備，雜交(hybridization)，掃描審視(scanning)…………………………………………………………………………21
2.4 微陣列資料正常化(microarray data normalization)及分析………………...21
2.5定量即時聚合酵素連鎖反應 (quantitative real-time PCR)…………………22
2.6免疫組織螢光分析( immunohistochemistry)………………………………...23
2.7 統計分析……………………………………………………………………..24
第三章 結果 ……………………………………………………………………….25
3.1葛瑞夫茲氏眼病變病人眼窩脂肪組織肥大與溶酶體相關基因有關………25
3.2基因篩選………………………………………………………………………25
3.3 葛瑞夫茲氏眼病變病人眼窩脂肪組織肥大與CLN2, CLN3, HEXB基因表現減少有關……………………………………………………………………….26
3.4使用CLN2抗體的免疫組織螢光染色主要在非脂肪細胞部分……………27
3.5 葛瑞夫茲氏眼病變病人眼窩脂肪組織肥大與CD68 gene 表現增加有關..27
3.6 巨噬細胞在葛瑞夫茲氏眼病變病人眼窩脂肪組織的浸潤增加…………..27
3.61 巨噬細胞在葛瑞夫茲氏眼病變病人眼窩脂肪組織中分佈的情形…27
3.62 巨噬細胞浸潤的程度…………………………………………………28
3.63 巨噬細胞浸潤在病程較長的病人眼窩組織中也可見到……………28
3.7巨噬細胞在葛瑞夫茲氏眼病變病人眼窩脂肪組織的浸潤增加與CCL2 (MCP-1)基因有關………………………………………………………………...28
第四章 討論…………………………………………………………………………...30
4.1基因群組增強分析的微陣列研究給我們更具有生理意義的疾病假說…...30
4.2溶酶體…………………………………………………………………………32
4.21溶酶體分布在不同細胞有不同名稱…………………………………..33
4.22溶酶體相關基因在葛瑞夫茲氏眼病變病人眼窩脂肪組織中可能扮演的角色……………………………………………………………………….34
4.221 CLN2及CLN3…………………………………………………35
4.222 HEXB……………………………………………………………36
4.223 CD68……………………………………………………………..37
4.3 巨噬細胞在葛瑞夫茲氏眼病變眼窩脂肪組織病理中所扮演的角色……..38
4.4眼窩脂肪組織中各種細胞及基因的變化與脂肪組織肥大的關係…………42
4.5脂肪組織具有多元的生理及病理角色以及區域特異性，葛瑞夫茲氏眼病變眼窩脂肪組織肥大也是其中的一部分………………………………………….42
4.51脂肪組織是內分泌器官……………………………………………….43
4.52脂肪組織是發炎器官………………………………………………….44
4.53脂肪組織的區域特異性……………………………………………….45
第五章 展望…………………………………………………………………………...46
5.1研究結果在臨床上的應用及貢獻……………………………………………46
5.11從了解病人的需要及治療的困難處著手……………………………..46
5.12繼往開來，全面檢討…………………………………………….…….46
5.13確實可行的方向………………………………………………………..47
5.2研究工作於將來的研究方向及貢獻…………………………………………48
5.21基礎方面………………………………………………………………..48
5.211眼病變中的脂肪組織病理………………………………………48
5.2111脂肪細胞脂質堆積………………………………………..49
5.2112纖維母細胞分泌及降解glycosaminoglycans的機轉……49
5.2113 各種細胞內溶酶體與antigen presenting的關係………..49
5.2114脂肪細胞、纖維母細胞，以及巨噬細胞的共同培養……..50
5.212脂肪組織病理研究的擴大………………………………………50
5.22臨床方面………………………………………………………………..51
5.3結語……………………………………………………………………………52
第六章 論文英文簡述………………………………………………………………...53
參考文獻……………………………………………………………………………….67
附錄…………………………………………………………………………………….81

圖目錄
圖1. 由上而下：眼瞼內縮(lid retraction)、眼瞼水腫(lid edema)、凸眼(proptosis)…...81
圖2. 凸眼側面觀………………………………………………………………………82
圖3. orbital CT, coronal(上) and sagittal(下) view：眼窩脂肪組織肥大合併眼外肌肥大………………………………………………………………………….……………83
圖4. orbital CT, coronal(上) and sagittal(下) view：只有眼窩脂肪組織肥大………..84
圖5. orbital CT, coronal(上) and sagittal(下) view：只有眼外肌肥大……….……….85
圖6. 脂肪細胞分化不同的時程………………………………………………………86
圖7. 脂肪細胞分化，一些原本抑制分化的基因表現減弱…………………………..87
圖8. 定量即時聚合酵素連鎖反應結果………………………………………………88
圖9. 脂肪組織冷凍切片使用anti-CLN2抗體的免疫組織化學染色…….…………89
圖10. 葛瑞夫茲氏眼病變眼窩脂肪組織肥大與CD68 表現增加有關………….….90
圖11. 免疫組織染色觀察巨噬細胞在眼窩脂肪組織中的浸潤……………………..91
圖12. 巨噬細胞浸潤的程度…………………………………………….…………….92
圖13. 葛瑞夫茲氏眼病變眼窩脂肪組織中，巨噬細胞浸潤的程度增加………....93
圖14. 巨噬細胞浸潤為一種慢性的過程……………………………………………94
圖15. 葛瑞夫茲氏眼病變眼窩脂肪組織的CCL2 (MCP-1) mRNA表現增加……95
圖16. 巨噬細胞在葛瑞夫茲氏眼病變眼窩脂肪組織的浸潤增加與CCL2 (MCP-1) 基因有關…………………………………………………96
圖17. Oil-Red染色於3T3-L1脂肪細胞分化初期…………………………………..97
圖18. 眼窩脂肪組織中各種細胞及基因的變化與脂肪組織肥大的關係…………98

表目錄
表1. Demographics and clinical characteristics of patients with Graves’ ophthalmopathy and controls………………………………100
表2. Primers for QPCR of candidate genes, CD68, CCL2 (MCP-1), osteopontin and β-actin………………………………………………101
表3. Summary results of GSEA of the mRNA expressions between subjects with Graves’ ophthalmopathy v.s. controls………………………………………………102
表4. Details of the selected individual genes in gene ontology ID 323, 5764, 5773………v103
表5. Characteristics of lysosome and related organelles……………………………104

Aniszewski JP, Valyasevi RW and Bahn RS (2000). "Relationship between disease duration and predominant orbital T cell subset in Graves'' ophthalmopathy." J Clin Endocrinol Metab 85: 776-780.
Antonelli A, Rotondi M, Fallahi P, Romagnani P, Ferrari SM, Paolicchi A, Ferrannini E and Serio M (2005). "Increase of interferon-gamma inducible alpha chemokine CXCL10 but not beta chemokine CCL2 serum levels in chronic autoimmune thyroiditis." Eur J Endocrinol 152: 171-177.
Bahn RS (2003). "Clinical review 157: Pathophysiology of Graves'' ophthalmopathy: the cycle of disease." J Clin Endocrinol Metab 88: 1939-1946.
Bahn RS and Heufelder AE (1993). "Pathogenesis of Graves'' ophthalmopathy." N Engl J Med 329: 1468-1475.
Bartalena L, Marcocci C, Bogazzi F, Panicucci M, Lepri A and Pinchera A (1989). "Use of corticosteroids to prevent progression of Graves'' ophthalmopathy after radioiodine therapy for hyperthyroidism." N Engl J Med 321: 1349-1352.
Bartley GB and Gorman CA (1995). "Diagnostic criteria for Graves'' ophthalmopathy." Am J Ophthalmol 119: 792-795.
Blum AM, Metwali A, Mathew RC, Cook G, Elliott D and Weinstock JV (1992). "Granuloma T lymphocytes in murine schistosomiasis mansoni have somatostatin receptors and respond to somatostatin with decreased IFN-gamma secretion." J Immunol 149: 3621-3626.
Brownlie BE and Wells JE (1990). "The epidemiology of thyrotoxicosis in New Zealand: incidence and geographical distribution in north Canterbury, 1983-1985." Clin Endocrinol (Oxf) 33: 249-259.
Bruun JM, Lihn AS, Pedersen SB and Richelsen B (2005). "Monocyte chemoattractant protein-1 release is higher in visceral than subcutaneous human adipose tissue (AT): implication of macrophages resident in the AT." J Clin Endocrinol Metab 90: 2282-2289.
Burch HB and Wartofsky L (1993). "Graves'' ophthalmopathy: current concepts regarding pathogenesis and management." Endocr Rev 14: 747-793.
Case J, Horvath TL, Howell JC, Yoder MC, March KL and Srour EF (2005). "Clonal multilineage differentiation of murine common pluripotent stem cells isolated from skeletal muscle and adipose stromal cells." Ann N Y Acad Sci 1044: 183-200.
Chang TC and Liao SL (2006). "Slow-release lanreotide in Graves'' ophthalmopathy: A double-blind randomized, placebo-controlled clinical trial." J Endocrinol Invest 29: 413-422.
Charo IF and Ransohoff RM (2006). "The many roles of chemokines and chemokine receptors in inflammation." N Engl J Med 354: 610-621.
Charo IF and Taubman MB (2004). "Chemokines in the pathogenesis of vascular disease." Circ Res 95: 858-866.
Charriere G, Cousin B, Arnaud E, Andre M, Bacou F, Penicaud L and Casteilla L (2003). "Preadipocyte conversion to macrophage. Evidence of plasticity." J Biol Chem 278: 9850-9855.
Chen CA, Tang NL, Chien YH, Zhang WM, Wang JK and Hwu WL (2005). "Type I Gaucher disease with exophthalmos and pulmonary arteriovenous malformation." BMC Med Genet 6: 25.
Chen MH, Chen MH, Liao SL, Chang TC and Chuang LM (2008). "Role of macrophage infiltration in the orbital fat of patients with Graves'' ophthalmopathy." Clin Endocrinol (Oxf) 69: 332-337.
Chen MH, Liao SL, Chen MH, Tsou PL, Shih MJ, Chang TC and Chuang LM (2008). "Lysosome-related genes are regulated in the orbital fat of patients with Graves'' ophthalmopathy." Invest Ophthalmol Vis Sci.
Chen PL, Fann CS, Chang CC, Wu IL, Chiu WY, Lin CY, Yang WS and Chang TC (2008). "Family-based association study of cytotoxic T-lymphocyte antigen-4 with susceptibility to Graves'' disease in Han population of Taiwan." Genes Immun 9: 87-92.
Colao A, Lastoria S, Ferone D, Pivonello R, Macchia PE, Vassallo P, Bonavolonta G, Muto P, Lombardi G and Fenzi G (1998). "Orbital scintigraphy with [111In-diethylenetriamine pentaacetic acid-D-phe1]-octreotide predicts the clinical response to corticosteroid therapy in patients with Graves'' ophthalmopathy." J Clin Endocrinol Metab 83: 3790-3794.
Costagliola S, Morgenthaler NG, Hoermann R, Badenhoop K, Struck J, Freitag D, Poertl S, Weglohner W, Hollidt JM, Quadbeck B, Dumont JE, Schumm-Draeger PM, Bergmann A, Mann K, Vassart G and Usadel KH (1999). "Second generation assay for thyrotropin receptor antibodies has superior diagnostic sensitivity for Graves'' disease." J Clin Endocrinol Metab 84: 90-97.
Costagliola S, Rodien P, Many MC, Ludgate M and Vassart G (1998). "Genetic immunization against the human thyrotropin receptor causes thyroiditis and allows production of monoclonal antibodies recognizing the native receptor." J Immunol 160: 1458-1465.
Crombie AL and Lawson AA (1967). "Long-term trial of local guanethidine in treatment of eye signs of thyroid dysfunction and idiopathic lid retraction." Br Med J 4: 592-595.
Cuervo AM and Dice JF (1998). "Lysosomes, a meeting point of proteins, chaperones, and proteases." J Mol Med 76: 6-12.
Curat CA, Miranville A, Sengenes C, Diehl M, Tonus C, Busse R and Bouloumie A (2004). "From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes." Diabetes 53: 1285-1292.
Dani C (1999). "Embryonic stem cell-derived adipogenesis." Cells Tissues Organs 165: 173-180.
Day RM and Carroll FD (1968). "Corticosteroids in the treatment of optic nerve involvement associated with thyroid dysfunction." Arch Ophthalmol 79: 279-282.
Dell''Angelica EC, Mullins C, Caplan S and Bonifacino JS (2000). "Lysosome-related organelles." Faseb J 14: 1265-1278.
Desreumaux P, Ernst O, Geboes K, Gambiez L, Berrebi D, Muller-Alouf H, Hafraoui S, Emilie D, Ectors N, Peuchmaur M, Cortot A, Capron M, Auwerx J and Colombel JF (1999). "Inflammatory alterations in mesenteric adipose tissue in Crohn''s disease." Gastroenterology 117: 73-81.
Dickinson AJ, Vaidya B, Miller M, Coulthard A, Perros P, Baister E, Andrews CD, Hesse L, Heverhagen JT, Heufelder AE and Kendall-Taylor P (2004). "Double-blind, placebo-controlled trial of octreotide long-acting repeatable (LAR) in thyroid-associated ophthalmopathy." J Clin Endocrinol Metab 89: 5910-5915.
Dyer JA (1976). "The oculorotary muscles in Graves'' disease." Trans Am Ophthalmol Soc 74: 425-456.
Feldon SE, Lee CP, Muramatsu SK and Weiner JM (1985). "Quantitative computed tomography of Graves'' ophthalmopathy. Extraocular muscle and orbital fat in development of optic neuropathy." Arch Ophthalmol 103: 213-215.
Garrity JA and Bahn RS (2006). "Pathogenesis of Graves'' ophthalmopathy: implications for prediction, prevention, and treatment." Am J Ophthalmol 142: 147-153.
Garrity JA and Bahn RS (2006). "Pathogenesis of graves ophthalmopathy: implications for prediction, prevention, and treatment." Am J Ophthalmol 142: 147-153.
Gerding MN, van der Meer JW, Broenink M, Bakker O, Wiersinga WM and Prummel MF (2000). "Association of thyrotrophin receptor antibodies with the clinical features of Graves'' ophthalmopathy." Clin Endocrinol (Oxf) 52: 267-271.
Gerding MN, van der Zant FM, van Royen EA, Koornneef L, Krenning EP, Wiersinga WM and Prummel MF (1999). "Octreotide-scintigraphy is a disease-activity parameter in Graves'' ophthalmopathy." Clin Endocrinol (Oxf) 50: 373-379.
Gerhardt CC, Romero IA, Cancello R, Camoin L and Strosberg AD (2001). "Chemokines control fat accumulation and leptin secretion by cultured human adipocytes." Mol Cell Endocrinol 175: 81-92.
Greenberg AS and Obin MS (2006). "Obesity and the role of adipose tissue in inflammation and metabolism." Am J Clin Nutr 83: 461S-465S.
Hackett NR, Redmond DE, Sondhi D, Giannaris EL, Vassallo E, Stratton J, Qiu J, Kaminsky SM, Lesser ML, Fisch GS, Rouselle SD and Crystal RG (2005). "Safety of direct administration of AAV2(CU)hCLN2, a candidate treatment for the central nervous system manifestations of late infantile neuronal ceroid lipofuscinosis, to the brain of rats and nonhuman primates." Hum Gene Ther 16: 1484-1503.
Hagg E and Asplund K (1987). "Is endocrine ophthalmopathy related to smoking?" Br Med J (Clin Res Ed) 295: 634-635.
Hallengren B, Forsgren A and Melander A (1980). "Effects of antithyroid drugs on lymphocyte function in vitro." J Clin Endocrinol Metab 51: 298-301.
Harada T, Shimaoka K, Arita S and Nakanishi Y (1984). "Follow-up evaluation of thyroid function after thyroidectomy for thyrotoxicosis." World J Surg 8: 436-444.
Haraguchi K, Shimura H, Lin L, Endo T and Onaya T (1996). "Differentiation of rat preadipocytes is accompanied by expression of thyrotropin receptors." Endocrinology 137: 3200-3205.
Hardisty CA, Fowles A and Munro DS (1984). "The effect of radioiodine and antithyroid drugs on serum long acting thyroid stimulator protector (IATS-P). A three year prospective study." Clin Endocrinol (Oxf) 20: 597-605.
Hedley AJ, Bewsher PD, Jones SJ, Khir AS, Clements P, Matheson NA and Gunn A (1983). "Late onset hypothyroidism after subtotal thyroidectomy for hyperthyroidism: implications for long term follow-up." Br J Surg 70: 740-743.
Henrikson RC and Smith TJ (1994). "Ultrastructure of cultured human orbital fibroblasts." Cell Tissue Res 278: 629-631.
Hinterberger W, Cerny C, Kinast H, Pointner H and Tragl KH (1978). "Somatostatin reduces the release of colony-stimulating activity (CSA) from PHA-activated mouse spleen lymphocytes." Experientia 34: 860-862.
Holness CL and Simmons DL (1993). "Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins." Blood 81: 1607-1613.
Hufnagel TJ, Hickey WF, Cobbs WH, Jakobiec FA, Iwamoto T and Eagle RC (1984). "Immunohistochemical and ultrastructural studies on the exenterated orbital tissues of a patient with Graves'' disease." Ophthalmology 91: 1411-1419.
Hunziker W and Geuze HJ (1996). "Intracellular trafficking of lysosomal membrane proteins." Bioessays 18: 379-389.
Itano N and Kimata K (1996). "Expression cloning and molecular characterization of HAS protein, a eukaryotic hyaluronan synthase." J Biol Chem 271: 9875-9878.
Jarvela I, Sainio M, Rantamaki T, Olkkonen VM, Carpen O, Peltonen L and Jalanko A (1998). "Biosynthesis and intracellular targeting of the CLN3 protein defective in Batten disease." Hum Mol Genet 7: 85-90.
Kaback LA and Smith TJ (1999). "Expression of hyaluronan synthase messenger ribonucleic acids and their induction by interleukin-1beta in human orbital fibroblasts: potential insight into the molecular pathogenesis of thyroid-associated ophthalmopathy." J Clin Endocrinol Metab 84: 4079-4084.
Kadowaki T and Yamauchi T (2005). "Adiponectin and adiponectin receptors." Endocr Rev 26: 439-451.
Kahaly G, Hansen C, Felke B and Dienes HP (1994). "Immunohistochemical staining of retrobulbar adipose tissue in Graves'' ophthalmopathy." Clin Immunol Immunopathol 73: 53-62.
Kasai K, Banba N, Motohashi S, Hattori Y, Manaka K and Shimoda SI (1996). "Expression of monocyte chemoattractant protein-1 mRNA and protein in cultured human thyrocytes." FEBS Lett 394: 137-140.
Kershaw EE and Flier JS (2004). "Adipose tissue as an endocrine organ." J Clin Endocrinol Metab 89: 2548-2556.
Kikuoka S, Shimojo N, Yamaguchi KI, Watanabe Y, Hoshioka A, Hirai A, Saito Y, Tahara K, Kohn LD, Maruyama N, Kohno Y and Niimi H (1998). "The formation of thyrotropin receptor (TSHR) antibodies in a Graves'' animal model requires the N-terminal segment of the TSHR extracellular domain." Endocrinology 139: 1891-1898.
Kim MS, Park MJ, Moon EJ, Kim SJ, Lee CH, Yoo H, Shin SH, Song ES and Lee SH (2005). "Hyaluronic acid induces osteopontin via the phosphatidylinositol 3-kinase/Akt pathway to enhance the motility of human glioma cells." Cancer Res 65: 686-691.
Kimata H, Yoshida A, Fujimoto M and Mikawa H (1993). "Effect of vasoactive intestinal peptide, somatostatin, and substance P on spontaneous IgE and IgG4 production in atopic patients." J Immunol 150: 4630-4640.
Kinyoun JL, Kalina RE, Brower SA, Mills RP and Johnson RH (1984). "Radiation retinopathy after orbital irradiation for Graves'' ophthalmopathy." Arch Ophthalmol 102: 1473-1476.
Kohn LD, Shimojo N, Kohno Y and Suzuki K (2000). "An animal model of Graves'' disease: understanding the cause of autoimmune hyperthyroidism." Rev Endocr Metab Disord 1: 59-67.
Kornfeld S and Mellman I (1989). "The biogenesis of lysosomes." Annu Rev Cell Biol 5: 483-525.
Kraiem Z, Lahat N, Glaser B, Baron E, Sadeh O and Sheinfeld M (1987). "Thyrotrophin receptor blocking antibodies: incidence, characterization and in-vitro synthesis." Clin Endocrinol (Oxf) 27: 409-421.
Kroll AJ and Kuwabara T (1966). "Dysthyroid ocular myopathy. Anatomy, histology, and electron microscopy." Arch Ophthalmol 76: 244-247.
Kumar S and Bahn RS (2003). "Relative overexpression of macrophage-derived cytokines in orbital adipose tissue from patients with Graves'' ophthalmopathy." J Clin Endocrinol Metab 88: 4246-4250.
Kumar S, Coenen MJ, Scherer PE and Bahn RS (2004). "Evidence for enhanced adipogenesis in the orbits of patients with Graves'' ophthalmopathy." J Clin Endocrinol Metab 89: 930-935.
Kung AW, Yau CC and Cheng A (1994). "The incidence of ophthalmopathy after radioiodine therapy for Graves'' disease: prognostic factors and the role of methimazole." J Clin Endocrinol Metab 79: 542-546.
Lankisch PG and Schirren CA (1990). "Increased body weight as a prognostic parameter for complications in the course of acute pancreatitis." Pancreas 5: 626-629.
Lantz M, Vondrichova T, Parikh H, Frenander C, Ridderstrale M, Asman P, Aberg M, Groop L and Hallengren B (2005). "Overexpression of immediate early genes in active Graves'' ophthalmopathy." J Clin Endocrinol Metab 90: 4784-4791.
Lee TC, Coffey RJ, Currier BM, Ma XP and Canary JJ (1982). "Propranolol and thyroidectomy in the treatment of thyrotoxicosis." Ann Surg 195: 766-773.
Lehrke M and Lazar MA (2004). "Inflamed about obesity." Nat Med 10: 126-127.
Livak KJ and Schmittgen TD (2001). "Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method." Methods 25: 402-408.
Luo Q, He W, Tang L, Zhou X, Xia R, Zhang S and Zhang J (2000). "[Ultrastructure study on extraocular muscle of infiltrative exophthalmos]." Zhonghua Yan Ke Za Zhi 36: 366-368, 323.
Many MC, Costagliola S, Detrait M, Denef F, Vassart G and Ludgate MC (1999). "Development of an animal model of autoimmune thyroid eye disease." J Immunol 162: 4966-4974.
Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR and Flier JS (2001). "A transgenic model of visceral obesity and the metabolic syndrome." Science 294: 2166-2170.
Matsuzawa Y (2005). "Adipocytokines: emerging therapeutic targets." Curr Atheroscler Rep 7: 58-62.
McGregor AM, Petersen MM, McLachlan SM, Rooke P, Smith BR and Hall R (1980). "Carbimazole and the autoimmune response in Graves'' disease." N Engl J Med 303: 302-307.
McLachlan SM, Pegg CA, Atherton MC, Middleton SL, Dickinson A, Clark F, Proctor SJ, Proud G and Rees Smith B (1986). "Subpopulations of thyroid autoantibody secreting lymphocytes in Graves'' and Hashimoto thyroid glands." Clin Exp Immunol 65: 319-328.
Mole SE, Mitchison HM and Munroe PB (1999). "Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5." Hum Mutat 14: 199-215.
Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D and Groop LC (2003). "PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes." Nat Genet 34: 267-273.
Neels JG and Olefsky JM (2006). "Inflamed fat: what starts the fire?" J Clin Invest 116: 33-35.
Nomiyama T, Perez-Tilve D, Ogawa D, Gizard F, Zhao Y, Heywood EB, Jones KL, Kawamori R, Cassis LA, Tschop MH and Bruemmer D (2007). "Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice." J Clin Invest 117: 2877-2888.
Otto TC and Lane MD (2005). "Adipose development: from stem cell to adipocyte." Crit Rev Biochem Mol Biol 40: 229-242.
Parsons JT, Fitzgerald CR, Hood CI, Ellingwood KE, Bova FJ and Million RR (1983). "The effects of irradiation on the eye and optic nerve." Int J Radiat Oncol Biol Phys 9: 609-622.
Paschke R and Ludgate M (1997). "The thyrotropin receptor in thyroid diseases." N Engl J Med 337: 1675-1681.
Pasquali D, Notaro A, Bonavolonta G, Vassallo P, Bellastella A and Sinisi AA (2002). "Somatostatin receptor genes are expressed in lymphocytes from retroorbital tissues in Graves'' disease." J Clin Endocrinol Metab 87: 5125-5129.
Pasquali D, Vassallo P, Esposito D, Bonavolonta G, Bellastella A and Sinisi AA (2000). "Somatostatin receptor gene expression and inhibitory effects of octreotide on primary cultures of orbital fibroblasts from Graves'' ophthalmopathy." J Mol Endocrinol 25: 63-71.
Patwardhan NA, Moront M, Rao S, Rossi S and Braverman LE (1993). "Surgery still has a role in Graves'' hyperthyroidism." Surgery 114: 1108-1112; discussion 1112-1103.
Peyster RG, Ginsberg F, Silber JH and Adler LP (1986). "Exophthalmos caused by excessive fat: CT volumetric analysis and differential diagnosis." AJR Am J Roentgenol 146: 459-464.
Pfeilschifter J and Ziegler R (1996). "Smoking and endocrine ophthalmopathy: impact of smoking severity and current vs lifetime cigarette consumption." Clin Endocrinol (Oxf) 45: 477-481.
Porter KA and Banks PA (1991). "Obesity as a predictor of severity in acute pancreatitis." Int J Pancreatol 10: 247-252.
Raikow RB, Dalbow MH, Kennerdell JS, Compher K, Machen L, Hiller W and Blendermann D (1990). "Immunohistochemical evidence for IgE involvement in Graves'' orbitopathy." Ophthalmology 97: 629-635.
Rawlings ND and Barrett AJ (1999). "Tripeptidyl-peptidase I is apparently the CLN2 protein absent in classical late-infantile neuronal ceroid lipofuscinosis." Biochim Biophys Acta 1429: 496-500.
Reinwein D, Benker G, Konig MP, Pinchera A, Schatz H and Schleusener A (1988). "The different types of hyperthyroidism in Europe. Results of a prospective survey of 924 patients." J Endocrinol Invest 11: 193-200.
Rotondi M, Chiovato L, Romagnani S, Serio M and Romagnani P (2007). "Role of chemokines in endocrine autoimmune diseases." Endocr Rev 28: 492-520.
Sango K, McDonald MP, Crawley JN, Mack ML, Tifft CJ, Skop E, Starr CM, Hoffmann A, Sandhoff K, Suzuki K and Proia RL (1996). "Mice lacking both subunits of lysosomal beta-hexosaminidase display gangliosidosis and mucopolysaccharidosis." Nat Genet 14: 348-352.
Santavuori P (1988). "Neuronal ceroid-lipofuscinoses in childhood." Brain Dev 10: 80-83.
Sartipy P and Loskutoff DJ (2003). "Monocyte chemoattractant protein 1 in obesity and insulin resistance." Proc Natl Acad Sci U S A 100: 7265-7270.
Schäffler A and Herfarth H (2005). "Creeping fat in Crohn''s disease: travelling in a creeper lane of research?" Gut 54: 742-744.
Schäffler A, Müller-Ladner U, Schölmerich J and Büchler C (2006). "Role of adipose tissue as an inflammatory organ in human diseases." Endocr Rev 27: 449-467.
Schäffler A, Schölmerich J and Büchler C (2005). "Mechanisms of disease: adipocytokines and visceral adipose tissue--emerging role in intestinal and mesenteric diseases." Nat Clin Pract Gastroenterol Hepatol 2: 103-111.
Sell H, Dietze-Schroeder D, Kaiser U and Eckel J (2006). "Monocyte chemotactic protein-1 is a potential player in the negative cross-talk between adipose tissue and skeletal muscle." Endocrinology 147: 2458-2467.
Sheehan AL, Warren BF, Gear MW and Shepherd NA (1992). "Fat-wrapping in Crohn''s disease: pathological basis and relevance to surgical practice." Br J Surg 79: 955-958.
Shewring G and Smith BR (1982). "An improved radioreceptor assay for TSH receptor antibodies." Clin Endocrinol (Oxf) 17: 409-417.
Shih MJ, Liao SL, Kuo KT, Smith TJ and Chuang LM (2006). "Molecular pathology of Muller''s muscle in Graves'' ophthalmopathy." J Clin Endocrinol Metab 91: 1159-1167.
Shimojo N, Kohno Y, Yamaguchi K, Kikuoka S, Hoshioka A, Niimi H, Hirai A, Tamura Y, Saito Y, Kohn LD and Tahara K (1996). "Induction of Graves-like disease in mice by immunization with fibroblasts transfected with the thyrotropin receptor and a class II molecule." Proc Natl Acad Sci U S A 93: 11074-11079.
Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K, Nakamura T, Yamashita S, Miura M, Fukuda Y, Takemura K, Tokunaga K and Matsuzawa Y (1996). "Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity." Nat Med 2: 800-803.
Shine B, Fells P, Edwards OM and Weetman AP (1990). "Association between Graves'' ophthalmopathy and smoking." Lancet 335: 1261-1263.
Shyjan AM, Heldin P, Butcher EC, Yoshino T and Briskin MJ (1996). "Functional cloning of the cDNA for a human hyaluronan synthase." J Biol Chem 271: 23395-23399.
Smith TJ, Bahn RS and Gorman CA (1989). "Connective tissue, glycosaminoglycans, and diseases of the thyroid." Endocr Rev 10: 366-391.
Smith TJ, Koumas L, Gagnon A, Bell A, Sempowski GD, Phipps RP and Sorisky A (2002). "Orbital fibroblast heterogeneity may determine the clinical presentation of thyroid-associated ophthalmopathy." J Clin Endocrinol Metab 87: 385-392.
Solomon B, Glinoer D, Lagasse R and Wartofsky L (1990). "Current trends in the management of Graves'' disease." J Clin Endocrinol Metab 70: 1518-1524.
Sorisky A, Pardasani D, Gagnon A and Smith TJ (1996). "Evidence of adipocyte differentiation in human orbital fibroblasts in primary culture." J Clin Endocrinol Metab 81: 3428-3431.
Spalton DJ, Taylor DS and Sanders MD (1980). "Juvenile Batten''s disease: an ophthalmological assessment of 26 patients." Br J Ophthalmol 64: 726-732.
Spicer AP, Augustine ML and McDonald JA (1996). "Molecular cloning and characterization of a putative mouse hyaluronan synthase." J Biol Chem 271: 23400-23406.
Spicer AP, Olson JS and McDonald JA (1997). "Molecular cloning and characterization of a cDNA encoding the third putative mammalian hyaluronan synthase." J Biol Chem 272: 8957-8961.
Stan MN, Garrity JA, Bradley EA, Woog JJ, Bahn MM, Brennan MD, Bryant SC, Achenbach SJ and Bahn RS (2006). "Randomized, double-blind, placebo-controlled trial of long-acting release octreotide for treatment of Graves'' ophthalmopathy." J Clin Endocrinol Metab 91: 4817-4824.
Starkey K, Heufelder A, Baker G, Joba W, Evans M, Davies S and Ludgate M (2003). "Peroxisome proliferator-activated receptor-gamma in thyroid eye disease: contraindication for thiazolidinedione use?" J Clin Endocrinol Metab 88: 55-59.
Stuhlmeier KM (2007). "Prostaglandin E2: a potent activator of hyaluronan synthase 1 in type-B-synoviocytes." Biochim Biophys Acta 1770: 121-129.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES and Mesirov JP (2005). "Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles." Proc Natl Acad Sci U S A 102: 15545-15550.
Sugrue DD, Drury MI, McEvoy M, Heffernan SJ and O''Malley E (1983). "Long term follow-up of hyperthyroid patients treated by subtotal thyroidectomy." Br J Surg 70: 408-411.
Tallstedt L, Lundell G, Blomgren H and Bring J (1994). "Does early administration of thyroxine reduce the development of Graves'' ophthalmopathy after radioiodine treatment?" Eur J Endocrinol 130: 494-497.
Taylor S (1986). "Graves of Graves'' disease, 1796-1853." J R Coll Physicians Lond 20: 298-300.
Trokel SL and Jakobiec FA (1981). "Correlation of CT scanning and pathologic features of ophthalmic Graves'' disease." Ophthalmology 88: 553-564.
Trzepacz PT, Klein I, Roberts M, Greenhouse J and Levey GS (1989). "Graves'' disease: an analysis of thyroid hormone levels and hyperthyroid signs and symptoms." Am J Med 87: 558-561.
Valyasevi RW, Erickson DZ, Harteneck DA, Dutton CM, Heufelder AE, Jyonouchi SC and Bahn RS (1999). "Differentiation of human orbital preadipocyte fibroblasts induces expression of functional thyrotropin receptor." J Clin Endocrinol Metab 84: 2557-2562.
Vestergaard H and Laurberg P (1989). "Radioiodine and aggravation of Graves'' ophthalmopathy." Lancet 2: 47.
Villanueva R, Inzerillo AM, Tomer Y, Barbesino G, Meltzer M, Concepcion ES, Greenberg DA, MacLaren N, Sun ZS, Zhang DM, Tucci S and Davies TF (2000). "Limited genetic susceptibility to severe Graves'' ophthalmopathy: no role for CTLA-4 but evidence for an environmental etiology." Thyroid 10: 791-798.
Vines DJ and Warburton MJ (1999). "Classical late infantile neuronal ceroid lipofuscinosis fibroblasts are deficient in lysosomal tripeptidyl peptidase I." FEBS Lett 443: 131-135.
Volpé R (1994). "Evidence that the immunosuppressive effects of antithyroid drugs are mediated through actions on the thyroid cell, modulating thyrocyte-immunocyte signaling: a review." Thyroid 4: 217-223.
Wall JR, Manwar GL, Greenwood DM and Walters BA (1976). "The in vitro suppression of lectin induced 3H-thymidine incorporation into DNA of peripheral blood lymphocytes after the addition of propylthiouracil." J Clin Endocrinol Metab 43: 1406-1409.
Wang HS, Tung WH, Tang KT, Wong YK, Huang GJ, Wu JC, Guo YJ and Chen CC (2005). "TGF-beta induced hyaluronan synthesis in orbital fibroblasts involves protein kinase C betaII activation in vitro." J Cell Biochem 95: 256-267.
Watanabe K and Yamaguchi Y (1996). "Molecular identification of a putative human hyaluronan synthase." J Biol Chem 271: 22945-22948.
Weetman AP, McGregor AM and Hall R (1984). "Evidence for an effect of antithyroid drugs on the natural history of Graves'' disease." Clin Endocrinol (Oxf) 21: 163-172.
Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, Charo I, Leibel RL and Ferrante AW, Jr. (2006). "CCR2 modulates inflammatory and metabolic effects of high-fat feeding." J Clin Invest 116: 115-124.
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL and Ferrante AW, Jr. (2003). "Obesity is associated with macrophage accumulation in adipose tissue." J Clin Invest 112: 1796-1808.
Wellen KE and Hotamisligil GS (2003). "Obesity-induced inflammatory changes in adipose tissue." J Clin Invest 112: 1785-1788.
Wemeau JL, Caron P, Beckers A, Rohmer V, Orgiazzi J, Borson-Chazot F, Nocaudie M, Perimenis P, Bisot-Locard S, Bourdeix I and Dejager S (2005). "Octreotide (long-acting release formulation) treatment in patients with Graves'' orbitopathy: clinical results of a four-month, randomized, placebo-controlled, double-blind study." J Clin Endocrinol Metab 90: 841-848.
Wiersinga WM (1992). "Immunosuppressive treatment of Graves'' ophthalmopathy." Thyroid 2: 229-233.
Williams I, Ankrett VO, Lazarus JH and Volpé R (1983). "Aetiology of hyperthyroidism in Canada and Wales." J Epidemiol Community Health 37: 245-248.
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA and Chen H (2003). "Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance." J Clin Invest 112: 1821-1830.
Yang WS, Chen MH, Lee WJ, Lee KC, Chao CL, Huang KC, Chen CL, Tai TY and Chuang LM (2003). "Adiponectin mRNA levels in the abdominal adipose depots of nondiabetic women." Int J Obes Relat Metab Disord 27: 896-900.