可變淋巴細胞受體

"ol.

1)可變淋巴細胞受體VLR的結構特徵
2004年Pancer等人發現了除Ig外的第二個適應性免疫系統,在《Nature》雜誌上首次報導無頜脊椎動物(七鰓鰻和盲鰻)體內有一種新型受體--可變淋巴細胞受體(VLR)。通過VLR的重複亮氨酸單元(LRR)特異性識別細菌、病毒、異源紅細胞等顆粒型抗原,一個胚系VLR基因可以生成10個特異性抗原受體,其多樣性足以應對外界多變的抗原。成熟VLR的基本結構是由多個LRR的插入形成,它包括一個信號肽(SP),30~38殘基的N末端LRR(LRRNT),18殘基的首位LRR(LRR1),24殘基的可變LRR(LRRVs)(一般含3~5個LRR),13殘基連線肽(CP),48~65殘基的C末端LRR(LRRCT),富含蘇氨酸/脯氨酸柄(Stalk),糖基磷脂醯肌醇(GPI) 錨定區和一個疏水尾。晶體衍射分析發現VLRs 單體是由LRR構成的一種“馬蹄”型結構。在VLRs分子內由β摺疊形成的凹槽部位具有高度的可變性,通過此區域與特異性抗原結合。VLR既可在無頜脊椎動物類淋巴細胞表面表達,也存在分泌型。表達細胞型VLR的類淋巴細胞相當於T細胞,表達分泌型VLR的細胞類似於B細胞。分泌型VLR是由4~5 個二聚體通過二硫鍵連線而成的四聚體或五聚體, 它們分別具有8~10 個抗原結合位點。在形態學上,與高等哺乳動物IgM 存在高度相似性。
2VLRIg的區別
七鰓鰻體內沒有基於Ig的適應性免疫分子,其獨特的VLR產生於5億年前,是與Ig平行進化而來的,是構成七鰓鰻適應性免疫系統的分子基礎,其與Ig類分子區別在於:1Brantley R. Herrin等在VLR與IgG結合抗原親和力比較實驗中發現,同樣濃度下其對特異性抗原的親和力比Ig體高G類抗1000倍,顯現出其有更好的抗原識別靈敏性及更高的親和力。2、在室溫放置一個月,56℃放置36小時仍保持活性,其穩定性優於抗體分子,使其更容易保存。3、VLR與抗原結合後,與抗體不同的是,其不能被高鹽或強酸緩衝液洗脫,只有在強鹼性條件下(PH>11)才能被洗脫,且在極端條件下不能改變VLR結構及與抗原的親和力,如此穩定的理化性質將賦予其更廣泛的用途。4VLR五聚體/四聚體由同一單體組成,而抗體是由輕鏈和重鏈異源二聚體組成,這有利於對VLR抗原結合位點處的基因採用隨機突變法建立一定容量的VLR 庫,便於從庫中篩選到與抗原具有高親和力的VLR,也有利於與其他因子融合(如酶、毒素及表位標籤分子等)以拓展VLR的套用價值。5七鰓鰻與其他哺乳動物親緣關係較遠,VLR能夠突破因哺乳動物免疫耐受而不能產生Ig的限制,可以識別更廣泛的抗原表位,在免疫性疾病的治療上具有潛在的藥用價值。6目前基於Ig的重組抗體藥物大多被專利保護,而VLR是一種新型分子,關於該領域的套用開發仍是一片空白,目前國際上和國內只有我們實驗室申請了PCT國際專利《無頜脊椎動物可變淋巴細胞受體VLR的臨床套用》。總之,可變淋巴細胞受體(VLR)在識別並特異性結合抗原方面比抗體具有更強的特異性及靈敏度,具有甚至更優於抗體分子的功效。隨著對VLR功能研究的愈來愈深入,其作為診斷試劑、防治藥物和其他潛在套用價值也將會更加廣泛而有效。
3VLR對抗原的識別
在動物和植物體內,含有LRR基序的蛋白是執行先天性免疫反應的主要受體,它們能夠結合廣泛的病原體。如,脊椎動物Toll樣受體(TLR)可以識別病毒、細菌、真菌和原蟲的保守抗原表位,激活信號轉導級聯反應,引發炎症。cd14,一個GPI錨定LRR蛋白,以可溶形式與TLR4受體、細菌脂多糖和磷脂結合成複合物。NBS-LRRs是另一個表達於細胞內的LRR蛋白,能夠識別細胞內病原菌。植物抗性基因家族中包括幾百個NBS-LRRs蛋白、LRR受體樣激酶和LRR受體樣蛋白。他們參與抗病原體的特定免疫反應。七鰓鰻體內由LRR構成的高度可變的VLR,作為獨特的適應性免疫分子,具有龐大的多樣性LRR庫,能夠更加特異和高效地識別許多病原體,其多樣性使得他們成為重要的體液和細胞免疫分子。
參考文獻:
[1] Z. Pancer, C. T. AMEMIYA, G. R. Ehrhardt, J. Ceitlin, G. L. Gartland, and M. D. Cooper, Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey, Nature, 430 (2004) 174-180.
[2] M. N. Alder, I. B. Rogozin, L. M. Iyer, G. V. Glazko, M. D. Cooper, and Z. Pancer, Diversity and function of adaptive immune receptors in a jawless vertebrate, Science, 310 (2005) 1970-1973.
[3] M. N. Alder, B. R. Herrin, A. Sadlonova, C. R. Stockard, W. E. Grizzle, L. A. Gartland, G. L. Gartland, J. A. Boydston, C. L. Turnbough, Jr., and M. D. Cooper, Antibody responses of variable lymphocyte receptors in the lamprey, Nat. Immunol., 9 (2008) 319-327.
[4] B. W. Han, B. R. Herrin, M. D. Cooper, and I. A. Wilson, Antigen recognition by variable lymphocyte receptors, Science, 321 (2008) 1834-1837.
[5] Z. Pancer, N. R. Saha, J. Kasamatsu, T. Suzuki, C. T. Amemiya, M. Kasahara, and M. D. Cooper, Variable lymphocyte receptors in hagfish, Proc. Natl. Acad. Sci. U. S. A, 102 (2005) 9224-9229.
[6] H. M. Kim, S. C. Oh, K. J. Lim, J. Kasamatsu, J. Y. HEO, B. S. Park, H. Lee, O. J. Yoo, M. Kasahara, and J. O. Lee, Structural diversity of the hagfish variable lymphocyte receptors, J. Biol. Chem., 282 (2007) 6726-6732.
[7] P. Guo, M. Hirano, B. R. Herrin, J. Li, C. Yu, A. Sadlonova, and M. D. Cooper, Dual nature of the adaptive immune system in lampreys, Nature, 459 (2009) 796-801.
[8] S. Tasumi, C. A. Velikovsky, G. Xu, S. A. Gai, K. D. Wittrup, M. F. Flajnik, R. A. Mariuzza, and Z. Pancer, High-affinity lamprey VLRA and VLRB monoclonal antibodies, Proc. Natl. Acad. Sci. U. S. A, 106 (2009) 12891-12896.
[9] B. R. Herrin, M. N. Alder, K. H. Roux, C. Sina, G. R. Ehrhardt, J. A. Boydston, C. L. Turnbough, Jr., and M. D. Cooper, Structure and specificity of lamprey monoclonal antibodies, Proc. Natl. Acad. Sci. U. S. A, 105 (2008) 2040-2045.
[10] B. Beutler, Innate immunity: an overview, Mol. Immunol., 40 (2004) 845-859.
[11] L. Zhang, L. Li, and G. Zhang, A Crassostrea gigas Toll-like receptor and comparative analysis of TLR pathway in invertebrates, Fish. Shellfish. Immunol., 30 (2011) 653-660.
[12] J. Harder, L. Franchi, R. Munoz-Planillo, J. H. Park, T. Reimer, and G. Nunez, Activation of the Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-kappa B activation but proceeds independently of TLR signaling and P2X7 receptor, J. Immunol., 183 (2009) 5823-5829.
[13] A. K. Mayer, M. Muehmer, J. Mages, K. Gueinzius, C. Hess, K. Heeg, R. bals, R. Lang, and A. H. Dalpke, Differential recognition of TLR-dependent microbial ligands in human bronchial epithelial cells, J. Immunol., 178 (2007) 3134-3142.
[14] R. Landmann, B. Muller, and W. Zimmerli, CD14, new aspects of ligand and signal diversity, Microbes. Infect., 2 (2000) 295-304.
[15] A. Sumegi, A. Szegedi, M. Gal, J. Hunyadi, G. Szegedi, and P. ntal-Szalmas, Analysis of components of the CD14/TLR system on leukocytes of patients with atopic dermatitis, Int. Arch. Allergy Immunol., 143 (2007) 177-184.
[16] E. Levy, G. Xanthou, E. Petrakou, V. Zacharioudaki, C. Tsatsanis, S. Fotopoulos, and M. Xanthou, Distinct roles of TLR4 and CD14 in LPS-induced inflammatory responses of neonates, Pediatr. Res., 66 (2009) 179-184.
[17] G. Schabbauer, J. Luyendyk, K. Crozat, Z. Jiang, N. Mackman, S. Bahram, and P. Georgel, TLR4/CD14-mediated PI3K activation is an essential component of interferon-dependent VSV resistance in macrophages, Mol. Immunol., 45 (2008) 2790-2796.
[18] M. Chamaillard, S. E. Girardin, J. Viala, and D. J. Philpott, Nods, NALPs and Naip: intracellular regulators of bacterial-induced inflammation, Cell Microbiol., 5 (2003) 581-592.
[19] J. Li, J. Ding, W. Zhang, Y. Zhang, P. Tang, J. Q. Chen, D. Tian, and S. Yang, Unique evolutionary pattern of numbers of gramineous NBS-LRR genes, Mol. Genet. Genomics, 283 (2010) 427-438.
[20] D. A. Jones and D. Takemoto, Plant innate immunity - direct and indirect recognition of general and specific pathogen-associated molecules, Curr. Opin. Immunol., 16 (2004) 48-62.
[21] B. J. DeYoung and R. W. Innes, Plant NBS-LRR proteins in pathogen sensing and host defense, Nat. Immunol., 7 (2006) 1243-1249.

相關詞條

熱門詞條

聯絡我們