IgE為可引致第一型過敏症的免疫球蛋白，它是由分泌IgE的漿細胞所生產，而此種分泌IgE的漿細胞在分化過程中，必須經歷表現膜鑲嵌型IgE (mIgE) 的淋巴母細胞，此細胞會表現兩種膜鑲嵌型ε(mε) 鏈，長鏈 (mεL)的表現量遠高於短鏈(mεS)，且mεL在細胞膜上與CH4區域之間，比mεS多了一段52氨基酸的片段，稱之為CεmX，CεmX的產生是由於ε RNA transcript在RNA splicing的過程中，使用了位於mεS上游156 bp的splicing acceptor site，此多出來的序列在比對已知的資料庫中後，顯示其非常的獨特，因此，CεmX提供了一具吸引力的位置可供標的mIgE+ B細胞。

此論文中，九株新製備的anti-CεmX單株抗體連同之前實驗室所建立的a20單株抗體皆可結合上表現mIgE.FcL的CHO細胞，然而僅有anti-CεmX單株抗體4B12及26H2可結合上表現mIgE.FcL的Ramos細胞。4B12可辨識N端區域的CεmX，26H2可辨識中間端區域的CεmX，其餘的單株抗體包含a20辨識C端區域的CεmX。a20在辨識同時表現Igα、Igβ及mIgE.FcL的CHO細胞之能力上，低於4B12及26H2。4B12及26H2之小鼠人類嵌合抗體在使用二級抗體的交叉連結下，可誘發表現mIgE.FcL的Ramos細胞透過caspase的路徑進行細胞凋亡。使用人類周邊血單核球細胞作為作用細胞，4B12及26H2之小鼠人類嵌合抗體可透過ADCC的機制來毒殺表現mIgE.FcL的Ramos細胞。在培養異位性皮膚炎患者的周邊血單核球細胞之過程中，加入4B12及26H2之小鼠人類嵌合抗體可抑制anti-CD40及IL-4所刺激的IgE生成。上述的結果顯示4B12及26H2可用來標的mIgE+ B細胞，進一步控制IgE的產生。

藉由分析320位台灣受試者的CεmX序列，分別在第46及93的位置（沿CεmX的156個bp來做標示），發現兩個單一核苷酸多型性，分別從G變成T及A變成G，第46位置的變化造成氨基酸從Val變成Leu，第93位置的變化仍維持氨基酸為Gly。在640條定序出來的序列中，已知的46G93A allelic form出現293次，新發現的46T93A allelic form (GeneBank accession no. GU208817) 及46G93G allelic form (GU208818)分別出現26及321次，沒有發現46T93G allelic form。所發現在CεmX上的兩個單一核苷酸多型性，與病人血清IgE皆沒有相關性。anti-CεmX單株抗體4B12可等效結合mIgE.FcL(16V)及mIgE.FcL(16L)。雖然需要更多的族群來探討CεmX序列的變異性，就目前所分析的台灣族群而言，在CεmX上新發現的兩個單一核苷酸多型性，不會影響到anti-CεmX單株抗體結合mIgE+ B細胞的可行性。

IgE produced by IgE-secreting plasma cells mediates type-I hypersensitivity reactions responsible for various allergic diseases. The differentiation of IgE-secreting plasma cells must go through the membrane-bound IgE+ (mIgE+) lymphoblast stage. On mIgE+ B cells, the membrane-bound ε-chain (mε) exists predominantly in the long isoform, mεL, containing an extra 52-a.a. CεmX domain between CH4 and the C-terminal membrane-anchoring segment; the short isoform of mε, mεS, exists in minor proportions. CεmX, which resulted from an alternative splicing of the ε RNA transcript at 156-bp upstream of the splicing acceptor site used by mεS, is unique in the existing DNA and protein databases. CεmX thus provides an attractive site for immunologic targeting of mIgE+ B cells.

In this thesis, nine newly prepared CεmX-specific monoclonal antibodies (mAbs), as well as the previously reported a20, bound to mIgE.FcL-expressing CHO cells, while only 4B12 and 26H2 bound to mIgE.FcL-expressing B cell line Ramos cells. The mAb 4B12 bound to the N-terminal part, 26H2 the middle part and all others the C-terminal part of CεmX. Expression of Igα and Igβ on the mIgE.FcL-CHO cells reduces the binding of a20 to CεmX as compared with that of 4B12 and 26H2. The chimeric mAbs c4B12 and c26H2, when cross-linked by secondary antibodies, lysed mIgE.FcL-Ramos cells by apoptosis through a BCR-dependent caspase pathway. Using PBMCs as the source of effector cells, c4B12 and c26H2 demonstrated antibody-dependent cellular cytotoxicity (ADCC) toward mIgE.FcL-Ramos cells in a dose-dependent fashion. In cultures of PBMCs from atopic dermatitis patients, c4B12 and c26H2 inhibited the synthesis of IgE driven by anti-CD40 and IL-4. These results suggest that 4B12 and 26H2 are potentially useful for targeting mIgE+ B cells to control IgE production.

Based on an analysis of the CεmX genomic DNA sequences of 320 subjects residing in Taiwan, single-nucleotide polymorphisms (SNPs) have been found at two positions, namely, G/T at #46 and A/G at #93 (along the 156 bp of CεmX), with the former creating an amino acid change from Val to Leu at #16 (along the 52 a.a. of CεmX) and the latter resulting in no change (Gly). Among the 640 CεmX sequences identified, the previously known 46G93A allelic form appeared 293 times, the newly discovered 46T93A allelic form (GeneBank accession no. GU208817) 26 times, and the 46G93G allelic form (GU208818) 321 times. No 46T93G allelic form was found. Serum IgE measurements showed that the SNPs did not correlate with the levels of serum IgE. The anti-CεmX mAb, 4B12, could bind equally well to mIgE.FcL(16V) and mIgE.FcL(16L). While genetic variation of CεmX of broader populations should also be investigated, these newly discovered genetic variants of CεmX in the Taiwanese population do not seem to affect the feasibility of using an anti-CεmX mAb, such as 4B12, to target mIgE+ B cells.

1.Ishizaka, K., and T. Ishizaka. 1966. Physicochemical properties of reaginic antibody. 1. Association of reaginic activity with an immunoglobulin other than gamma A- or gamma G-globulin. J Allergy 37:169-185.

2.Ishizaka, K., T. Ishizaka, and M. M. Hornbrook. 1966. Physico-chemical properties of human reaginic antibody. IV. Presence of a unique immunoglobulin as a carrier of reaginic activity. J Immunol 97:75-85.

3.Ishizaka, K., T. Ishizaka, and M. M. Hornbrook. 1966. Physicochemical properties of reaginic antibody. V. Correlation of reaginic activity with gamma-E-globulin antibody. J Immunol 97:840-853.

4.Burrows, B., F. D. Martinez, M. Halonen, R. A. Barbee, and M. G. Cline. 1989. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med 320:271-277.

5.Sears, M. R., B. Burrows, E. M. Flannery, G. P. Herbison, C. J. Hewitt, and M. D. Holdaway. 1991. Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children. N Engl J Med 325:1067-1071.

6.Lichtenstein, L. M., K. Ishizaka, P. S. Norman, A. K. Sobotka, and B. M. Hill. 1973. IgE antibody measurements in ragweed hay fever. Relationship to clinical severity and the results of immunotherapy. J Clin Invest 52:472-482.

7.Naclerio, R. M., N. F. Adkinson, Jr., P. S. Creticos, F. M. Baroody, R. G. Hamilton, and P. S. Norman. 1993. Intranasal steroids inhibit seasonal increases in ragweed-specific immunoglobulin E antibodies. J Allergy Clin Immunol 92:717-721.

8.Johnson, E. E., J. S. Irons, R. Patterson, and M. Roberts. 1974. Serum IgE concentration in atopic dermatitis. Relationship to severity of disease and presence of atopic respiratory disease. J Allergy Clin Immunol 54:94-99.

9.Joishy, M., M. Alfaham, and D. Tuthill. 2005. Does the severity of atopic dermatitis correlate with serum IgE levels? Pediatr Allergy Immunol 16:283.

10.Galli, S. J., M. Tsai, and A. M. Piliponsky. 2008. The development of allergic inflammation. Nature 454:445-454.

11.Chang, T. W., P. C. Wu, C. L. Hsu, and A. F. Hung. 2007. Anti-IgE antibodies for the treatment of IgE-mediated allergic diseases. Adv Immunol 93:63-119.

12.Hellman, L. 2007. Regulation of IgE homeostasis, and the identification of potential targets for therapeutic intervention. Biomed Pharmacother 61:34-49.

13.Casale, T. B., and J. R. Stokes. 2008. Immunomodulators for allergic respiratory disorders. J Allergy Clin Immunol 121:288-296; quiz 297-288.

14.Broide, D. H. 2009. Immunomodulation of allergic disease. Annu Rev Med 60:279-291.

15.Geha, R. S., H. H. Jabara, and S. R. Brodeur. 2003. The regulation of immunoglobulin E class-switch recombination. Nat Rev Immunol 3:721-732.

16.Gould, H. J., and B. J. Sutton. 2008. IgE in allergy and asthma today. Nat Rev Immunol 8:205-217.

17.Gauchat, J. F., G. Aversa, H. Gascan, and J. E. de Vries. 1992. Modulation of IL-4 induced germline epsilon RNA synthesis in human B cells by tumor necrosis factor-alpha, anti-CD40 monoclonal antibodies or transforming growth factor-beta correlates with levels of IgE production. Int Immunol 4:397-406.

18.Oettgen, H. C. 2000. Regulation of the IgE isotype switch: new insights on cytokine signals and the functions of epsilon germline transcripts. Curr Opin Immunol 12:618-623.

19.Lipsky, P. E., J. F. Attrep, A. C. Grammer, M. J. McIlraith, and Y. Nishioka. 1997. Analysis of CD40-CD40 ligand interactions in the regulation of human B cell function. Ann N Y Acad Sci 815:372-383.

20.Dedeoglu, F., B. Horwitz, J. Chaudhuri, F. W. Alt, and R. S. Geha. 2004. Induction of activation-induced cytidine deaminase gene expression by IL-4 and CD40 ligation is dependent on STAT6 and NFkappaB. Int Immunol 16:395-404.

21.Delker, R. K., S. D. Fugmann, and F. N. Papavasiliou. 2009. A coming-of-age story: activation-induced cytidine deaminase turns 10. Nat Immunol 10:1147-1153.

22.Wyczolkowska, J., E. Brzezinska-Blaszczyk, and C. Maslinski. 1983. Kinetics of specific IgE antibody and total IgE responses in mice: the effect of immunosuppressive treatment. Int Arch Allergy Appl Immunol 72:16-21.

23.Holt, P. G., J. D. Sedgwick, C. O'Leary, K. Krska, and S. Leivers. 1984. Long-lived IgE- and IgG-secreting cells in rodents manifesting persistent antibody responses. Cell Immunol 89:281-289.

24.Radbruch, A., G. Muehlinghaus, E. O. Luger, A. Inamine, K. G. Smith, T. Dorner, and F. Hiepe. 2006. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat Rev Immunol 6:741-750.

25.Durham, S. R., H. J. Gould, and Q. A. Hamid. 1997. Local IgE production in nasal allergy. Int Arch Allergy Immunol 113:128-130.

26.KleinJan, A., J. G. Vinke, L. W. Severijnen, and W. J. Fokkens. 2000. Local production and detection of (specific) IgE in nasal B-cells and plasma cells of allergic rhinitis patients. Eur Respir J 15:491-497.

27.Wilson, D. R., T. G. Merrett, E. M. Varga, L. Smurthwaite, H. J. Gould, M. Kemp, J. Hooper, S. J. Till, and S. R. Durham. 2002. Increases in allergen-specific IgE in BAL after segmental allergen challenge in atopic asthmatics. Am J Respir Crit Care Med 165:22-26.

28.Max, E. E., J. Battey, R. Ney, I. R. Kirsch, and P. Leder. 1982. Duplication and deletion in the human immunoglobulin epsilon genes. Cell 29:691-699.

29.Nishida, Y., T. Miki, H. Hisajima, and T. Honjo. 1982. Cloning of human immunoglobulin epsilon chain genes: evidence for multiple C epsilon genes. Proc Natl Acad Sci U S A 79:3833-3837.

30.Hisajima, H., Y. Nishida, S. Nakai, N. Takahashi, S. Ueda, and T. Honjo. 1983. Structure of the human immunoglobulin C epsilon 2 gene, a truncated pseudogene: implications for its evolutionary origin. Proc Natl Acad Sci U S A 80:2995-2999.

31.Battey, J., E. E. Max, W. O. McBride, D. Swan, and P. Leder. 1982. A processed human immunoglobulin epsilon gene has moved to chromosome 9. Proc Natl Acad Sci U S A 79:5956-5960.

32.Ueda, S., S. Nakai, Y. Nishida, H. Hisajima, and T. Honjo. 1982. Long terminal repeat-like elements flank a human immunoglobulin epsilon pseudogene that lacks introns. EMBO J 1:1539-1544.

33.Ueda, S., O. Takenaka, and T. Honjo. 1985. A truncated immunoglobulin epsilon pseudogene is found in gorilla and man but not in chimpanzee. Proc Natl Acad Sci U S A 82:3712-3715.

34.Chang, T. W., F. M. Davis, N. C. Sun, C. R. Sun, D. W. MacGlashan, Jr., and R. G. Hamilton. 1990. Monoclonal antibodies specific for human IgE-producing B cells: a potential therapeutic for IgE-mediated allergic diseases. Biotechnology (N Y) 8:122-126.

35.Davis, F. M., L. A. Gossett, K. L. Pinkston, R. S. Liou, L. K. Sun, Y. W. Kim, N. T. Chang, T. W. Chang, K. Wagner, J. Bews, and et al. 1993. Can anti-IgE be used to treat allergy? Springer Semin Immunopathol 15:51-73.

36.Kolbinger, F., J. Saldanha, N. Hardman, and M. M. Bendig. 1993. Humanization of a mouse anti-human IgE antibody: a potential therapeutic for IgE-mediated allergies. Protein Eng 6:971-980.

37.Presta, L. G., S. J. Lahr, R. L. Shields, J. P. Porter, C. M. Gorman, B. M. Fendly, and P. M. Jardieu. 1993. Humanization of an antibody directed against IgE. J Immunol 151:2623-2632.

38.Chang, T. W. 2000. The pharmacological basis of anti-IgE therapy. Nat Biotechnol 18:157-162.

39.MacGlashan, D. W., Jr., B. S. Bochner, D. C. Adelman, P. M. Jardieu, A. Togias, J. McKenzie-White, S. A. Sterbinsky, R. G. Hamilton, and L. M. Lichtenstein. 1997. Down-regulation of Fc(epsilon)RI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 158:1438-1445.

40.Prussin, C., D. T. Griffith, K. M. Boesel, H. Lin, B. Foster, and T. B. Casale. 2003. Omalizumab treatment downregulates dendritic cell FcepsilonRI expression. J Allergy Clin Immunol 112:1147-1154.

41.Chang, T. W., and Y. Y. Shiung. 2006. Anti-IgE as a mast cell-stabilizing therapeutic agent. J Allergy Clin Immunol 117:1203-1212; quiz 1213.

42.Ames, S. A., C. D. Gleeson, and P. Kirkpatrick. 2004. Omalizumab. Nat Rev Drug Discov 3:199-200.

43.Davis, F. M., L. A. Gossett, and T. W. Chang. 1991. An epitope on membrane-bound but not secreted IgE: implications in isotype-specific regulation. Biotechnology (N Y) 9:53-56.

44.Chen, H. Y., F. T. Liu, C. M. Hou, J. S. Huang, B. B. Sharma, and T. W. Chang. 2002. Monoclonal antibodies against the C(epsilon)mX domain of human membrane-bound IgE and their potential use for targeting IgE-expressing B cells. Int Arch Allergy Immunol 128:315-324.

45.Feichtner, S., D. Infuhr, G. Achatz-Straussberger, D. Schmid, A. Karnowski, M. Lamers, C. Rhyner, R. Crameri, and G. Achatz. 2008. Targeting the extracellular membrane-proximal domain of membrane-bound IgE by passive immunization blocks IgE synthesis in vivo. J Immunol
180:5499-5505.

46.Batista, F. D., S. Anand, G. Presani, D. G. Efremov, and O. R. Burrone. 1996. The two membrane isoforms of human IgE assemble into functionally distinct B cell antigen receptors. J Exp Med 184:2197-2205.

47.Peng, C., F. M. Davis, L. K. Sun, R. S. Liou, Y. W. Kim, and T. W. Chang. 1992. A new isoform of human membrane-bound IgE. J Immunol 148:129-136.

48.Zhang, K., A. Saxon, and E. E. Max. 1992. Two unusual forms of human immunoglobulin E encoded by alternative RNA splicing of epsilon heavy chain membrane exons. J Exp Med 176:233-243.

49.Batista, F. D., D. G. Efremov, and O. R. Burrone. 1995. Characterization and expression of alternatively spliced IgE heavy chain transcripts produced by peripheral blood lymphocytes. J Immunol 154:209-218.

50.Poggianella, M., M. Bestagno, and O. R. Burrone. 2006. The extracellular membrane-proximal domain of human membrane IgE controls apoptotic signaling of the B cell receptor in the mature B cell line A20. J Immunol 177:3597-3605.

51.Sato, M., T. Adachi, and T. Tsubata. 2007. Augmentation of signaling through BCR containing IgE but not that containing IgA due to lack of CD22-mediated signal regulation. J Immunol 178:2901-2907.

52.Achatz, G., L. Nitschke, and M. C. Lamers. 1997. Effect of transmembrane and cytoplasmic domains of IgE on the IgE response. Science 276:409-411.

53.Achatz, G., E. Luger, R. Geisberger, G. Achatz-Straussberger, M. Breitenbach, and M. Lamers. 2001. The IgE antigen receptor: a key regulator for the production of IgE antibodies. Int Arch Allergy Immunol 124:31-34.

54.Donjerkovic, D., and D. W. Scott. 2000. Activation-induced cell death in B lymphocytes. Cell Res 10:179-192.

55.Labrijn, A. F., R. C. Aalberse, and J. Schuurman. 2008. When binding is enough: nonactivating antibody formats. Curr Opin Immunol 20:479-485.

56.Yanagihara, Y., K. Kajiwara, K. Ikizawa, T. Koshio, K. Okumura, and C. Ra. 1994. Recombinant soluble form of the human high-affinity immunoglobulin E (IgE) receptor inhibits IgE production through its specific binding to IgE-bearing B cells. J Clin Invest 94:2162-2165.

57.Kajiwara, K., M. Shinazawa, H. Morishima, and Y. Yanagihara. 2004. Differential effect of IL-4 and IL-13 on the expression of recombination-activating genes in mature B cells from human peripheral blood. Cell Immunol 227:121-128.

58.Essono, S., Y. Frobert, J. Grassi, C. Creminon, and D. Boquet. 2003. A general method allowing the design of oligonucleotide primers to amplify the variable regions from immunoglobulin cDNA. J Immunol Methods 279:251-266.

59.Liou, R. S., E. M. Rosen, M. S. Fung, W. N. Sun, C. Sun, W. Gordon, N. T. Chang, and T. W. Chang. 1989. A chimeric mouse-human antibody that retains specificity for HIV gp120 and mediates the lysis of HIV-infected cells. J Immunol 143:3967-3975.

60.Reff, M. E., K. Carner, K. S. Chambers, P. C. Chinn, J. E. Leonard, R. Raab, R. A. Newman, N. Hanna, and D. R. Anderson. 1994. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83:435-445.

61.Neuberger, M. S., and K. Rajewsky. 1981. Switch from hapten-specific immunoglobulin M to immunoglobulin D secretion in a hybrid mouse cell line. Proc Natl Acad Sci U S A 78:1138-1142.

62.Sun, X., H. C. Hia, P. E. Goh, and M. G. Yap. 2008. High-density transient gene expression in suspension-adapted 293 EBNA1 cells. Biotechnol Bioeng 99:108-116.

63.Kobayashi, S., N. Haruo, K. Sugane, H. D. Ochs, and K. Agematsu. 2009. Interleukin-21 stimulates B-cell immunoglobulin E synthesis in human beings concomitantly with activation-induced cytidine deaminase expression and differentiation into plasma cells. Hum Immunol 70:35-40.

64.Renz, H., C. Brodie, K. Bradley, D. Y. Leung, and E. W. Gelfand. 1994. Enhancement of IgE production by anti-CD40 antibody in atopic dermatitis. J Allergy Clin Immunol 93:658-668.

65.Zhang, K., E. A. Clark, and A. Saxon. 1991. CD40 stimulation provides an IFN-gamma-independent and IL-4-dependent differentiation signal directly to human B cells for IgE production. J Immunol 146:1836-1842.

66.Brouns, G. S., E. de Vries, and J. Borst. 1995. Assembly and intracellular transport of the human B cell antigen receptor complex. Int Immunol 7:359-368.

67.Bestagno, M., L. Vangelista, P. A. Mandiola, S. Mukherjee, J. Sepulveda, and O. R. Burrone. 2001. Membrane immunoglobulins are stabilized by interchain disulfide bonds occurring within the extracellular membrane-proximal domain. Biochemistry 40:10686-10692.

68.Vervoordeldonk, S. F., P. A. Merle, E. F. van Leeuwen, C. E. van der Schoot, A. E. von dem Borne, and I. C. Slaper-Cortenbach. 1994. Fc gamma receptor II (CD32) on malignant B cells influences modulation induced by anti-CD19 monoclonal antibody. Blood 83:1632-1639.

69.Eldering, E., and R. A. VanLier. 2005. B-cell antigen receptor-induced apoptosis: looking for clues. Immunol Lett 96:187-194.

70.van der Kolk, L. E., L. M. Evers, C. Omene, S. M. Lens, S. Lederman, R. A. van Lier, M. H. van Oers, and E. Eldering. 2002. CD20-induced B cell death can bypass mitochondria and caspase activation. Leukemia 16:1735-1744.

71.Pittner, B. T., and E. C. Snow. 1998. Strength of signal through BCR determines the fate of cycling B cells by regulating the expression of the Bcl-2 family of survival proteins. Cell Immunol 186:55-62.

72.Shan, D., J. A. Ledbetter, and O. W. Press. 1998. Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies. Blood 91:1644-1652.

73.Pogue, S. L., and C. C. Goodnow. 1994. Ig heavy chain extracellular spacer confers unique glycosylation of the Mb-1 component of the B cell antigen receptor complex. J Immunol 152:3925-3934.

74.Schamel, W. W., and M. Reth. 2000. Stability of the B cell antigen receptor complex. Mol Immunol 37:253-259.

75.Cameron, L., Q. Hamid, E. Wright, Y. Nakamura, P. Christodoulopoulos, S. Muro, S. Frenkiel, F. Lavigne, S. Durham, and H. Gould. 2000. Local synthesis of epsilon germline gene transcripts, IL-4, and IL-13 in allergic nasal mucosa after ex vivo allergen exposure. J Allergy Clin Immunol 106:46-52.

76.Takhar, P., L. Smurthwaite, H. A. Coker, D. J. Fear, G. K. Banfield, V. A. Carr, S. R. Durham, and H. J. Gould. 2005. Allergen drives class switching to IgE in the nasal mucosa in allergic rhinitis. J Immunol 174:5024-5032.

77.Gould, H. J., P. Takhar, H. E. Harries, S. R. Durham, and C. J. Corrigan. 2006. Germinal-centre reactions in allergic inflammation. Trends Immunol 27:446-452.

78.McMenamin, C., B. Girn, and P. G. Holt. 1992. The distribution of IgE plasma cells in lymphoid and non-lymphoid tissues of high-IgE responder rats: differential localization of antigen-specific and 'bystander' components of the IgE response to inhaled antigen. Immunology 77:592-596.

79.Achatz-Straussberger, G., N. Zaborsky, S. Konigsberger, E. O. Luger, M. Lamers, R. Crameri, and G. Achatz. 2008. Migration of antibody secreting cells towards CXCL12 depends on the isotype that forms the BCR. Eur J Immunol 38:3167-3177.

80.Yu, L. M., C. Peng, S. M. Starnes, R. S. Liou, and T. W. Chang. 1990. Two isoforms of human membrane-bound alpha Ig resulting from alternative mRNA splicing in the membrane segment. J Immunol 145:3932-3936.

81.Leduc, I., M. Drouet, M. C. Bodinier, A. Helal, and M. Cogne. 1997. Membrane isoforms of human immunoglobulins of the A1 and A2 isotypes: structural and functional study. Immunology 90:330-336.

82.Hung, A. F., J. B. Chen, and T. W. Chang. 2008. Alleles and isoforms of human membrane-bound IgA1. Mol Immunol 45:3624-3630.

83.Nanjo, K., T. Sanke, M. Miyano, K. Okai, R. Sowa, M. Kondo, S. Nishimura, K. Iwo, K. Miyamura, B. D. Given, and et al. 1986. Diabetes due to secretion of a structurally abnormal insulin (insulin Wakayama). Clinical and functional characteristics of [LeuA3] insulin. J Clin Invest 77:514-519.

84.Sakura, H., Y. Iwamoto, Y. Sakamoto, T. Kuzuya, and H. Hirata. 1986. Structurally abnormal insulin in a diabetic patient. Characterization of the mutant insulin A3 (Val----Leu) isolated from the pancreas. J Clin Invest 78:1666-1672.

85.Wan, Z. L., K. Huang, B. Xu, S. Q. Hu, S. Wang, Y. C. Chu, P. G. Katsoyannis, and M. A. Weiss. 2005. Diabetes-associated mutations in human insulin: crystal structure and photo-cross-linking studies of a-chain variant insulin Wakayama. Biochemistry 44:5000-5016.

86.Catto, A. J., H. P. Kohler, S. Bannan, M. Stickland, A. Carter, and P. J. Grant. 1998. Factor XIII Val 34 Leu: a novel association with primary intracerebral hemorrhage. Stroke 29:813-816.

87.Corral, J., J. A. Iniesta, R. Gonzalez-Conejero, M. Villalon, J. Rivera, and V. Vicente. 2000. Factor XIII Val34Leu polymorphism in primary intracerebral haemorrhage. Hematol J 1:269-273.

88.Jones, R. T., H. I. Saiontz, C. Head, D. T. Shih, and V. F. Fairbanks. 1990. Hb Johnstown [beta 109 (G11) Val----Leu]: a new electrophoretically silent variant that causes erythrocytosis. Hemoglobin 14:147-156.

89.Ropero, P., A. Villegas, A. F. Gonzalez, E. Anguita, J. Sanchez, D. L. Carreno, B. Arrizabalaga, and L. Atuxta. 2000. Hb Johnstown [beta 109 (G11) Val-->Leu]: second case described and associated for the first time with beta(0)-thalassemia in two Spanish families. Am J Hematol 65:298-301.