在人體中，免疫球蛋白(immunoglobulin，簡稱Ig)分成五種類型(classes)：免疫球蛋白M、D、G、A和E，即IgM、IgD、IgG、IgA和IgE；而IgG又分成四個次類型(subclasses)， G1-4；IgA也分成兩個次類型，A1和A2。以可溶性形式(soluble form)存在的Ig，即所謂的抗體(antibody)，可直接與外來的病菌結合，引導各種免疫機制，以清除病菌。IgA不同於其他Igs，除了存在於血液和細胞間質中，也額外分布在腸胃道、呼吸道等分泌管道的粘膜表面。另一種鑲嵌在B細胞膜表面的Ig稱為”膜鑲嵌型Ig (membrane-bound Ig，簡稱mIg)”，主要扮演的角色是與抗原結合和訊號傳遞，來調控B細胞的活性。此篇論文研究的主題是分析mIgA1及mIgA2之長鏈(heavy chain)，即ma1及ma2，所存在的多種異構型(isofroms)，並近一步探討不同的異構型在不同的B細胞上可能扮演的功能。
在1990年，指導教授的實驗群發現ma1存在著兩種長度的異構型，長型(long form)的ma1在CH3區域(domain)和穿膜(transmembrane)區段之間，比短型(short form)多出6個胺基酸(amino acid residues)，序列為GSCSVA。這是由於RNA進行選擇性的接合現象(alternative splicing)，導致有兩種長度的胜肽。這個現象同時也出現在mIgE的me鏈。我們感興趣的是，除了mIgE及mIgA會有這種現象外，其他mIg是否也會出現類似的情形。在這研究過程中，我們對膜鑲嵌型ma1及ma2異構型和對偶構型(allele)有更新的發現。
我們把二十個正常人的周邊血液淋巴球(peripheral blood lymphocytes) 的mRNA萃取出來並逆轉錄成cDNA，經PCR把不同類型的膜鑲嵌型ma1及ma2的DNA片段放大，作定序，並進行比對。我們利用ma1及ma2在CH2區域的DNA序列上些微的差異所設計引子(Primer)來區分出兩者。我們意外發現了一個ma1的對偶基因，而這條新的對偶基因也會產生兩個不同構型的ma1，和原對偶基因存在的兩種異構型一樣，長型比短型多出6個胺基酸，序列為GSCCVA。新發現的與原對偶基因的差異在第456號胺基酸，因此這兩個對偶基因分別命名為ma1(456C)與ma1(456S)。此外，從ma2的DNA序列分析得知，ma2只有以短型的異構型出現。

In humans, IgA has two subclasses, IgA1 and IgA2, which contain, respectively, a1 and a2 heavy chains, respectively. For both subclasses, there are also membrane-bound forms, mIgA1, and mIgA2, containing ma1 and ma2 heavy chains. Ma1 and ma2 differ from a1 and a2 by having a “membrane-anchor” peptide segment extending from the C-termini of a1 and a2. The membrane-anchor segment has three parts: an extracellular, a trans-membrane, and an intracellular segments. It was found previously that ma1 exists in a short and a long isoforms, referred to as ma1(S) and ma1(L), with the later containing extra 6 amino acid residues, GSCSVA (numbered 453-458), at the N-terminal of the extracellular segment. By studying the genomic and mRNA sequences of 20 Taiwanese individuals, we have found that, in addition to ma1(456S), ma1 has a previously unknown allele, referred to as ma1(456C). Moreover, with m□1(456S) allele, both the long and short forms are produced, while the former is more abundant. However, ma1(456C) allele exists predominantly or entirely in long form. Furthermore, we have clarified that ma2 exist as short isoform only. Future studies will examine the variations in mIgA1 in other races and the possible association of such variations with the regulation of IgA synthesis.

1. Niiro, H., and E. A. Clark. 2002. Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol 2:945.
2. Wang, L. D., and M. R. Clark. 2003. B-cell antigen-receptor signaling in lymphocyte development. Immunology 110:411.
3. Lam, K. P., R. Kuhn, and K. Rajewsky. 1997. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90:1073.
4. Fuentes-Panana, E. M., G. Bannish, and J. G. Monroe. 2004. Basal B-cell receptor signaling in B lymphocytes: mechanisms of regulation and role in positive selection, differentiation, and peripheral survival. Immunol Rev 197:26.
5. DeFranco, A. L. 1993. Structure and function of the B cell antigen receptor. Annu Rev Cell Biol 9:377.
6. van Noesel, C. J., and R. A. van Lier. 1993. Architecture of the human B-cell antigen receptors. Blood 82:363.
7. Fearon, D. T., and R. H. Carter. 1995. The CD19/CR2/TAPA-1 complex of B lymphocytes: linking natural to acquired immunity. Annu Rev Immunol 13:127.
8. Sato, S., N. Ono, D. A. Steeber, D. S. Pisetsky, and T. F. Tedder. 1996. CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity. J Immunol 157:4371.
9. Callard, R. E., K. P. Rigley, S. H. Smith, S. Thurstan, and J. G. Shields. 1992. CD19 regulation of human B cell responses. B cell proliferation and antibody secretion are inhibited or enhanced by ligation of the CD19 surface glycoprotein depending on the stimulating signal used. J Immunol 148:2983.
10. Sato, S., D. A. Steeber, P. J. Jansen, and T. F. Tedder. 1997. CD19 expression levels regulate B lymphocyte development: human CD19 restores normal function in mice lacking endogenous CD19. J Immunol 158:4662.
11. Engel, P., L. J. Zhou, D. C. Ord, S. Sato, B. Koller, and T. F. Tedder. 1995. Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. Immunity 3:39.
12. Major, J. G., Jr., F. M. Davis, R. S. Liou, and T. W. Chang. 1996. Structural features of the extracellular portion of membrane-anchoring peptides on membrane-bound immunoglobulins. Mol Immunol 33:179.
13. 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.
14. Cogne, M., and J. L. Preud'homme. 1990. Gene deletions force nonsecretory alpha-chain disease plasma cells to produce membrane-form alpha-chain only. J Immunol 145:2455.
15. 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.
16. 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.
17. Leduc, I., M. Drouet, M. C. Bodinier, A. Helal, M. Cogne, and J. L. Preud'homme. 1997. Membrane isoforms of human immunoglobulins of the A1 and A2 isotypes: structural and functional study
Gene deletions force nonsecretory alpha-chain disease plasma cells to produce membrane-form alpha-chain only. Immunology 90:330.
18. Kerr, M. A. 1990. The structure and function of human IgA. Biochem J 271:285.
19. Steinitz, M., and G. Klein. 1980. EBV-transformation of surface IgA-positive human lymphocytes. J Immunol 125:194.
20. Bensmana, M., and M. P. Lefranc. 1990. Gene segments encoding membrane domains of the human immunoglobulin gamma 3 and alpha chains. Immunogenetics 32:321.
21. Kikutani, H., R. Sitia, R. A. Good, and J. Stavnezer. 1981. Synthesis and processing of the alpha heavy chains of secreted and membrane-bound IgA. Proc Natl Acad Sci U S A 78:6436.
22. Word, C. J., J. F. Mushinski, and P. W. Tucker. 1983. The murine immunoglobulin alpha gene expresses multiple transcripts from a unique membrane exon. Embo J 2:887.
23. Flanagan, J. G., M. P. Lefranc, and T. H. Rabbitts. 1984. Mechanisms of divergence and convergence of the human immunoglobulin alpha 1 and alpha 2 constant region gene sequences. Cell 36:681.
24. Chintalacharuvu, K. R., M. Raines, and S. L. Morrison. 1994. Divergence of human alpha-chain constant region gene sequences. A novel recombinant alpha 2 gene. J Immunol 152:5299.
25. Breathnach, R., C. Benoist, K. O'Hare, F. Gannon, and P. Chambon. 1978. Ovalbumin gene: evidence for a leader sequence in mRNA and DNA sequences at the exon-intron boundaries. Proc Natl Acad Sci U S A 75:4853.
26. Rabbitts, T. H., A. Forster, and C. P. Milstein. 1981. Human immunoglobulin heavy chain genes: evolutionary comparisons of C mu, C delta and C gamma genes and associated switch sequences. Nucleic Acids Res 9:4509.
27. Flanagan, J. G., and T. H. Rabbitts. 1982. Arrangement of human immunoglobulin heavy chain constant region genes implies evolutionary duplication of a segment containing gamma, epsilon and alpha genes. Nature 300:709.
28. 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.
29. Galla, J. H. 1995. IgA nephropathy. Kidney Int 47:377.
30. Donadio, J. V., and J. P. Grande. 2002. IgA nephropathy. N Engl J Med 347:738.
31. Baskin, B., E. Pettersson, S. Rekola, C. I. Smith, and K. B. Islam. 1996. Studies of the molecular basis of IgA production, subclass regulation and class-switch recombination in IgA nephropathy patients. Clin Exp Immunol 106:509.
32. Allen, A. C., P. S. Topham, S. J. Harper, and J. Feehally. 1997. Leucocyte beta 1,3 galactosyltransferase activity in IgA nephropathy. Nephrol Dial Transplant 12:701.
33. Coppo, R., and A. Amore. 2004. Aberrant glycosylation in IgA nephropathy (IgAN). Kidney Int 65:1544.
34. Liu, Y. S., T. L. Low, A. Infante, and F. W. Putnam. 1976. Complete covalent structure of a human IgA1 immunoglobulin. Science 193:1017.