„Glycosidic exclusion“ not protecting the „Oh“ or Bombay Type

"Glycosidic exclusion" not protecting the "Oh" or Bombay Type <b> </b>Peter Arend<b> *,**.</b> The molecular biological relationship between human fertility and the ABO(H) blood group phenotype formation becomes visible through special cell surface structures and immunoglobulin M specificities arising in people with the rare Oh or <i>Bombay</i> blood type (1), whom Charles Darwin would, by the history of his own family, the “<i>Darwin/Wedgewood Dynasty” </i>(2; 3), have analyzed to result from reduced fertility in consanguinities. The classical <i>Bombay type</i> is characterized by the lack of expression of any ABO(H) epitope and instead shows the development of high isoagglutinin levels, additionally exerting strong binding of complement to anti-H agglutinin. The red cell surface presents with the naked structure Gal-β1-R, which has not been completed for the H-receptor (Fuc-α1-2-Gal-β1-R), thereby representing the structural fundament for ABOH epitopes. In its native form, the <i>Bombay</i> type occurs in individuals with the extremely rare genotype (h/h;se/se). This molecular biological phenomenon is explained by point mutations at the H- and Se genes on chromosome 19 such that the fucosyltransferases FUT1 and FUT2 are not encoded. FUT1 and FUT2 are epistatically connected with the A and B allelic glycotransferase functions encoded on chromosome 9, and fucosyl residues provide the functional-structural basis of the formation of any ABOH phenotype on the cell surface or in secretions and plasma proteins. Moreover, immunoglobulins are heavily fucosylated and fucosyl residues appear, through developmental varying of the positions between the cell surfaces and the heavy chains of immunoglobulins to augment or reduce antibody-mediated cellular cytotoxicity (4; 5; 6). In fact, the seminal IgG of leucocytospermic infertile men appears to be characterized by poor core fucosylation (7), while the rest of the seminal plasma demonstrates high levels of non-immunoglobulin-linked fucosyl residues (8; 9; 10). Thus, in <i>Bombay type</i> individuals, the non-somatic glycosylation processes of embryogenic stem cell-to-germ cell transformation involving modification and <i>O</i>-fucosylation of EGF (11) are most likely exposed to metabolic competition with multiple glycosidic sites of poorly fucosylated, glycan-depleted immunoglobulins. *Arend, Peter: ABO phenotype and innate isoagglutinin specificities as they arise from “glycosidic exclusion” and relate to human reproduction. A hypothesis* https://dx.doi.org/10.6084/m9.figshare.1368271**Arend, Peter: Human fertility and ABO(H) histo (blood) group completenes as they relate to somatic fucosylations, https://dx.doi.org/10.6084/m9.figshare.2007132 References. 1.) Y.M. Bhende, C.K. Deshpande, H.M. Bhatia, R. Sanger, R.R. Race, W.T. Morgan, &amp; W. M.Watkins, A “new” blood-group character related to the ABO system. 1952., Natl. Med. J. India. 21 (2008) 3 p. doi:10.1016/S0140-6736(52)92356-8. 2.) T.M. Berra, G. Alvarez &amp; F.C. Ceballos, Was the Darwin/Wedgwood Dynasty Adversely Affected by Consanguinity?, Bioscience. 60 (2010) 376–383. doi:10.1525/bio.2010.60.5.7. 3.) G. Álvarez, F.C. Ceballos &amp;T.M. Berra, Darwin was right : inbreeding depression on male fertility in the Darwin family, Biol. J. Linn. Soc. (2014) 1–10. doi:10.1111/bij.12433. 4.) K. Masuda, K., Kubota, T., Kaneko, E., Iida, S., Wakitani, M., Kobayashi-Natsume, Y., Kubota, A., Shitara, K. &amp; Nakamura, Enhanced binding affinity for FcgammaRIIIa of fucose-negative antibody is sufficient to induce maximal antibody-dependent cellular cytotoxicity.Mol.Immunol.44(2007)3122–31. http://www.sciencedirect.com/science/article/pii/S0161589007000776. 5.) M. Iida, S., Kuni-Kamochi, R., Mori, K., Misaka, H., Inoue, M., Okazaki, A., Shitara, K. &amp; Satoh, Two mechanisms of the enhanced antibody-dependent cellular cytotoxicity (ADCC) efficacy of non-fucosylated therapeutic antibodies in human blood., BMC Cancer. 9 (2009) 58. doi:10.1186/1471-2407-9-58. 6.) N. Yamane-Ohnuki &amp; M. Satoh, Production of therapeutic antibodies with controlled fucosylation., MAbs. 1 (2009) 230–6. doi:10.4161/mabs.1.3.8328. 7.) E.M. Kratz, M. Ferens-Sieczkowska, R. Faundez, &amp; I. Kątnik-Prastowska, Changes in fucosylation of human seminal IgG and secretory component of IgA in leukocytospermic patients, Glycoconj. J. 31 (2014) 51–60. doi:10.1007/s10719-013-9501-y. 8.) G.C. Domino, S.E. Hurd, E.A. Thomsson, K.A. Karnak, D.M. Holmen Larsson, J.M. Thomsson, E. Bäckström, M., &amp; Hansson, Cervical mucins carry alpha(1,2)fucosylated glycans that partly protect from experimental vaginal candidiasis., Glycoconj. J. 26 (2009) 1125–34. doi:10.1007/s10719-009-9234-0. 9.) J. Smith, P. Myers, J. Rogers, C., Zhou, L. Petryniak, B. Becker, D. Homeister, &amp; J. Lowe, Conditional control of selectin ligand expression and global fucosylation events in mice with a targeted mutation at the FX locus., J. Cell Biol. 158 (2002) 801–15. doi:10.1083/jcb.200203125. 10.) B. Olejnik, E.M. Kratz &amp; M. Zimmer, Glycoprotein fucosylation is increased in seminal plasma of subfertile men., Asian J Androl. 17 (2015) 274–80. doi:2524865. 11.) Y. Wang, L. Shao, S. Shi, R.J. Harris, M.W. Spellman, P. Stanley, et al., Modification of epidermal growth factor-like repeats with O-fucose: Molecular cloning and expression of a novel GDP-fucose protein O-fucosyltransferase, J. Biol. Chem. 276 (2001) 40338–40345. doi:10.1074/jbc.M107849200. Abbreviations: ESC = embryonic stem cells; EGF= epidermal growth factor.GC = germ cells. <br> <br>

"糖苷排除效应"（Glycosidic exclusion）无法保护"Oh"型或孟买型（Bombay Type）

Peter Arend*,**.

人类生育力与ABO(H)血型表型形成之间的分子生物学关联，可通过罕见的Oh型或孟买型（Bombay）个体所特有的特殊细胞表面结构与免疫球蛋白M特异性得以展现（1）。基于自身家族谱系，查尔斯·达尔文曾针对"达尔文/韦奇伍德家族（Darwin/Wedgewood Dynasty）"（2；3）开展研究，认为该家族的生育力衰退源于近亲婚配。

经典孟买型（Bombay type）的核心特征为不表达任何ABO(H)表位，反而会产生高滴度的同种凝集素，同时可与抗H凝集素强力结合并激活补体。红细胞表面呈现未完成H受体（Fuc-α1-2-Gal-β1-R）修饰的裸露结构Gal-β1-R，该结构正是ABOH表位形成的结构基础。天然状态下，孟买型（Bombay）个体携带极为罕见的纯合基因型（h/h; se/se）。这一分子生物学现象可由19号染色体上H基因与Se基因的点突变解释：此类突变无法编码岩藻糖基转移酶FUT1与FUT2。FUT1与FUT2与9号染色体上编码的A、B等位基因糖基转移酶功能存在上位性关联，而岩藻糖基残基则为细胞表面、分泌液及血浆蛋白中所有ABOH表型的形成提供了功能-结构基础。

此外，免疫球蛋白会发生广泛的岩藻糖基化修饰；岩藻糖基残基可通过改变其在细胞表面与免疫球蛋白重链之间的空间位置，增强或减弱抗体介导的细胞毒性作用（4；5；6）。研究证实，白细胞精子症不育男性的精浆IgG呈现核心岩藻糖基化水平低下的特征（7），而其余精浆成分则含有大量与免疫球蛋白无关的游离岩藻糖基残基（8；9；10）。因此，在孟买型（Bombay type）个体中，涉及胚胎干细胞向生殖细胞转化过程中的非体细胞糖基化通路——包括表皮生长因子（EGF）的O-岩藻糖基化与结构修饰（11）——极有可能与大量岩藻糖基化不足、聚糖缺失的免疫球蛋白的多个糖苷位点发生代谢竞争。

*Arend, Peter: ABO表型与天然同种凝集素特异性：源于"糖苷排除效应"且与人类生殖相关的假说 https://dx.doi.org/10.6084/m9.figshare.1368271
**Arend, Peter: 人类生育力与ABO(H)组织（血型）组学完整性：与体细胞岩藻糖基化的关联 https://dx.doi.org/10.6084/m9.figshare.2007132

参考文献
1.) Y.M. Bhende, C.K. Deshpande, H.M. Bhatia, R. Sanger, R.R. Race, W.T. Morgan, & W. M. Watkins, 一种与ABO血型系统相关的"新型"血型抗原. 1952, 《印度国家医学杂志》21(2008) 3页. doi:10.1016/S0140-6736(52)92356-8.
2.) T.M. Berra, G. Alvarez & F.C. Ceballos, 达尔文/韦奇伍德家族是否因近亲婚配受到不利影响, 《生物科学》60(2010) 376–383. doi:10.1525/bio.2010.60.5.7.
3.) G. Álvarez, F.C. Ceballos & T.M. Berra, 达尔文的论断正确：达尔文家族男性生育力的近交衰退效应, 《林奈学会生物学杂志》(2014) 1–10. doi:10.1111/bij.12433.
4.) K. Masuda, K., Kubota, T., Kaneko, E., Iida, S., Wakitani, M., Kobayashi-Natsume, Y., Kubota, A., Shitara, K. & Nakamura, 去岩藻糖基化抗体对FcγRIIIa的结合亲和力足够诱导最大抗体依赖性细胞介导的细胞毒性作用, 《分子免疫学》44(2007) 3122–31. http://www.sciencedirect.com/science/article/pii/S0161589007000776.
5.) M. Iida, S., Kuni-Kamochi, R., Mori, K., Misaka, H., Inoue, M., Okazaki, A., Shitara, K. & Satoh, 非岩藻糖基化治疗性抗体增强抗体依赖性细胞介导的细胞毒性作用的两种机制, 《BMC癌症》9(2009) 58. doi:10.1186/1471-2407-9-58.
6.) N. Yamane-Ohnuki & M. Satoh, 可控岩藻糖基化治疗性抗体的生产, 《单克隆抗体》1(2009) 230–6. doi:10.4161/mabs.1.3.8328.
7.) E.M. Kratz, M. Ferens-Sieczkowska, R. Faundez, & I. Kątnik-Prastowska, 白细胞精子症患者精浆IgG与分泌型IgA组分的岩藻糖基化变化, 《糖结合杂志》31(2014) 51–60. doi:10.1007/s10719-013-9501-y.
8.) G.C. Domino, S.E. Hurd, E.A. Thomsson, K.A. Karnak, D.M. Holmen Larsson, J.M. Thomsson, E. Bäckström, M., & Hansson, 宫颈黏液携带α(1,2)岩藻糖基化聚糖，可部分抵抗实验性阴道念珠菌病, 《糖结合杂志》26(2009) 1125–34. doi:10.1007/s10719-009-9234-0.
9.) J. Smith, P. Myers, J. Rogers, C. Zhou, L. Petryniak, B. Becker, D. Homeister, & J. Lowe, 靶向FX位点突变小鼠中选择素配体表达与全局岩藻糖基化事件的条件性调控, 《细胞生物学杂志》158(2002) 801–15. doi:10.1083/jcb.200203125.
10.) B. Olejnik, E.M. Kratz & M. Zimmer, 不育男性精浆中糖蛋白岩藻糖基化水平升高, 《亚洲男科学杂志》17(2015) 274–80. doi:2524865.
11.) Y. Wang, L. Shao, S. Shi, R.J. Harris, M.W. Spellman, P. Stanley, et al., O-岩藻糖修饰表皮生长因子样重复序列：一种新型GDP-岩藻糖蛋白O-岩藻糖基转移酶的分子克隆与表达, 《生物化学杂志》276(2001) 40338–40345. doi:10.1074/jbc.M107849200.

缩写说明：ESC=胚胎干细胞（embryonic stem cells）；EGF=表皮生长因子（epidermal growth factor）；GC=生殖细胞（germ cells）.