In addition to antibody isotypes and subtypes, allelic variation is found among the antibody subtypes. These polymorphic epitopes of immunoglobulins that can differ between individuals and ethnic groups are known as allotypes. Exposure of an individual to a non-self allotype can induce an anti-allotype response (1, 2). However, not all variations are immunogenic because this sequence may be found in other isotypes or subtypes and so these are known as isoallotypic variants. In fact, a recent study suggests that allotypic differences in human IgG1 do not represent a significant risk for induction of immunogenicity (3) and to date little evidence has been found for significant anti-allotype responses to therapeutic antibodies, e.g. adalimumab (4) or infliximab (5).
Allotpyes have been identified on the g1, g3 and a2 heavy chains (designated G1m, G3m and A2m allotypes respectively) and on the kappa light chain (Km allotypes). Although variants of g2 and g4 exist these are isoallotypic as the amino acids present are also found in other subclasses.
G1m17 and G1m3
G1m17, also known as G1m(z), corresponds to Lys (K) at position 214 in the CH1 domain (EU numbering).
G1m3, also known as G1m(f), corresponds to Arg (R) at position 214 in the CH1 domain.
G1m1 and nG1m1
G1m1, also known as G1m(a), corresponds to Asp (D) and Leu (L) at positions 356 and 358 in the CH3 domain (EU numbering).
nG1m1, also known as nG1m(a) corresponds to Glu (E) and Met (M) at positions 356 and 358.
G1m2 and nG1m2
G1m2, also known as G1m(x), corresponds to Gly (G) at position 431 in the CH3 domain (EU numbering).
nG1m2, also known as nG1m(x), corresponds to Ala (A) at position 431 in the CH3 domain.
Figure. Sequence alignment of human G1m allotypes.
The main allelic forms for IgG1 are G1m (z,a), G1m (f), and G1m (f,a) (6,7). The G1m (f) allele is only found in Caucasians, whereas the G1m (f,a) allele is common in Orientals, but other variants, G1m (z,a,x) and G1m (z,a,v), have also been described (8,9).
- Fudenberg, H.H., and Fudenberg, B.R. (1964). Antibody to hereditary human gamma-globulin (gm) factor resulting from maternal-fetal incompatibility. Science 145, 170–171.
- Jefferis, R., and Lefranc, M.-P. (2009). Human immunoglobulin allotypes: possible implications for immunogenicity. MAbs 1, 332–338.
- Webster, C.I., Bryson, C.J., Cloake, E.A., Jones, T.D., Austin, M.J., Karle, A.C., Spindeldreher, S., Lowe, D.C., and Baker, M.P. (2016). A comparison of the ability of the human IgG1 allotypes G1m3 and G1m1,17 to stimulate T-cell responses from allotype matched and mismatched donors. mAbs 8, 253–263.
- Bartelds, G.M., de Groot, E., Nurmohamed, M.T., Hart, M.H.L., van Eede, P.H., Wijbrandts, C.A., Crusius, J.B.A., Dijkmans, B.A.C., Tak, P.P., Aarden, L., et al. (2010). Surprising negative association between IgG1 allotype disparity and anti-adalimumab formation: a cohort study. Arthritis Res. Ther. 12, R221.
- Magdelaine-Beuzelin, C., Vermeire, S., Goodall, M., Baert, F., Noman, M., Assche, G.V., Ohresser, M., Degenne, D., Dugoujon, J.-M., Jefferis, R., et al. (2009). IgG1 heavy chain-coding gene polymorphism (G1m allotypes) and development of antibodies-to-infliximab. Pharmacogenet. Genomics 19, 383–387.
- De Lange, G.G. (1989). Polymorphisms of human immunoglobulins: Gm, Am, Em and Km allotypes. Exp. Clin. Immunogenet. 6, 7–17.
- De Lange, G., Zhong, F.M., Henke, J., Feng, Z.C., Bernhardt, R., van Leeuwen, F., and van Eede, P. (1985). Immunoglobulin allotypes in a Chinese population: comparison of haplotype frequencies with other Asian groups. J. Immunogenet. 12, 191–195.
- Cook, C.E., and Steinberg, A.G. (1979). An amino acid substitution in the gamma 1 chain of human immunoglobulin G associated with the Gm (2) allotype. Mol. Immunol. 16, 555–558.
- Goetze, A.M., Zhang, Z., Liu, L., Jacobsen, F.W., and Flynn, G.C. (2011). Rapid LC-MS screening for IgG Fc modifications and allelic variants in blood. Mol. Immunol. 49, 338–352.