The human G1m1 allotype associates with CD4+ T-cell responsiveness to a highly conserved IgG1 constant region peptide and confers an asparaginyl endopeptidase cleavage site

Abstract

The human G1m1 allotype comprises two amino acids, D12 and L14, in the CH3 domain of IGHG1. Although the G1m1 allotype is prevalent in human populations, ∼40% of Caucasiods are homozygous for the nG1m1 allotype corresponding to E12 and M14. Peptides derived from the G1m1 region were tested for their ability to induce CD4+ T-cell proliferative responses in vitro. A peptide immediately downstream from the G1m1 sequence was recognized by CD4+ T cells in a large percentage of donors (peptide CH315−29). CD4+ T-cell proliferative responses to CH315−29 were found at an increased frequency in nG1m1 homozygous donors. Homozygous nG1m1 donors possessing the HLA-DRB1*07 allele displayed the highest magnitudes of proliferation. CD4+ T cells from donors homozygous for nG1m1 proliferated to G1m1-carrying Fc-fragment proteins, whereas CD4+ T cells from G1m1 homozygous donors did not. The G1m1 sequence creates an enzymatic cleavage site for asparaginyl endopeptidase in vitro. Proteolytic activity at D12 may allow the presentation of the CH315−29 peptide, which in turn may result in the establishment of tolerance to this peptide in G1m1-positive donors. Homozygous nG1m1 patients may be more likely to develop CD4+ T-cell-mediated immune responses to therapeutic antibodies carrying the G1m1 allotype.

Cross-reactive and pre-existing antibodies to therapeutic antibodies—Effects on treatment and immunogenicity

“…58 Interestingly, one study reported increased in vitro CD4 T cell responsiveness to peptides derived from G1m1 antibodies in donors homozygous for the non-G1m1 allele versus those homozygous for the G1m1 allele. 61 However, a cohort study comprising 250 adalimumabtreated RA patients examined the formation of anti-adalimumab antibodies and determined their binding to the G1m17,1 allotype, and anti-allotype antibodies were detected in none of the patients. 62 Another cohort study examined anti-allotype antibody formation in 118 Crohn's disease patients treated with infliximab.…”

Rheumatoid arthritis response to treatment across IgG1 allotype – anti-TNF incompatibility: a case-only study

“…In effect, our results are concordant with the initial hypothesis involving induction of immune responses against the incompatible allotype of INX. These immune responses could include anti-allotype antibodies [ 16 , 17 , 19 ] or a T cell response independent of anti-allotype antibodies [ 18 ]. The anti-allotype antibodies would target the INX molecule leading to its accelerated clearance.…”

“…Our approach, at the DNA level instead of the anti-allotype antibodies, has avoided these technical difficulties, has permitted us to use patients lacking sera at the relevant point in the treatment course, and allows for other forms of involvement of the allotypes beyond the induction of antibodies. One of these alternative mechanisms is a different type of immune response against the G1m1 allotype that involves CD4 T cell activation and production of cytokines [ 18 ]. The T cell antigen does not include the allotype but a nearby peptide that becomes accessible to antigen processing and presentation because the G1m1 allotype introduces an asparaginyl endopeptidase cleavage site [ 18 ].…”

“…The G1m allotypes were studied at the DNA level [ 17 , 18 ]. We have genotyped two nsSNPs encoding them: rs1071803 (which A allele codes for the G1m17 allotype, whereas the G allele codes for the G1m3 allotype) and rs11621259 (which C allele codes for one of the two amino-acids comprising the G1m1 allotype, whereas the A allele codes for a protein that does not induce antibodies, namely a null allotype).…”

“…Detection of the anti-allotype antibodies targeting biologics has been rare, but this could be due to the technical challenges presented by these antibodies [ 16 , 17 , 19 , 22 ]. In addition, exposition to the G1m1 allotype in incompatible subjects induces T-cell responses directed against a different peptide in the IgG1 molecule [ 18 ]. The G1m1,17 allotypes could also influence treatment response by modifying the strength of antibody immune responses, as has been shown for several antigens, for rheumatoid factor (RF), and for anti-ADM antibodies [ 20 , 23 - 25 ].…”