T Cell Tolerance to Germline-Encoded Antibody Sequences in a Lupus-Prone Mouse

Guo, Wenzhong; Smith, Diana S.; Guth, Amanda; Aviszus, Katja; Wysocki, Lawrence J.

doi:10.4049/jimmunol.175.4.2184

Cited by 11 publications

(15 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…14, 15 Anti-allotype antibodies have been detected when individuals who do not possess the allotype in their genome are exposed to antibodies that carry the allotypic amino-acid sequence, such as after platelet transfusion or after multiple childbirths 16, 17, 18 However, the presence of novel amino acids in a normally conserved sequence may also function as a CD4+ T helper cell epitope, as has been shown in mice. 19, 20, 21, 22, 23 Productive, cognate interactions between immunoglobulin allotype-specific helper T cells and B cells in rodents have been demonstrated in vitro . 24, 25, 26, 27 Therefore, a CD4+ T helper cell epitope in the constant region of an exogenously administered antibody could potentially support the development of antibody responses to other novel regions of the protein, as exemplified by the complementarity determining regions, in humans.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

View full text Add to dashboard Cite

show abstract

“…The exception is the ability to generate CD4 + T cell hybridomas to mouse constant region allotypes that represent novel immunoglobulin sequences in mouse strains that do not carry the identical allotype sequence. 47 Antibody V regions, by contrast, contain CDRs that are unique to each B cell and are usually present in vanishingly small quantities. This is especially true of the somatically mutated CDR3 regions.…”

Section: Cd4mentioning

confidence: 99%

The immunogenicity of humanized and fully human antibodies

Harding¹,

Stickler²,

Razo³

et al. 2010

mAbs

593

258

View full text Add to dashboard Cite

“…This same Arg was also required for the chromatin-specificity of the original anti-nuclear monoclonal antibody that defines our system (37). Moreover, the SWR genome carries the same Vκ10.2 gene that encodes the light chain V region of the original anti-chromatin monoclonal antibody (47). …”

Section: Discussionmentioning

confidence: 99%

Spontaneous autoimmunity in mice that carry an IghV partial transgene: a required arginine in VHCDR3

Guth

Detanico

Smith

et al. 2009

Lupus

View full text Add to dashboard Cite

We describe a unique spontaneous mouse model of autoimmunity, which occurs on a nonautoimmune-prone SWR genetic background. In this model, SWR mice carry an IghV partial transgene encoding only the heavy chain variable domain of an antibody directed against chromatin. Autoimmune disease in partial transgene mice was manifested by some of the features of systemic lupus erythematosus (SLE), including the presence of serum anti-nuclear antibodies, splenomegaly, skin lesions and a moderate degree of kidney pathology, in various combinations among individuals. Autoimmunity was observed in three independent transgenic lines, but not in three control lines carrying a nearly identical partial transgene, in which a VHCDR3 codon for Arg was replaced by one for Ser in order to ablate chromatin-reactivity. Various features of disease were often but not always accompanied by anti-chromatin antibodies. Unexpectedly, the anti-chromatin antibodies detected in seropositive animals were not encoded by the partial transgene. These observations strongly implicate a role for the transgene product in disease initiation but not necessarily for endstate pathology, and they raise the possibility that autoreactive B cells may play a previously unappreciated role in initiating the development of systemic autoimmunity.

show abstract

T Cell Tolerance to Germline-Encoded Antibody Sequences in a Lupus-Prone Mouse

Cited by 11 publications

References 60 publications

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

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

The immunogenicity of humanized and fully human antibodies

Spontaneous autoimmunity in mice that carry an IghV partial transgene: a required arginine in VHCDR3

Contact Info

Product

Resources

About