Antigen selection of anti-DSG1 autoantibodies during and before the onset of endemic pemphigus foliaceus.
Fogo selvagem (FS), the endemic form of pemphigus foliaceus (PF), is characterized by pathogenic anti-desmoglein 1 (DSG1) autoantibodies. To study the etiology of FS, hybridomas that secrete either IgM or IgG (predominantly IgG1 subclass) autoantibodies were generated from the B cells of eight FS patients and one individual 4 years before FS onset, and the H and L chain V genes of anti-DSG1 autoantibodies were analyzed. Multiple lines of evidence suggest that these anti-DSG1 autoantibodies are antigen selected. First, clonally related sets of anti-DSG1 hybridomas characterize the response in individual FS patients. Second, H and L chain V gene use seems to be biased, particularly among IgG hybridomas, and third, most hybridomas are mutants and exhibit a bias in favor of CDR (complementary determining region) amino acid replacement (R) mutations. Strikingly, pre-FS hybridomas also exhibit evidence of antigen selection, including an overlap in V(H) gene use and shared multiple R mutations with anti-DSG1 FS hybridomas, suggesting selection by the same or a similar antigen. We conclude that the anti-DSG1 response in FS is antigen driven and that selection for mutant anti-DSG1 B cells begins well before the onset of disease.
Qian
Ye
Y
Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Clarke
Stephen H
SH
Aoki
Valeria
V
Hans-Filhio
Gunter
G
Rivitti
Evandro A
EA
Diaz
Luis A
LA
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001323:Autoantibodies / Q000235:genetics* / Q000276:immunology*; D002461:Cell Line, Transformed; D022801:Complementarity Determining Regions / Q000235:genetics / Q000276:immunology; D051183:Desmoglein 1 / Q000276:immunology*; D019353:Endemic Diseases; D005260:Female; D006801:Humans; D006825:Hybridomas; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D010392:Pemphigus / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D055815:Young Adult
D001323:Autoantibodies; D022801:Complementarity Determining Regions; C495297:DSG1 protein, human; D051183:Desmoglein 1; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains