Fine binding characteristics of human autoantibodies-partial molecular characterization.
The fine binding characteristics of three well-characterized human autoantibodies B3, RH14 (anti-DNA) and UK4 (anti-cardiolipin) in their IgG and cloned Fab formats, were investigated. Although in severe combined immunodeficiency (SCID) mice B3 and RH14 both induce proteinuria, only RH14 induces early features of lupus nephritis, whereas UK4 exhibits lupus anticoagulant activity. RH14 exhibited up to 10 fold higher binding to DNA compared to that shown by B3 or UK4 and involved significant electrostatic and phosphate group interactions. Only RH14 exhibited strong anti-Sm cross-reactivity residing on the C-terminus of the antigen as determined by the use of 76 overlapping 15mer peptides. Chain shuffling experiments indicate that anti-Sm/RNP and anti-Jo-1 activities of B3 and UK4 co-exist on one of the two chains (light, B3; heavy, UK4). The present study provides evidence that a human anti-DNA antibody can also be an anti-ENA antibody. Furthermore, the anti-DNA antibodies also exhibited cross-reactivity against glutathione-S-transferase and DNA polymerase PolIV of bacterial origin. This is the first demonstration of the presence of such cross-reactivities on lupus anti-DNA antibodies. We now demonstrate that subsets of sera from the patients with lupus, recognise these antigens. This observation may in some cases provide a mechanism for the common expression of a variety of autoantibodies observed in systemic lupus erythematosus (SLE).
Kumar
Sanjeev
S
Bloomsbury Rheumatology Unit, Department of Medicine, Centre for Rheumatology, University College London W1P 9PG, UK. sanjeev.kumar@antisome.com
Kalsi
Jatinderpal
J
Bunting
Karen
K
Ravirajan
Chelliah T
CT
Latchman
David S
DS
Pearl
Laurence H
LH
Isenberg
David A
DA
D000328:Adult; D017153:Antibodies, Anticardiolipin; D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000915:Antibody Affinity; D000937:Antigen-Antibody Reactions; D001323:Autoantibodies / Q000276:immunology*; D016022:Case-Control Studies; D003429:Cross Reactions / Q000276:immunology*; D019951:DNA Polymerase beta / Q000276:immunology; D005260:Female; D005982:Glutathione Transferase / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008181:Lupus Nephritis / Q000276:immunology; D008297:Male; D008875:Middle Aged
D017153:Antibodies, Anticardiolipin; D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D007140:Immunoglobulin Fab Fragments; D005982:Glutathione Transferase; D019951:DNA Polymerase beta