Kumar, S;
Nagl, S;
Kalsi, JK;
Ravirajan, CT;
Athwal, D;
Latchman, DS;
Pearl, LH;
(2005)
Beta-2-glycoprotein specificity of human anti-phospholipid antibody resides on the light chain: a novel mechanism for acquisition of cross-reactivity by an autoantibody.
MOL IMMUNOL
, 42
(1)
39 - 48.
10.1016/j.molimm.2004.07.012.
Abstract
We have recently shown that the anti-cardiolipin activity of human anti-phospholipid antibody UK4 (lambda) resides on its heavy chain. We now show that UK4 possesses strong reactivity to the plasma-protein beta(2)-Glycoprotein I (beta(2)-GPI) also. Utilizing chain shuffling experiments involving an unrelated anti-p185 antibody 4D5 (kappa) with no reactivity to beta2-GPI, we now demonstrate that both the constructs possessing the auto-antibody-derived light chain exhibited significant binding to beta(2)-GPI. However, the construct possessing UK4 heavy chain in association with 4D5 light chain, exhibited no anti-beta(2)-GPI activity. Furthermore, there was a low increase (congruent to10%) in the binding of UK4 to cardiolipin in the presence Of beta(2)-GPI. The results demonstrate that anti-beta(2)-GPI activity resides on UK4 light chain and, importantly, this activity could be transferred to a novel antibody construct via the light chain alone. Computer-generated models of the three-dimensional structures of UK4 and its hybrids, suggest predominant interaction of UK4 light chain with domain IV Of beta(2)-GPI. Molecular docking experiments highlight a number of potential sites on beta(2)-GPI for interaction of UK4 and indicate as to how beta(2)-GPI recognition may occur primarily via the autoantibody light chain. The study provides first demonstration of the occurrence of anti-phospholipid and anti-beta(2)-GPI activities separately on heavy and light chains of an autoantibody. The possible mechanisms that such antibodies may employ to recognise their antigens, are discussed. (C) 2004 Elsevier Ltd. All rights reserved.
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