Rahman, Mohammed Abbas Anisur; (1998) Molecular properties of human monoclonal anti-DNA and antiphospholipid antibodies. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Autoantibodies are found in the bloodstream in a number of diseases in humans. Systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS) are two diseases in which there is evidence that such antibodies actually cause tissue damage. In SLE, antibodies which bind to double stranded DNA (anti-dsDNA) are most strongly linked to disease activity and renal damage. In APS, anti-phospholipid antibodies (APL) are similarly implicated in the disease process. In both cases, analysis of patients' sera shows that IgG antibodies which bind antigen with high affinity and high specificity are the most closely associated with disease activity. Analysis of the sequences of monoclonal anti-dsDNA and APL derived from humans or mice suggests that these binding properties are derived by antigen driven accumulation of mutations in the complementarity determining regions (CDRs) of the heavy and Ight chains. These mutations often increase the content of basic amino acids in the CDRs. This thesis describes the determination and analysis of variable region sequences of four high affinity human IgG APL and one high affinity human IgG anti-DNA antibody. They show evidence of antigen driven somatic mutation and some accumulation of basic residues in CDRs. A particular Vh gene, 2a2, was found to encode both APL and anti-DNA antibodies but different mutations were present in the two types of antibody. A system for expressing cloned variable region cDNA from human monoclonal autoantibodies was developed. The products of the expression system were whole IgG molecules which showed very similar binding properties to the monoclonal antibodies from which the cloned cDNA had been derived. This system was used to demonstrate that both chains are important in conferring the ability to bind DNA upon these antibodies.

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