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Light Chain Dimer: A Unique Human Miniautoantibody Against Complement Factor H1
*
Complement Research Unit, Department of Bacteriology and Immunology, Haartman Institute/HD Diagnostics, Helsinki, Finland;
Human Immunology and Cancer Program, Department of Medicine, University of Tennessee Medical Center/Graduate School of Medicine, Knoxville, TN 37920;
Department of Biochemistry, University of Texas Health Science Center, Tyler, TX 75710; and
§
Department of Molecular Biology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
A unique monoclonal Ig 
light chain dimer (protein LOI) was
isolated from the serum and urine of a patient with hypocomplementemic
membranoproliferative glomerulonephritis. In vitro the light chain
dimer efficiently activated the alternative pathway of complement (AP).
When added to normal human serum, LOI temporarily enhanced AP hemolytic
activity, but during a prolonged incubation the hemolytic activity was
depleted. Protein LOI was found to bind to factor H, the main regulator
molecule of AP. By binding to the short consensus repeat domain 3 of
factor H, the dimer LOI blocked one of three interaction sites between
H and C3b and thus inhibited the activity of H and induced an
uncontrolled activation of the AP. Structural analysis showed that LOI
belonged to the V3a subgroup of light chains. The variable (V)
region of LOI was most closely related to the predicted product of the
V3 germline gene Iglv3s2, although it contained
several unique residues that in a tertiary homology model structure
form an unusual ring of charged residues around a hydrophobic groove in
the putative Ag binding site. This site fitted considerably well with a
putative binding site in the molecular model of domain 3 of factor H
containing a reciprocal ring of charged amino acids around a
hydrophobic area. Apparently, functional blocking of factor H by the Ab
fragment-like light chain dimer had initiated the development of a
severe form of membranoproliferative glomerulonephritis. Thus, the
light chain dimer LOI represents the first described pathogenic
miniautoantibody in human disease.
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