Nephritogenic λ light chain dimer

A unique human miniautoantibody against complement factor H

T. Sakari Jokiranta, Alan Solomon, Michael K. Pangburn, Peter F. Zipfel, Seppo Meri

Research output: Contribution to journalArticle

131 Citations (Scopus)

Abstract

A unique monoclonal Ig λ light chain dimer (protein LOI) was isolated from the serum and urine of a patient with hypocomplementemic membranoproliferative glomerulonephritis. In vitro the λ 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 Vλ3a subgroup of λ light chains. The variable (V) region of LOI was most closely related to the predicted product of the Vλ3 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 λ light chain dimer had initiated the development of a severe form of membranoproliferative glomerulonephritis. Thus, the λ light chain dimer LOI represents the first described pathogenic miniautoantibody in human disease.

Original languageEnglish (US)
Pages (from-to)4590-4596
Number of pages7
JournalJournal of Immunology
Volume163
Issue number8
StatePublished - Oct 20 1999

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Complement Factor H
Alternative Complement Pathway
Membranoproliferative Glomerulonephritis
Light
Binding Sites
Molecular Models
Serum
Proteins
Urine
Amino Acids
Genes

All Science Journal Classification (ASJC) codes

  • Immunology

Cite this

Jokiranta, T. S., Solomon, A., Pangburn, M. K., Zipfel, P. F., & Meri, S. (1999). Nephritogenic λ light chain dimer: A unique human miniautoantibody against complement factor H. Journal of Immunology, 163(8), 4590-4596.

Nephritogenic λ light chain dimer : A unique human miniautoantibody against complement factor H. / Jokiranta, T. Sakari; Solomon, Alan; Pangburn, Michael K.; Zipfel, Peter F.; Meri, Seppo.

In: Journal of Immunology, Vol. 163, No. 8, 20.10.1999, p. 4590-4596.

Research output: Contribution to journalArticle

Jokiranta, TS, Solomon, A, Pangburn, MK, Zipfel, PF & Meri, S 1999, 'Nephritogenic λ light chain dimer: A unique human miniautoantibody against complement factor H', Journal of Immunology, vol. 163, no. 8, pp. 4590-4596.
Jokiranta, T. Sakari ; Solomon, Alan ; Pangburn, Michael K. ; Zipfel, Peter F. ; Meri, Seppo. / Nephritogenic λ light chain dimer : A unique human miniautoantibody against complement factor H. In: Journal of Immunology. 1999 ; Vol. 163, No. 8. pp. 4590-4596.
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