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Monomeric Complement-Activating IgG Paraproteins¹

Marten Trendelenburg^2,*, Christoph Hess^*, Mitsuko Kondo-Oestreicher, Jean D. Tissot, Peter Späth^§ and Jürg A. Schifferli^*

^* Immunonephrology Laboratory, Department of Research, University Hospital, Basel, Switzerland; Department of Medicine, University Hospital, Geneva, Switzerland; Blood Transfusion Center, University Hospital, Lausanne, Switzerland; and ^§ Zentrallaboratorium Blood Donor Service, Bern, Switzerland

Three patients presented a unique syndrome of recurrent panniculitis with an IgG paraprotein and depletion of the early components of the classical pathway of complement. The IgG paraproteins were monomers with a normal structure, and with no evidence for aggregation, as assessed by electron microscopy and ultracentrifugation. Both heavy and light chains were of normal molecular size (SDS-PAGE), and the paraproteins were not heavily glycosylated. However, the paraproteins from all three patients had unusual features that included abnormal behavior on gel filtration chromatography and a heavy chain of high pI. When analyzed by fast protein liquid chromatography (Superdex 200), elution of the paraproteins was retarded, particularly when the ionic strength was increased. This retardation was partially reversed in 20% alcohol, and fully reversed in 6 M guanidine-HCl. Neither anti-C1 inhibitor nor anti-C1q autoantibodies were found in any of the patients’ sera. However, the paraproteins bound to the globular heads of C1q at normal ionic strength. They activated C4 in normal human serum, but not in C1q-deficient serum. Activation led to the formation of C1s-C1 inhibitor complexes. Taken together, the data suggest that the unusual paraproteins have the capacity to bind C1q, which then leads to activation of C1. The ability of these paraproteins to activate C1, in spite of their being soluble monomers, is likely to be related to their unique physicochemical features.