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Monomeric complement-activating IgG paraproteins
M Trendelenburg1, C Hess, M Kondo-Oestreicher
1Immunonephrology Laboratory, Department of Research, University Hospital, Basel, Switzerland. trendelenbur@ubaclu.unibas.ch
Insights
This study identifies unique IgG-kappa paraproteins causing recurrent panniculitis by activating complement. These abnormal proteins bind C1q, initiating complement cascade despite being soluble monomers.
Area of Science:
- Immunology
- Clinical Medicine
- Biochemistry
Background:
- Recurrent panniculitis is a rare inflammatory condition.
- Complement system activation plays a role in various autoimmune diseases.
- Paraproteins can sometimes trigger autoimmune responses.
Observation:
- Three patients presented with recurrent panniculitis, IgG-kappa paraprotein, and depleted early complement components.
- Paraproteins exhibited abnormal gel filtration chromatography and high heavy chain pI.
- These paraproteins bound C1q and activated C4 in normal serum, forming C1s-C1 inhibitor complexes.
Findings:
- The unique IgG-kappa paraproteins bind to C1q, initiating the classical complement pathway.
- Despite being soluble monomers, these paraproteins activate complement due to unusual physicochemical properties.
- Activation involves C1q binding, leading to C4 cleavage and C1s-C1 inhibitor complex formation.
Implications:
- Understanding this mechanism could lead to novel diagnostic markers for panniculitis.
- Targeting this specific complement activation pathway may offer new therapeutic strategies.
- This research highlights the complex interplay between paraproteins and the complement system in disease pathogenesis.
Abstract:
Three patients presented a unique syndrome of recurrent panniculitis with an IgGkappa paraprotein and depletion of the early components of the classical pathway of complement. The IgGkappa 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.