Pathological crystallization of human immunoglobulins

Abstract

Condensation of Igs has been observed in pharmaceutical formulations and in vivo in cases of cryoglobulinemia. We report a study of monoclonal IgG cryoglobulins overexpressed by two patients with multiple myeloma. These cryoglobulins form crystals, and we measured their solubility lines. Depending on the supersaturation, we observed a variety of condensate morphologies consistent with those reported in clinical investigations. Remarkably, the crystallization can occur at quite low concentrations. This suggests that, even within the regular immune response to infections, cryoprecipitation of Ig can be possible.

Fig. 1.

Solubility of two cryoglobulins in isotonic phosphate saline buffer, pH 7.4. Crystals grow at temperatures below the solid symbols, and dissolve at temperatures above the open symbols; dashed lines represent eye guides for the solubility lines.

Fig. 2.

(A) Correlation between morphologies of patient M23 condensates and the degree of supersaturation. (Scale bars: 100 μm.) (B–E) Various forms of patient M23 condensates produced under different conditions: (B) 3.5 mg/mL at 19 °C, (C) 10 mg/mL at 4 °C, (D) 50 mg/mL at 4 °C, and (E) in plasma at 19 °C.

Fig. 3.

Condensates of patient M31 cryoglobulin formed in solution with different supersaturation: (A) crystals grown from a 17 mg/mL solution at 22 °C and (B) aggregates grown from a 32 mg/mL solution at −3.6 °C.