IgG subclasses in cryoglobulins: link to composition and clinical manifestations

Abstract

Background Cryoglobulins (CG) are immunoglobulins which precipitate at low temperature. The analysis of IgG subclass composition of CG is poorly reported. The aim of this study was to determine the subclasses of IgG-containing type I and mixed type II and III CG in relation to clinical manifestations. Methods Out of a previous series of 1675 patients, inclusion criteria were a cryoprecipitate > 1 mL and a total IgG > 300 mg/L. IgG subclasses were quantified by immunoturbidimetry, rheumatoid factor (RF), and C4 by immunonephelometry. Clinical parameters were collected from hospital charts. Results CG samples from 86 patients were included, 10 type I CG and 76 mixed CG. Type I CG subclasses were IgG1 (6/10) and IgG2/IgG3 (4/10), never IgG4. IgG subclass in type II vs. III CG were 73.3 ± 15.2% vs. 52.5 ± 20.7% for IgG1 (p < 0.0001), 15.4 ± 8.2% vs. 25.9 ± 14% for IgG2 (p < 0.0001), 8.4 ± 12.4 vs. 21.2 ± 14% for IgG3 (p < 0.0001), and 3 ± 5.2% vs. 0.5 ± 1.2 for IgG4 (p < 0.0001). In mixed CG, the higher proportion of IgG4 was associated with RF positive CG (p = 0.01) and low C4 (p = 0.01). In type I CG, IgG1 were associated with severe vasculitis manifestations, IgG2/IgG3 with cutaneous or renal manifestations. In mixed CG, IgG2 was the only subclass associated with CG manifestations, with a higher concentration in asymptomatic (162.6 ± 29.5 mg/L) vs. symptomatic patients with cutaneous (103 ± 17.8 mg/L, p = 0.04) and neurological (108 ± 24 mg/L, p = 0.04) manifestations. Conclusion In type I IgG CG, IgG1 was the main CG subclass associated with CG vasculitis. In mixed CG, low IgG2 concentration was linked to CG cutaneous and neurological manifestations.

A Case of IgG1-Lambda Multiple Myeloma With Hyperviscosity Syndrome and Cryoglobulinemia: Identification of the Subclass Fraction by Immunoelectrophoresis and Immunofixation Electrophoresis

“…According to a previous report, IgG causes cryoglobulinemia frequently by forming an immune complex and activating complement; among IgG subclasses, IgG1 and IgG3 are reported to form a larger immune complex and to more easily activate complement than others [ 10 ]. Furthermore, IgG1-derived cryoglobulin is reportedly likely to cause serious vasculitis [ 11 ]. In other words, IgG1-derived cryoglobulin is considered to have an affinity for the microvascular system.…”

IgM-Associated Cryoglobulinaemia

“…Decreased levels of complement and increased rheumatoid factor activity have been variably reported in up to a third in some series [11,18]. This has also been observed in cases of monoclonal type I IgG cryoglobulin (predominantly IgG1 subclass) [21]. Virology screening is necessary as most cases of type II cryoglobulins are associated with hepatitis.…”

Renal Disease in Cryoglobulinemia

“…In contrast, cryoglobulins type II and III always contain several subclasses. Usually, IgG1 is the most prevalent subclass and the percentage of IgG4 is very low or absent [ 23 ].…”