IgG3 subclass: A possible trigger of mixed cryoglobulin cascade in hepatitis C virus chronic infection

Abstract

HCV is a hepatotropic and lymphotropic virus and is the most frequent cause of "benign" mono-oligoclonal B-lymphocyte proliferation, observed in mixed cryoglobulinemia (MC). The study aims to investigate the presence, prevalence and characteristics of the subclasses of cryoglobulins in HCV-patients to look for a relationship with MC. Fifty HCV-infected patients with cryoglobulins were enrolled. IgG subclasses were characterized in cryoprecipitate, and serum IgG and IgM Rheumatoid Factor (RF) were determined. Patients were stratified into two subgroups according to the presence of IgG3 subclass. Differences were observed in supernatant IgM, IgG3-positive and IgG3-negative patients with a higher IgM concentration in the IgG3-negative cohort (p=0.03). Higher IgM-RF was detected in the IgG3-negative group (p=0.01). IgG3-positive group showed higher IgG-RF compared to the IgG3-negative group (p<0.0001). IgG3-negative/monoclonal-IgM patients had higher cryocrit compared to IgG3-negative/polyclonal-IgM patients (p<0.01). C4 levels were higher in the polyclonal-IgM group compared to monoclonal-IgM group (p<0.01). We speculate that cryoglobulins are part of a progressive clonal selection process in which, B-cells are stimulated to produce oligoclonal IgG3 with RF activity. The persistence of the antigenic stimulus elicits the production of polyclonal IgM-RF and subsequently the formation of oligoclonal IgG/polyclonal IgM containing cryoglobulins. In the last stage, a monoclonal IgM-RF clone is formed which may coexist with a monoclonal IgG3-RF clone.

Serological profile of asymptomatic HCV positive patients with low level of cryoglobulins

“…They described an increased risk of death correlated to an increase of polyclonal FLCs, occurring independently from renal function, sex, and age. This risk maintained its predictive value regardless of the eventual cause of death . These results strengthen the role of FLCs as biomarkers and provide valuable insight into the involvement of inflammatory mechanisms in HCV‐related disorders.…”

“…); if we considered patients subgroups, we observed the higher levels of free k and of k + λ sum in asymptomatic patients with low levels of microheterogeneous type III CGs and in symptomatic patients with type II CGs (Table ): this result strengthens the hypothesis that the microheterogeneous type III subgroup may represent an intermediate state from a polyclonal to a monoclonal selection of CGs and we suggest that free k could represent a marker of this transition. Type II CGs seem to cause systemic vasculitis mediated by the intravascular immune complex ; keeping in mind data on mortality and comorbidity occurring in patients with CGs and low cryocrit but without HCV infection reported by Eble , we can hypothesize that even low levels of CGs can trigger immunological disorders in HCV‐positive patients .…”

Correlation of CCR5 and NLRP3 gene polymorphisms with renal damage due to hepatitis C virus-related cryoglobulinemia

“…IgMκ is an IgG antibody, which can combine with anti-HCV IgG to form immune complex precipitation, glomerular subendothelial space and glomerular mesangium. Finally, renal damage is triggered by activation of partial complements, formation of chemokines and other factors (14,15). …”

Cryoglobulins: Identification, classification, and novel biomarkers of mysterious proteins

“…1 ) [20] . HCV plays an important role both in the induction and persistence of cryoglobulinemia, as well as the transition from type III to II [21] , [22] . The new subtype of CGs, i.e., the transitional step between types II and III, places increased attention on immunochemical and histopathologic findings as well as the development of more accurate diagnostic and therapeutic tools.…”

“…Currently, little is known about the involvement of HCV infection in the evolution of lymphoproliferative and/or autoimmune diseases, although several factors seem to contribute to their pathogenesis and their progression, and specific IgG subclasses seem to play a role [22] . According to the literature regarding the distribution of IgG subclasses in patients with cryoglobulinemic syndrome and HCV infection, monoclonal IgG1 and IgG3 are often detected [52] , [53] .…”