Rheumatoid Factor, Complement, and Mixed Cryoglobulinemia

Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2012, Article ID 439018, 6 pages doi:10.1155/2012/439018 Review Article Rheumatoid Factor, Complement, and Mixed Cryoglobulinemia Peter D. Gorevic Mount Sinai School of Medicine, Division of Rheumatalogy, Annenberg Building, Room 21-056, One Gustave L. Levy Place, New York, NY 10029-6574, USA Correspondence should be addressed to Peter D. Gorevic, Received 21 May 2012; Accepted 26 June 2012 Academic Editor: Domenico Sansonno Copyright © 2012 Peter D. Gorevic. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Low serum level of complement component 4 (C4) that occurs in mixed cryoglobulinemia (MC) may be due to in vivo or ex vivo activation of complement by the classical pathway. Potential activators include monoclonal IgM rheumatoid factor (RF), IgG antibodies, and the complexing of the two in the cold, perhaps modulated by the rheology and stoichiometry of cryocomplexes in specific microcirculations. There is also the potential for activation of complement by the alternative and lectin pathways, particularly in the setting of chronic infection and immune stimulation caused by hepatitis C virus (HCV). Engagement of C1q and interaction with specific cell surface receptors serve to localize immune complexes (ICs) to the sites of pathology, notably the cutaneous and glomerular microcirculations. Defective or saturated clearance of ICs by CR1and/or Fc receptors may explain persistence in the circulation. The phlogistic potential of cryoprecipitable ICs depends upon the cleavage of complement components to generate fragments with anaphylatoxin or leukocyte mobilizing activity, and the assembly of the membrane attack complex (C5b-9) on cell surfaces. A research agenda would include further characterization of the effector arm of complement activation in MC, and elucidation of activation mechanisms due to virus and viral antigens in HCV infection. 1. Introduction Mixed cryoglobulins (MCs) are cold-precipitable rheumatoid factors (RFs) that are easily identifiable and characterized by immunofixation of cryoprecipitate obtained from serum carefully collected from blood kept at and allowed to clot at core body temperature, and then cooled to 4◦ C [1]. Type 2 MCs are almost invariably composed of monoclonal IgM kappa RF and polyclonal IgG, and it is the complexing of the two that is a requisite for the formation of cold-precipitable immune complexes (ICs); both the IgM heavy-and light-chain variable regions display a striking clonality that is mirrored in cross reactive idiotypes (CRIs) as well as mu heavy chain and kappa light-chain V-region gene usage. Type 2 MCs are heavily represented among cryoglobulins associated with chronic hepatitis C virus (HCV) infection, and those found in patients with primary Sjögrens syndrome, both of which may be complicated by clonal B-cell proliferations and specific types (e.g., mucosa-associated (MALT); Splenic) of non-Hodgkin’s lymphoma [2]. Among patients with type 2 MCs associated with HCV, prominent associations with extrahepatic disease manifestations such as leukocytoclastic vasculitis, arthropathy, neuropathy, and membranoproliferative glomerulonephritis have been found in multiple series. Complement abnormalities were described in early series of “essential mixed cryoglobulinemia” [3], and type 2 MCs are likely to have a striking complement profile notable for normal or low levels of component 3 (C3) and often undetectable levels of component 4 (C4); the latter (Figure 1) provides a “signature” which may in fact be used to anticipate the presence of significant (>1 mg/mL) amounts of type 2 cryoglobulin in blood [4]. The purpose of this paper is to update older information with regard to complement measurements in type 2 MC, with particular attention to the various effects of HCV infection and the central role of RF. 2. The Complement System The complement system comprises 30 serum and cellsurface proteins tightly regulated to respond to activators 2 Clinical and Developmental Immunology CH50 C4 Hemolytic units C3 50 193 K 120 mg 25 70 K 55 Factor B mg (%) 30 12 Figure 1: C3, C4, and factor Bb levels determined by hemolytic assay in patients with type 2 MC (4). by three independent pathways (classical: CP, alternative, AP, and Mannan-binding lectin: MBL), evolved primarily to recognize and destroy pathogenic microorganisms [5]. Temperature-dependent activation of both CP and AP in vitro has been reported among mixed (IgM-IgG, IgMlipoprotein) and monoclonal (IgG) cryoglobulins. Activation of AP has been correlated with the presence of IgA in mixed cryoglobulins and with an IgG3 monoclonal cryoglobulin occurring in a patient with membranoproliferative glomerulonephritis [6]. The selective depression of C4 noted in type 2 MC implicates the CP and is reflected in an extended serum profile, which includes variably low levels of C1q and C2, normal levels of factor Bb (Factor 1), and elevated levels of MBL; C3 levels may be normal, except in patients with severe disease manifestations (glomerulonephritis, neuropathy) [7]. In HCV-associated MC, this profile (a) correlates inexactly with the level of cryoglobulin and titer of RF, (b) may occasionally be found in the absence of a detectable cryoglobulin, (c) may occur in the absence of RF in the serum supernatant after cryoprecipitation, (d) correlates only poorly with symptomatology in serial studies, and (e) may persist with cryoglobulinemia after apparent clearance of the virus [8–10]; these observations suggest a complexity of pathways to C4 depletion extending beyond IC activation and HCV infection. The mechanism responsible for the selective depression of C4 remains unclear; whereas a novel control mechanism involving Cb-binding protein (C4bp) and C3b inactivator was implicated in one early study [11], this was not reflected in the levels of C4-bp in sera of patients with MC [12]. Whether cryo-RF might interfere with complement activation at the level of C3 has not been addressed. 3. Rheumatoid Factors Rheumatoid factors are IgM antibodies with specificity largely for the Fc portion of IgG; potential triggers to mRF production include (a) direct infection by virus, (b) chronic antigenic stimulation by ICs, (c) stimulation in the form of repetitively arranged epitopes on viral particles, or (d) molecular mimicry. Early studies suggested additional reactivities of MC IgM with idiotypic determinants in the F(ab’)2 of MC IgG, possibly reflecting the fact that in MC the IgG is reactive with viral antigens [13], some of which can also be demonstrated within the cryoprecipitates [6]. ICs containing IgG and IgM isotypes are well known to be activators of the CP, providing several mechanisms by which C1q binding to the CH2 domain of IgG, and/ (...truncated)