title: Clonal expansion and functional exhaustion of monoclonal marginal zone B cells in mixed cryoglobulinemia: the yin and yang of HCV-driven lymphoproliferation and autoimmunity.
abstract: Monoclonal marginal zone (MZ) B cells expressing a V(H)1-69-encoded idiotype accumulate in HCV-associated mixed cryoglobulinemia (MC). These cells recognize the E2 protein of HCV and their massive clonal expansion reflects the propensity of MZ B cells to proliferate robustly upon antigenic stimulation by microorganisms, a property that makes them prone to neoplastic transformation. V(H)1-69(+) B cells of MC patients are phenotypically heterogeneous and resemble either mature MZ B cells (IgM(+)CD27(+)CD21(high)) or the unusual CD21(low) B cells that accumulate in other immunological disorders such as common variable immunodeficiency (CVID) or HIV infection. The CD21(low) V(H)1-69(+) B cells of MC patients, like those of CVID and HIV patients, are anergic to BCR and TLR9 stimulation and display deregulation of several anergy-related genes; proliferative anergy is also observed in CD21(high) MZ-like V(H)1-69(+) B cells, that over-express the antiproliferative transcriptional repressor Stra13. Upon evolution to splenic marginal zone lymphoma, MZ-like V(H)1-69(+) B cells down-regulate Stra13 and partially recover their capacity to proliferate in response to TLR9 ligation. Like yin and yang, robust clonal expansion and early proliferative anergy may be viewed as the opposite forces balancing the responses of human MZ B cells to chronic microbial stimuli. Disruption of this balance facilitates autoimmunity and lymphoproliferation.
authors.affiliation: Department of Clinical Immunology, Sapienza University of Rome, Rome, Italy. marcella.visentini@uniroma1.it
authors.forename: Marcella
authors.initials: M
authors.lastname: Visentini
authors.forename: Valentina
authors.initials: V
authors.lastname: Conti
authors.forename: Cristina
authors.initials: C
authors.lastname: Cristofoletti
authors.forename: Cristina
authors.initials: C
authors.lastname: Lazzeri
authors.forename: Ramona
authors.initials: R
authors.lastname: Marrapodi
authors.forename: Giandomenico
authors.initials: G
authors.lastname: Russo
authors.forename: Milvia
authors.initials: M
authors.lastname: Casato
authors.forename: Massimo
authors.initials: M
authors.lastname: Fiorilli
mesh_terms: D015551:Autoimmunity; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D003449:Cryoglobulinemia / Q000235:genetics / Q000276:immunology* / Q000821:virology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology / Q000473:pathology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D017464:Receptors, Complement 3d / Q000378:metabolism; D013154:Spleen / Q000276:immunology
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D017464:Receptors, Complement 3d