title: The development of mixed cryoglobulinemia in Capillaria hepatica-infected mice is associated with the capillaria antigen-induced selective proliferation of splenic B-1a cells in response to interleukin-5 stimulation.
abstract: Chronic infection by pathogens such as hepatitis C virus induces monoclonal or oligoclonal proliferation of B cells, which produce IgM rheumatoid factor, leading to the development of mixed cryoglobulinemia (MC). Antigen-driven lymphoproliferation is essential to the onset of MC; however, the underlying mechanism is largely unknown. Herein, we show that type II MC is induced by Capillaria hepatica infection through a mechanism in which splenic B-1a cells reacting to C. hepatica-specific antigen selectively proliferate, producing IgM rheumatoid factor under co-stimulation of the specific worm antigen and IL-5. In vitro assays using B-1a cells from infected mice showed that stimulation by C. hepatica soluble fraction promoted the proliferation of B-1a cells and the secretion of IgM, which reacted with the 75-kDa antigen in the soluble fraction. The severity of MC was correlated with the increase in serum IL-5 levels in the infected mice. Furthermore, i.p. injection of the soluble worm fraction caused MC without an inflammatory response in IL-5 transgenic mice, indicating that IL-5 is critical for the development of MC. These results indicate that the selective proliferation of IgM rheumatoid factor-secreting B-1a cells is induced by co-stimulation by the specific pathogen antigen and IL-5 in the development of MC in C. hepatica-infected mice.
authors.affiliation: Laboratory of Veterinary Pathology, School of Veterinary Medicine, Azabu University, Sagamihara, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Aihara
authors.affiliation: Laboratory of Veterinary Pathology, School of Veterinary Medicine, Azabu University, Sagamihara, Japan. Electronic address: kamiie@azabu-u.ac.jp.
authors.forename: Junichi
authors.initials: J
authors.lastname: Kamiie
authors.affiliation: Laboratory of Veterinary Pathology, School of Veterinary Medicine, Azabu University, Sagamihara, Japan.
authors.forename: Moe
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Laboratory of Veterinary Pathology, School of Veterinary Medicine, Azabu University, Sagamihara, Japan; Research Institute of Biosciences, Azabu University, Sagamihara, Japan.
authors.forename: Kinji
authors.initials: K
authors.lastname: Shirota
mesh_terms: D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000469:parasitology*; D002195:Capillaria; D049109:Cell Proliferation; D003449:Cryoglobulinemia / Q000276:immunology / Q000469:parasitology*; D003450:Cryoglobulins / Q000276:immunology; D017189:Enoplida Infections / Q000276:immunology*; D004804:Eosinophils / Q000166:cytology; D005260:Female; D007075:Immunoglobulin M / Q000276:immunology; D015848:Interleukin-5 / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010641:Phenotype; D012217:Rheumatoid Factor / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000469:parasitology*; D018417:Th1 Cells / Q000166:cytology; D018418:Th2 Cells / Q000166:cytology
chemical_list: D000947:Antigens, Helminth; D003450:Cryoglobulins; D007075:Immunoglobulin M; D015848:Interleukin-5; D012217:Rheumatoid Factor