Development of Murine Lupus Involves the Combined Genetic Contribution of the SLAM and FcγR Intervals within the Nba2 Autoimmune Susceptibility Locus

Autor: Troy E. Metzger, Chao Jiang, Stephanie Atencio, Christina M. Mailloux, Hilda L. Enriquez, Loren D. Erickson, María Rosa Bono, Trine N. Jørgensen, William M. Loo, Jennifer Alfaro, Mario Rosemblatt, Brian L. Kotzin, Shannon Flannery, Stephen J. Rozzo, Melanie R. Gubbels Bupp
Rok vydání: 2009
Předmět:
Genetic Markers
Cellular differentiation
Plasma Cells
Immunology
Congenic
Apoptosis
Receptors
Cell Surface
Susceptibility gene
Locus (genetics)
Bioinformatics
Article
CD19
Immune tolerance
Mice
Mice
Congenic
Signaling Lymphocytic Activation Molecule Family Member 1
Antigens
CD
Murine lupus
Plasma cell differentiation
medicine
Animals
Lupus Erythematosus
Systemic
Immunology and Allergy
Genetic Predisposition to Disease
skin and connective tissue diseases
Gene
Autoantibodies
Genetics
Ifi202
B-Lymphocytes
Lupus erythematosus
Mice
Inbred NZB
biology
Receptors
IgG
Intracellular Signaling Peptides and Proteins
Autoantibody
Germinal center
Cell Differentiation
medicine.disease
Lupus Nephritis
Mice
Inbred C57BL
Antibodies
Antinuclear
Disease Progression
Susceptibility locus
biology.protein
Cytokines
Kidney Diseases
Inflammation Mediators
Zdroj: JOURNAL OF IMMUNOLOGY
Artículos CONICYT
CONICYT Chile
instacron:CONICYT
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.0901322
Popis: Autoantibodies are of central importance in the pathogenesis of Ab-mediated autoimmune disorders. The murine lupus susceptibility locus Nba2 on chromosome 1 and the syntenic human locus are associated with a loss of immune tolerance that leads to antinuclear Ab production. To identify gene intervals within Nba2 that control the development of autoantibody-producing B cells and to determine the cellular components through which Nba2 genes accomplish this, we generated congenic mice expressing various Nba2 intervals where genes for the FcγR, SLAM, and IFN-inducible families are encoded. Analysis of congenic strains demonstrated that the FcγR and SLAM intervals independently controlled the severity of autoantibody production and renal disease, yet are both required for lupus susceptibility. Deregulated homeostasis of terminally differentiated B cells was found to be controlled by the FcγR interval where FcγRIIb-mediated apoptosis of germinal center B cells and plasma cells was impaired. Increased numbers of activated plasmacytoid dendritic cells that were distinctly CD19+ and promoted plasma cell differentiation via the proinflammatory cytokines IL-10 and IFNα were linked to the SLAM interval. These findings suggest that SLAM and FcγR intervals act cooperatively to influence the clinical course of disease through supporting the differentiation and survival of autoantibody-producing cells.
Databáze: OpenAIRE
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