Title |
Accelerated Systemic Autoimmunity in the Absence of Somatic Hypermutation in 564Igi: A Mouse Model of Systemic Lupus with Knocked-In Heavy and Light Chain Genes
|
---|---|
Published in |
Frontiers in immunology, September 2017
|
DOI | 10.3389/fimmu.2017.01094 |
Pubmed ID | |
Authors |
Gabrielle McDonald, Carlos O. Medina, Monika Pilichowska, John F. Kearney, Reiko Shinkura, Erik Selsing, Henry H. Wortis, Tasuku Honjo, Thereza Imanishi-Kari |
Abstract |
564Igi mice have knocked-in immunoglobulin (Ig) heavy (H) and light (L) chain genes that encode an autoantibody recognizing RNA. Previously, we showed that these mice produce pathogenic IgG autoantibodies when activation-induced deaminase (AID) is expressed in pre-B and immature B cells but not when it is expressed only in mature B cells. AID has two functions; it is necessary for somatic hypermutation (SHM) and class switch recombination (CSR). To determine the role of each of these functions in the generation of pathogenic autoantibodies, we generated 564Igi mice that carry a mutant AID-encoding gene, Aicda (Aicda(G23S)), which is capable of promoting CSR but not SHM. We found that 564Igi Aicda(G23S) mice secreted class-switched antibodies (Abs) at levels approximately equal to 564Igi mice. However, compared to 564Igi mice, 564Igi Aicda (G23S) mice had increased pathogenic IgG Abs and severe systemic lupus erythematosus-like disease, including, glomerulonephritis, and early death. We suggest that in 564Igi mice SHM by AID changes Ig receptors away from self reactivity, thereby mitigating the production of autoantibody, providing a novel mechanism of tolerance. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 17 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 5 | 29% |
Student > Bachelor | 3 | 18% |
Student > Master | 3 | 18% |
Unknown | 6 | 35% |
Readers by discipline | Count | As % |
---|---|---|
Immunology and Microbiology | 4 | 24% |
Biochemistry, Genetics and Molecular Biology | 3 | 18% |
Agricultural and Biological Sciences | 2 | 12% |
Medicine and Dentistry | 2 | 12% |
Unknown | 6 | 35% |