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

被引：16

作者：

McDonald, Gabrielle ^{[1
]}

Medina, Carlos O. ^{[1
]}

Pilichowska, Monika ^{[2
]}

Kearney, John F. ^{[3
]}

Shinkura, Reiko ^{[4
]}

Selsing, Erik ^{[1
]}

Wortis, Henry H. ^{[1
]}

Honjo, Tasuku ^{[5
]}

Imanishi-Kari, Thereza ^{[1
]}

机构：

[1] Tufts Univ, Sch Med, Sackler Sch Grad Biomed Sci, Dept Integrat Physiol & Pathobiol, Boston, MA 02111 USA

[2] Tufts Med Ctr, Dept Pathol & Lab Med, Boston, MA USA

[3] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA

[4] Nagahama Inst Biosci & Technol, Dept Immunol, Nagahama, Japan

[5] Kyoto Univ, Grad Sch Med, Dept Immunol & Genom Med, Kyoto, Japan

来源：

FRONTIERS IN IMMUNOLOGY | 2017年 / 8卷

基金：

美国国家卫生研究院;

关键词：

activation-induced cytidine deaminase; somatic hypermutation; class switch recombination; systemic lupus erythematosus; autoantibodies; pathogenic antibodies; B cell central tolerance; RNA-specific antibodies; INDUCED CYTIDINE DEAMINASE; B-CELL TOLERANCE; ACTIVATION-INDUCED DEAMINASE; CLASS SWITCH RECOMBINATION; AUTOANTIBODY PRODUCTION; IMMUNOGLOBULIN EXPRESSION; MURINE MODEL; AID; ANTIBODIES; RECEPTOR;

D O I：

10.3389/fimmu.2017.01094

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页数：15