Development of murine lupus involves the combined genetic contribution of the SLAM and FcgammaR intervals within the Nba2 autoimmune susceptibility locus.
Development of murine lupus involves the combined genetic contribution of the SLAM and FcgammaR intervals within the Nba2 autoimmune susceptibility locus.
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DOI：
10.4049/jimmunol.0901322
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发表时间：
2010-01-15
期刊：
影响因子：
--
通讯作者：
Erickson LD
中科院分区：
文献类型：
--
作者：
Jørgensen TN;Alfaro J;Enriquez HL;Jiang C;Loo WM;Atencio S;Bupp MR;Mailloux CM;Metzger T;Flannery S;Rozzo SJ;Kotzin BL;Rosemblatt M;Bono MR;Erickson LD
自身抗体在抗体介导的自身免疫性疾病的发病机制中起着核心作用。1号染色体上的小鼠狼疮易感基因Nba2和人类同线基因与免疫耐受的丧失有关，从而导致抗核抗体的产生。为了确定NBA2内控制产生自身抗体的B细胞发育的基因间隔，并确定NBA2基因完成这一任务的细胞成分，我们产生了表达不同NBA2间隔的同源小鼠，其中编码FcγR、SLAM和干扰素诱导的家族的基因。对同源菌株的分析表明，FcγR和SLAM间隔独立控制自身抗体产生和肾脏疾病的严重程度，但两者都是狼疮易感性所必需的。终末分化B细胞的去调节动态平衡受控于FcγR间期，其中FcγRIIb介导的生发中心B细胞和浆细胞的凋亡受到损害。活化的浆细胞样树突状细胞数量的增加与SLAM间期有关，这些树突状细胞明显为CD19+，并通过促炎细胞因子IL-10和干扰素α促进浆细胞分化。这些发现表明，SLAM和FcγR间期通过支持自身抗体产生细胞的分化和生存而协同作用，影响临床病程。
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.
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DOI：
10.1084/jem.179.1.305
发表时间：
1994-01-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ishida H;Muchamuel T;Sakaguchi S;Andrade S;Menon S;Howard M
通讯作者：
Howard M
影响因子：
4.4
作者：
Baban, B;Hansen, AM;Mellor, AL
通讯作者：
Mellor, AL
影响因子：
9.1
作者：
Chun, Hye-Young;Chung, Jae-Wook;Suh, Chang-Hee
通讯作者：
Suh, Chang-Hee
影响因子：
32.4
作者：
Jego, G;Palucka, AK;Banchereau, J
通讯作者：
Banchereau, J
影响因子：
56.9
作者：
Kumar, Kirthi Raman;Li, Liunan;Mohan, Chandra
通讯作者：
Mohan, Chandra