Lupus · 2021
Potential genetic basis of B cell hyperactivation in murine lupus models.
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Ju J Y, Xu Z W
Аннотация
BACKGROUND: Lupus B cells not only produce autoantibodies against nuclear antigens but also provide co-stimulation to T cells. However, there is still a lack of comprehensive understanding of the mechanism underlying lupus B cell hyperactivation.
METHODS: This study focuses on the detection of B cell activation status, analysis of early BCR signaling response, DNA sequencing, and quantity determination of BCR signaling regulators in murine lupus models.
RESULTS: Our result showed that there is a B cell hyperactivation with a significant elevation of B cell activation markers, and a BCR signaling hyperactivity with an abnormal increase of phosphorylated BCR signaling molecules and cytoplasmic calcium in the early response to BCR crosslinking in B6.Sle1/2/3 lupus mouse. Whole exome sequencing identified a multiple point mutation in the exon of many BCR signaling regulators in common murine lupus models, MRL/lpr, NZM2410, BXSB, NZB, and NZW strains. cNDA sequencing confirmed FcγR2b, Ly9, Pirb, Siglecg, and CD22 BCR signaling regulator variants in B6.Sle1/2/3 lupus mouse, but surface protein expression of these regulators on B cells showed an abnormal increase.
CONCLUSION: Our findings support that these BCR signaling regulator variants are potential causative genes of B cell hyperactivation in murine lupus models through their possible functional reduction.
METHODS: This study focuses on the detection of B cell activation status, analysis of early BCR signaling response, DNA sequencing, and quantity determination of BCR signaling regulators in murine lupus models.
RESULTS: Our result showed that there is a B cell hyperactivation with a significant elevation of B cell activation markers, and a BCR signaling hyperactivity with an abnormal increase of phosphorylated BCR signaling molecules and cytoplasmic calcium in the early response to BCR crosslinking in B6.Sle1/2/3 lupus mouse. Whole exome sequencing identified a multiple point mutation in the exon of many BCR signaling regulators in common murine lupus models, MRL/lpr, NZM2410, BXSB, NZB, and NZW strains. cNDA sequencing confirmed FcγR2b, Ly9, Pirb, Siglecg, and CD22 BCR signaling regulator variants in B6.Sle1/2/3 lupus mouse, but surface protein expression of these regulators on B cells showed an abnormal increase.
CONCLUSION: Our findings support that these BCR signaling regulator variants are potential causative genes of B cell hyperactivation in murine lupus models through their possible functional reduction.