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MicroRNAs prevent the generation of autoreactive antibodies.

ABSTRACT: MicroRNAs have been shown to be critical for a number of aspects of immune system regulation and function. Here, we have examined the role of microRNAs in terminal B cell differentiation by analyzing Cd19-Cre(ki/+) Dicer1(fl/fl) mice. We found that in the absence of Dicer, the transitional and marginal zone (MZ) B cell compartments were overrepresented and follicular (FO) B cell generation was impaired. microRNA analysis revealed that miR185, a microRNA overexpressed in FO cells, dampened B cell receptor (BCR) signaling through Bruton tyrosine kinase downregulation. Dicer-deficient B cells had a skewed BCR repertoire with hallmarks of autoreactivity, which correlated with high titers of autoreactive antibodies in serum and autoimmune features in females. Together, our results reveal a crucial role for microRNAs in late B cell differentiation and in the establishment of B cell tolerance.

SUBMITTER: Belver L

PROVIDER: S-EPMC3687137 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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MicroRNAs prevent the generation of autoreactive antibodies.

Belver Laura L de Yébenes Virginia G VG Ramiro Almudena R AR

Immunity 20101101 5

MicroRNAs have been shown to be critical for a number of aspects of immune system regulation and function. Here, we have examined the role of microRNAs in terminal B cell differentiation by analyzing Cd19-Cre(ki/+) Dicer1(fl/fl) mice. We found that in the absence of Dicer, the transitional and marginal zone (MZ) B cell compartments were overrepresented and follicular (FO) B cell generation was impaired. microRNA analysis revealed that miR185, a microRNA overexpressed in FO cells, dampened B cell ...[more]

PMID: 21093320

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Project description:A major problem in autoimmunity has been identification of the earliest events that lead to breach of tolerance. Although there have been major advances in dissecting effector pathways and the multilineage immune responses to mitochondrial self-antigens in primary biliary cholangitis, the critical links between environmental factors and tolerance remain elusive. We hypothesized that environmental xenobiotic modification of the E2 subunit of the pyruvate dehydrogenase (PDC-E2) inner lipoyl domain can lead to loss of tolerance to genetically susceptible hosts. Previously we demonstrated that serum anti-PDC-E2 autoantibodies cross-react with the chemical xenobiotics 2-octynoic acid and 6,8-bis (acetylthio) octanoic acid and further that there is a high frequency of PDC-E2-specific peripheral plasmablasts. Herein we generated 104 recombinant monoclonal antibodies (mAbs) based on paired heavy-chain and light-chain variable regions of individual plasmablasts derived from primary biliary cholangitis patients. We identified 32 mAbs reactive with native PDC-E2, including 20 specific for PDC-E2 and 12 cross-reactive with both PDC-E2 and 2-octynoic acid and 6,8-bis (acetylthio) octanoic acid. A lower frequency of replacement somatic hypermutations, indicating a lower level of affinity maturation, was observed in the complementarity-determining regions of the cross-reactive mAbs in comparison to mAbs exclusively recognizing PDC-E2 or those for irrelevant antigens. In particular, when the highly mutated heavy-chain gene of a cross-reactive mAb was reverted to the germline sequence, the PDC-E2 reactivity was reduced dramatically, whereas the xenobiotic reactivity was retained. Importantly, cross-reactive mAbs also recognized lipoic acid, a mitochondrial fatty acid that is covalently bound to PDC-E2.ConclusionOur data reflect that chemically modified lipoic acid or lipoic acid itself, through molecular mimicry, is the initial target that leads to the development of primary biliary cholangitis. (Hepatology 2017;66:885-895).

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MicroRNAs prevent the generation of autoreactive antibodies.

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MicroRNAs prevent the generation of autoreactive antibodies.

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