Tracking Differential Gene Expression in MRL/MpJ versus C57BL/6 Anergic B Cells: Molecular Markers of Autoimmunity

Clark, Amy G.; Mackin, Katherine M.; Foster, Mary H.

doi:10.4137/bmi.s840

Cited by 4 publications

(4 citation statements)

References 95 publications

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“…Additional support for the immunomodulatory role of the miR-17∼92 cluster in the identified regulatory circuit was obtained by the experimental validation that cluster members miR19b and miR-17, as well as miR-15a, target certain MAPKs with key roles in B cell immune signaling. More specifically, we found that miR-15a and miR-17 posttranscriptionally regulate MAPK8/ JNK, whereas miR-19b regulates MAP2K3, whose target is p38-MAPK; likely relevant to this discussion, the p38-MAPK signaling axis has been reported to regulate anergy in lupus-prone MRL mice (52). Altogether, our results suggest that the entire axis of MAPK signaling has a central role in anergy regulation in CLL subset #4.…”

Section: Discussionsupporting

confidence: 59%

B Cell Anergy Modulated by TLR1/2 and the miR-17∼92 Cluster Underlies the Indolent Clinical Course of Chronic Lymphocytic Leukemia Stereotyped Subset #4

Ntoufa

Papakonstantinou

Apollonio

et al. 2016

The Journal of Immunology

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Chronic lymphocytic leukemia (CLL) patients assigned to stereotyped subset #4 (mutated IGHV4-34/IGKV2-30 BCR Ig) display a particularly indolent disease course. Immunogenetic studies of the clonotypic BCR Ig of CLL subset #4 suggested a resemblance with B cells rendered anergic through chronic autoantigenic stimulation. In this article, we provide experimental evidence that subset #4 CLL cells show low IgG levels, constitutive ERK1/2 activation, and fail to either release intracellular Ca2+ or activate MAPK signaling after BCR cross-linking, thus displaying a signature of B cell anergy at both biochemical and functional levels. Interestingly, TLR1/2 triggering restored BCR functionality, likely breaching the anergic state, and this was accompanied by induction of the miR-17∼92 cluster, whose members target critical BCR-associated molecules, including MAPKs. In conclusion, we demonstrate BCR anergy in CLL subset #4 and implicate TLR signaling and the miR-17∼92 cluster in the regulation of the anergic state. This detailed signaling profiling of subset #4 has implications for advanced understanding of the complex regulation of intracellular signaling pathways in CLL, currently a major therapeutic target of the disease.

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Section: Discussionsupporting

confidence: 59%

B Cell Anergy Modulated by TLR1/2 and the miR-17∼92 Cluster Underlies the Indolent Clinical Course of Chronic Lymphocytic Leukemia Stereotyped Subset #4

Ntoufa

Papakonstantinou

Apollonio

et al. 2016

The Journal of Immunology

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“…Residual B6 Tg spleen B cells are shortlived and fail to secrete anti-laminin Ig after endotoxin stimulation. This cell phenotype is preserved in the MRL/MpJ strain [21], although notably microarray analyses reveal strain differences in anergic B cell gene expression [23]. Thus, the LamH Ig Tg model provides a stable, well defined tolerance phenotype useful for the study of autoreactive B cell fates in the context of aggressive SLE models.…”

Section: Introductionmentioning

confidence: 99%

Regulation of basement membrane-reactive B cells in BXSB, (NZBxNZW)F1, NZB, and MRL/lpr lupus mice

et al. 2013

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Autoantibodies to diverse antigens escape regulation in systemic lupus erythematosus under the influence of a multitude of predisposing genes. To gain insight into the differential impact of diverse genetic backgrounds on tolerance mechanisms controlling autoantibody production in lupus, we established a single lupus-derived nephritis associated anti-basement membrane Ig transgene on each of four inbred murine lupus strains, including BXSB, (NZBxNZW)F1, NZB, and MRL/lpr, as approved by the Duke University and the Durham Veterans Affairs Medical Centers’ Animal Care and Use Committees. In nonautoimmune C57BL/6 mice, B cells bearing this anti-laminin Ig transgene are stringently regulated by central deletion, editing, and anergy. Here, we show that tolerance is generally intact in unmanipulated Ig transgenic BXSB, (NZBxNZW)F1, and NZB mice, based on absence of serum transgenic anti-laminin autoantibodies and failure to recover spontaneous anti-laminin monoclonal antibodies. Four- to six-fold depletion of splenic B cells in transgenic mice of these strains, as well as in MRL/lpr transgenic mice, and reduced frequency of IgM+ bone marrow B cells suggest that central deletion is grossly intact. Nonetheless the four strains demonstrate distinct transgenic B cell phenotypes, including endotoxin-stimulated production of anti-laminin antibodies by B cells from transgenic NZB mice, and in vitro hyperproliferation of both endotoxin- and BCR-stimulated B cells from transgenic BXSB mice, which are shown to have an enrichment of CD21-high marginal zone cells. Rare anti-laminin transgenic B cells spontaneously escape tolerance in MRL/lpr mice. Further study of the mechanisms underlying these strain-specific B cell fates will provide insight into genetic modification of humoral autoimmunity in lupus.

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“…LG/J and MRL/MpJ are also models for autoimmune disease, although with late onset compared with mutant MRL/ MpJ-Fas lpr /Fas lpr mice (Shirai and Klinman 1994;Clark et al 2008). Interestingly, MRL/MpJ and LG/J display accelerated wound healing relative to other strains (Heber-Katz et al 2004;Blankenhorn et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Several Classical Mouse Inbred Strains, Including DBA/2, NOD/Lt, FVB/N, and SJL/J, Carry a Putative Loss-of-Function Allele of Gpr84

Pérez

Dumas

Vallières

et al. 2013

Journal of Heredity

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G protein-coupled receptor 84 (GPR84) is a 7-transmembrane protein expressed on myeloid cells that can bind to medium-chain free fatty acids in vitro. Here, we report the discovery of a 2-bp frameshift deletion in the second exon of the Gpr84 gene in several classical mouse inbred strains. This deletion generates a premature stop codon predicted to result in a truncated protein lacking the transmembrane domains 4-7. We sequenced Gpr84 exon 2 from 58 strains representing different groups in the mouse family tree and found that 14 strains are homozygous for the deletion. Some of these strains are DBA/1J, DBA/2J, FVB/NJ, LG/J, MRL/MpJ, NOD/LtJ, and SJL/J. However, the deletion was not found in any of the wild-derived inbred strains analyzed. Haplotype analysis suggested that the deletion originates from a unique mutation event that occurred more than 100 years ago, preceding the development of the first inbred strain (DBA), from a Mus musculus domesticus source. As GPR84 ostensibly plays a role in the biology of myeloid cells, it could be relevant 1) to consider the existence of this Gpr84 nonsense mutation in several mouse strains when choosing a mouse model to study immune processes and 2) to consider reevaluating data obtained using such strains.

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Tracking Differential Gene Expression in MRL/MpJ versus C57BL/6 Anergic B Cells: Molecular Markers of Autoimmunity

Cited by 4 publications

References 95 publications

B Cell Anergy Modulated by TLR1/2 and the miR-17∼92 Cluster Underlies the Indolent Clinical Course of Chronic Lymphocytic Leukemia Stereotyped Subset #4

B Cell Anergy Modulated by TLR1/2 and the miR-17∼92 Cluster Underlies the Indolent Clinical Course of Chronic Lymphocytic Leukemia Stereotyped Subset #4

Regulation of basement membrane-reactive B cells in BXSB, (NZBxNZW)F1, NZB, and MRL/lpr lupus mice

Several Classical Mouse Inbred Strains, Including DBA/2, NOD/Lt, FVB/N, and SJL/J, Carry a Putative Loss-of-Function Allele of Gpr84

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