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1.
J Immunol ; 196(4): 1507-16, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26773143

RESUMO

C57BL/6 mice bearing the Sle2(z) lupus-susceptibility congenic interval on chromosome 4 display high titers of polyclonal autoantibodies with generalized B cell hyperactivity, hallmarks of systemic lupus erythematosus. In B6.Sle2(z)HEL(Ig).sHEL BCR-transgenic mice, Sle2(z) did not breach central tolerance, but it led to heightened expression of endogenous Ig H and L chains in splenic B cells, upregulation of RAG, and serological polyreactivity, suggestive of excessive receptor revision. Fatty acid amide hydrolase (FAAH), a gene in the minimal subcongenic interval generated through recombinant mapping, was found to be upregulated in Sle2(z) B cells by microarray analysis, Western blot, and functional assays. Pharmacological inhibition of FAAH reversed the increase in receptor revision, RAG expression, and polyreactive autoantibodies in lupus-prone mice. These studies indicate that increased peripheral BCR revision, or selective peripheral expansion of BCR-revised B cells, may lead to systemic autoimmunity and that FAAH is a lupus-susceptibility gene that might regulate this process.


Assuntos
Amidoidrolases/metabolismo , Subpopulações de Linfócitos B/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Amidoidrolases/genética , Animais , Autoanticorpos/imunologia , Linfócitos B/imunologia , Linfócitos B/fisiologia , Predisposição Genética para Doença , Tolerância Imunológica/genética , Lúpus Eritematoso Sistêmico/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise em Microsséries , Receptores de Antígenos de Linfócitos B/metabolismo , Baço/citologia , Baço/imunologia
2.
Immunol Res ; 40(3): 208-23, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-17943232

RESUMO

The appearance of autoantibodies in autoimmune diseases such as lupus suggests that B-cell tolerance to self is breached. Hence it becomes important to unravel the precise cellular and molecular mechanisms that are responsible for violations in various B-cell tolerance checkpoints in autoimmune diseases. B-cell immunoglobulin or B-cell receptor transgenic models have been of immense aid in uncovering many of these key tolerance checkpoints during normal B-cell development. By breeding these transgenic models onto mice that are engineered to lack or hyperexpress various B-cell molecules, including signaling intermediates, researchers have delineated the role of these molecules in B-cell tolerance. These transgenic models have also been useful in delineating the impact of various lupus prone genomes and lupus susceptibility loci on B-cell tolerance. This review focuses on some of the more well-studied B-cell receptor transgenic models and the lessons they have taught us over the past two decades.


Assuntos
Autoimunidade , Linfócitos B/imunologia , Citocinas/metabolismo , Tolerância Imunológica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Receptores de Antígenos de Linfócitos B/imunologia , Animais , Apoptose , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Citocinas/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunoglobulinas/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Transgênicos , Muramidase/imunologia
3.
J Immunol ; 179(2): 1340-52, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17617627

RESUMO

An NZM2410-derived lupus susceptibility locus on murine chromosome 4, Sle2(z), has previously been noted to engender generalized B cell hyperactivity. To study how Sle2(z) impacts B cell tolerance, two Ig H chain site-directed transgenes, 3H9 and 56R, with specificity for DNA were backcrossed onto the C57BL/6 background with or without Sle2(z). Interestingly, the presence of the NZM2410 "z" allele of Sle2 on the C57BL/6 background profoundly breached B cell tolerance to DNA, apparently by thwarting receptor editing. Whereas mAbs isolated from the spleens of B6.56R control mice demonstrated significant usage of the endogenous (i.e., nontargeted) H chain locus and evidence of vigorous L chain editing; Abs isolated from B6.Sle2(z).56R spleens were largely composed of the transgenic H chain paired with a spectrum of L chains, predominantly recombined to J(k)1 or J(k)2. In addition, Sle2(z)-bearing B cells adopted divergent phenotypes depending on their Ag specificity. Whereas Sle2(z)-bearing anti-DNA transgenic B cells were skewed toward marginal zone B cells and preplasmablasts, B cells from the same mice that did not express the transgene were skewed toward the B1a phenotype. This work illustrates that genetic loci that confer lupus susceptibility may influence B cell differentiation depending on their Ag specificity and potentially contribute to antinuclear autoantibody formation by infringing upon B cell receptor editing. Taken together with a recent report on Sle1(z), these studies suggest that dysregulated receptor-editing of nuclear Ag-reactive B cells may be a major mechanism through which antinuclear Abs arise in lupus.


Assuntos
Anticorpos Antinucleares/imunologia , Linfócitos B/imunologia , DNA/imunologia , Tolerância Imunológica , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Animais , Anticorpos Antinucleares/sangue , Antígenos Nucleares/imunologia , Linfócitos B/citologia , Diferenciação Celular/imunologia , Imunofluorescência , Genes de Cadeia Pesada de Imunoglobulina/imunologia , Predisposição Genética para Doença , Imunofenotipagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transgenes
4.
J Clin Invest ; 117(8): 2186-96, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17641780

RESUMO

Though B cells play key roles in lupus pathogenesis, the molecular circuitry and its dysregulation in these cells as disease evolves remain poorly understood. To address this, a comprehensive scan of multiple signaling axes using multiplexed Western blotting was undertaken in several different murine lupus strains. PI3K/AKT/mTOR (mTOR, mammalian target of rapamycin), MEK1/Erk1/2, p38, NF-kappaB, multiple Bcl-2 family members, and cell-cycle molecules were observed to be hyperexpressed in lupus B cells in an age-dependent and lupus susceptibility gene-dose-dependent manner. Therapeutic targeting of the AKT/mTOR axis using a rapamycin (sirolimus) derivative ameliorated the serological, cellular, and pathological phenotypes associated with lupus. Surprisingly, the targeting of this axis was associated with the crippling of several other signaling axes. These studies reveal that lupus pathogenesis is contingent upon the activation of an elaborate network of signaling cascades that is shared among genetically distinct mouse models and raise hope that targeting pivotal nodes in these networks may offer therapeutic benefit.


Assuntos
Linfócitos B/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Transdução de Sinais/imunologia , Fatores Etários , Animais , Linfócitos B/patologia , Modelos Animais de Doenças , Dosagem de Genes/imunologia , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/imunologia , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Fenótipo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Quinases/genética , Proteínas Quinases/imunologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR
5.
Science ; 312(5780): 1665-9, 2006 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-16778059

RESUMO

The susceptibility locus for the autoimmune disease lupus on murine chromosome 1, Sle1z/Sle1bz, and the orthologous human locus are associated with production of autoantibody to chromatin. We report that the presence of Sle1z/Sle1bz impairs B cell anergy, receptor revision, and deletion. Members of the SLAM costimulatory molecule family constitute prime candidates for Sle1bz, among which the Ly108.1 isoform of the Ly108 gene was most highly expressed in immature B cells from lupus-prone B6.Sle1z mice. The normal Ly108.2 allele, but not the lupus-associated Ly108.1 allele, was found to sensitize immature B cells to deletion and RAG reexpression. As a potential regulator of tolerance checkpoints, Ly108 may censor self-reactive B cells, hence safeguarding against autoimmunity.


Assuntos
Antígenos Ly/genética , Linfócitos B/imunologia , Predisposição Genética para Doença , Tolerância Imunológica , Lúpus Eritematoso Sistêmico/genética , Animais , Autoantígenos/imunologia , Células da Medula Óssea/imunologia , Morte Celular , Linhagem Celular Tumoral , Células Cultivadas , Anergia Clonal , Deleção Clonal , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Transgênicos , Herança Multifatorial , Muramidase/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Baço/imunologia , Transfecção
6.
J Autoimmun ; 25(3): 215-22, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16246522

RESUMO

B6.Sle1 mice, congenic for the NZM2410-derived lupus susceptibility locus, Sle1 on chromosome 1 exhibit many of the features seen in human lupus including activated lymphocytes and high titers of antinuclear autoantibodies. Among the different surface molecules that were aberrantly expressed on the B6.Sle1 lymphocytes was Ly-6A/E. Splenic B- and T-lymphocytes but not myeloid cells from B6.Sle1 mice exhibited enhanced levels of Ly-6A/E compared to B6 controls. In particular, MZ B cells, GC B cells and B-cell blasts expressed the highest levels of Ly-6A/E in both strains, with the levels being even higher on B6.Sle1 derived cells. Following stimulation with LPS or anti-IgM, there was a profound up-regulation in Ly-6A/E, particularly on MZ B cells and B-cell blasts. CD4 and CD8 T cells also up-regulated Ly-6A/E after stimulation with anti-CD3 and anti-CD28. These studies were extended to additional autoimmune strains including B6.Sle3, B6.Sle1.lpr and BXSB. Importantly, Ly-6A/E levels on lymphocytes were commensurate with the degree of disease exhibited by these lupus strains. Finally, it appears that increased interferon levels, in addition to antigen receptor stimulation, may also be a factor accounting for elevated Ly-6A/E in lupus. Given these observations it is important to elucidate the functional role of Ly-6A/E in lupus in future studies.


Assuntos
Antígenos Ly/biossíntese , Antígenos Ly/genética , Lúpus Eritematoso Sistêmico/metabolismo , Subpopulações de Linfócitos/metabolismo , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Animais , Subpopulações de Linfócitos B/metabolismo , Células Cultivadas , Regulação da Expressão Gênica/imunologia , Interferon gama/metabolismo , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Índice de Gravidade de Doença , Células-Tronco/imunologia , Células-Tronco/metabolismo
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