Role of MHC-Linked Genes in Autoantigen Selection and Renal Disease in a Murine Model of Systemic Lupus Erythematosus

Sekine, Hideharu; Graham, Kareem; Zhao, Shenru; Elliott, Margaret K.; Ruiz, Philip; Utz, Paul J.; Gilkeson, Gary S.

doi:10.4049/jimmunol.177.10.7423

Cited by 24 publications

(22 citation statements)

References 58 publications

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“…1A). H-2 b/b MRL/lpr mice exhibited no differences in disease compared with wild-type animals (24). Strikingly, however, 11/16 (68%) H-2 b/b congenics had undetectable serum IgG3 antibodies ( Fig.…”

Section: H-2 B Congenic Mrl/lpr Mice Show Defects In Csrmentioning

confidence: 87%

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Role for Msh5 in the regulation of Ig class switch recombination

Sekine

Ferreira

Pan‐Hammarström

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Ig class switch recombination (CSR) and somatic hypermutation serve to diversify antibody responses and are orchestrated by the activity of activation-induced cytidine deaminase and many proteins involved in DNA repair and genome surveillance. Msh5, a gene encoded in the central MHC class III region, and its obligate heterodimerization partner Msh4 have a critical role in regulating meiotic homologous recombination and have not been implicated in CSR. Here, we show that MRL/lpr mice carrying a congenic H-2 b/b MHC interval exhibit several abnormalities regarding CSR, including a profound deficiency of IgG3 in most mice and long microhomologies at Ig switch (S) joints. We found that Msh5 is expressed at low levels on the H-2 b haplotype and, importantly, a similar long S joint microhomology phenotype was observed in both Msh5 and Msh4-null mice. We also present evidence that genetic variation in MSH5 is associated with IgA deficiency and common variable immune deficiency (CVID) in humans. One of the human MSH5 alleles identified contains two nonsynonymous polymorphisms, and the variant protein encoded by this allele shows impaired binding to MSH4. Similar to the mice, Ig S joints from CVID and IgA deficiency patients carrying disease-associated MSH5 alleles show increased donor/acceptor microhomology, involving pentameric DNA repeat sequences and lower mutation rates than controls. Our findings suggest that Msh4/5 heterodimers contribute to CSR and support a model whereby Msh4/5 promotes the resolution of DNA breaks with low or no terminal microhomology by a classical nonhomologous end-joining mechanism while possibly suppressing an alternative microhomology-mediated pathway.immunoglobulin subclass deficiency ͉ mismatch repair ͉ Msh4 A fter appropriate stimulation, B cells undergo class switch recombination (CSR), whereby the functionally rearranged V(D)J DNA segment is recombined with a downstream Ig constant region segment. The biochemistry of CSR is complex and involves the B cell-specific gene activation-induced cytidine deaminase, which initiates both CSR and somatic hypermutation (1). CSR also requires many ubiquitously expressed genes important for detecting DNA mismatches and breaks and regulating DNA repair (2). CSR occurs at specific DNA segments called switch (S) regions, which lie upstream of each constant region and contain hotspots for activation-induced cytidine deaminase-mediated cytosine deamination. The ligation of the S region with the downstream S regions is carried out by protein factors that comprise the nonhomologous end joining machinery for DNA repair (1, 2).Mismatch repair proteins play a critical role in safeguarding genetic stability. The key proteins for initiation of eukaryotic mismatch repair are homologues of bacterial MutS and MutL. In mammals, there are five MutS (Msh2, Msh3, Msh4, Msh5, and Msh6) and four MutL (Mlh1, Mlh3, Pms1, and Pms2) homologues. Each Mut homologue acts at the DNA repair or recombination site by forming heterodimers; Msh2-Msh6 (MutS␣), Msh2-Msh3 (MutS␤), M...

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Section: H-2 B Congenic Mrl/lpr Mice Show Defects In Csrmentioning

confidence: 87%

“…H-2 b/b MRL/lpr mice were generated as described in ref. 24. Msh5-deficient mice were described in ref.…”

Section: Methodsmentioning

confidence: 99%

Role for Msh5 in the regulation of Ig class switch recombination

Sekine

Ferreira

Pan‐Hammarström

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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140

101

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“…The founder fB -/-mice had normal C2 levels and function, indicating that its expression had not been compromised [30]. The MHC genes have a clear effect on the autoantibody response, but this has not been shown for the disease, although experiments from others would argue for an effect [31].…”

Section: Introductionmentioning

confidence: 98%

Absence of functional alternative complement pathway alleviates lupus cerebritis

et al. 2007

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The complement inhibitor, Crry, which blocks both the classical and alternative pathways, alleviates CNS disease in the lupus model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice. To understand the role of the alternative pathway, we studied mice deficient in a key alternative pathway protein, complement factor B (fB). Immune deposits (IgG and C3) were reduced in the brains of MRL/lpr fB-deficient (fB -/-MRL/lpr) compared to fBsufficient (MRL/lpr) mice, indicating reduced complement activation. Reduced neutrophil infiltration (22% of MRL/lpr mice) and apoptosis (caspase-3 activity was reduced to 33% of MRL/lpr mice) in these mice indicates that the absence of the alternative pathway was neuroprotective. Furthermore, expression of phospho (p)-Akt (0.16 AE 0.02 vs. 0.35 AE 0.13, p <0.03) was increased, while expression of p-PTEN (0.40 AE 0.06 vs. 0.11 AE 0.07, p <0.05) was decreased in fB -/-MRL/lpr mice compared to their MRL/lpr counterparts. The expression of fibronectin, laminin and collagen IV was significantly decreased in fB -/-MRL/lpr mice compared to MRL/lpr mice, indicating that in the lupus setting, tissue integrity was maintained in the absence of the alternative pathway. Absence of fB reduced behavioral alterations in MRL/lpr mice. Our results suggest that in lupus, the alternative pathway may be the key mechanism through which complement activation occurs in brain, and therefore it might serve as a therapeutic target for lupus cerebritis. IntroductionSystemic lupus erythematosus (SLE) is an autoimmune disease, with central nervous system (CNS) involvement occurring in 20-70% of patients. Complement activation is believed to play a key role in the pathogenesis of SLE [1]. The relevance of complement in lupus cerebritis is supported by enhanced C3 and C4 index values in the cerebrospinal fluid of patients [2] and increased levels of the anaphylatoxins, C3a and C5a, which correlate with the CNS flares [3]. This is also true in experimental lupus cerebritis, and is supported by our recent studies, in which systemic inhibition of the C3/C5 convertases reduced pathological alterations in the CNS of the lupus mouse model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice [4,5]. Complement can be activated through classical, alternative and lectin pathways. Complement factor B (fB) is a key protein required for the activation of the alternative pathway [6] and is increased in circulation and in tissues of lupus mice [7][8][9]. In addition, fB solubilizes immune complexes, inhibits proliferation, acts as a B cell growth factor and activates monocytes 15]. Mice with targeted deletion of the fB gene (fB -/-) were protected from lupus nephritis and ischemiareperfusion injury [7,16]. However, the role of fB in the pathogenesis of lupus cerebritis has not been defined. Bb, one of the split products of fB, can induce apoptosis [17], which is a key feature in the brains of MRL/lpr mice [5,18]. Apoptosis can also be induced by several other factors such as nitric oxide (NO), edema, and the extracellular matrix (ECM) proteins through integrin si...

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“…We have previously used autoantigen microarrays to profile the autoantibody response in human and murine autoimmune diseases (16,(36)(37)(38)(39)(40)(41). In the current study, we used this technology to profile the autoantibody response in pristane-treated mice deficient for the IFN-I signaling molecules IRF9 and STAT1.…”

Section: Introductionmentioning

confidence: 99%

IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice

Thibault

Chu²,

Graham³

et al. 2008

J. Clin. Invest.

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A hallmark of SLE is the production of high-titer, high-affinity, isotype-switched IgG autoantibodies directed against nucleic acid-associated antigens. Several studies have established a role for both type I IFN (IFN-I) and the activation of TLRs by nucleic acid-associated autoantigens in the pathogenesis of this disease. Here, we demonstrate that 2 IFN-I signaling molecules, IFN regulatory factor 9 (IRF9) and STAT1, were required for the production of IgG autoantibodies in the pristane-induced mouse model of SLE. In addition, levels of IgM autoantibodies were increased in pristane-treated Irf9 -/-mice, suggesting that IRF9 plays a role in isotype switching in response to self antigens. Upregulation of TLR7 by IFN-α was greatly reduced in Irf9 -/-and Stat1 -/-B cells. Irf9 -/-B cells were incapable of being activated through TLR7, and Stat1 -/-B cells were impaired in activation through both TLR7 and TLR9. These data may reveal a novel role for IFN-I signaling molecules in both TLR-specific B cell responses and production of IgG autoantibodies directed against nucleic acid-associated autoantigens. Our results suggest that IFN-I is upstream of TLR signaling in the activation of autoreactive B cells in SLE.

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Role of MHC-Linked Genes in Autoantigen Selection and Renal Disease in a Murine Model of Systemic Lupus Erythematosus

Cited by 24 publications

References 58 publications

Role for Msh5 in the regulation of Ig class switch recombination

Role for Msh5 in the regulation of Ig class switch recombination

Absence of functional alternative complement pathway alleviates lupus cerebritis

IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice

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