Development of Murine Lupus Involves the Combined Genetic Contribution of the SLAM and FcγR Intervals within the Nba2 Autoimmune Susceptibility Locus

Jørgensen, Trine N.; Alfaro, Jennifer; Enriquez, Hilda L.; Jiang, Chao; Loo, William; Atencio, Stephanie; Bupp, Melanie R. Gubbels; Mailloux, Christina M.; Metzger, Troy E.; Flannery, S.; Rozzo, Stephen J.; Kotzin, Brian L.; Rosemblatt, Mario; Bono, Marı́a Rosa; Erickson, Loren D.

doi:10.4049/jimmunol.0901322

Cited by 63 publications

(103 citation statements)

References 70 publications

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“…The SLAM family genes, located in the telomeric end of chromosome 1 in autoimmune mice (i.e., NZM2410/NZW-derived Sle1b interval) and human SLE patients, are implicated in altering B cell tolerance (3, 16–18). To definitively determine the contribution of particular Slamf genes within the Sle1b sublocus in autoimmunity, a panel of B6-derived BACs spanning the entire Sle1b interval was used to generate a series of transgenic mouse lines (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

B Cell–Intrinsic CD84 and Ly108 Maintain Germinal Center B Cell Tolerance

Wong

Soni

Chan

et al. 2015

The Journal of Immunology

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Signaling lymphocyte activation molecules (SLAMs) play an integral role in immune regulation. Polymorphisms in the SLAM family receptors are implicated in human and mouse model of lupus disease. The lupus-associated, somatically mutated and class-switched pathogenic autoantibodies are generated in spontaneously developed germinal centers (Spt-GCs) in secondary lymphoid organs. The role and mechanism of B cell-intrinsic expression of polymorphic SLAM receptors that affect B cell tolerance at the GC checkpoint is not clear. Here, we generated several bacterial artificial chromosome (BAC) transgenic mice that overexpress B6 alleles of different SLAM family genes in autoimmune-prone B6.Sle1b mice. B6.Sle1b mice overexpressing B6-derived Ly108 and CD84 exhibit a significant reduction in the Spt-GC response and autoantibody production compared to B6.Sle1b mice. These data suggest a prominent role of Sle1b-derived Ly108 and CD84 in altering the GC checkpoint. We further confirm that expression of lupus-associated CD84 and Ly108 specifically on GC B cells in B6.Sle1b mice is sufficient to break B cell tolerance leading to an increase in autoantibody production. In addition, we observe that B6.Sle1b B cells have reduced BCR signaling, and a lower frequency of B cell-T cell conjugates, which are reversed in B6.Sle1b mice overexpressing B6 alleles of CD84 and Ly108. Finally, we find a significant decrease in apoptotic GC B cells in B6.Sle1b mice compared to B6 controls. Our study establishes the central role of GC B cell-specific CD84 and Ly108 expression in maintaining B cell tolerance in GCs and in preventing autoimmunity.

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Section: Resultsmentioning

confidence: 99%

B Cell–Intrinsic CD84 and Ly108 Maintain Germinal Center B Cell Tolerance

Wong

Soni

Chan

et al. 2015

The Journal of Immunology

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“…26 This group also concluded that the Fcgr2b locus augments the autoimmune phenotype, since a shorter interval containing the Slam locus alone had a milder phenotype than a longer interval containing both the Slam and Fcgr2b loci. However, the autoantibody profile of the mice with the shorter interval containing just the Slam locus is similar to that observed for our B6.NZBc1(96-100) mice that contain the Fcgr2b locus, whereas that of the longer interval is similar to our B6.NZBc1(88-100) mice (notably, both intervals have similar centromeric crossovers).…”

Section: Discussionmentioning

confidence: 99%

The lupus phenotype in B6.NZBc1 congenic mice reflects interactions between multiple susceptibility loci and a suppressor locus

Landolt-Marticorena

Lajoie

et al. 2011

Genes Immun

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Lupus susceptibility loci on chromosome 1 have an important role in the development of autoimmunity in the New Zealand Black (NZB) mouse. We have previously shown that C57BL/6 congenic mice with an introgressed homozygous NZB chromosome 1 interval extending from B35 to 106 cM develop anti-nuclear antibodies and mild glomerulonephritis. In this study, we produced subcongenic mouse strains to localize the susceptibility loci in this interval and investigate how they promote autoimmunity. Our results indicate at least four susceptibility alleles and a suppressor allele. One allele is located in the 96-100 cM region and is sufficient to breach tolerance to chromatin. Addition of a second locus in the 88-96 cM interval enhances anti-dsDNA antibody production and promotes renal disease, which together with a third susceptibility allele in the 70-88 interval results in significant mortality. We further demonstrate the presence of a suppressor locus in the 35-70 or 100-102 cM interval that abrogates these phenotypes and an additional susceptibility allele in the 102-106 cM interval that restores a milder autoimmune phenotype. Several of these loci alter T-cell function. Thus, there is substantial genetic complexity in the NZB 35-106 cM interval, with disease reflecting a balance between susceptibility and suppressor loci.

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“…The Nba2 congenic strain has this region of chromosome 1 from NZB backcrossed onto C57BL/6. Dissection of Nba2 into smaller subregions suggested a major role for other loci such as genes for signaling lymphocytic activation molecule factors and FcgRIIb, with little or no role for Ifi202 (65). However, it appears that the high expression of p202 seen in NZB may not be fully maintained in the Nba2 congenic (43), and if there are epistatic effects of other NZB loci on Ifi202 expression, the Nba2 congenic is not a suitable system to investigate the role of p202.…”

Section: Discussionmentioning

confidence: 96%

Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice

Sester

Sagulenko

Thygesen

et al. 2015

The Journal of Immunology

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Inflammasomes are protein complexes that promote caspase activation, resulting in processing of IL-1β and cell death, in response to infection and cellular stresses. Inflammasomes have been anticipated to contribute to autoimmunity. The New Zealand Black (NZB) mouse develops anti-erythrocyte Abs and is a model of autoimmune hemolytic anemia. These mice also develop anti-nuclear Abs typical of lupus. In this article, we show that NZB macrophages have deficient inflammasome responses to a DNA virus and fungal infection. Absent in melanoma 2 (AIM2) inflammasome responses are compromised in NZB by high expression of the AIM 2 antagonist protein p202, and consequently NZB cells had low IL-1β output in response to both transfected DNA and mouse CMV infection. Surprisingly, we also found that a second inflammasome system, mediated by the NLR family, pyrin domain containing 3 (NLRP3) initiating protein, was completely lacking in NZB cells. This was due to a point mutation in an intron of the Nlrp3 gene in NZB mice, which generates a novel splice acceptor site. This leads to incorporation of a pseudoexon with a premature stop codon. The lack of full-length NLRP3 protein results in NZB being effectively null for Nlrp3, with no production of bioactive IL-1β in response to NLRP3 stimuli, including infection with Candida albicans. Thus, this autoimmune strain harbors two inflammasome deficiencies, mediated through quite distinct mechanisms. We hypothesize that the inflammasome deficiencies in NZB alter the interaction of the host with both microflora and pathogens, promoting prolonged production of cytokines that contribute to development of autoantibodies.

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Development of Murine Lupus Involves the Combined Genetic Contribution of the SLAM and FcγR Intervals within the Nba2 Autoimmune Susceptibility Locus

Cited by 63 publications

References 70 publications

B Cell–Intrinsic CD84 and Ly108 Maintain Germinal Center B Cell Tolerance

B Cell–Intrinsic CD84 and Ly108 Maintain Germinal Center B Cell Tolerance

The lupus phenotype in B6.NZBc1 congenic mice reflects interactions between multiple susceptibility loci and a suppressor locus

Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice

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