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1.  Development of systemic lupus erythematosus in NZM 2328 mice in the absence of any single BAFF receptor 
Arthritis and rheumatism  2013;65(4):1043-1054.
To determine the necessity for any individual BAFF receptor in the development of SLE.
Bcma, Taci, and Br3 null mutations were introgressed into NZM 2328 mice. NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice were evaluated for lymphocyte phenotype and BAFF receptor expression by flow cytometry, B cell responsiveness to BAFF by in vitro culture, serum BAFF and total IgG and IgG anti-dsDNA levels by ELISA, renal immunopathology by immunofluorescence and histopathology, and clinical disease.
NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice failed to surface-express BCMA, TACI, and BR3, respectively. Transitional and follicular B cells from NZM.Br3−/− mice were much less responsive to BAFF than the corresponding cells from wild-type (WT), NZM.Bcma−/−, or NZM.Taci−/− mice. In comparison to WT mice, NZM.Bcma−/− and NZM.Taci−/− mice harbored increased spleen B cells, T cells, and plasma cells (PC), whereas serum total IgG and IgG anti-dsDNA levels were similar. Despite their paucity of B cells, NZM.Br3−/− mice harbored increased T cells and WT-like numbers of PC and levels of IgG anti-dsDNA. Serum BAFF levels were increased in NZM.Taci−/− and NZM.Br3−/− mice but were decreased in NZM.Bcma−/− mice. Despite their phenotypic differences, renal immunopathology and clinical disease in NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice were at least as severe as in WT mice.
Any single BAFF receptor, including BR3, is dispensable to development of SLE in NZM mice. Development of disease in NZM.Br3−/− mice demonstrates that BAFF/BCMA and/or BAFF/TACI interactions contribute to SLE and that profound, life-long reduction in B cells does not guarantee protection from SLE.
PMCID: PMC3618582  PMID: 23334904
2.  Dispensability of APRIL to development of systemic lupus erythematosus in NZM 2328 mice 
Arthritis and Rheumatism  2012;64(5):1610-1619.
To determine the role for APRIL in the development of SLE.
Wild-type (WT) NZM 2328, NZM.April-/-, NZM.Baff-/-, and NZM.Baff-/-.April-/- mice were evaluated for lymphocyte phenotype by flow cytometry, for serum total IgG and IgG autoantibody levels by ELISA, for glomerular deposition of IgG and C3 by immunofluorescence, for renal histopathology, and for clinical disease (severe proteinuria).
In comparison to WT mice, NZM.April-/- mice harbored increased spleen B cells, T cells, and plasma cells (PC); increased serum levels of IgG anti-chromatin antibodies; and decreased numbers of bone marrow (BM) PC. In addition, glomerular deposition of IgG and C3 was similar in NZM.April-/- and WT mice; renal histopathology tended to be more severe in NZM.April-/- mice than in WT mice; and development of clinical disease was identical in NZM.April-/- and WT mice. BM (but not spleen) PC and serum IgG anti-chromatin and anti-dsDNA antibody levels were lower in NZM.Baff-/-.April-/- mice than in NZM.Baff-/- mice, whereas renal immunopathology in each cohort was equally mild.
APRIL is dispensable for development of full-blown SLE in NZM mice. Moreover, the elimination of both APRIL and BAFF has no discernable effect on development of renal immunopathology or clinical disease beyond that of elimination of BAFF alone. The reduction in BM PC in hosts doubly-deficient in APRIL and BAFF beyond that in hosts deficient only in BAFF raises concern that combined antagonism of APRIL and BAFF may lead to greater immunosuppression without concomitant increase in therapeutic efficacy.
PMCID: PMC3292707  PMID: 22127792
3.  B cell- and BAFF-dependence of IFNα-exaggerated disease in SLE-prone NZM 2328 mice1 
IFNα is a potent activator of innate and adaptive immunity, and its administration to pre-autoimmune (NZBxNZW)F1 mice promotes virulent systemic lupus erythematosus (SLE) disease. Given the known contributions of B cells and BAFF to SLE, we evaluated the ability of IFNα administration to induce disease in wild-type (WT), B cell-deficient, and BAFF-deficient NZM 2328 mice. Whereas WT mice rapidly developed proliferative glomerulonephritis (GN), marked proteinuria, and increased mortality in response to IFNα administration, B cell-deficient mice developed neither renal pathology nor clinical disease. Moreover, BAFF-deficient mice, despite developing limited glomerular IgG and C3 deposition, also remained free of histological GN and clinical disease. Strikingly, similar T cell expansion and serum IgG responses were observed in Adv-IFN-treated WT and BAFF-deficient mice despite their disparate pathological and clinical responses, whereas numbers of activated B cells increased in WT mice but not in BAFF-deficient mice. Nonetheless, B cell, plasma cell, and T cell infiltration of the kidneys in Adv-IFN-treated WT mice was similar to that in WT mice treated with Adv-control. Its ability to promote SLE disease in WT mice notwithstanding, IFNα administration failed to drive the preferential expansion of CD4+ memory T cells that occurs during the natural course of disease, and glomerular infiltration of macrophages failed to associate with development of disease. These results collectively suggest that therapeutic targeting in SLE of BAFF and/or B cells in SLE could be successful even in states of IFNα overexpression. Moreover, our results document important biological differences between IFNα-driven and spontaneous “natural” SLE disease.
PMCID: PMC3074466  PMID: 21383240
rodent; systemic lupus erythematosus; cytokines
4.  Cytokine disturbances in systemic lupus erythematosus 
The pathogenesis of systemic lupus erythematosus (SLE) is complex, and the resulting disease manifestations are heterogeneous. Cytokine dysregulation is pervasive, and their protein and gene expression profiles may serve as markers of disease activity and severity. Importantly, biologic agents that target specific cytokines may represent novel therapies for SLE. Four cytokines (IL-6, TNFα, IFNα, and BLyS) are being evaluated as therapeutic targets in SLE. The present review will examine the roles of each of these cytokines in murine and human SLE, and will summarize results from clinical trials of agents that target these cytokines.
PMCID: PMC3239336  PMID: 21745419
5.  Constitutive overexpression of BAFF in autoimmune-resistant hosts drives only some aspects of systemic lupus erythematosus-like autoimmunity 
Arthritis and rheumatism  2010;62(8):2432-2442.
To determine whether overexpression of BAFF can promote SLE-like autoimmunity in hosts that otherwise are autoimmune-resistant.
We utilized MHC II-deficient C57BL/6 (B6) mice as a model of resistance to SLE and Sles1-bearing B6 mice as a model of resistance to the autoantibody-promoting capacity of the Sle1 region. We generated BAFF transgenic (Tg) counterparts to these respective mice and evaluated lymphocyte phenotype, serologic autoimmunity, renal immunopathology, and clinical disease in the BAFF-Tg and non-Tg mouse sets.
Although constitutive BAFF overexpression did not lead to B cell expansion in MHC II-deficient B6 mice, it did lead to increased serum IgG autoantibody levels. Nevertheless, renal immunopathology was limited, and clinical disease did not develop. In B6 and B6.Sle1 mice, constitutive BAFF overexpression led to increased B cells, CD4+ memory cells, and serum IgG and IgA autoantibody levels. Renal immunopathology was modestly greater in BAFF-Tg mice than in their non-Tg counterparts, but, again, clinical disease did not develop. Introduction of the Sles1 region into B6.Sle1.Baff mice abrogated the BAFF-driven increase in CD4+ memory cells and the Sle1-driven, but not the BAFF-driven, increase in serum IgG anti-chromatin levels. Renal immunopathology was substantially ameliorated.
Although constitutive BAFF overexpression in otherwise autoimmune-resistant mice led to humoral autoimmunity, meaningful renal immunopathology and clinical disease did not develop. This raises the possibility that BAFF overexpression, even when present, may not necessarily drive disease in some SLE patients. This may help explain the heterogeneity in clinical response to BAFF antagonists in human SLE.
PMCID: PMC2921019  PMID: 20506216
6.  Autoantibody-dependent and autoantibody-independent roles for B cells in systemic lupus erythematosus: past, present, and future 
Autoimmunity  2010;43(1):84-97.
It has long been known that B cells produce autoantibodies and, thereby, contribute to the pathogenesis of many autoimmune diseases. Systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disorder, is characterized by high circulating autoantibody titers and immune-complex deposition that can trigger inflammatory damage in multiple organs/organ systems. Although the interest in B cells in SLE has historically focused on their autoantibody production, we now appreciate that B cells have multiple autoantibody-independent roles in SLE as well. B cells can efficiently present antigen and activate T cells, they can augment T cell activation through co-stimulatory interactions, and they can produce numerous cytokines which affect inflammation, lymphogenesis, and immune regulation. Not surprisingly, B cells have become attractive therapeutic targets in SLE. With these points in mind, this review will focus on the autoantibody-dependent and autoantibody-independent roles for B cells in SLE and on therapeutic approaches that target B cells.
PMCID: PMC2809122  PMID: 20014977
Antigen presentation; Autoantibodies; B cells; Co-stimulation; Cytokines; Systemic Lupus Erythematosus
7.  Deficiency of type I IFN receptor in lupus-prone NZM 2328 mice decreases dendritic cell numbers and activation and protects from disease 1 
Type I interferons are potent regulators of innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus. Here we report that clinical and pathological lupus nephritis and serum anti-nuclear antibody levels are greatly attenuated in NZM 2328 mice deficient in type I IFN receptors (IFNAR). To determine if the inflammatory environment in NZM 2328 mice leads to IFNAR-regulated changes in dendritic cells (DC), the number, activation, and function of DC subsets were compared in 2 and 5 month-old (clinically healthy) female NZM and NZM-IFNAR-/- mice. Numbers of activated CD40hi plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2 month-old NZM but not NZM-IFNAR-/- mice, suggesting an early IFNAR-dependent expansion and activation of pDC at disease sites. Relative to NZM spleens, NZM-IFNAR-/- spleens in 5 month-old mice were significantly decreased in size and contained reduced numbers of conventional DC (cDC) subsets, but not pDC. Splenic and renal lymph node NZM-IFNAR-/- DC analyzed directly ex vivo expressed significantly less CD40, CD86 and PDL1 than NZM DC. Upon activation with synthetic TLR9 ligands in vitro, splenic NZM-IFNAR-/- DC produced less IL-12p40/70 and TNFα than NZM DC. The limited IFNAR-/- DC response to endogenous activating stimuli correlated with reduced numbers of splenic activated memory CD4+ T cells and CD19+ B cells in older mice. Thus, IFNAR signaling significantly increases DC numbers, acquisition of antigen presentation competence, and pro-inflammatory function prior to onset of clinically apparent lupus disease.
PMCID: PMC2766036  PMID: 19812195
Systemic lupus erythematosus; dendritic cells; autoimmunity; cell activation; cell differentiation
8.  High density genotyping of STAT4 gene reveals multiple haplotypic associations with Systemic Lupus Erythematosus in different racial groups 
Arthritis and rheumatism  2009;60(4):1085-1095.
Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disorder with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in SLE pathogenesis. STAT1 and STAT4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for SLE susceptibility.
Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 genes on chromosome 2 were genotyped using Illumina platform as a part of extensive association study in a large collection of 9923 lupus cases and controls from different racial groups. DNA from patients and controls was obtained from peripheral blood. Principal component analyses and population based case-control association analyses were performed and the p values, FDR q values and Odds ratios with 95% confidence intervals (95% CIs) were calculated.
We observed strong genetic associations with SLE and multiple SNPs located within the STAT4 gene in different ethnicities (Fisher combined p= 7.02×10−25). In addition to strong confirmation of the association in the 3rd intronic region of this gene reported previously, we identified additional haplotypic association across STAT4 gene and in particular a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to the proximity to STAT4.
Our findings indicate that the STAT4 gene is likely to be a crucial component in SLE pathogenesis among multiple racial groups. The functional effects of this association, when revealed, might improve our understanding of the disease and provide new therapeutic targets.
PMCID: PMC2776081  PMID: 19333953
9.  Accelerated Pathological and Clinical Nephritis in Systemic Lupus Erythematosus-Prone New Zealand Mixed 2328 Mice Doubly Deficient in TNF Receptor 1 and TNF Receptor 2 via a Th17-Associated Pathway1 
TNF-α has both proinflammatory and immunoregulatory functions. Whereas a protective role for TNF administration in systemic lupus erythematosus (SLE)-prone (New Zealand Black × New Zealand White)F1 mice has been established, it remains uncertain whether this effect segregates at the individual TNFR. We generated SLE-prone New Zealand Mixed 2328 mice genetically deficient in TNFR1, in TNFR2, or in both receptors. Doubly-deficient mice developed accelerated pathological and clinical nephritis with elevated levels of circulating IgG anti-dsDNA autoantibodies and increased numbers of CD4+ T lymphocytes, especially activated memory (CD44highCD62Llow) CD4+ T cells. We show that these cells expressed a Th17 gene profile, were positive for IL-17 intracellular staining by FACS, and produced exogenous IL-17 in culture. In contrast, immunological, pathological, and clinical profiles of mice deficient in either TNFR alone did not differ from those in each other or from those in wild-type controls. Thus, total ablation of TNF-α-mediated signaling was highly deleterious to the host in the New Zealand Mixed 2328 SLE model. These observations may have profound ramifications for the use of TNF and TNFR antagonists in human SLE and related autoimmune disorders, as well as demonstrate, for the first time, the association of the Th17 pathway with an animal model of SLE.
PMCID: PMC2790862  PMID: 19201910
10.  Global T cell dysregulation in non-autoimmune-prone mice promotes rapid development of BAFF-independent, SLE-like autoimmunity1 
In otherwise non-autoimmune-prone C57BL/6 (B6) mice rendered genetically deficient in CD152 (CTLA-4), polyclonal hypergammaglobulinemia with increased levels of SLE-associated IgG autoantibodies, glomerular IgG and C3 deposition, and interstitial nephritis all developed by 3-5 weeks of age. Remarkably, superimposing genetic deficiency of BAFF onto CD152 deficiency did not substantially attenuate humoral autoimmunity and immunopathology in these mice, despite the resulting marked reduction in B-lineage cells. Although superimposing a BAFF transgene (resulting in constitutive BAFF overexpression) onto CD152-deficient mice did lead to increases in B-lineage cells and serum levels of certain SLE-associated IgG autoantibodies, renal immunopathology remained largely unaffected. Taken together, these results demonstrate that global T cell dysregulation, even in an otherwise non-autoimmune-prone host, can promote systemic humoral autoimmunity and immunopathology in a BAFF-independent manner. Moreover, supra-physiologic expression of BAFF in the setting of ongoing autoimmunity does not necessarily lead to greater immunopathology. These findings may help explain the limited clinical efficacy appreciated to date of BAFF antagonists in human SLE.
PMCID: PMC2587218  PMID: 18566449
rodent; autoimmunity; cytokines

Results 1-10 (10)