Failure of CD25+ T Cells from Lupus-Prone Mice to Suppress Lupus Glomerulonephritis and Sialoadenitis (original) (raw)
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A Spontaneous Mouse Model of Lupus: Physiology and Therapy
Lupus - New Advances and Challenges
Spontaneous models of lupus were recognized four decades ago beginning in the early 1960s with the NZB/NZW F1 (NZB/W F1) mouse, an F1 hybrid between the New Zealand Black (NZB) and New Zealand White (NZW) mice. Although the parental strains display limited autoimmunity, the NZB/W F1 develops severe lupuslike features similar to that of human lupus patients. Here, we will address the genetic characteristics of the model and discuss its main characteristics such as the presence of serum antinuclear autoantibodies (ANA) including anti-dsDNA, mild vasculitis, and the development of immune complex-mediated glomerulonephritis. Similar to human lupus, the disease develops primarily in female mice after six months of age, with a lesser percentage and severity in male mice. The relation of this phenomenon will be examined in the context of estrogen levels. The participation of both innate and adaptive immunity will be addressed as well as the contribution of both T and B cells in the development of the clinical aspects of the disease. We will focus on the use of the model as a valuable tool for elucidating the pathogenic mechanisms of the disease, as well as its use as preclinical testing of therapeutic for human use.
Effects of MHC and Gender on Lupus-Like Autoimmunity in Nba2 Congenic Mice
The Journal of Immunology, 2005
The lupus-like disease that develops in hybrids of NZB and NZW mice is genetically complex, involving both MHC-and non-MHC-encoded genes. Studies in this model have indicated that the H2 d/z MHC type, compared with H2 d/d or H2 z/z , is critical for disease development. C57BL/6 (B6) mice (H2 b/b) congenic for NZB autoimmunity 2 (Nba2), a NZB-derived susceptibility locus on distal chromosome 1, produce autoantibodies to nuclear Ags, but do not develop kidney disease. Crossing B6.Nba2 to NZW results in H2 b/z F 1 offspring that develop severe lupus nephritis. Despite the importance of H2 z in past studies, we found no enhancement of autoantibody production or nephritis in H2 b/z vs H2 b/b B6.Nba2 mice, and inheritance of H2 z/z markedly suppressed autoantibody production. (B6.Nba2 ؋ NZW)F 1 mice, compared with MHC-matched B6.Nba2 mice, produced higher levels of IgG autoantibodies to chromatin, but not to dsDNA. Although progressive renal damage with proteinuria only occurred in F 1 mice, kidneys of some B6.Nba2 mice showed similar extensive IgG and C3 deposition. We also studied male and female B6.Nba2 and F 1 mice with different MHC combinations to determine whether increased susceptibility to lupus among females was also expressed within the context of the Nba2 locus. Regardless of MHC or the presence of NZW genes, females produced higher levels of antinuclear autoantibodies, and female F 1 mice developed severe proteinuria with higher frequencies. Together, these studies help to clarify particular genetic and sex-specific influences on the pathogenesis of lupus nephritis.
A Central Role for αβ T Cells in the Pathogenesis of Murine Lupus
The Journal of Immunology
We have previously shown that female transgenic mice expressing IFN-γ in the epidermis, under the control of the involucrin promoter, develop inflammatory skin disease and a form of murine lupus. To investigate the pathogenesis of this syndrome, we generated female IFN-γ transgenic mice congenitally deficient in either αβ or γδ T cells. TCRδ−/− transgenics continued to produce antinuclear autoantibodies and to develop severe kidney lesions. In contrast, TCRβ−/− IFN-γ transgenic mice failed to produce antinucleosome, anti-dsDNA, or antihistone autoantibodies, and kidney disease was abolished. Both αβ- and γδ-deficient transgenics continued to develop IFN-γ-associated skin disease, lymphadenopathy, and splenomegaly. The data show that the autoantibody-mediated pathology of murine lupus in IFN-γ transgenic mice is completely αβ T cell dependent and that γδ T cells cannot drive autoantibody production. These results imply that production of antinuclear autoantibodies in IFN-γ transgenic...
(SWR x SJL)F1 mice: a new model of lupus-like disease
Journal of Experimental Medicine
During the study of autoimmune models we found that (SWR x SJL)F1 mice (both parental strains with the V3 a phenotype) spontaneously produced immunoglobulin G (IgG) antibodies directed against SIn/U1 small nuclear ribonucleoproteins (snRNPs). In some of these females, the presence of these autoantibodies was found as early as 10 wk of age. Their frequency increased with age i.e., 70% at 40 wk. At that time, only 10% of males developed anti-Sm/UlsnRNP antibodies. Anti-Sm/UlsnRNP antibodies from positive mice generally recognized the peptides BB', D, 70 kD, and A from RNPs. These polypeptides are known to bear the autoantigenic epitopes that are recognized by human sera containing anti-Sm and anti-UlsnRNP antibodies. Reactivity of IgG antibodies with the octapeptide sequence PPPGMRPP was also found in 30% of anti-Sm/UlsnRNP positive (SWR x SJL)F1 mice that precipitated BB' peptides. This octapeptide has been described as the most immunoreactive linear epitope in systemic lupus erythematosus (SLE) patients with anti-Sm and anti-UlsnRNP antibodies. Approximately 30% of anti-Sn/UlsnRNP positive females, later produced anti-dsDNA antibodies. This fact was accompanied by the development of proteinuria due to glomerulonephritis mediated by immunocomplexes. In addition to the specific autoimmune response, (SWR x SJL)F1 females also showed other immunologic abnormalities such as hypergammaglobulinemia, and an approximately twofold increase in spleen cell number compared with control mice. These results indicate that (SWR x SJL)F1 females develop clinical and serological abnormalities similar to those observed in human SLE and constitute a novel model for the study of the genetic mechanisms that result in autoimmunity.
Genetic and cellular mechanisms of autoimmunity in lupus-prone B6.129-Sle16 mice
2017
The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work. ْم س ِ ب يم حِ الره ِ ن First and foremost, I would like to thank my supervisor Professor Marina Botto for her guidance and direction throughout my PhD. Non-hypotheses approaches, as fancy as it might sound, is like finding a needle in a haystack, and I am extremely grateful for her patience and her commitment, taking the time to go through my data with me whenever I need, and setting me up to courses and other experts in the field. I also would like to thank my co-supervisor Dr Francesco Carlucci, for his guidance and his encouragements to keep me motivated throughout my PhD. Coming from non-immunological background, I especially would like to thank our postdoc, Dr Heidi Ling for teaching me most of immunological assays I have known so far, always listening to my questions and gave me suggestions to improve my project. Although I can't do it formally, I have always acknowledged her as my third supervisor. I also would like to extend my appreciation to the members of CCIR lab, particularly, Dr Chiara Giacomassi, Dr Greg Crawford, Dr Marieta Ruseva, and Dr Rocio Castro Seone, for always willing to help (in the lab and outside) and making my stay in the CCIR lab enjoyable. Thank you to my sponsor, Malaysian Government and Majlis Amanah Rakyat (MARA) for funding my PhD. Finally, I am grateful to have my mom, Mrs Aminah Ali, and my friends and families for their endless support and encouragements. Without them, I may not able to make it to the end.
Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies
Journal of Clinical Investigation, 1999
Sle1 and Sle3 are 2 loci that confer susceptibility to lupus nephritis in the NZM2410 strain of mice. Our previous work has shown that B6.NZMc1 mice, congenic for Sle1, exhibit loss of tolerance to chromatin but do not develop any pathogenic autoantibodies or disease. B6.NZMc7 mice, congenic for Sle3, exhibit low-grade polyclonal Band T-cell activation, elevated CD4/CD8 ratios, and mildly penetrant glomerulonephritis. In contrast to these monocongenics, the present study reveals that B6.NZMc1|c7 mice, bicongenic for Sle1 and Sle3, exhibit splenomegaly, significantly expanded populations of activated B and CD4 + T cells, and a robust, variegated IgG autoantibody response targeting multiple components of chromatin (including double-stranded DNA), intact glomeruli, and basement membrane matrix antigens. As one might predict, these mice, particularly the females, exhibit highly penetrant glomerulonephritis. These findings lend strong support to a two-step epistatic model for the formation of pathogenic, nephrophilic autoantibodies in lupus. Whereas loci such as Sle1 may serve to breach tolerance to chromatin, full-blown pathogenic maturation of the autoantibody response appears to require additional input from other loci (such as Sle3) and gender-based factors.
Knocking out of CD38 accelerates development of a lupus-like disease in lpr mice
Rheumatology, 2011
Objectives. CD38 participates in lymphocyte ontogeny and function and may be involved in autoimmunity. Absence of CD38 accelerates development of non-obese diabetic (NOD) mice diabetes and anti-CD38 antibodies are good markers of human disease. Little is known regarding systemic autoimmunity. Active SLE patients have higher numbers of CD38 + T and B cells. CD38 is a candidate gene for the murine Lmb2 lupus locus. We aimed to investigate whether CD38 was involved in lupus development. Methods. We developed Cd38 À/À-Fas lpr /Fas lpr mice and monitored them for development of a lupus-like disease through measurement of protein excretion in urine, histological assessment of the kidneys, quantification of circulating immunoglobulins and autoantibodies. We have also immunophenotyped 2-and 6-month old Cd38 À/À-Fas lpr /Fas lpr mice. Results. We found that absence of CD38 accelerated disease development: female Cd38 À/À-Fas lpr /Fas lpr mice presented severe proteinuria, GN, deposition of ICs in the renal medulla and increased amounts of circulating immunoglobulin G (IgG), although anti-dsDNA autoantibodies and RF were not significantly increased at disease onset. We have found that Cd38 À/À-Fas lpr /Fas lpr male mice, similarly to other murine models of lupus, were able to control disease. Absence of CD38 in lpr mice altered differentiation of T cells and dendritic cells (DC). Conclusion. Although the role of CD38 in tolerance is still to be elucidated, we provide evidence that it may play an active role in the control of a murine lupus-like disease.
Enhanced susceptibility to end-organ disease in the lupus-facilitating NZW mouse strain
Arthritis and Rheumatism, 2003
ObjectiveAlthough the NZW mouse strain is phenotypically normal, fulminant lupus glomerulonephritis (GN) develops when NZW mice are bred to several other strains, such as NZB, BXSB, B6.Sle1, and B6.Yaa. Based on the observation that aging NZW mice exhibit histologic evidence of GN, we sought to test our hypothesis that NZW mice may be more susceptible to immune-mediated renal damage.Although the NZW mouse strain is phenotypically normal, fulminant lupus glomerulonephritis (GN) develops when NZW mice are bred to several other strains, such as NZB, BXSB, B6.Sle1, and B6.Yaa. Based on the observation that aging NZW mice exhibit histologic evidence of GN, we sought to test our hypothesis that NZW mice may be more susceptible to immune-mediated renal damage.MethodsNZW mice, as well as C57BL/6 (B6) and BALB/c control mice, were challenged with rabbit anti–glomerular basement membrane nephrotoxic sera (NTS), to induce renal disease. The different mouse strains were monitored for the degree of clinical disease, renal pathology, chemokine profiles, and cellular infiltrates.NZW mice, as well as C57BL/6 (B6) and BALB/c control mice, were challenged with rabbit anti–glomerular basement membrane nephrotoxic sera (NTS), to induce renal disease. The different mouse strains were monitored for the degree of clinical disease, renal pathology, chemokine profiles, and cellular infiltrates.ResultsAlthough the NZW and control strains showed similar glomerular deposits of rabbit Ig and exhibited similar levels of anti-rabbit xenogeneic immune response, the NZW mice had significantly worse pathologic changes and disease. Compared with the control strains, the NTS-injected NZW mice demonstrated significantly increased proteinuria, elevated blood urea nitrogen levels, more severe histologic GN and tubulointerstitial nephritis, increased glomerular crescent formation with macrophage and neutrophil infiltrates, elevated expression of CC and CXC chemokines (monocyte chemoattractant protein 1, RANTES, KC), and significantly accelerated mortality. Importantly, these changes occurred within a few days after NTS administration. Finally, (B6 × NZW)F1 mice were as susceptible as the NZW parents, which indicates dominant NZW contributions.Although the NZW and control strains showed similar glomerular deposits of rabbit Ig and exhibited similar levels of anti-rabbit xenogeneic immune response, the NZW mice had significantly worse pathologic changes and disease. Compared with the control strains, the NTS-injected NZW mice demonstrated significantly increased proteinuria, elevated blood urea nitrogen levels, more severe histologic GN and tubulointerstitial nephritis, increased glomerular crescent formation with macrophage and neutrophil infiltrates, elevated expression of CC and CXC chemokines (monocyte chemoattractant protein 1, RANTES, KC), and significantly accelerated mortality. Importantly, these changes occurred within a few days after NTS administration. Finally, (B6 × NZW)F1 mice were as susceptible as the NZW parents, which indicates dominant NZW contributions.ConclusionCollectively, these findings support the notion that a lupus-facilitating genome may contribute to disease susceptibility by modulating the degree of immune-mediated end-organ damage. The availability of B6-based congenic strains bearing individual NZW-derived lupus susceptibility loci will permit future genetic dissection of end-organ susceptibility in murine lupus.Collectively, these findings support the notion that a lupus-facilitating genome may contribute to disease susceptibility by modulating the degree of immune-mediated end-organ damage. The availability of B6-based congenic strains bearing individual NZW-derived lupus susceptibility loci will permit future genetic dissection of end-organ susceptibility in murine lupus.
Journal of immunology research, 2018
Type I interferons (IFN) are pathogenic in systemic lupus erythematosus (SLE) and were proposed to control the immunometabolism of dendritic cells (DCs). We previously reported that DCs from female lupus-prone mice constitutively overexpress IFN-responsive genes resembling the IFN signature found in SLE patients. As SLE has higher incidence in women than men, more so in women of reproductive age, estrogens are suggested to affect lupus pathogenesis. We investigated the effects of sex and estrogens on the IFN signature in conventional GM-CSF-bone marrow-derived DCs (cDCs), from male and female Triple Congenic B6.NZM. (TCSle) lupus-prone mice or from wild-type C57BL/6 mice, generated with titrations of 17-beta-estradiol (E2). We found that cDCs from prediseased TCSle male mice express the IFN signature as female TCSle cDCs do. Estrogens are necessary but not sufficient to express this IFN signature, but high doses of E2 can compensate for other steroidal components. E2 stimulation, re...