The Roles of B Cells in MRL/lpr Murine Lupus

Chan, Owen; Madaio, Michael P.; Shlomchik, Mark J.

doi:10.1111/j.1749-6632.1997.tb52046.x

Cited by 53 publications

(37 citation statements)

References 58 publications

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“…At week 20, serum was collected and analyzed for BUN (IDEXX) and mouse anti-dsDNA antibody levels (ELISA; Alpha Diagnostic). Kidney histology was scored according to established criteria (26). No drug-induced weight loss was observed at any of the dose levels tested.…”

Section: Methodsmentioning

confidence: 99%

The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

Honigberg

Smith

Sirisawad

et al. 2010

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

1,364

1,246

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Activation of the B-cell antigen receptor (BCR) signaling pathway contributes to the initiation and maintenance of B-cell malignancies and autoimmune diseases. The Bruton tyrosine kinase (Btk) is specifically required for BCR signaling as demonstrated by human and mouse mutations that disrupt Btk function and prevent B-cell maturation at steps that require a functional BCR pathway. Herein we describe a selective and irreversible Btk inhibitor, PCI-32765, that is currently under clinical development in patients with B-cell nonHodgkin lymphoma. We have used this inhibitor to investigate the biologic effects of Btk inhibition on mature B-cell function and the progression of B cell-associated diseases in vivo. PCI-32765 blocked BCR signaling in human peripheral B cells at concentrations that did not affect T cell receptor signaling. In mice with collagen-induced arthritis, orally administered PCI-32765 reduced the level of circulating autoantibodies and completely suppressed disease. PCI-32765 also inhibited autoantibody production and the development of kidney disease in the MRL-Fas(lpr) lupus model. Occupancy of the Btk active site by PCI-32765 was monitored in vitro and in vivo using a fluorescent affinity probe for Btk. Active site occupancy of Btk was tightly correlated with the blockade of BCR signaling and in vivo efficacy. Finally, PCI-32765 induced objective clinical responses in dogs with spontaneous B-cell non-Hodgkin lymphoma. These findings support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway.lymphoma | X-linked agammaglobulinemia

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Section: Methodsmentioning

confidence: 99%

The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

Honigberg

Smith

Sirisawad

et al. 2010

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

1,364

1,246

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“…The sections were examined in a blinded fashion for glomerular, tubular, and interstitial pathology. Disease was scored on a semiquantitative scale using the published criteria with modifications (35)(36)(37). For glomerulonephritis (GN): 0, normal; 1, mild to moderate increase in cellularity with mesangial proliferation; 2, moderate increase in cellularity with endocapillary and mesangial proliferation, increased matrix, and/or karyorrhexis; and 3, marked increase in cellularity with endocapillary proliferation, crescent formation, and/or necrosis, and/or sclerosis.…”

Section: Renal Function and Histopathologymentioning

confidence: 99%

Expression of Natural Autoantibodies in MRL-lpr Mice Protects from Lupus Nephritis and Improves Survival

Mannoor

Matejuk

et al. 2012

The Journal of Immunology

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Natural autoantibodies (NAA) and their associated B cells constitute a substantial proportion of the normal Ab and B cell repertoire. They often have weak reactivity toward a variety of self-Ags such as DNA, nucleoproteins, and phospholipids. It remains controversial whether NAA contribute to or protect from autoimmune diseases. Using site-directed transgenic (sd-tg) mice expressing a prototypic NAA, we investigated the effect of NAA and NAA-producing B cells in disease development in the autoimmune-prone MRL/MpJ-Faslpr (MRL-lpr) mice. We found that the expression of NAA in MRL-lpr mice prevented proteinuria and reduced kidney immune complex formation. The mice had significantly improved survival. Administration of the IgM NAA to MRL-lpr mice also delayed the onset of nephritis. The sd-tg MRL-lpr mice had decreased levels of anti-dsDNA Abs, anti-Hep2 nuclear Abs, and anti-Sm/ribonucleoprotein Abs. There is a shift in the IgG subclass profile from IgG2a and IgG3 to IgG1 in the sd-tg MRL-lpr mice. The CD4+ T cells from the sd-tg MRL-lpr mice had increased expression of the negative costimulatory molecule CTLA-4 and increased production of IL-10 as compared with those from the wild-type mice. Furthermore, the NAA B cells produced large amounts of IL-10 upon TLR stimulation. These results indicate that NAA and NAA-producing B cells play an important role in protection from lupus nephritis and suggest that the NAA B cells may have an immune regulatory function via the provision of IL-10.

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“…Two such strains are the MRL/MPJ-Fas lpr (MRL/lpr) and the NZB/NZW F1 mouse strain. The common immunological and clinical manifestations of SLE in both of these strains include hyperactive B and T cells, high titers of several autoantibodies directed against nuclear antigens, a defect in the clearance of immune complexes, and immune complex-mediated glomerulonephritis that eventually leads to renal failure and death (46)(47)(48)(49). MRL/MPJ mice with a mutation in the lpr gene alters the Fas receptor and prevents autoreactive T cells from undergoing deletion in the thymus (50).…”

Section: Lupus Models For Hdac Inhibitionmentioning

confidence: 99%