eagle-i University of PennsylvaniaUniversity of Pennsylvania
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Luning Prak Laboratory

Summary:

B cells produce antibodies and are important for innate and adaptive immunity. B cells that are improperly regulated can also cause or contribute to autoimmunity. Our major research interest is in defining B cell tolerance checkpoint defects in mouse models and patients with autoimmune diseases. B cells with a functional antibody can undergo further rearrangement, a process termed receptor editing. Receptor editing is a significant mechanism for central (early) B cell tolerance. Recent work from our lab demonstrates lower levels of editing in approximately 30% of patients with lupus and 30% of patients with type 1 diabetes, as well as in mouse models of these diseases. These findings suggest that a significant proportion of patients with different autoimmune diseases have defects in early B cell tolerance, and may provide insights into which patients will respond best to B cell targeted therapy.

Affiliations:

People:

    Member: Tsao, Patricia., MD, PhD
    Role: Director of Basic & Translational Research, Center for Study & Treatment of Castleman & Inflammatory Lymphadenopathies (CSTL)

Resources:

Organisms and Viruses

  • B6 ( Mus musculus )

  • B6.56R ( Mus musculus )

    Anti-dsDNA antibody heavy chain knock-in mouse bred on B6 background.

    The heterozygous B6.56R mouse has an in-frame 56R H chain rearrangement inserted in the JH locus on one allele (the 56R allele).

    The B6.56R model has three important properties that can be exploited to study H chain rearrangement. First, the H chain is well characterized and is known to produce anti-dsDNA antibodies with all but a handful of L chains. Second, there is a clear precursor-product relationship because all B cells start out with the rearranged 56R H chain DNA. Third, additional H chain rearrangements can be detected phenotypically and genetically.

  • B6.bm12 ( Mus musculus )

  • B6.bm12-huk ( Mus musculus )

  • B6.CreT2-RAG2KO ( Mus musculus )

  • B6.H2g7 ( Mus musculus )

  • B6.huk ( Mus musculus )

  • B6.k0-GFP ( Mus musculus )

  • B6.k0-GFPxB6.huk ( Mus musculus )

  • B6.KRN ( Mus musculus )

  • B6.Rag1-GFP ( Mus musculus )

  • B6.RAG1KO ( Mus musculus )

  • B6.RAG2f.f-56R ( Mus musculus )

  • B6.RAG2f.f-huk ( Mus musculus )

  • B6.VK8-J5 ( Mus musculus )

  • kdel ( Mus musculus )

    Mice lack the ability to produce immunoglobulin (Ig) kappa light chains by targeted deletion of J kappa and C kappa gene segments and the intervening sequences.

  • MRL/lpr-Thy1.1-Igh(b)-56R ( Mus musculus )

  • MRL/MpJ ( Mus musculus )

    "The MRL/MpJ mice are large but docile to the point that males rarely fight. They are the parent and control strain for for MRL/MpJ-Faslpr (Stock Nos. 000485, 006825). Despite carrying the normal Fas gene, MRL/MpJ mice also exhibit autoimmune disorders, but symptoms are manifested much later in life compared to those the MRL/MpJ-Faslpr mice. Starting at about three months of age, levels of circulating immune complexes rise greatly in the MRL-Faslpr mouse but not in the wildtype control, MRL/MpJ. Also beginning at 3 months Faslpr mice exhibit very severe poliferative glomerulonephritis, whereas in the MRL/MpJ controls usually only mild glomerular lesions are detected. MRL/MpJ inbred female typically die at 73 weeks of age and males die at 93 weeks. This compares to a lifespan of 17 weeks in the female and 22 weeks for males in the mouse homozygous for Faslpr. See MRL/MpJ-Faslpr (Stock No. 000485) for additional information. As a strain developed as the control for MRL/MpJ-Faslpr, MRL/MpJ mice are useful in the study of their comparable defects and diseases.

    MRL/MpJ, and one of its ancestral strains LG/J, display heightened wound healing relative to a panel of other inbred strains. At 4 weeks post-injury, 2mm ear punch wounds heal to 0-0.4mm in MRL/MpJ mice but are still 1.2-1.6mm in C57BL/6 mice. At 15 days post-injury C57BL/6 show a maximal closure of 30% reduction in ear hole size while MRL show 85% reduction. The process of healing in MRL/MpJ mice is faster, more complete, showed increased swelling, angiogenesis, fibroblast migration, extracellular matrix deposition, and decreased scarring and fibrosis. Additionally, hair follicles and accompanying sebaceous glands regenerate to a much greater degree. The other ancestral strains of MRL/MpJ (C3H, C57BL/6, and AKR) do not display this enhanced healing. Bone marrow transplantation shows that the MRL/MpJ healing phenotype does not readily transfer with bone marrow and remains in the irradiated host tissues. Enhanced healing of cardiac wounds has also been reported in MRL/MpJ mice. In this model, a very high mitotic index (10-20%) is found, similar to that seen in non-mammalian tissue regeneration. Using F2 and backcross mapping of MRL/MpJ-Faslpr x B6 progeny McBrearty et al. identified multiple wound healing QTLs, Heal2 and Heal3 ,on MRL/MpJ chromosome 13 in the region of D13Mit115 and D13Mit129 respectively; Heal5 on MRL/MpJ chromosome 12 in the region of D12Mit233; Heal1 on chromosome 8 of C57BL/6 in the region of D8Mit211; and a highly suggestive locus on MRL/MpJ chromosome 7 in the region of D7Mit220. In crosses between MRL/MpJ x SJL/J, Masinde et al. identified 10 QTL for wound healing, confirming and extending the findings of McBrearty et al. Chromosomes 1, 3, 6, and 13 each have a single QTL with that on chromosome 13 being statistically suggestive but not significant, while chromosomes 4, 7, and 9 each have two statistically significant QTLs. (Clark et al., 1998; Leferovich et al., 2001; Kench et al., 1999; McBrearty et al., 1998; Masinde et al., 2001.)

    Microarray analysis and SELDI ProteinChip analysis identified multiple genes and proteins that have varied expression in the ear punch wounds of MRL/MpJ-Faslpr versus C57BL/6. The changes in expression patterns suggest that in MRL/MpJ mice there is less of an inflammatory response and an earlier transition into tissue repair than is seen in C57BL/6. (Li et al., 2000 and 2001.)

    Blankenhorn et al. found that MRL/MpJ females heal faster and more completely than males. Some Heal QTLs are sexually dimorphic with Heal2, 3, 7, 8, 10, and 11 having greater effects in males and Heal4, 5, and 9 having greater effects in females. Castration improves wound healing in MRL/MpJ males to nearly the degree seen in females, but ovariectomy does not improve the degree of healing seen in MRL/MpJ females. (Blankenhorn et al., 2003)

    Relative to B10.D2nSnJ mice, MRL/MpJ mice have decreased Neutrophil accumulation in the bronchiolar lavage in response to LPS infusion, and tests using bone marrow chimeras reveal= that the pulmonary inflammatory response transfers with bone marrow. Transforming growth factor beta 1 autologous induction is reduced in MRL/MpJ splenocytes while macrophages show a reduction in the transforming growth factor beta 1 induction of interleukin 1 beta and tumor necrosis factor alpha production but no significant reduction in transforming growth factor beta 1 production. (Kench et al., 1999.)"

  • Vκ8 L chain knock-in ( Mus musculus )

    Vk8 antibody light chain knock-in on B6 background.


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Last updated: 2019-12-13T10:40:50.422-05:00

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The eagle-i Consortium is supported by NIH Grant #5U24RR029825-02 / Copyright 2016