Nonobese Diabetic Congenic Strain Analysis of Autoimmune Diabetes Reveals Genetic Complexity of the <i>Idd18</i> Locus and Identifies <i>Vav3</i> as a Candidate Gene

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We previously described the NOD.c3c4 mouse, which is protected from type 1 diabetes (T1D) due to protective alleles at multiple insulin-dependent diabetes (Idd) genes, but develops autoimmune biliary disease (ABD) resembling primary biliary cirrhosis (PBC). Here we characterize the NOD.ABD strain, which is genetically-related to the NOD.c3c4 strain but develops both ABD and T1D. Histologically, NOD.ABD biliary disease is indistinguishable from that in NOD.c3c4 mice. The frequency of effector memory (CD44+CD62L-) and central memory (CD44+CD62L+) CD8 T cells is significantly increased in the intrahepatic lymphocyte fraction of NOD.ABD mice, and NOD.ABD CD8 T cells produce more IFN-γ and TNF-α, compared to controls. NOD.ABD splenocytes can transfer ABD and T1D to NOD.c3c4 scid mice, but only T1D to NOD scid mice, suggesting that the genetic origin of the target organ and/or its innate immune cells is critical to disease pathogenesis. The disease transfer model, importantly, shows that biliary duct damage (characteristic of PBC) and inflammation precede biliary epithelial cell proliferation. Unlike T1D where both CD4 and CD8 T cells are required for disease transfer, purified NOD.ABD CD8 T cells can transfer liver inflammation into NOD.c3c4 scid recipients, and disease transfer is ameliorated by co-transferring T regulatory cells. Unlike NOD.c3c4 mice, NOD.ABD mice do not develop antinuclear or anti-Smith autoantibodies; however, NOD.ABD mice do develop the anti-pyruvate dehydrogenase antibodies typical of human PBC. The NOD.ABD strain is a model of immune dysregulation affecting two organ systems, most likely by mechanisms that do not completely coincide.

Section: Methodsmentioning

confidence: 99%

CD8 T Cells Mediate Direct Biliary Ductule Damage in Nonobese Diabetic Autoimmune Biliary Disease

Yang

Tsukamoto

et al. 2011

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“…NOD/MrkTac (NOD) and C57BL/6NTac (B6) mice were purchased from Taconic Inc. (Germantown, NY). The NOD.B6 Idd10 (N16) strain (Taconic line 3538) was developed from the NOD.B6 Idd3 Idd10 (N12) strain (Taconic line 1100) (9), by backcrossing to NOD and genotyping progeny using NOD/B6 polymorphic markers to isolate the Idd10 congenic segment. NOD.A/J Idd10 (N10) and NOD.CAST Idd10 (N9) were developed by backcrossing A/J and CAST/EiJ mice that were obtained from The Jackson Laboratory (Bar Harbor, ME) to the NOD background using polymorphic markers near and in the Idd10 region to define recombination events.…”

Section: Methodsmentioning

confidence: 99%

Evidence thatCd101Is an Autoimmune Diabetes Gene in Nonobese Diabetic Mice

Rainbow

Moule

Fraser

et al. 2011

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We have previously proposed that sequence variation of the CD101 gene between NOD and C57BL/6 (B6) mice accounts for the protection from type 1 diabetes (T1D) provided by the Idd10 region, a <1 Mb region on mouse chromosome 3. Here, we provide further support for the hypothesis that Cd101 is Idd10 using haplotype and expression analyses of novel Idd10 congenic strains coupled to the development of a CD101 knockout mouse. Susceptibility to T1D was correlated with genotype-dependent CD101 expression on multiple cell subsets, including FoxP3+ regulatory CD4+ T cells, CD11c+ dendritic cells and Gr1+ myeloid cells. The correlation of CD101 expression on immune cells from four independent Idd10 haplotypes with the development of T1D supports the identity of Cd101 as Idd10. Since CD101 has been associated with T regulatory and antigen presentation cell functions, our results provide a further link between immune regulation and susceptibility to T1D.

“…B6 CD45.1, B6 CD101 −/− , B6 CD1d −/− , NOD, NOD.B6 Ptprc CD45.2 (line 6908) (48), NOD.B6 Idd10/18 (lines 1101 and 7754, both having the same Idd10/18 segment (49–50), NOD.B6 Idd10 (line 3538), and NOD.B6 Idd18 (line 3539), NOD.A/J Idd10 , and NOD.CAST Idd10 mice were maintained in our laboratories. Additional information about the NOD congenic strains can be obtained at http://www.t1dbase.org/page/DrawStrains.…”

Section: Methodsmentioning

confidence: 99%

“…The generation of the CD101-knockout B6, NOD.B6 Idd10 (line 3538), NOD.A/J Idd10 and NOD.CAST Idd10 strains is detailed in the co-submitted manuscript (47). NOD.B6 Idd18 (line 3539) N16 mice were developed by selectively breeding a mouse having a recombination event in the distal region of the Idd10/18 congenic segment present in the NOD.B6 Idd3 Idd10 Idd18 (line 1538) strain (49) that was discovered when line 1538 was being backcrossed to the NOD strain. The T1D phenotype of line 3539 will be detailed in a separate publication.…”

Section: Methodsmentioning

confidence: 99%

Identification of Cd101 as a Susceptibility Gene for Novosphingobium aromaticivorans-Induced Liver Autoimmunity

Mohammed

Fusakio

Rainbow

et al. 2011

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Environmental and genetic factors define the susceptibility of an individual to autoimmune disease. Although common genetic pathways affect general immunological tolerance mechanisms in autoimmunity, the effects of such genes could vary under distinct immune challenges within different tissues. Here we demonstrate this by observing that autoimmune type 1 diabetes (T1D) protective haplotypes at the susceptibility region 10 (Idd10) introgressed from chromosome 3 of B6 and A/J mice onto the NOD background increase the severity of autoimmune primary biliary cirrhosis (PBC) induced by infection with Novosphingobium aromaticivorans (N. aro), an ubiquitous alphaproteobacterium, when compared to mice having the NOD and NOD.CAST Idd10 T1D susceptible haplotypes. Substantially increased liver pathology in mice having the B6 and A/J Idd10 haplotypes correlates with reduced expression of CD101 on dendritic cells (DCs), macrophages and granulocytes following infection, delayed clearance of N. aro and the promotion of overzealous, IFN-γ- and IL-17-dominated T cell responses essential for the adoptive transfer of liver lesions. CD101-knockout mice generated on the B6 background also exhibit substantially more severe N.aro-induced liver disease correlating with increased IFN-γ and IL-17 responses compared to wild type mice. These data strongly support the hypothesis that allelic variation of the Cd101 gene, located in the Idd10 region, alters the severity of liver autoimmunity induced by N. aro.