Evidence that Cd101 Is an Autoimmune Diabetes Gene in Nonobese Diabetic Mice

Self Cite

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.

Section: Introductionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 74%

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

Mohammed

Fusakio

Rainbow

et al. 2011

Self Cite

“…Genetic mapping and gene-phenotype studies in mice and humans have revealed that, in addition to the MHC locus, more than 20 insulin-dependent diabetes (Idd) loci contribute to T1D development (7). One of these loci, the Idd10 locus on mouse chromosome three, contains the B7x gene (8), suggesting a potential role of B7x in T1D. Murine studies support this notion as B7x suppresses CD4 T cell-mediated T1D (4).…”

Section: Introductionmentioning

confidence: 99%

B7x in the Periphery Abrogates Pancreas-Specific Damage Mediated by Self-reactive CD8 T Cells

Lee

Scandiuzzi

Ray

et al. 2012

B7x (B7-H4 or B7S1) is the seventh member of the B7 family and the in vivo function remains largely unknown. Despite new genetic data linking the B7x gene with autoimmune diseases, how exactly it contributes to peripheral tolerance and autoimmunity is unclear. Here we showed that B7x protein was not detected on antigen-presenting cells or T cells in both human and mice, which is unique in the B7 family. As B7x protein is expressed in some peripheral cells such as pancreatic β cells, we utilized a CD8 T cell-mediated diabetes model (AI4αβ) in which CD8 T cells recognize an endogenous self-antigen, and found that mice lacking B7x developed more severe diabetes than control AI4αβ mice. Conversely, mice overexpressing B7x in the β cells (Rip-B7xAI4αβ) were diabetes free. Furthermore, adoptive transfer of effector AI4αβ CD8 T cells induced diabetes in control mice, but not in Rip-B7xAI4αβ mice. Mechanistic studies revealed that pathogenic effector CD8 T cells were capable of migrating to the pancreas but failed to robustly destroy tissue when encountering local B7x in Rip-B7xAI4αβ mice. Although AI4αβ CD8 T cells in Rip-B7xAI4αβ mice and AI4αβ mice showed similar cytotoxic function, cell death, and global gene expression profiles, these cells had greater proliferation in AI4αβ mice than in RIP-B7xAI4αβ mice. These results suggest that B7x in nonlymphoid organs prevents peripheral autoimmunity partially through inhibiting proliferation of tissue-specific CD8 T cells and that local overexpression of B7x on pancreatic β cells is sufficient to abolish CD8 T cell-induced diabetes.

“…The predicted consequence of B6/BALB coding nonsynonymous genetic variation was assessed using SIFT (29) (http://sift.jcvi.org/), PANTHER (30) (http:/www.pantherdb.org/), and PolyPhen (31) (http://genetics.bwh.harvard.edu/pph/) algorithms. This approach to candidate gene identification has been used by others (32)(33)(34).…”

Section: Candidate Gene Identificationmentioning

confidence: 99%

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Bazett

Stefanov

Paun

et al. 2012

We previously observed the lungs of naive BALB/cJ Cftrtm1UNC mice to have greater numbers of lymphocytes, by immunohistochemical staining, than did BALB wild type littermates or C57BL/6J Cftrtm1UNC mice. In the present study, we initially investigated whether this mutation in Cftr alters the adaptive immunity phenotype by measuring the lymphocyte populations in the lungs and spleens by FACS and by evaluating CD3-stimulated cytokine secretion, proliferation, and apoptosis responses. Next, we assessed a potential influence of this lymphocyte phenotype on lung function through airway resistance measures. Finally, we mapped the phenotype of pulmonary lymphocyte counts in BALB × C57BL/6J F2 Cftrtm1UNC mice and reviewed positional candidate genes. By FACS analysis, both the lungs and spleens of BALB Cftrtm1UNC mice had more CD3+ (both CD4+ and CD8+) cells than did littermates or C57BL/6J Cftrtm1UNC mice. Cftrtm1UNC and littermate mice of either strain did not differ in anti-CD3–stimulated apoptosis or proliferation levels. Lymphocytes from BALB Cftrtm1UNC mice produced more IL-4 and IL-5 and reduced levels of IFN-γ than did littermates, whereas lymphocytes from C57BL/6J Cftrtm1UNC mice demonstrated increased Il-17 secretion. BALB Cftrtm1UNC mice presented an enhanced airway hyperresponsiveness to methacholine challenge compared with littermates and C57BL/6J Cftrtm1UNC mice. A chromosome 7 locus was identified to be linked to lymphocyte numbers, and genetic evaluation of the interval suggests Itgal and Il4ra as candidate genes for this trait. We conclude that the pulmonary phenotype of BALB Cftrtm1UNC mice includes airway hyperresponsiveness and increased lymphocyte numbers, with the latter trait being influenced by a chromosome 7 locus.