A novel myelin P0–specific T cell receptor transgenic mouse develops a fulminant autoimmune peripheral neuropathy

Diabetes Center and the Department of Medicine, University of California, San Francisco, San Francisco, CA 94143
Journal of Experimental Medicine (Impact Factor: 12.52). 03/2009; 206(3):507-14. DOI: 10.1084/jem.20082113
Source: PubMed


Autoimmune-prone nonobese diabetic mice deficient for B7-2 spontaneously develop an autoimmune peripheral neuropathy mediated by inflammatory CD4(+) T cells that is reminiscent of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. To determine the etiology of this disease, CD4(+) T cell hybridomas were generated from inflamed tissue-derived CD4(+) T cells. A majority of T cell hybridomas were specific for myelin protein 0 (P0), which was the principal target of autoantibody responses targeting nerve proteins. To determine whether P0-specific T cell responses were sufficient to mediate disease, we generated a novel myelin P0-specific T cell receptor transgenic (POT) mouse. POT T cells were not tolerized or deleted during thymic development and proliferated in response to P0 in vitro. Importantly, when bred onto a recombination activating gene knockout background, POT mice developed a fulminant form of peripheral neuropathy that affected all mice by weaning age and led to their premature death by 3-5 wk of age. This abrupt disease was associated with the production of interferon gamma by P0-specific T cells and a lack of CD4(+) Foxp3(+) regulatory T cells. Collectively, our data suggest that myelin P0 is a major autoantigen in autoimmune peripheral neuropathy.

Download full-text


Available from: Cedric Louvet,
  • Source
    • "Autoimmune peripheral polyneuropathy has also been described in NOD mice after disruption of various pathways involved in immune tolerance such as IL-2, PD-1 or the autoimmune regulator (Aire) and appears to have comparable immunopathogenic properties as the NOD-B7-2KO disease [31e33]. In particular, NOD mice partially deficient in Aire function develop peripheral neuropathy that is mediated by CD4þ T cells targeting myelin P0 and IFN-g is required for disease to develop [33e35], similar to what has been observed in NOD-B7-2KO mice [4] [29] [30]. In contrast, peripheral polyneuropathy does not occur in mice deficient for B7-2, Aire or PD-1 on B6 or mixed B6-129 backgrounds. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The non-obese diabetic (NOD) mouse is susceptible to the development of autoimmune diabetes but also multiple other autoimmune diseases. Over twenty susceptibility loci linked to diabetes have been identified in NOD mice and progress has been made in the definition of candidate genes at many of these loci (termed Idd for insulin-dependent diabetes). The susceptibility to multiple autoimmune diseases in the NOD background is a unique opportunity to examine susceptibility genes that confer a general propensity for autoimmunity versus susceptibility genes that control individual autoimmune diseases. We previously showed that NOD mice deficient for the costimulatory molecule B7-2 (NOD-B7-2KO mice) were protected from diabetes but spontaneously developed an autoimmune peripheral neuropathy. Here, we took advantage of multiple NOD mouse strains congenic for Idd loci to test the role of these Idd loci the development of neuropathy and determine if B6 alleles at Idd loci that are protective for diabetes will also be for neuropathy. Thus, we generated NOD-B7-2KO strains congenic at Idd loci and examined the development of neuritis and clinical neuropathy. We found that the NOD-H-2(g7) MHC region is necessary for development of neuropathy in NOD-B7-2KO mice. In contrast, other Idd loci that significantly protect from diabetes did not affect neuropathy when considered individually. However, we found potent genetic interactions of some Idd loci that provided almost complete protection from neuritis and clinical neuropathy. In addition, defective immunoregulation by Tregs could supersede protection by some, but not other, Idd loci in a tissue-specific manner in a model where neuropathy and diabetes occurred concomitantly. Thus, our study helps identify Idd loci that control tissue-specific disease or confer general susceptibility to autoimmunity, and brings insight to the Treg-dependence of autoimmune processes influenced by given Idd region in the NOD background.
    Journal of Autoimmunity 07/2013; 45. DOI:10.1016/j.jaut.2013.06.005 · 8.41 Impact Factor
  • Source
    • "Humoral autoimmunity in T1D has been shown to target pancreatic nervous system tissue structures, suggesting the possibility that nonb-cell elements can elicit immune responses in T1D (Rabinowe et al. 1989; Winer et al. 2003; Louvet et al. 2009). One of these molecular targets seems to be peripherin (Boitard et al. 1992). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Type 1 diabetes mellitus (T1D) is an autoimmune disease encompassing the T-cell-mediated destruction of pancreatic β cells and the production of autoantibodies against islet proteins. In humoral autoimmunity in T1D, the detection of islet autoantibodies and the examination of their associations with genetic factors and cellular autoimmunity constitute major areas in both basic research and clinical practice. Although insulin is a key autoantigen and may be primus inter pares in importance among T1D autoantigens, an abundant body of research has also revealed other autoantigens associated with the disease process. Solid evidence indicates that autoantibodies against islet targets serve as key markers to enroll newly diagnosed T1D patients and their family members in intervention trials aimed at preventing or halting the disease process. The next challenge is perfecting mechanistic bioassays to be used as end points for disease amelioration following immunomodulatory therapies aimed at blocking immune-mediated β-cell injury and, in turn, preserving β-cell function in type 1 diabetes mellitus.
    Cold Spring Harbor Perspectives in Medicine 10/2012; 2(10). DOI:10.1101/cshperspect.a012831 · 9.47 Impact Factor
  • Source
    • "From the 1B3 hybridoma cDNA, the full-length coding sequences for the TCR- and - chains were cloned by PCR and were subcloned into a CD2 and CD4 expression vector, respectively, allowing expression of the transgenes in both CD4 and CD8 T cells (Wang et al., 2001). Tg mice were generated by microinjection of CD2–TCR- and CD4–TCR- constructs into NOD embryos as described earlier (Louvet et al., 2009). Vectors were provided by N. Killeen (UCSF, San Francisco, CA). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Foxp3(+) CD4(+) T helper cells called regulatory T (T reg) cells play a key role in controlling reactivity to self-antigens and onset of autoimmunity. T reg cells either arise in thymus and are called natural T reg (nT reg) cells or are generated in the periphery through induction of Foxp3 and are called inducible T reg (iT reg) cells. The relative contributions of iT reg cells and nT reg cells in peripheral tolerance remain unclear as a result of an inability to separate these two subsets of T reg cells. Using a combination of novel TCR transgenic mice with a defined self-antigen specificity and conventional mouse models, we demonstrate that a cell surface molecule, neuropilin-1 (Nrp-1), is expressed at high levels on nT reg cells and can be used to separate nT reg versus iT reg cells in certain physiological settings. In addition, iT reg cells generated through antigen delivery or converted under homeostatic conditions lack Nrp-1 expression. Nrp-1(lo) iT reg cells show similar suppressive activity to nT reg cells in controlling ongoing autoimmune responses under homeostatic conditions. In contrast, their activity might be compromised in certain lymphopenic settings. Collectively, our data show that Nrp-1 provides an excellent marker to distinguish distinct T reg subsets and will be useful in studying the role of nT reg versus iT reg cells in different disease settings.
    Journal of Experimental Medicine 09/2012; 209(10):1713-22. DOI:10.1084/jem.20120822 · 12.52 Impact Factor
Show more