Thymic Epithelium Determines a Spontaneous Chronic Neuritis in Icam1tm1JcgrNOD Mice

Abstract

The NOD mouse strain spontaneously develops autoimmune diabetes. A deficiency in costimulatory molecules, such as B7-2, on the NOD genetic background prevents diabetes but instead triggers an inflammatory peripheral neuropathy. This constitutes a shift in the target of autoimmunity, but the underlying mechanism remains unknown. In this study, we demonstrate that NOD mice deficient for isoforms of ICAM-1, which comediate costimulatory functions, spontaneously develop a chronic autoimmune peripheral neuritis instead of diabetes. The disease is transferred by CD4+ T cells, which infiltrate peripheral nerves together with macrophages and B cells and are autoreactive against peripheral myelin protein zero. These Icam1tm1JcgrNOD mice exhibit unaltered numbers of regulatory T cells, but increased IL-17–producing T cells, which determine the severity, but not the target specificity, of autoimmunity. Ab-mediated ICAM-1 blockade triggers neuritis only in young NOD mice. Thymic epithelium from Icam1tm1JcgrNOD mice features an altered expression of costimulatory molecules and induces neuritis and myelin autoreactivity after transplantation into nude mice in vivo. Icam1tm1JcgrNOD mice exhibit a specifically altered TCR repertoire. Our findings introduce a novel animal model of chronic inflammatory neuropathies and indicate that altered expression of ICAM-1 on thymic epithelium shifts autoimmunity specifically toward peripheral nerves. This improves our understanding of autoimmunity in the peripheral nervous system with potential relevance for human diseases.

Redefining the heterogeneity of peripheral nerve cells in health and autoimmunity

“…We next aimed to understand how autoimmunity shapes the composition and phenotype of PNS cells. We therefore extracted nerve cells from a mouse model of spontaneous chronic peripheral neuritis (43). We thereby generated single cell transcriptomes from PNS cells of young and clinically unaffected ICAM-1 −/− nonobese diabetic (NOD) mice (5,250 cells, n = 12 female mice) that histologically did not show PNS inflammation (SI Appendix, Fig.…”

Deciphering immune mechanisms in chronic inflammatory demyelinating polyneuropathies

“…Although the role of ICAM1 has been extensively characterized in the peripheral immune response, studies using NOD.ICAM1 tm1Jcgr mice reveal its importance in editing the T cell repertoire through central tolerance mechanisms. Transplantation of NOD.ICAM1 tm1Jcgr thymic stromal cells is sufficient to provoke PNS autoimmunity in athymic recipients, resulting in increased frequency of autoreactive P0-specific CD4 + T cells in the periphery (13). Together, these findings implicate defective central tolerance toward P0 in driving aberrant immune responses against the PNS ( Figure 1A).…”

“…In support of the possible contribution of these cells, increased levels of IL-17 were observed during the late stage of chronic experimental autoimmune neuritis in Lewis rats, possibly indicating a role for Th17 cells in the development of chronic forms of autoimmune peripheral neuropathy. Moreover, Th17 cells were also shown to increase in neuropathic NOD.ICAM1 tm1Jcgr mice (13). Moreover, in an inflammation/ injury model, where peripheral neuropathy was induced in C57BL/6 mice by partial ligation of the sciatic nerve, mice lacking IL-17 had significantly fewer infiltrating T cells and macrophages and decreased pain hypersensitivity (36).…”

Animal models of chronic inflammatory demyelinating polyneuropathy

“…A partial loss of the Aire gene leads to reduced P0 expression in the thymus, resulting in an escape of P0 self‐antigen‐recognizing T cells from negative selection and thus central tolerance. NOD intercellular adhesion molecule 1‐deficient mice are also known as spontaneous chronic neuritis model animals . T cells as well as macrophages and B cells infiltrate peripheral nerves and show autoreactivity against P0 and an altered T‐cell receptor repertoire.…”

“…NOD intercellular adhesion molecule 1-deficient mice are also known as spontaneous chronic neuritis model animals. 50 T cells as well as macrophages and B cells infiltrate peripheral nerves and show autoreactivity against P0 and an altered T-cell receptor repertoire. Altered costimulation might affect the thymic selection process and shift autoimmunity to the peripheral nerves.…”