Development of Spontaneous Autoimmune Peripheral Polyneuropathy in B7-2–Deficient Nod Mice

Abstract

An increasing number of studies have documented the central role of T cell costimulation in autoimmunity. Here we show that the autoimmune diabetes-prone nonobese diabetic (NOD) mouse strain, deficient in B7-2 costimulation, is protected from diabetes but develops a spontaneous autoimmune peripheral polyneuropathy. All the female and one third of the male mice exhibited limb paralysis with histologic and electrophysiologic evidence of severe demyelination in the peripheral nerves beginning at 20 wk of age. No central nervous system lesions were apparent. The peripheral nerve tissue was infiltrated with dendritic cells, CD4+, and CD8+ T cells. Finally, CD4+ T cells isolated from affected animals induced the disease in NOD.SCID mice. Thus, the B7-2–deficient NOD mouse constitutes the first model of a spontaneous autoimmune disease of the peripheral nervous system, which has many similarities to the human disease, chronic inflammatory demyelinating polyneuropathy (CIDP). This model demonstrates that NOD mice have “cryptic” autoimmune defects that can polarize toward the nervous tissue after the selective disruption of CD28/B7-2 costimulatory pathway.

First Signature of Islet β-Cell-Derived Naturally Processed Peptides Selected by Diabetogenic Class II MHC Molecules

“…The early work in NOD and humans implicated glutamic acid decarboxylase, a neuronal protein, as an autoimmune target in islet ␤ cells (20). NOD mice deficient in B7-2 develop spontaneous peripheral poly-neuropathy, but not diabetes (19). And, the peri-islet Schwann cells have been shown to be an early target in NOD diabetes and, more recently, an important role for pancreatic sensory neurons in islet inflammation has been uncovered (18,22).…”

CD40/CD40L interaction regulates CD4+CD25+ T reg homeostasis through dendritic cell‐produced IL‐2

“…Blocking the CD28/B7 pathway using CTLA-4 Ig molecule or anti-B7-1/2 Ab has been reported to reduce the number of T reg in both thymus and periphery [4,35]. Bluestone and collaborators [4] demonstrated that CD28 act directly on T reg to sustain their CD25 expression and therefore their response to IL-2.…”

Alterations of peripheral CD4+CD25+Foxp3+ T regulatory cells in mice with STZ-induced diabetes

“…In addition to autoimmune diabetes, they are prone to developing multi-organ autoimmune diseases such as autoimmune sialitis, thyroiditis and peripheral polyneuropathy. [20][21][22] Therefore, NOD mice are not suitable for studying the direct effect of hyperglycemia or other diabetes-induced alterations on the immune system and immunity. In this study, in order to address whether diabetes itself can impact the level and function of CD4 …”