Development of a major histocompatibility complex class II conditional knockout mouse to study cell-specific and...

Area of Science:

• Neuroimmunology
• Molecular immunology
• Autoimmunity

Background:

• The precise relationship between molecular mimicry and tissue-specific autoimmunity remains unclear.
• Major histocompatibility complex (MHC) class II antigen-presenting cell-CD4+ T-cell receptor interactions are vital for adaptive immunity.
• The role of endoneurial endothelial cell MHC class II in autoimmune polyneuropathy is not well understood.

Purpose of the Study:

• To investigate the role of endoneurial endothelial cell MHC class II in the pathogenesis of autoimmune polyneuropathy.
• To develop a conditional knockout mouse model for studying cell- and time-dependent adaptive immune responses in vivo.

Main Methods:

• Studied human Guillain-Barré syndrome (GBS) sural nerve biopsies and murine experimental autoimmune neuritis (EAN) sciatic nerves.
• Generated conditional MHC class II knockout mice (H2-Aaflox/flox; vWF-iCre/+) on an SJL background.
• Induced EAN in knockout and control mice, followed by neurobehavioral, electrophysiological, and histopathological assessments.

Main Results:

• Endoneurial endothelial cell MHC class II expression was present in normal and inflamed human and mouse peripheral nerves.
• Tamoxifen-treated knockout mice were resistant to EAN, despite MHC class II expression in other tissues.
• This suggests a critical role for microvascular endothelial cell MHC class II in peripheral nerve autoimmunity.

Conclusions:

• A novel conditional MHC class II knockout mouse model was successfully developed for in vivo studies.
• Microvascular endothelial cell MHC class II expression is essential for the development of peripheral nerve-specific autoimmunity.
• Findings support human in vitro and ex vivo studies on adaptive immunity and transplant rejection.