Antigen-based immunotherapy drives the precocious development of autoimmunity

Area of Science:

• Immunology
• Endocrinology
• Autoimmunity

Background:

• Type 1 diabetes mellitus involves T cell autoimmunity spreading to beta cell antigens in nonobese diabetic (NOD) mice.
• The impact of autoantigen-based immunotherapies on this autoimmune spreading hierarchy is poorly understood.

Purpose of the Study:

• To investigate how administering specific beta cell autoantigens affects the natural hierarchy of T cell autoimmunity development in NOD mice.
• To determine if immunotherapy limits or alters the natural progression of self-tolerance loss in the context of type 1 diabetes.

Main Methods:

• Newborn NOD mice were treated with different beta cell peptides in adjuvant.
• T cell responses were characterized at 4 weeks of age to assess the development of autoimmunity to various beta cell autoantigen determinants.

Main Results:

• Autoimmunity to all tested beta cell autoantigen determinants arose precociously, irrespective of the peptide administered.
• Immunotherapy bypassed the natural spreading hierarchy, leading to premature autoreactivity development.
• Precocious autoreactivities were predominantly Th2-biased, with exceptions for the injected antigen and glutamic acid decarboxylase (GAD).

Conclusions:

• Young NOD mice possess a broad repertoire of beta cell-reactive T cells that can be rapidly activated by single autoantigen administration.
• Autoantigen administration can trigger a cascade of autoimmune responses in genetically susceptible mice, mimicking a bypass of natural tolerance.
• These findings suggest potential clinical implications for understanding and managing type 1 diabetes autoimmunity.