AIRE expression controls the peripheral selection of autoreactive B cells

Area of Science:

• Immunology
• Endocrinology
• Genetics

Background:

• Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome arises from Autoimmune Regulator (AIRE) mutations.
• AIRE is crucial for central T cell tolerance, preventing autoimmune diseases.

Purpose of the Study:

• To investigate the role of AIRE and T cells in the peripheral accumulation of autoreactive B cells.
• To identify self-antigens recognized by autoreactive B cells in AIRE-deficient individuals.

Main Methods:

• Analysis of CD3- and AIRE-deficient patients.
• Proteomic arrays and Biacore affinity measurements.
• T cell receptor (TCR) repertoire analysis in regulatory T cells (Tregs).

Main Results:

• Lack of T cells or AIRE function caused peripheral accumulation of autoreactive mature naive B cells.
• These B cells produced antibodies recognizing AIRE-dependent antigens like insulin, IL-17A, and IL-17F.
• AIRE-deficient patients showed reduced Treg frequencies with a restricted TCR repertoire.

Conclusions:

• AIRE-mediated T cell and Treg selection is essential for preventing the expansion of autoreactive naive B cells.
• Defects in AIRE lead to autoimmunity by allowing autoreactive B cells to target self-antigens presented in the thymus.