B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice

Area of Science:

• Immunology
• Neuroscience
• Autoimmunity

Background:

• Self-tolerance in B cells is crucial for preventing autoimmune diseases.
• Myelin oligodendrocyte glycoprotein (MOG) is a key autoantigen in central nervous system (CNS) demyelinating diseases.

Purpose of the Study:

• To investigate the cellular basis of B cell self-tolerance to brain autoantigens.
• To understand the consequences of autoreactive B cells specific for MOG in vivo.

Main Methods:

• Generation of "knock-in" transgenic mice expressing MOG-specific immunoglobulin (Ig) H chain variable (V) genes.
• Analysis of B cell populations, autoantibody production, and disease development in transgenic mice.
• Assessment of experimental autoimmune encephalitis (EAE) in the presence of MOG-specific B cells.

Main Results:

• Transgenic mice produced high titers of MOG-specific autoantibodies.
• A significant proportion of B cells bound MOG, indicating a lack of active tolerization.
• Peritoneal B-1 lymphocytes were depleted, while conventional B cells were normal.
• MOG-specific B cells underwent normal differentiation, isotype switching, and somatic mutation upon immunization.
• Naive transgenic mice did not develop spontaneous neurological disease or demyelination.
• The presence of MOG-specific B cells accelerated and exacerbated experimental autoimmune encephalitis.

Conclusions:

• Autoreactive B cells specific for MOG can exist without active tolerization and do not cause spontaneous disease.
• These autoreactive B cells can accelerate and worsen experimental autoimmune encephalitis, suggesting a role in CNS autoimmune pathology.