神経系自己抗体産生のメカニズムとその病的意義

Pathomechanism of Autoantibody Production in the Nervous System Diseases

自己免疫性神経疾患では次々と新しい疾患特異的自己抗体が同定され，臨床症状と密接に関わるバイオマーカーとして臨床的に用いられている。これらの自己抗体は血液脳関門を通過して，その標的である神経抗原，非神経抗原に到達し，補体介在性，抗体介在性の標的細胞傷害をきたす。神経系に対する自己抗体産生は中枢性・末梢性自己免疫寛容の破綻，自然免疫の関与が考えられている。自己抗体産生機序の解明は自己免疫性神経疾患の治療に直結する。

Abstract

Antibodies to different brain and peripheral nerve proteins have recently been found to be associated with several different autoimmune diseases. They can bind to either neuronal or non-neuronal antigens and may have a pathogenic role by themselves or in synergy with other inflammatory mediators after penetrating the blood-brain barrier or the blood-nerve barrier. In this review, we will describe the association with the impairment of immune tolerance, innate immunity, and autoantibody production of myasthenia gravis (MG), systemic lupus erythematosus (SLE), and Guillain-Barré syndrome (GBS). Impairment of central tolerance, which is characterized by the repertoire selection of immature T-lymphocytes in the thymus, is seen in patients with MG who are positive for anti-Ach R antibodies. Impairment of peripheral tolerance due to activation of autoreactive T-cells and suppression of regulatory T-cells is seen in SLE. In addition, molecular mimicry between the lipooligosaccharides of Campylobacter jejuni and gangliosides of the peripheral nerves results in the production of anti-gangliosides antibodies in GBS. Next, we will describe the antibody-mediated pathology in neuromyelitis optica and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. The binding of anti-aquaporin-4 antibodies or anti-NMDAR antibodies to their respective targets initiates target internalization and complement- or antibody-dependent cellular cytotoxicity of the target cells. Further understanding of antibody-mediated pathology may suggest novel therapeutic strategies.