ナタリズマブ誘発性PMLの病理

Neuropathology of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy

ナタリズマブ関連進行性多巣性白質脳症（PML）では，古典的なPMLの病理所見に加えてナタリズマブの除去に伴って発症する免疫再構築症候群（IRIS）の病理像の重畳がみられる。肥大アストロサイトと核内封入体を伴う巨大なオリゴデンドログリア，ミエリン貪食マクロファージの浸潤が前者に属し，後者の病理像としてCD8⁺T細胞を中心とする細胞浸潤と脳内JCウイルスの著減が観察される。本症の細胞浸潤はHIV関連PML-IRISのそれと比較してはるかに激烈であり，これは全身の免疫抑制を行わず血液脳関門での細胞移入を操作するナタリズマブの特性を反映した病理所見と考えられる。

Abstract

The pathological findings of natalizumab-associated progressive multifocal leukoencephalopathy (PML) are reviewed. In addition to the classical pathology of PML including the presence of enlarged abnormal astrocytes, intranuclear inclusions mainly found within large swollen oligodendrocytes and abundant myelin-laden macrophages/microglia, massive perivascular and parenchymal mononuclear cell infiltration was observed. The latter pathologic picture is that of immune reconstitution inflammatory syndrome (IRIS), and most of these infiltrating cells are CD8-positive T cells. Because IRIS inevitably occurs after the cessation of natalizumab therapy due to the development of PML and subsequent plasma exchange, most of the published pathologic pictures of natalizumab-associated PML patients were a mixture of PML and PML-IRIS. PML-IRIS is also characterized by fewer oligodendroglial viral inclusions and fewer cells that are immunoreactive against anti-JCV antibodies. These findings suggest the effective removal of JCV after the return of normal immune-surveillance in the central nervous system, but clinicians should be aware that JCV elimination is not complete under the IRIS condition, and the immunosuppressive therapy against IRIS should be carefully performed. Mononuclear cell infiltration in natalizumab-associated PML-IRIS patients was much more prominent than that in HIV-associated PML-IRIS patients, reflecting the retained, even enhanced, systemic immunities in patients treated by natalizumab.