Staging of astrocytopathy and complement activation in neuromyelitis optica spectrum disorders

Abstract

Aquaporin 4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) is an autoimmune astrocytopathic disease pathologically characterized by the massive destruction and regeneration of astrocytes with diverse types of tissue injury with or without complement deposition. However, it is unknown whether this diversity is derived from differences in pathological processes or temporal changes. Furthermore, unlike for the demyelinating lesions in multiple sclerosis, there has been no staging of astrocytopathy in AQP4-IgG+NMOSD based on astrocyte morphology. Therefore, we classified astrocytopathy of the disease by comparing the characteristic features, such as AQP4 loss, inflammatory cell infiltration, complement deposition and demyelination activity, with the clinical phase. We performed histopathological analyses in eight autopsied cases of AQP4-IgG+NMOSD. There were six women and two men, with a median age of 56.5 years (range, 46–71 years) and a median disease duration of 62.5 months (range, 0.6–252 months). Astrocytopathy in AQP4-IgG+NMOSD was classified into the following four stages defined by the astrocyte morphology and immunoreactivity for glial fibrillary acidic protein (GFAP): (a) astrocyte lysis: Extensive loss of astrocytes with fragmented and/or dust-like particles; (b) progenitor recruitment: Loss of astrocytes except small nucleated cells with GFAP-positive fibre-forming foot processes; (c) protoplasmic gliosis: Presence of star-shaped astrocytes with abundant GFAP-reactive cytoplasm; and (d) fibrous gliosis: Lesions composed of densely packed mature astrocytes. The astrocyte lysis and progenitor recruitment stages dominated in clinically acute cases (within 2 months after the last recurrence). Findings common to both stages were the loss of AQP4, a decreased number of oligodendrocytes, the selective loss of myelin-associated glycoprotein and active demyelination with phagocytic macrophages. The infiltration of polymorphonuclear cells and T cells (CD4-dominant) and the deposition of activated complement (C9neo), which reflects the membrane attack complex, a hallmark of acute NMOSD lesions, were selectively observed in the astrocyte lysis stage (98.4% in astrocyte lysis, 1.6% in progenitor recruitment, and 0% in protoplasmic gliosis and fibrous gliosis). Although most of the protoplasmic gliosis and fibrous gliosis lesions were accompanied by inactive demyelinated lesions with a low amount of inflammatory cell infiltration, the deposition of complement degradation product (C3d) was observed in all four stages, even in fibrous gliosis lesions, suggesting the past or chronic occurrence of complement activation, which is a useful finding to distinguish chronic lesions in NMOSD from those in multiple sclerosis. Our staging of astrocytopathy is expected to be useful for understanding the unique temporal pathology of AQP4-IgG+NMOSD.

Anti-AQP4 autoantibodies promote ATP release from astrocytes and induce mechanical pain in rats

“…However, larger lesion formation was confirmed in rAQP4 antibody-treated group in certain sections, supporting the pathogenic effect of rAQP4 antibody. Whether the astrogliosis observed in our study represent the mechanically induced injurious pathological changes, or the chronological alteration as recently reported in NMOSD pathology remains to be elucidated in a future study [20]. These control IgGtreated rats also served as the control to examine the effect of surgical injury on the development of neuropathic pain.…”

Short- and Long-Lived Autoantibody-Secreting Cells in Autoimmune Neurological Disorders

“…Cellular approaches, both histopathological and ex vivo bulk and single-cell, have added important pieces of information on the nature of ASCs. First, biopsy and autopsy CNS studies have shown (i) perivascular B cells to a varying degree in addition to T cells (231,267,268); (ii) perivascular CD138 + cell infiltrates in one patient (232); and (iii) IL-6 transcripts in another patient (269). Second, peripheral blood CD19 + CD27 hi CD38 hi SLPBs were shown to increase in AQP4 autoantibody-positive NMO patients, more so during relapses.…”

RGMa Signal in Macrophages Induces Neutrophil‐Related Astrocytopathy in NMO

“…In most cases, NMO is caused by pathogenic autoantibodies against the water channel protein aquaporin‐4 (AQP4), called AQP4‐immunoglobulin G (IgG). Based on the accumulating evidence, AQP4 antibodies are likely to be produced peripherally, and during acute attacks, the circulating AQP4‐IgGs leak into the CNS parenchyma 5,6 and react with AQP4s expressed on the astrocytic endfeet, causing cellular cytotoxicity 7,8 …”