Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ

Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the CNS characterized by the production of disease-specific autoantibodies against aquaporin-4 (AQP4) water channels. Animal model studies suggest that anti-AQP4 antibodies cause a loss of AQP4-expressing astrocytes, primarily via complement-dependent cytotoxicity. Nonetheless, several aspects of the disease remain unclear, including: how anti-AQP4 antibodies cross the blood-brain barrier from the periphery to the CNS; how NMOSD expands into longitudinally extensive transverse myelitis or optic neuritis; how multiphasic courses occur; and how to prevent attacks without depleting circulating anti-AQP4 antibodies, especially when employing B-cell-depleting therapies. To address these knowledge gaps, we conducted a comprehensive 'stage-dependent' investigation of immune cell elements in situ in human NMOSD lesions, based on neuropathological techniques for autopsied/biopsied CNS materials. The present study provided three major findings. First, activated or netting neutrophils and melanoma cell adhesion molecule-positive (MCAM⁺) helper T (T_H) 17/cytotoxic T (T_C) 17 cells are prominent, and the numbers of these correlate with the size of NMOSD lesions in the initial or early-active stages. Second, forkhead box P3-positive (FOXP3⁺) regulatory T (T_reg) cells are recruited to NMOSD lesions during the initial, early-active or late-active stages, suggesting rapid suppression of proinflammatory autoimmune events in the active stages of NMOSD. Third, compartmentalized resident memory immune cells, including CD103⁺ tissue-resident memory T (T_RM) cells with long-lasting inflammatory potential, are detected under "standby" conditions in all stages. Furthermore, CD103⁺ T_RM cells express high levels of granzyme B/perforin-1 in the initial or early-active stages of NMOSD in situ. We infer that stage-dependent compartmentalized immune traits orchestrate the pathology of anti-AQP4 antibody-guided NMOSD in situ. Our work further suggests that targeting activated/netting neutrophils, MCAM⁺ T_H17/T_C17 cells, and CD103⁺ T_RM cells, as well as promoting the expansion of FOXP3⁺ T_reg cells, may be effective in treating and preventing relapses of NMOSD.

Keywords: Forkhead box P3-positive (FOXP3+) regulatory T cells; Melanoma cell adhesion molecule-positive (MCAM+) helper T 17 cells; Multiple sclerosis; Neuromyelitis optica spectrum disorder; Neutrophil extracellular DNA traps; Tissue-resident memory T cells.