Variable sensitivity to complement-dependent cytotoxicity in murine models of neuromyelitis optica

Area of Science:

• Neuroimmunology
• Autoimmune CNS diseases
• Complement-mediated cytotoxicity

Background:

• Neuromyelitis optica (NMO) involves autoantibodies against aquaporin-4 (AQP4) causing astrocyte damage via complement-dependent cytotoxicity (CDC).
• Experimental NMO models often use mouse cells with human complement (HC), but the sensitivity of mouse CNS cells to HC and CDC is unknown.

Purpose of the Study:

• To investigate the sensitivity of mouse central nervous system (CNS) cells to human complement (HC) and complement-dependent cytotoxicity (CDC).
• To evaluate HC and CDC effects on mouse neurons, astrocytes, oligodendrocytes (OLs), and oligodendrocyte progenitors (OPCs) in various culture models.

Main Methods:

• Used HC and recombinant monoclonal antibodies against AQP4.
• Tested CDC on mouse neurons, astrocytes, OLs, and OPCs in monocultures, mixed neuroglial cultures, and organotypic cerebellar slices.

Main Results:

• Mouse neurons, OLs, and OPCs were sensitive to HC in monocultures.
• Astrocyte damage in mixed cultures and slices increased neuronal and oligodendroglial loss, while sensitizing OPCs in slices.
• Some injury resulted from HC activation by anti-tissue antibodies.

Conclusions:

• Mouse neurons and oligodendroglia exhibit variable complement sensitivity depending on differentiation and culture conditions.
• Targeted astrocyte destruction eliminates protection for neurons, OLs, and OPCs in organotypic cultures.
• Caution is needed when interpreting NMO mouse models using HC due to complement activation on mouse CNS cells.