ProfG wants the real MS to stand-up and asks about smouldering lesions. We think that hot microglia at the centre of these. A few years ago MD2 came up with the idea that antibodies within the oligoclonal bands could activate microglial by binding to receptors on the microglia and that may mean that it doesn’t matter what the antibodies are reactive against, so stop looking for anti-myelin antibodies.
Oligoclonal bands in multiple sclerosis; Functional significance and therapeutic implications. Does the specificity matter? Pryce G, Baker D.Mult Scler Relat Disord. 2018 Oct;25:131-137.
This new paper (below) still hangs onto the view that the oligoclonal bands are anti-myelin….they are not! There are hundreds of papers that fail to show anything consistent but the point here is that a complex of myelin and antibodies activate microglia, but surely a complex of any old protein/lipid and antibodies will do the same thing. Will MD2 get a mention? What do you think?
IgG Immune Complexes Break Immune Tolerance of Human Microglia.van der Poel M, Hoepel W, Hamann J, Huitinga I, Dunnen JD.J Immunol. 2020 Sep 23:ji2000130. doi: 10.4049/jimmunol.2000130. Online ahead of print.
Microglia are phagocytic cells involved in homeostasis of the brain and are key players in the pathogenesis of multiple sclerosis (MS). A hallmark of MS diagnosis is the presence of IgG Abs, which appear as oligoclonal bands in the cerebrospinal fluid. In this study, we demonstrate that myelin obtained post mortem from 8 out of 11 MS brain donors is bound by IgG (Antibodies) Abs. Importantly, we show that IgG immune complexes strongly potentiate activation of primary human microglia by breaking their tolerance for microbial stimuli, such as LPS and Poly I:C, resulting in increased production of key proinflammatory cytokines, such as TNF and IL-1β. We identified FcγRI and FcγRIIa as the two main responsible IgG receptors for the breaking of immune tolerance of microglia. Combined, these data indicate that IgG immune complexes potentiate inflammation by human microglia, which may play an important role in MS-associated inflammation and the formation of demyelinating lesions.