Myelin oligodendrocyte glycoprotein-specific antibodies from multiple sclerosis patients exacerbate disease in a humanized mouse model

Abstract

Myelin oligodendrocyte glycoprotein (MOG) is exposed on the outer surface of the myelin sheath, and as such, represents a possible target antigen for antibodies in multiple sclerosis (MS) and other demyelinating diseases. However, despite extensive analyses, whether MOG-specific antibodies contribute to pathogenesis in human MS remains an area of uncertainty. In the current study we demonstrate that antibodies derived from adult MS patients exacerbate experimental autoimmune encephalomyelitis (EAE) in 'humanized' mice that transgenically express human FcγRs (hFcγRs). Importantly, this exacerbation is dependent on MOG recognition by the human-derived antibodies. The use of mice that express hFcγRs has allowed us to also investigate the contribution of these receptors to disease in the absence of confounding effects of cross-species differences. Specifically, by engineering the Fc region of MOG-specific antibodies to modulate FcγR and complement (C1q) binding, we reveal that FcγRs but not complement activation contribute to EAE pathogenesis. Importantly, selective enhancement of the affinities of these antibodies for specific FcγRs reveals that FcγRIIA is more important than FcγRIIIA in mediating disease exacerbation. These studies not only provide definitive evidence for the contribution of MOG-specific antibodies to MS, but also reveal mechanistic insight that could lead to new therapeutic targets.

An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence

“…Because neither model fully recapitulates mouse endogenous FcRn expression 38 , we constructed new models in which hFcRn and hβ2m are expressed from the respective mouse promoters. The binding of antibodies to FcγRs, and in particular to FcγRs expressed by liver-resident cells, is known to affect antibody clearance 41,42 . However, since human antibodies bind to mouse FcγRs with very different affinities than those of their human counterparts 61,62 , the effect of FcγR-mediated clearance of human IgG cannot be properly accounted for in animals expressing murine IgG receptors.…”

“…However, the currently available hFcRn Tg mouse models do not recapitulate many of the mechanisms that affect antibody clearance. Key limitations of the existing mouse models used for antibody PK studies arise from: (i) non-physiological levels of transgene hFcRn expression relative to mouse FcRn in wild-type animals 38 ; (ii) expression of mouse β2m instead of human β2m (hβ2m) in many of the currently used models 36,37,39 ; (iii) absence of endogenously produced human IgG to compete for hFcRn binding 40 ; and (iv) no ability to account for the effect of binding to human FcγRs in clearance 41,42 . To address these limitations, as part of this work we constructed new knock-in mouse models that express hFcRn, hβ2m, and hFcγRs; and, in addition, produce endogenously chimeric mouse–human IgG1, composed of mouse variable regions and human constant regions for the heavy and light chain (hIgG1,κ).…”

Therapeutic effect of oligomeric proanthocyanidin in cuprizone‐induced demyelination

“…* P < 0.05, ** P < 0.01, *** P < 0.001 compared with the CPZ+NS group in destabilizing myelin through MBP breakdown (Menon, Piddlesden, & Bernard, 1997). Multiple sclerosis patients have MOG-specific antibodies, which can promote the progress of Experimental Autoimmune Encephalomyelitis (EAE) in a transfer model (Khare et al, 2018). Experimental spinal contusion injury elicits synthesis of autoantibodies that cause neuropathology, with marked dysregulation of B-cell function (Daniel, Zhen, & Phillip, 2009).…”

The Glycosylation Site of Myelin Oligodendrocyte Glycoprotein Affects Autoantibody Recognition in a Large Proportion of Patients

“…High levels of such autoantibodies were initially detected in pediatric patients (1–3), then also in adults, and MOG-Abs are implicated in prognosis and therapy optimization (4–11). MOG-Abs are assumed to be pathogenic based on in vitro experiments (12–15) and injection of total IgG from anti-MOG positive patients into experimental animals (16–19). We have recently reported that affinity-purified MOG-Abs from two patients who show cross-reactivity to rodent MOG were pathogenic upon transfer into EAE animals by two different mechanisms, namely by enhancing T cell activation of cognate T cells and by inducing MS type II like demyelination when the blood-brain barrier is breached (20).…”