Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen

Abstract

In the pathogenesis of central nervous system (CNS) demyelinating disorders, antigen-specific B cells are implicated to act as potent antigen-presenting cells (APC), eliciting waves of inflammatory CNS infiltration. Here, we provide the first evidence that CNS-reactive antibodies (Ab) are similarly capable of initiating an encephalitogenic immune response by targeting endogenous CNS antigen to otherwise inert myeloid APC. In a transgenic mouse model, constitutive production of Ab against myelin oligodendrocyte glycoprotein (MOG) was sufficient to promote spontaneous experimental autoimmune encephalomyelitis (EAE) in the absence of B cells, when mice endogenously contained MOG-recognizing T cells. Adoptive transfer studies corroborated that anti-MOG Ab triggered activation and expansion of peripheral MOG-specific T cells in an Fc-dependent manner, subsequently causing EAE. To evaluate the underlying mechanism, anti-MOG Ab were added to a co-culture of myeloid APC and MOG-specific T cells. At otherwise undetected concentrations, anti-MOG Ab enabled Fc-mediated APC recognition of intact MOG; internalized, processed and presented MOG activated naïve T cells to differentiate in an encephalitogenic manner. In a series of translational experiments, anti-MOG Ab from two patients with an acute flare of CNS inflammation likewise facilitated detection of human MOG. Jointly, these observations highlight Ab-mediated opsonization of endogenous CNS auto-antigen as a novel disease- and/or relapse-triggering mechanism in CNS demyelinating disorders.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1559-8) contains supplementary material, which is available to authorized users.

Isotype-Switched Autoantibodies Are Necessary To Facilitate Central Nervous System Autoimmune Disease in Aicda−/− and Ung−/− Mice

“…However, it has been recently described that myelin-specific autoantibodies can contribute to EAE pathogenesis by making available scarce endogenous myelin Ags to autoreactive T cells in the meninges of the CNS. Autoantibodies provide a means for concentrated delivery of opsonized myelin Ags to both peripheral and local Fc receptor-bearing phagocytes, which in turn can process myelin Ags and present them to T cells (39,46). In agreement, autoantibodies derived from neuromyelitis optica and MS patients have the capacity to opsonize myelin Ags, potentially contributing to disease pathogenesis (39,46).…”

“…Autoantibodies provide a means for concentrated delivery of opsonized myelin Ags to both peripheral and local Fc receptor-bearing phagocytes, which in turn can process myelin Ags and present them to T cells (39,46). In agreement, autoantibodies derived from neuromyelitis optica and MS patients have the capacity to opsonize myelin Ags, potentially contributing to disease pathogenesis (39,46). Thus, in cases in which anti-myelin T cell responses are weak or CNS Ag availability is limited, autoantibodies may play a crucial role in CNS inflammation by focusing Ag to local APCs, thus providing a means for perivascular T cells to enter the CNS parenchyma (47,48).…”

Amelioration of EAE by a cryptic epitope of myelin oligodendrocyte glycoprotein

“…Complementing the role of antigen-specific B cells as APCs in the activation of myelin-reactive T cells, a recent report clearly demonstrates that opsonization of myelin antigen by MOG-specific antibody and subsequent antigen processing and presentation by an FcγR-dependent mechanism is also capable of activating MOG-reactive T cells in vivo (Kinzel et al, 2016). High titer antibody facilitated the processing and presentation of limiting amounts of neuroantigen to myelin-reactive T cells by antigen nonspecific myeloid cells.…”

“…A role for B cells and/or antibodies in the induction of EAE is recently recognized (Kinzel, Lehmann-Horn, 2016, Molnarfi, Schulze-Topphoff, 2013, Parker Harp, Archambault, 2015). Thus, hrMOG immunization of WT mice, in the presence of B cells/antibody, leads to the activation of the encephalitogenic MOG35-55 T cell response and the onset of clinical EAE.…”

Aktuelles aus der Forschung

“…Hierdurch könnte zum einen die periphere Produktion von Ak gegen MOG initial getriggert werden, zum anderen könnte die Ak-vermittelte Opsonisierung geringer, kontinuierlich drainierter Antigenmengen eine periphere Immunantwort auslösen, die sekundär das ZNS infiltriert und hierdurch Erkrankungsschübe auslöst. Dieses Szenario konnten wir in einer rezenten experimentellen Studie nach-stellen, in der wir allein durch die periphere Applikation von MOG-Ak eine Invivo-Aktivierung myelinreaktiver T-Zellen auslösen konnten [20]. Auch ohne Bindung der Ak an ZNS-ständiges Gewebe erkrankten die Tiere in der Folge an einer klinisch fulminanten Entzündung des ZNS.…”