Cellular targets and mechanistic strategies of remyelination-promoting IgMs as part of the naturally occurring autoantibody repertoire

Abstract

Immunoglobulins with germline sequences occur in invertebrates and vertebrates and are named naturally occurring autoantibodies (NAbs). NAbs may target foreign antigens, self- or altered self-components and are part of the normal immunoglobulin repertoire. Accumulating evidence indicates that naturally occurring antibodies can act as systemic surveillance molecules, which tag, damaged or stressed cells, invading pathogens and toxic cellular debris for elimination by the immune system. In addition to acting as detecting molecules, certain types of NAbs actively signal in different cell types with a broad range of responses from induction of apoptosis in cancer cells to stimulation of remyelination in glial cells. This review emphasizes functions and characteristics of NAbs with focus on remyelination-promoting mouse and human antibodies. Human remyelination-promoting NAbs are potential therapeutics to combat a wide spectrum of disease processes including demyelinating diseases like multiple sclerosis. We will highlight the identified glycosphingolipid (SL) antigens of polyreactive remyelination-promoting antibodies and their proposed mechanism(s) of action. The nature of the identified antigens suggests a lipid raft-based mechanism for remyelination-promoting antibodies with SLs as most essential raft components. However, accumulating evidence also suggests involvement of other antigens in stimulation of remyelination, which will be discussed in the text.

Keywords::

• autoantibodies
• apoptosis
• demyelination
• multiple sclerosis
• proliferation
• TMEV animal model

Financial & competing interests disclosure

This work was supported by grants from the NIH (R01 GM092993, R01 NS048357 and R21 NS073684) and the National Multiple Sclerosis Society (CA 1060A). This work was also supported by a High-Impact Pilot and Feasibility Award (HIPFA) and Novel Methodology Award (NMDA) from the Mayo Clinic Center for Translational Science Activities (CTSA) and Mayo Clinic CTSA grant number UL1 TR000135 from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH). The authors also acknowledge with thanks support from the Applebaum, Hilton, Peterson and Sanford Foundations, the Minnesota Partnership Award for Biotechnology and Medical Genomics and the McNeilus family. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Naturally occurring autoantibodies (NAbs) are of germline origin with little or no somatic mutations. They are often polyreactive and bind with rather low affinity to one or multiple structurally unrelated antigens.

• • NAbs are part of the innate immunity and involved in tissue homeostasis, defense against pathogens, tumor surveillance and stimulation of brain repair.

• • NAbs often bind to carbohydrate epitopes on glycosphingolipids (SLs) and, potentially, proteins in normal, apoptotic or cancer cells.

• • Remyelination-promoting antibodies belong to the group of natural occurring antibodies.

• • Most known remyelination-promoting antibodies are of the IgM isotype and bind to myelin and oligodendrocytes. Their molecular targets are cell surface SLs and, to some extent, cytoskeletal proteins.

• • Repair of brain lesions by remyelination-promoting antibodies may be mediated through increased lesion clearance with IgM-tagged myelin debris ready for opsonization or through lipid-raft formation in oligodendrocyte progenitor cells with higher levels of PDGF-receptor activation.

• • Stimulation of oligodendrocyte progenitor proliferation in vitro by remyelination-promoting antibodies (rHIgM22) requires the presence of astrocytes and microglial cells.

• • The remyelination-promoting antibody rHIgM22 stimulates remyelination in Theiler’s murine encephalomyelitis virus-infected mice after a single minimal dose of 500 ng per animal.

• • The integrity of the IgM molecule appears to be essential for stimulation of remyelination in vivo.

• • Remyelination-promoting antibodies show efficacy in multiple sclerosis animal models with extensive (chronic) demyelination (Theiler’s virus-induced demyelination) but not in primarily immune-mediated animal models (experimental autoimmune encephalomyelitis).