Abstract
Background and Objectives Describe the unique functions of immunoglobulin G4 (IgG4) in IgG4-neurologic disorders (IgG4-ND) and explain why, in contrast to their IgG1-counterparts, they respond poorly to intravenous immune globulin (IVIg) but effectively to anti–B cell therapies.
Methods The IgG4 structure and isotype switch, B cells and plasmablasts relevant to IgG4 production, and IgG4-induced disruption of the targeted antigens are reviewed and compared with IgG1-mediated autoimmune ND, where IVIg inhibits IgG1-triggered inflammatory effects.
Results The main IgG4-ND include muscle-specific kinase myasthenia; nodal/paranodal chronic inflammatory demyelinating polyradiculoneuropathy with antibodies to neurofascin-155, contactin-1/caspr-1, or pan-neurofascins; antileucine-rich, glioma-inactivated-1 and contactin-associated protein-like 2 associated-limbic encephalitis, Morvan syndrome, or neuromyotonia; and anti-IgLON5 disorder. The IgG4, because of its unique structural features in the hinge region, has noninflammatory properties being functionally monovalent and bispecific, unable to engage in cross-linking and internalization of the targeted antigen. In contrast to IgG1 subclass which is bivalent and monospecific, IgG4 does not activate complement and cannot bind to inhibitory Fcγ receptor (FcγRIIb) to activate cellular and complement-mediated immune responses, the key functions inhibited by IVIg. Because IVIg contains only 0.7%–2.6% IgG4, its idiotypes are of IgG1 subclass and cannot effectively neutralize IgG4 or sufficiently enhance IgG4 catabolism by saturating FcRn. In contrast, rituximab, by targeting memory B cells and IgG4-producing CD20-positive short-lived plasma cells, induces long-lasting clinical benefits.
Discussion Rituximab is the preferred treatment in IgG4-ND patients with severe disease by effectively targeting the production of pathogenic IgG-4 antibodies. In contrast, IVIG is ineffective because it inhibits immunoinflammatory functions irrelevant to the mechanistic effects of IgG4 and contains IgG-1 idiotypes that cannot sufficiently neutralize or possibly catabolize IgG4. Controlled studies with anti-CD19/20 monoclonals that also activate FcγRIIb may be more promising in treating IgG4-ND.
Glossary
- AChR=
- acetylcholine receptor;
- CASPR2=
- contactin-associated protein-like 2;
- CIDP=
- chronic inflammatory demyelinating polyradiculoneuropathy;
- CTL=
- cytotoxic T lymphocytes;
- FcγR=
- Fcγ receptor;
- IgG4=
- immunoglobulin G4;
- IgG4-ND=
- IgG4-neurologic disorder;
- IgG4-RD=
- IgG4-related disease;
- IVIG=
- intravenous immune globulin;
- LGI1=
- leucine-rich, glioma-inactivated-1;
- MAC=
- membranolytic attack complex;
- MG=
- myasthenia gravis;
- MuSK=
- muscle-specific kinase;
- PNS=
- peripheral nervous system
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by the author.
- Received August 23, 2021.
- Accepted in final form October 8, 2021.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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