IgG4-Mediated Neurologic Autoimmunities: Understanding the Pathogenicity of IgG4, Ineffectiveness of IVIg, and Long-Lasting Benefits of Anti-B Cell Therapies

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.

Figure. Immunopathogenic Network in IgG1-ND as Related to the Actions of IVIg (*1–5), Highlighting (*1–5 X) the Effects Irrelevant to IgG4-ND

In IgG1-ND, antigens presented via antigen presenting cells to CD4+T cells stimulate B cells to produce IgG1 antibodies which, by fixing complement at the target organ, lead to tissue damage. FcRn plays a role in catabolism of IgG1 antibodies, whereas the inhibitory FcγRIIB receptors on macrophages and B cells mediate inflammatory and immune effector functions. Induction of Tregs and proinflammatory cytokines sustain immune imbalance (adapted from 58). IVIg is effective in IgG1-ND collectively by supplying idiotypic antibodies of IgG1 subclass that exert neutralizing effects on circulating pathogenic IgG1 autoantibodies (*1); this function is irrelevant to IgG4-ND because IVIg contains only IgG1 isotypes that cannot neutralize IgG4 (*1-X); saturating the FcRn in endosomes resulting in increased catabolism of pathogenic IgG1(*2); this function is probably irrelevant to IgG4-ND because IgG1 isotypes may not sufficiently affect IgG4 catabolism (*2-X); binding to C3b, intercepting complement activation and the destructive effects of complement-fixing IgG1 antibodies (3*); this function is irrelevant to IgG4-ND because IgG4 does not fix complement (3*-X); upregulating FcγRIIB receptors on macrophages and B cells (*4); this function is irrelevant to IgG4-ND because IgG4 cannot bind to FcγRIIB (*4-X); and inhibiting proinflammatory cytokines (5*); this is irrelevant to IgG4-ND because IgG4 has anti-inflammatory effects and does not sufficiently induce such cytokines (*5-X). IgG1-ND = IgG1-neurologic disorder; FcγRIIb = Fcγ receptor; IVIg = intravenous immune globulin.