PMID- 34845096
OWN - NLM
STAT- MEDLINE
DCOM- 20220311
LR  - 20220311
IS  - 2332-7812 (Electronic)
IS  - 2332-7812 (Linking)
VI  - 9
IP  - 1
DP  - 2022 Jan
TI  - IgG4-Mediated Neurologic Autoimmunities: Understanding the Pathogenicity of IgG4, 
      Ineffectiveness of IVIg, and Long-Lasting Benefits of Anti-B Cell Therapies.
LID - 10.1212/NXI.0000000000001116 [doi]
LID - e1116
AB  - 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 Fcgamma receptor (FcgammaRIIb) 
      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 FcgammaRIIb may be more promising in treating IgG4-ND.
CI  - Copyright (c) 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on 
      behalf of the American Academy of Neurology.
FAU - Dalakas, Marinos C
AU  - Dalakas MC
AD  - From Thomas Jefferson University, Philadelphia, PA; and the University of Athens 
      Medical School, Greece. marinos.dalakas@jefferson.edu.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20211129
PL  - United States
TA  - Neurol Neuroimmunol Neuroinflamm
JT  - Neurology(R) neuroimmunology & neuroinflammation
JID - 101636388
RN  - 0 (Immunoglobulin G)
RN  - 0 (Immunoglobulins, Intravenous)
RN  - 0 (Immunologic Factors)
SB  - IM
MH  - Autoimmune Diseases of the Nervous System/*drug therapy/*immunology
MH  - B-Lymphocytes/*drug effects
MH  - Humans
MH  - Immunoglobulin G/*immunology
MH  - Immunoglobulins, Intravenous/*pharmacology
MH  - Immunologic Factors/*pharmacology
PMC - PMC8630661
EDAT- 2021/12/01 06:00
MHDA- 2022/03/12 06:00
PMCR- 2021/11/29
CRDT- 2021/11/30 06:09
PHST- 2021/08/23 00:00 [received]
PHST- 2021/10/08 00:00 [accepted]
PHST- 2021/11/30 06:09 [entrez]
PHST- 2021/12/01 06:00 [pubmed]
PHST- 2022/03/12 06:00 [medline]
PHST- 2021/11/29 00:00 [pmc-release]
AID - 9/1/e1116 [pii]
AID - NEURIMMINFL2021039399 [pii]
AID - 10.1212/NXI.0000000000001116 [doi]
PST - epublish
SO  - Neurol Neuroimmunol Neuroinflamm. 2021 Nov 29;9(1):e1116. doi: 
      10.1212/NXI.0000000000001116. Print 2022 Jan.