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Intravenous immunoglobulin in neurology—mode of action and clinical efficacy

Key Points

  • Intravenous immunoglobulin (IVIg) is established for the treatment of several inflammatory neurological diseases, including Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy, either as adjunctive or first-line therapy

  • IVIg was shown to be largely ineffective in Alzheimer disease, but was superior to placebo in apolipoprotein E ε4 carriers, suggesting possible benefits in this subgroup of patients

  • Subcutaneous IgG is currently being tested in controlled trials for neuromuscular diseases, owing to its effectiveness in primary immunodeficiency, ease of home administration relative to IVIg, and promising preliminary results

  • It has been difficult to develop a common mechanistic understanding of IVIg's mode of action, as different mechanisms may be involved depending on the pathology of IVIg-responsive diseases

  • A subset of patients do not benefit from IVIg therapy, and well-validated surrogate parameters that predict the response to therapy from the outset are needed

  • Modification of the Fc-glycosylation site might improve efficacy of IVIg, as fragments enriched for terminal sialic acid residues have a higher anti-inflammatory activity than conventional IVIg in animal models


Intravenous immunoglobulin (IVIg)—a preparation of polyclonal serum IgG pooled from thousands of blood donors—has been used for nearly three decades, and is proving to be an efficient anti-inflammatory and immunomodulatory treatment for a growing number of neurological diseases. Evidence from controlled clinical trials has established IVIg as a first-line therapy for Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. IVIg is also an effective rescue therapy in some patients with worsening myasthenia gravis, and is beneficial as a second-line therapy for dermatomyositis and stiff-person syndrome. IVIg has been tested in some neurodegenerative disorders, but a controlled study in Alzheimer disease yielded disappointing results. Despite its widespread use and therapeutic success, the mechanisms of action of IVIg are poorly understood. Several hypotheses, based on the function of either the variable or constant IgG fragments, have been proposed to explain IVIg's immunomodulatory activity. This Review highlights emerging data on the mechanisms of action of IVIg related to its anti-inflammatory activity, especially that involving the cellular Fcγ receptors and Fc glycosylation. We also summarize recent trials in neurological diseases, discuss potential biomarkers of efficacy, offer practical guidelines on administration, and provide a rationale for experimental trials in neuroinflammatory disorders.

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Figure 1: Potential mechanisms of intravenous immunoglobulin activity mediated by F(ab′)2-dependent and Fc-dependent pathways.
Figure 2: The family of Fc receptors for mouse and human IgG.


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The authors contributed equally to researching data and writing the article, and each made substantial contributions to the discussion of content and the review and editing of the manuscript before submission.

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Correspondence to Jan D. Lünemann.

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Lünemann, J., Nimmerjahn, F. & Dalakas, M. Intravenous immunoglobulin in neurology—mode of action and clinical efficacy. Nat Rev Neurol 11, 80–89 (2015).

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