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  • Review Article
  • Published:

Intravenous immunoglobulin therapy: how does IgG modulate the immune system?

Nature Reviews Immunology volume 13, pages 176–189 (2013)Cite this article

Subjects

Key Points

  • Intravenous immunoglobulin (IVIG) therapy can suppress a wide variety of autoimmune and chronic inflammatory diseases.

  • Both F(ab′)2- and Fc-dependent mechanisms have been suggested to be involved in the immunomodulatory effect of IVIG preparations.

  • F(ab′)2-dependent mechanisms may require the presence within IVIG preparations of cytotoxic antibodies, anti-idiotypic antibodies, immunomodulatory antibodies and antibodies that can scavenge activated complement components.

  • Fc-dependent mechanisms of IVIG activity are operative in mice and humans and may include the blockade of activating Fcγ receptors (FcγRs) or of the neonatal Fc receptor (FcRn), the expansion of regulatory T cell populations, the upregulation of the inhibitory receptor FcγRIIB and the modulation of dendritic cell activity.

  • Glycosylation of the IgG Fc fragment has been shown to be crucial for the anti-inflammatory activity of IVIG in several mouse models.

  • SIGNR1 (DC-SIGN-related protein 1) and its human counterpart DC-SIGN (DC-specific ICAM3-grabbing non-integrin) may represent novel, glycosylation-specific receptors for the IgG Fc region and are crucial for the glycosylation-dependent pathway of IVIG activity.

Abstract

Intravenous immunoglobulin (IVIG) preparations comprise pooled IgG antibodies from the serum of thousands of donors and were initially used as an IgG replacement therapy in immunocompromised patients. Since the discovery, more than 30 years ago, that IVIG therapy can ameliorate immune thrombocytopenia, the use of IVIG preparations has been extended to a wide range of autoimmune and inflammatory diseases. Despite the broad efficacy of IVIG therapy, its modes of action remain unclear. In this Review, we cover the recent insights into the molecular and cellular pathways that are involved in IVIG-mediated immunosuppression, with a particular focus on IVIG as a therapy for IgG-dependent autoimmune diseases.

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Figure 1: The family of mouse and human FcγRs.
Figure 2: F(ab′)2- and Fc-dependent pathways of IVIG activity.
Figure 3: Impact of glycosylation on IgG structure and function.
Figure 4: SIGNR1-dependent pathways of IVIG-mediated immunomodulation.

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Acknowledgements

We would like to apologize to all those colleagues whose important contributions could not be cited directly. This work was supported by grants from the German Research Foundation (SFB 643, SPP1468, GK1660 and FOR832), the Bavarian Genome Research Network, the Sander Foundation and the Collaboration for AIDS Vaccine Discovery network within the Bill and Melinda Gates Foundation.

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    Inessa Schwab & Falk Nimmerjahn

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Glossary

Rheumatoid arthritis

An immune disorder that is characterized by symmetrical polyarthritis, which often progresses to crippling deformation after years of synovitis. It is associated with systemic immune activation and with the presence in the peripheral blood of acute-phase reactants and of rheumatoid factor (antibodies specific for IgG), which forms immune complexes that are deposited in many tissues.

Systemic lupus erythematosus

(SLE). An autoimmune disease in which autoantibodies specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that damage small blood vessels, especially in the kidney. Despite extensive study, this disease is still not fully understood and differs from other autoimmune diseases in several respects.

Immunothrombocytopenia

(ITP). A disease in which autoantibodies lead to an abnormal drop in circulating platelet numbers. Platelet production may be normal or impaired, as the disorder can be caused by antibodies specific for megakaryocytes or by autoantibodies specific for platelets themselves.

Autoimmune haemolytic anaemia

(AIHA). A form of anaemia caused by autoantibodies specific for surface antigens on red blood cells, which become targets for destruction by complement and by erythrophagocytosis.

Chronic inflammatory demyelinating polyneuropathy

(CIDP). An autoimmune disease in which T cells and autoantibodies specific for peripheral nervous tissue trigger the demyelination of nerve cells, resulting in muscle weakness and paralysis.

Cytokine-release syndrome

(Also known as a cytokine storm). A sudden surge in the circulating levels of pro-inflammatory cytokines, such as interleukin-1, interleukin-6, tumour necrosis factor and interferon-γ.

Kawasaki's disease

(Also known as mucocutaneous lymph node syndrome). An acute, self-limited vasculitis of infants and the leading cause of acquired heart disease among children in developed countries.

Guillain–Barré syndrome

A possible autoimmune disease that is characterized generally by acute muscle weakness and the absence of reflexes, possibly owing to the production of autoantibodies specific for gangliosides on neuronal cells following Campylobacter jejuni enteritis.

Bullous pemphigoid

An autoimmune disorder characterized by the deposition of autoantibodies specific for components of the basement-membrane zone at the dermal–epidermal junction, leading to inflammation and blister formation.

Anti-idiotypic antibodies

Antibodies that are specific for the antigen-specific binding site of an immunoglobulin or a T cell receptor and therefore may compete with the antigen for binding.

Anaphylatoxins

The pro-inflammatory complement activation fragments C3a and C5a. These molecules mediate an inflammatory response through cell activation to induce, for example, chemotaxis and histamine release.

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Schwab, I., Nimmerjahn, F. Intravenous immunoglobulin therapy: how does IgG modulate the immune system?. Nat Rev Immunol 13, 176–189 (2013). https://doi.org/10.1038/nri3401

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