7^th International Immunoglobulin Conference: Mechanisms of Action

Abstract

Although intravenous immunoglobulin (IVIg) is widely used for replacement therapy in immunodeficiencies and to treat autoimmune and inflammatory diseases, its mechanisms of action are not fully understood. Examination of immunoglobulin (Ig) receptors, including the Fc-gamma receptors (FCγRs) and the neonatal Fc receptor, have revealed genetic variations that are linked to autoimmune diseases and to the efficacy of IVIg treatment. However, the beneficial effect of IVIg encompasses multiple mechanisms of action. One of these is scavenging of activated complement fragments, such as C3a, C5a, C3b and C4b, by infused Ig molecules. This interaction prevents binding of complement fragments to their receptors on target cells, thus attenuating the immune damage. Additionally, anti-inflammatory effects may be facilitated by IgA via specific receptors and/or complement scavenging. Glycosylation of both the Fc- and Fab-fragments has also been implicated in the anti-inflammatory action of IVIg. Although there is evidence to support a role for sialylated IgG glycovariants in mediating the effect of IVIg, evidence from animal models of inflammatory disease suggest that sialylation may not be a critical factor. However, an increase in IgG glycosylation has been observed following IVIg treatment in Guillain-Barré syndrome patients, and this has been associated with improved clinical outcomes.

Introduction

Intravenous immunoglobulin (IVIg) contains mostly normal immunoglobulin (IgG), with very low levels of residual IgM and IgA immunoglobulins. It is prepared from pooled plasma taken from many thousands of healthy donors. Although IVIg is used in autoimmune and inflammatory diseases and for replacement therapy in primary and secondary immunodeficiencies, the immunomodulatory mechanisms of IVIg are not fully understood. In this session, chaired by Drs Basta and Branch, current thinking regarding the mechanisms of action of IVIg are reviewed, and the potential impact of genetic and phenotypical variation is discussed.

Professor Kuijpers presents results using multiplex ligation probe amplification (MLPA) to study the association of genetic variations in Fc-gamma receptors (FcγRs) with autoimmune diseases such as immune thrombocytopenic purpura/immune thrombocytopenia (ITP), and describes the extensive ethnic variation and linkage disequilibrium observed using his methods. Professor Kuijpers also presents initial results of studies in human red pulp macrophages isolated from the spleen to examine how FcγR expression and regulation may affect the outcome of IVIg treatment. As well as FcγR, genetic polymorphisms altering the expression of the neonatal Fc receptor (FcRn) can influence the effect of IVIg treatment. A polymorphism in the promoter region of the FcRn gene consisting of a variable number of tandem repeats (VNTR) has been described, and the allele with two tandem repeats (VNTR2) is associated with decreased IgG binding compared with the predominant VNTR 3/3 homozygotes 1. In his presentation, Professor Oksenhendler describes the results of a prospective cohort study of patients with common variable immunodeficiency (CVID), and observes that VNTR 3/3 homozygotes with an infection-only phenotype display increased IgG trough levels and improved IgG replacement following treatment. In contrast, Dr Litzman notes no significant differences between CVID patients homozygous for VNTR 3/3 and VNTR 2 allele carriers in clinical or laboratory characteristics before diagnosis. However, VNTR 2 is associated with reduced FcRn mRNA expression 1, and Dr Litzman reports a link between FcRn mRNA expression and the development of lung structural abnormalities.

Although some of the effects of IVIg depend upon the binding of the Fc-fragment of IgG to FcγRs on target cells, others may be dependent upon the Fab variable region of IgG. Dr Kaveri provides an overview of the Fc-independent mechanisms of action of IVIg, including neutralization of anaphylatoxins by the constant domain of the Fab fragment, emphasizing that IVIg is not dependent upon a single mechanism of action. As well as IgG, plasma or serum-derived IgA may have anti-inflammatory potential. Professor Monteiro provides a review of the role of IgA in suppressing excessive immune responses through the SIGNR1 receptor or via the IgA Fc receptor, FcαR1, associating with the FcγR 2,3. Acting via these receptors, IgA modulates several inflammatory diseases, including asthma and diabetes 2,3. IgA molecules are known to have high capacity for complement scavenging 4, which may contribute to their anti-inflammatory action.

Other research has highlighted the role of the sugar domain attached to the IgG Fc-fragment in enhancing or blocking the pro- and anti-inflammatory effector functions 5. There is evidence to show that sialic acid containing sugar moieties can attach to the IgG Fc- or Fab-fragments. Dr Nimmerjahn reviews the evidence supporting a role for sialylated IgG glycovariants in mediating the anti-inflammatory action of IVIg, but notes that recent studies in animal models of ITP and rheumatoid arthritis (RA), as presented by Dr Käsermann, suggest that sialylation may not be critical for IVIg activity 6,7. Dr Käsermann describes studies using mouse RA models, and observes that no loss of treatment efficacy was observed with a therapeutic regimen of desialylated IVIg. However, Dr Fokkink presents results from Guillain-Barré syndrome patients demonstrating that treatment with IVIg results in increased serum IgG galactosylation and, to a lesser extent, sialylation 8. Additionally, Dr Fokkink explains that increased levels of IgG glycosylation following IVIg treatment were associated with improved clinical recovery.

Disclosure

M. B. has received research grants from CSL Behring. D. R. B. has received funding or in kind support from CSL Behring and Grifols. He has no other financial or other conflicts of interest.