Recently the role of glycans in the immune system has been reviewed by Maverakis and colleagues, pointing out the various critical implications the glycocalyx of eukaryotic cells as well as glycosylations of serum proteins including antibodies have on modulating immunity [ 1 ]. While few data are available, analyzed in relationship to vaccines the implications for immunity have become clear, signaling the need to include the glycome in future systems vaccinology analysis. Indeed the glycome is heavily underrepresented in the majority of current systems biology investigations, which is arguably caused by experimental complexity. Yet current evidence shows that it is of critical importance in modulation of immunity and may provide numerous markers of use in understanding current and future reaction of individuals to vaccines. Also it should be considered that each antigen may be target of numerous antibodies where each may potentially be differently glycosylated, potentially grossly altering the effect from pro- to anti-inflammatory or vice versa. High-dose intravenous immunoglobulin (IVIg) therapy is used to treat autoimmune disorders and transplant rejection where the effect is assumed to rest on anti- inflammatory antibodies, or specifically IgG with preference of anti-inflammatory Fc receptors [ 2 ]. The generation of anti- inflammatory glycosylation of IgG (specifically with terminal sialic acid) in tolerogenic therapies has recently been demonstrated to rest on antibody development in a non-inflammatory environment, suggesting the use of systems vaccinology for the deeper understanding of involved mechanisms and development of potentially supportive anti-inflammatory adjuvants [ 3 ]. Although the entire glycome can be analyzed using mass spectrometric approaches and great technical advances have recently been made using lectin microarrays and capillary electrophoresis, analysis of position-specific glycosylations is hindered by the non-template- based nature of glycosylations, as Maverakis et al. point out [ 4 , 5 ]. Now we are in the unsatisfying situation to know there is a critical component to understanding immunity, but essentially lack tools equivalent in ease of use to other omics technologies. Optimal resolution of antibody class, isotype, and relative abundance of these should be part of any comprehensive analysis of antibody- mediated immune reactions. High titers do not necessarily mean desired effect if Fc regions of generated antibodies do not activate the intended lectins and/or Fc receptors [ 6 , 7 ]. It is known that immunoglobulin Fc regions can take on hundreds of different structures with slightly or gravely different effects on targeted cell types and hence achieved effect in cancer, autoimmunity, and infectious diseases. Profiling of adjuvants should therefore consider the precise nature of produced antibodies, as biomedical effects can be diverse and at least theoretically inverse to the intended. Changes in immunoglobulin glycosylation have been described for numerous autoimmune disorders and infectious diseases [ 8 – 10 ]. While there has to the author’s knowledge been no definite proof that these changes are causative of disease they reflect changes in the immune system pinpointing towards biomarkers and very possibly at least contribute to development of an unbalanced immune phenotype. This assumption is based on the well-established dependence of immunoglobulin affinity to Fc receptors based on subclass and Fc glycosylation pattern as well as glycosylation of the receptor and resulting modification of antibody effect on various immune cell types [ 11 , 12 ]. At least in humans pro- and anti- inflammatory effect of Fc gammaRII receptor isoforms (FcγRIIa and FcγRIIb, respectively) is well established [ 6 ]. In addition these receptors are differently responsive to single antibodies, where the majority is only responsive to immune complexes [ 1 ]. The overall effect of a particular antibody should therefore depend on affinity to Fc receptors (particularly pro- and anti- inflammatory) and relative abundance of these Fc receptors on specific target cells. Therefore unless an antibody interacts solely with FcγRIIb it may still also elicit pro-inflammatory signals.

In the case of the human pathogen dengue virus where antibody- dependent enhancement (ADE) is currently understood as a major driver of pathology, the role of FcγRIIA may primarily be enrichment of virus/antibody complexes on the cell surface [ 13 ]. However the second receptor variant FcγRIIb (that stimulates an anti-inflammatory effect) has been suggested to provide only limited ADE effect in spite of equivalent antibody Fc affinity, implicating that subtype of generated antibodies in dengue natural infection and likely also dengue vaccines may critically impact pathology and efficacy of the vaccines [ 14 ].

References

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1] Maverakis E, Kim K, Shimoda M et al (2015) Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review. J Autoimmun. doi: 10.1016/j. jaut.2014.12.002

[ 2] Anthony RM, Nimmerjahn F (2011) The role of differential IgG glycosylation in the interaction of antibodies with FcγRs in vivo. Curr Opin Organ Transplant 16:7–14

 [3] Oefner CM, Winkler A, Hess C et al (2012) Tolerance induction with T cell-dependent protein antigens induces regulatory sialylated IgGs. J Allergy Clin Immunol 129:1647 1655, e13

[4] Hirabayashi J, Yamada M, Kuno A, Tateno H (2013) Lectin microarrays: concept, principle and applications. Chem Soc Rev 42: 4443–4458

[5] Mahan AE, Tedesco J, Dionne K et al (2015) A method for high-throughput, sensitive analysis of IgG Fc and Fab glycosylation by capillary electrophoresis. J Immunol Methods 417:34–44

[6] Pincetic A, Bournazos S, DiLillo DJ et al (2014) Type I and type II Fc receptors regulate innate and adaptive immunity. Nat Immunol 15:707–716

[7] Collin M, Ehlers M (2013) The carbohydrate switch between pathogenic and immunosuppressive antigen-specific antibodies. Exp Dermatol 22:511–514

[8] Selman MHJ, Niks EH, Titulaer MJ et al (2011) IgG fc N-glycosylation changes in Lambert-Eaton myasthenic syndrome and myasthenia gravis. J Proteome Res 10: 143–152

[9] Goulabchand R, Vincent T, Batteux F et al (2014) Impact of autoantibody glycosylation in autoimmune diseases. Autoimmun Rev 13:742–750

[10] Gardinassi LG, Dotz V, Hipgrave Ederveen A et al. (2014) Clinical severity of visceral leishmaniasis is associated with changes in immunoglobulin g fc N-glycosylation. mBio 5:e01844.

[11] Nimmerjahn F, Ravetch JV (2005) Divergent immunoglobulin g subclass activity through selective Fc receptor binding. Science 310:1510–1512

[12] Hayes JM, Frostell A, Cosgrave EFJ et al (2014) Fc gamma receptor glycosylation modulates the binding of IgG glycoforms: a requirement for stable antibody interactions. J Proteome Res 13:5471–5485

[13] Chotiwan N, Roehrig JT, Schlesinger JJ et al (2014) Molecular determinants of dengue virus 2 envelope protein important for virus entry in FcγRIIA-mediated antibody- dependent enhancement of infection. Virology 456–457:238–246

[14] Boonnak K, Slike BM, Donofrio GC, Marovich MA (2013) Human FcγRII cytoplasmic domains differentially influence antibody-mediated dengue virus infection. J Immunol 190:5659–5665

مواضيع ذات صلة

Immune Mechanisms of Graft Rejection

Induction of Immune Responses Against Transplants

Transplantation Antigens

Immune Responses Against Transplants

Cancer Immunotherapy : Stimulation of Host Antitumor Immune Responses by Vaccination With Tumor Antigens

Cancer Immunotherapy: Immune Checkpoint Blockade

Cancer Immunotherapy: Adoptive T Cell Therapy

Cancer Immunotherapy: Passive Immunotherapy With Monoclonal Antibodies

Evasion of Immune Responses by Tumors

PROCESS OF PHAGOCYTOSIS

GRANULOCYTIC CELLS

B Cell Epitope Binding Predictions