About this Research Topic
Given the success of Volume I of this Research Topic, we are pleased to announce the launch of Volume II: “Structure, Isotypes, Targets, and Post-Translational Modifications of Immunoglobulins and Their Role in Infection, Inflammation and Autoimmunity”.
Infection, autoimmunity, and cancer are accompanied by inflammation, which directly influence both the structure and function of immunoglobulins (Igs) and consequently, their pathogenicity. In addition, the isotype also influences the pathogenicity of Igs. For instance, in the context of viral infection, the removal of core fucose residues selectively enhances the affinity of IgG for FcγIIIa receptors, leading to increased antibody-dependent cell mediated cytotoxicity (ADCC) and decreased complement dependent cytotoxicity (CDC), as observed in dengue virus infection. Anti-gp120 antibodies of HIV-infected patients are less galactosylated and sialylated in long-term, asymptomatic non progressors, compared to symptomatic patients.
In the context of inflammation, the (Fc) fragment domain of IgGs can trigger pro- or anti-inflammatory responses. Numerous studies provided evidence that carbohydrates attached to the IgG Fc domain are essential for IgG function. The pro- or anti-inflammatory effector function of IgGs is mediated by different affinities for activating FcγRs (FcγRI, RIIa, RIIIa and RIIIb) and inhibiting FcγRIIb expressed by immune cells. A high level of sialylation of the IgG Fc fragment decreases ADCC potential through low affinity for activating receptors. Conversely, bisecting N-acetylglucosamines on the Fc fragment are pro-inflammatory and enhance ADCC. Different murine models have confirmed that the anti-inflammatory activity of intra-venous IgGs is due to their sialylated Fc fragments.
In autoimmune diseases, such as rheumatoid arthritis, patients show low levels of IgG Fc sialylation. During pregnancy, increased IgG sialylation is associated with remission of rheumatoid arthritis. In alloimmunity, anti-HLA donor specific antibodies are associated with reduced long-term transplant function and an increase in the prevalence of chronic rejection, whereas others do not. The glycosylation level of Igs may explain their “non-aggressive” and/or “protective” action. Similarly, the glycosylation of IgA1s plays an important role in IgA nephropathy. In this disease, circulating IgA1s are deficient in galactose and are not correctly cleared by anti-IgA1 antibodies conducing to glomerular lesions.
The targets of Igs are also of increasing interest in human pathology, and important antigenic drivers are being discovered in the context of monoclonal gammopathies of undetermined significance (MGUS) and multiple myeloma (MM). Lyso-glucosylceramide 1 (LGL1) and lyso-phosphatidylcholine (LPC), and several infectious pathogens, including Epstein-Barr virus and hepatitis C virus, were recently shown to be the targets of monoclonal IgGs in MGUS and MM. Monoclonal IgGs bear very lowly sialylated glycans, which suggests a pro-inflammatory state, reinforcing the notion that chronic antigenic stimulation and an abnormal immune response contribute to the pathogenesis of MGUS and MM.
IgA is the second most abundant immunoglobulin in human blood and the most abundant immunoglobulin in most mucosal secretions. Effector functions of human IgA are impacted by the subclass (IgA1, IgA2), glycosylation (IgA2 has more N-glycans and IgA1 has clustered O-glycans) and molecular form of IgA (monomer, polymer, secretory IgA). Recent findings indicate that IgA2 is more effective than IgA1 in induction of pro-inflammatory responses in neutrophils and macrophages. This is due to the extensive sialylation of IgA1 that imparts the anti-inflammatory properties, somewhat analogous to the glycan-dependent effector functions of IgG. Furthermore, abnormal O-glycosylation of IgA1 is involved in pathogeneses of several diseases, including IgA nephropathy and IgA vasculitis with nephritis. Recent progress in glycomics revealed more details about IgA glycans and their variability in health and disease.
This Research Topic aims to provide up-to-date knowledge on differences in structure, isotype, targets and post-translational modifications of immunoglobulins and their consequences in specific pathological contexts, especially infection, inflammation and autoimmunity.
We welcome the submission of Review, Mini-Review, Original Research, Technology and Code and Methods articles covering, but not limited to, the following sub-topics:
1) The role of Ig structures and isotypes in human disease.
2) The targets of Igs and their role in human pathology, including cancer.
3) The role of Ig glycosylation and other post-translational modifications in human disease.
Topic Editor Dr. Jan Novak has a sponsored research agreement with Travere, Inc., and a co-founder, co-owner and consultant for Reliant Glycosciences, LLC, providing consultancy and research services in IgA nephropathy. The other Topic Editors declare no potential competing interests in relation to the Research Topic theme.
Infection, autoimmunity, and cancer are accompanied by inflammation, which directly influence both the structure and function of immunoglobulins (Igs) and consequently, their pathogenicity. In addition, the isotype also influences the pathogenicity of Igs. For instance, in the context of viral infection, the removal of core fucose residues selectively enhances the affinity of IgG for FcγIIIa receptors, leading to increased antibody-dependent cell mediated cytotoxicity (ADCC) and decreased complement dependent cytotoxicity (CDC), as observed in dengue virus infection. Anti-gp120 antibodies of HIV-infected patients are less galactosylated and sialylated in long-term, asymptomatic non progressors, compared to symptomatic patients.
In the context of inflammation, the (Fc) fragment domain of IgGs can trigger pro- or anti-inflammatory responses. Numerous studies provided evidence that carbohydrates attached to the IgG Fc domain are essential for IgG function. The pro- or anti-inflammatory effector function of IgGs is mediated by different affinities for activating FcγRs (FcγRI, RIIa, RIIIa and RIIIb) and inhibiting FcγRIIb expressed by immune cells. A high level of sialylation of the IgG Fc fragment decreases ADCC potential through low affinity for activating receptors. Conversely, bisecting N-acetylglucosamines on the Fc fragment are pro-inflammatory and enhance ADCC. Different murine models have confirmed that the anti-inflammatory activity of intra-venous IgGs is due to their sialylated Fc fragments.
In autoimmune diseases, such as rheumatoid arthritis, patients show low levels of IgG Fc sialylation. During pregnancy, increased IgG sialylation is associated with remission of rheumatoid arthritis. In alloimmunity, anti-HLA donor specific antibodies are associated with reduced long-term transplant function and an increase in the prevalence of chronic rejection, whereas others do not. The glycosylation level of Igs may explain their “non-aggressive” and/or “protective” action. Similarly, the glycosylation of IgA1s plays an important role in IgA nephropathy. In this disease, circulating IgA1s are deficient in galactose and are not correctly cleared by anti-IgA1 antibodies conducing to glomerular lesions.
The targets of Igs are also of increasing interest in human pathology, and important antigenic drivers are being discovered in the context of monoclonal gammopathies of undetermined significance (MGUS) and multiple myeloma (MM). Lyso-glucosylceramide 1 (LGL1) and lyso-phosphatidylcholine (LPC), and several infectious pathogens, including Epstein-Barr virus and hepatitis C virus, were recently shown to be the targets of monoclonal IgGs in MGUS and MM. Monoclonal IgGs bear very lowly sialylated glycans, which suggests a pro-inflammatory state, reinforcing the notion that chronic antigenic stimulation and an abnormal immune response contribute to the pathogenesis of MGUS and MM.
IgA is the second most abundant immunoglobulin in human blood and the most abundant immunoglobulin in most mucosal secretions. Effector functions of human IgA are impacted by the subclass (IgA1, IgA2), glycosylation (IgA2 has more N-glycans and IgA1 has clustered O-glycans) and molecular form of IgA (monomer, polymer, secretory IgA). Recent findings indicate that IgA2 is more effective than IgA1 in induction of pro-inflammatory responses in neutrophils and macrophages. This is due to the extensive sialylation of IgA1 that imparts the anti-inflammatory properties, somewhat analogous to the glycan-dependent effector functions of IgG. Furthermore, abnormal O-glycosylation of IgA1 is involved in pathogeneses of several diseases, including IgA nephropathy and IgA vasculitis with nephritis. Recent progress in glycomics revealed more details about IgA glycans and their variability in health and disease.
This Research Topic aims to provide up-to-date knowledge on differences in structure, isotype, targets and post-translational modifications of immunoglobulins and their consequences in specific pathological contexts, especially infection, inflammation and autoimmunity.
We welcome the submission of Review, Mini-Review, Original Research, Technology and Code and Methods articles covering, but not limited to, the following sub-topics:
1) The role of Ig structures and isotypes in human disease.
2) The targets of Igs and their role in human pathology, including cancer.
3) The role of Ig glycosylation and other post-translational modifications in human disease.
Topic Editor Dr. Jan Novak has a sponsored research agreement with Travere, Inc., and a co-founder, co-owner and consultant for Reliant Glycosciences, LLC, providing consultancy and research services in IgA nephropathy. The other Topic Editors declare no potential competing interests in relation to the Research Topic theme.
Keywords: Immunoglobulins, glycosylation, targets, inflammation, infection
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