Many autoimmune diseases are induced by pathogenic autoantibodies, that bind to self-antigen expressed in cells and tissues, and induce disease by the recruitment of immune cells, activation of the classical complement pathway or induction of antigen cross-linking and endocytosis. These pathogenic mechanisms are, however, not available to antibodies of the IgG4 subclass, as these differ structurally from the other IgG subclasses, leaving them “immunologically inert”. In general, it is thought that IgG4 is part of an anti-inflammatory immune response to an overreactive pro-inflammatory response, e.g. in the context of helminth infection and allergy.
Intriguingly, a range of rare, severe autoimmune diseases are directly caused by pathogenic antibodies of the IgG4 subclass, which is an observation that breaks with immunological paradigms. IgG4 autoantibodies were found to be directly pathogenic by blocking the interaction between cells and molecules, which leads to altered tissue architecture, loss of enzyme function or block of signal transduction pathways. Diseases caused by pathogenic IgG4 include the blistering skin disease pemphigus vulgaris, the neuromuscular disease MuSK myasthenia gravis and thrombotic thrombocytopenic purpura. Due to the different organ predilection, kinship across these diseases was only appreciated recently, and these diseases are now collected under the umbrella term of “IgG4 autoimmune diseases”. We know to date very little about the underlying immunopathogenesis, predisposing factors or the (dys) regulation of the IgG4 pathway in IgG4-autoimmune diseases, and aim to instigate in this Special Research Topic a discussion and exchange across the different disciplines to share and further our knowledge.
The IgG4 subclass itself is a fascinating topic of study, since the structural uniqueness of its hinge and CH3 region allows the two heavy chains to dissociate into antibody half-molecules and randomly recombine with other half-molecules, which is a process called “Fab-arm exchange” that leads to the production of bi-specific antibodies, that are functionally monovalent. Furthermore, it’s immunological “harmlessness” induced antibody engineers to model therapeutic monoclonal antibodies on the basis of the IgG4 subclass. Biological drugs such as natalizumab that are de facto human IgG4 were also found to undergo Fab-arm exchange in the patients, leading to a change of approach in the development of newer generations of monoclonal antibodies to prevent Fab-arm exchange.
Lastly, IgG4 also takes center stage in a range of other disorders: 1. IgG4-related diseases, a group of mysterious inflammatory diseases hallmarked by tissue fibrosis, IgG4+ plasma cell infiltrates and increased serum IgG4 concentrations, where the cause of disease and the role of IgG4 in pathology are unknown. 2. Allergy, where IgG4 class switch is induced as a result of antigen immunotherapy. 3. Various cancers, such as melanoma, where tumor cells evade the host’s immune system by inducing anti-tumor antibodies to switch to IgG4. 4. Anti-drug antibodies (ADA) which are produced by patients as a response to treatment with biologics such as anti-TNF alpha, are often of the IgG4 subclass, and 4. IgG4 subclass antibodies were observed in patients with rheumatoid arthritis, including anti-citrullinated protein antibodies (ACPAs) and anti-hinge antibodies (AHAs), as well as in Wegener’s granulomatosis (ANCAs).
This Special Research topic aims to invite scientists from the different areas of research to a round table to exchange knowledge and ideas, and share their latest state-of-the-art research into IgG4 in health and disease. We invite the submission of Original Research and Review articles on the following topics:
1. IgG4, the “anti-inflammatory” antibody: structure, function and immunobiology of IgG4 in healthy individuals
i. emphasis on antibody characteristics (structure, glycosylation, valency/fab-arm exchange)
ii. emphasis on B cells (including regulation of class switch, regulation of IgG4 production)
iii. The usefulness of the IgG4 subclass as a model for engineering of therapeutic mAbs
2. Protective or pathogenic: The role of IgG4 in disease:
a. As pathogenic antibody in IgG4 autoimmune diseases: pathogenic mechanisms, commonalities among IgG4-AID
i. Pathogenic mechanisms (Blocking mechanisms, controversy: is there an activation of alternative/lectin complement pathway?)
ii. Animal models
iii. Epidemiology
b. The role of IgG4 in other diseases:
i. Benign: allergy, parasitic infections
ii. Pathogenic: cancer (including melanoma),
iii. Unclear: rheumatoid arthritis, anti-biological responses, IgG4-related diseases, ANCA, etc.
3. Therapies of IgG4 associated diseases:
a. Review of current therapies targeting IgG4 autoantibodies in IgG4-AID and IgG4-RLD
b. Reviews on potential new treatment strategies, aimed e.g. specifically at IgG4+ B-cells, IgG4 class switch or Fab-arm exchange
Many autoimmune diseases are induced by pathogenic autoantibodies, that bind to self-antigen expressed in cells and tissues, and induce disease by the recruitment of immune cells, activation of the classical complement pathway or induction of antigen cross-linking and endocytosis. These pathogenic mechanisms are, however, not available to antibodies of the IgG4 subclass, as these differ structurally from the other IgG subclasses, leaving them “immunologically inert”. In general, it is thought that IgG4 is part of an anti-inflammatory immune response to an overreactive pro-inflammatory response, e.g. in the context of helminth infection and allergy.
Intriguingly, a range of rare, severe autoimmune diseases are directly caused by pathogenic antibodies of the IgG4 subclass, which is an observation that breaks with immunological paradigms. IgG4 autoantibodies were found to be directly pathogenic by blocking the interaction between cells and molecules, which leads to altered tissue architecture, loss of enzyme function or block of signal transduction pathways. Diseases caused by pathogenic IgG4 include the blistering skin disease pemphigus vulgaris, the neuromuscular disease MuSK myasthenia gravis and thrombotic thrombocytopenic purpura. Due to the different organ predilection, kinship across these diseases was only appreciated recently, and these diseases are now collected under the umbrella term of “IgG4 autoimmune diseases”. We know to date very little about the underlying immunopathogenesis, predisposing factors or the (dys) regulation of the IgG4 pathway in IgG4-autoimmune diseases, and aim to instigate in this Special Research Topic a discussion and exchange across the different disciplines to share and further our knowledge.
The IgG4 subclass itself is a fascinating topic of study, since the structural uniqueness of its hinge and CH3 region allows the two heavy chains to dissociate into antibody half-molecules and randomly recombine with other half-molecules, which is a process called “Fab-arm exchange” that leads to the production of bi-specific antibodies, that are functionally monovalent. Furthermore, it’s immunological “harmlessness” induced antibody engineers to model therapeutic monoclonal antibodies on the basis of the IgG4 subclass. Biological drugs such as natalizumab that are de facto human IgG4 were also found to undergo Fab-arm exchange in the patients, leading to a change of approach in the development of newer generations of monoclonal antibodies to prevent Fab-arm exchange.
Lastly, IgG4 also takes center stage in a range of other disorders: 1. IgG4-related diseases, a group of mysterious inflammatory diseases hallmarked by tissue fibrosis, IgG4+ plasma cell infiltrates and increased serum IgG4 concentrations, where the cause of disease and the role of IgG4 in pathology are unknown. 2. Allergy, where IgG4 class switch is induced as a result of antigen immunotherapy. 3. Various cancers, such as melanoma, where tumor cells evade the host’s immune system by inducing anti-tumor antibodies to switch to IgG4. 4. Anti-drug antibodies (ADA) which are produced by patients as a response to treatment with biologics such as anti-TNF alpha, are often of the IgG4 subclass, and 4. IgG4 subclass antibodies were observed in patients with rheumatoid arthritis, including anti-citrullinated protein antibodies (ACPAs) and anti-hinge antibodies (AHAs), as well as in Wegener’s granulomatosis (ANCAs).
This Special Research topic aims to invite scientists from the different areas of research to a round table to exchange knowledge and ideas, and share their latest state-of-the-art research into IgG4 in health and disease. We invite the submission of Original Research and Review articles on the following topics:
1. IgG4, the “anti-inflammatory” antibody: structure, function and immunobiology of IgG4 in healthy individuals
i. emphasis on antibody characteristics (structure, glycosylation, valency/fab-arm exchange)
ii. emphasis on B cells (including regulation of class switch, regulation of IgG4 production)
iii. The usefulness of the IgG4 subclass as a model for engineering of therapeutic mAbs
2. Protective or pathogenic: The role of IgG4 in disease:
a. As pathogenic antibody in IgG4 autoimmune diseases: pathogenic mechanisms, commonalities among IgG4-AID
i. Pathogenic mechanisms (Blocking mechanisms, controversy: is there an activation of alternative/lectin complement pathway?)
ii. Animal models
iii. Epidemiology
b. The role of IgG4 in other diseases:
i. Benign: allergy, parasitic infections
ii. Pathogenic: cancer (including melanoma),
iii. Unclear: rheumatoid arthritis, anti-biological responses, IgG4-related diseases, ANCA, etc.
3. Therapies of IgG4 associated diseases:
a. Review of current therapies targeting IgG4 autoantibodies in IgG4-AID and IgG4-RLD
b. Reviews on potential new treatment strategies, aimed e.g. specifically at IgG4+ B-cells, IgG4 class switch or Fab-arm exchange