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The nodes of Ranvier in motoneuron axons are densely packed with IgG4 autoantigens. Schwann cells are providing electric insulation in motoneuron axons, and together with the gaps, the nodes of Ranvier, allow for saltatory conduction, the propagation of action potentials, in the axon. To this end, the membranes of axon and Schwann cell have to be tightly sealed. Many IgG4 autoantigens are, curiously, expressed at the juxtaparanodal junction, namely CNTN1, Caspr1, Caspr2, NF186, NF140 (not shown), and NF155. It is unclear why this structure seems to be so susceptible to IgG4 autoantibodies.
Source publication
Antibodies of IgG4 subclass are exceptional players of the immune system, as they are considered to be immunologically inert and functionally monovalent, and as such may be part of classical tolerance mechanisms. IgG4 antibodies are found in a range of different diseases, including IgG4-related diseases, allergy, cancer, rheumatoid arthritis, helmi...
Contexts in source publication
Context 1
... (CNTN1) is an adhesion molecule that are expressed on the surface of axons at the axoglial junction (Fig. 7). CNTN1 binds together with CNTN1-associated protein 1 (Caspr1) to the protein Neurofascin-155 (NF155) on the surface of oligodendroglia [150][151][152][153], and all three proteins have been suggested as targets for IgG4 autoantibodies. The CNTN1-Caspr1-NF155 complex is required to maintain paranode architecture and to maintain myelin ...
Context 2
... binding partner of CNTN1 in the axo-glial complex, Neurofascin 155 (NF155, Fig. 7), is also targeted by IgG4 autoantibodies. NF155 is an adhesion protein expressed on the glia cells in the paranodal septatelike junctions of myelinated axons [165,166,167]. Autoantibodies to NF155 (as to CNTN1 and perhaps also Caspr1) are thought to cause changes in the axo-glial complex that lead to peripheral neuropathies ...
Context 3
... [204,220,[224][225][226][227][228][229]. The wide range of disorders and symptoms is due to the different roles of CASPR2 in the peripheral and central nervous system. CASPR2 is a neurexin-related cell-adhesion molecule and is expressed in the peripheral and central nervous system, specifically in the juxtaparanodal region of myelinated axons (Fig. 7), hippocampal GABAergic interneurons and in excitatory synapses in the cortex [230,231](Fernandes, Santos et al., 2019). CASPR2 forms a complex with transient axonal glycoprotein-1 (TAG-1, also named Contactin-2) and shaker-type voltage-gated potassium channels Kv1.1 and Kv1.2, and may be relevant for different processes that are ...
Context 4
... are only few publications on patients with CIDP that have IgG4 subclass antibodies against Caspr1, which is another protein located at the paranode of motoneurons (Fig. 7) or complexed Caspr1/ CNTN1 [154,155,303]. Overall there is not enough data available yet to determine pathogenicity of ...
Context 5
... very few patients with CIDP, neurofascin −140 and −186 (NF140, NF186) which are also expressed at the paranodes of motoneurons ( Fig. 7) were found as the main targets of autoantibodies. IgG subclasses were described in one study, in which four were predominantly of IgG4 and one IgG3 [303], and in one case file additional antibodies against CNTN1 were present [304]. To date there is not enough information to determine the pathogenic status of NF140-and ...
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Citations
... Experiments have shown that most MuSK autoantibodies are bispecific and have Fab-arm exchange in vivo, and in vitro measurements of pathogenicity have confirmed that MuSK antibodies do not alter pathogenicity by FAE with IgG4 from healthy sera, implying that monovalent IgG4 is sufficient to induce pathogenicity (Koneczny et al., 2017). The pathogenicity of MuSK autoantibodies is thus thought not to be relied on immune inflammation and complement activation, but exerted through an Fc-independent mechanism also known as the blockade of protein-protein interactions (Koneczny, 2020), where the antibody interferes with the clustering of the AChR by blocking the LRP4-MuSK interaction, thereby disrupting the agrin/MuSK signaling pathway and its maintenance of the integrity of the NMJ structure and function, resulting in impaired neuromuscular transmission and forming symptoms of muscle weakness, the pathogenicity of which has been confirmed by passive transfer studies (Klooster et al., 2012;Gilhus et al., 2019) (Figure 2) Apart from the previously mentioned pathogenic mechanisms, MuSK antibodies possess the subsequent supplementary characteristics: MuSK antibodies that block the involvement of LRP4 in MuSK activation also inhibit ACh vesicle clustering in motor nerve terminals by controlling presynaptic membrane development through the retrograde signal. The pharmacological effects of the symptomatic drug 3,4-diaminopyridine are mediated by increased vesicle release and enhanced conduction (Cao et al., 2020). ...
Myasthenia gravis (MG) is an antibody-mediated autoimmune disease with a prevalence of 150–250 cases per million individuals. Autoantibodies include long-lived antibodies against the acetylcholine receptor (AChR), mainly of the IgG1 subclass, and IgG4, produced almost exclusively by short-lived plasmablasts, which are prevalent in muscle-specific tyrosine kinase (MuSK) myasthenia gravis. Numerous investigations have demonstrated that MG patients receiving conventional medication today still do not possess satisfactory symptom control, indicating a substantial disease burden. Subsequently, based on the type of the autoantibody and the pathogenesis, we synthesized the published material to date and reached a conclusion regarding the literature related to personalized targeted therapy for MG. Novel agents for AChR MG have shown their efficacy in clinical research, such as complement inhibitors, FcRn receptor antagonists, and B-cell activating factor (BAFF) inhibitors. Rituximab, a representative drug of anti-CD20 therapy, has demonstrated benefits in treatment of MuSK MG patients. Due to the existence of low-affinity antibodies or unidentified antibodies that are inaccessible by existing methods, the treatment for seronegative MG remains complicated; thus, special testing and therapy considerations are necessary. It may be advantageous to initiate the application of novel biologicals at an early stage of the disease. Currently, therapies can also be combined and individualized according to different types of antibodies. With such a wide range of drugs, how to tailor treatment strategies to patients with various conditions and find the most suitable solution for each MG profile are our necessary and urgent aims.
... Patients may present with other autoantibodies and have different clinical syndromes. Those presenting antibodies against neurofascin 186 (NF186), for instance, may present with renal impairment given both CNTN1 and NF186 are found in podocytes (62,82). ...
... In fact, many entry mechanisms have been studied, such as interaction of basic residues with a negatively charged cell membrane (150), Fc-receptor mediated entry (151), endocytosis (147,152,153), and nucleoside transporters (154). Among the six IgG4-AID that meet IgG4 autoimmunity criteria, however, all the antigens involved in their pathogenesis are found in the cell membrane or free in the blood circulation (62). ...
Immunoglobulins are an essential part of the humoral immune response. IgG4 antibodies are the least prevalent subclass and have unique structural and functional properties. In this review, we discuss IgG4 class switch and B cell production. We review the importance of IgG4 antibodies in the context of allergic responses, helminth infections and malignancy. We discuss their anti-inflammatory and tolerogenic effects in allergen-specific immunotherapy, and ability to evade the immune system in parasitic infection and tumour cells. We then focus on the role of IgG4 autoantibodies and autoantigens in IgG4-autoimmune diseases and IgG4-related disease, highlighting important parallels and differences between them. In IgG4-autoimmune diseases, pathogenesis is based on a direct role of IgG4 antibodies binding to self-antigens and disturbing homeostasis. In IgG4-related disease, where affected organs are infiltrated with IgG4-expressing plasma cells, IgG4 antibodies may also directly target a number of self-antigens or be overexpressed as an epiphenomenon of the disease. These antigen-driven processes require critical T and B cell interaction. Lastly, we explore the current gaps in our knowledge and how these may be addressed.
... IgG2 is mostly restricted to bacterial protection, IgG3 is the effector/proinflammatory antibody, and IgG4 is expressed after long-term exposure to antigens, becoming the dominant Ig subclass overtime (54). Specifically, IgG4 is often upregulated in autoimmune diseases because it arises during chronic (self-)antigen exposure (55)(56)(57). The known pathogenic role of IgGs in autoimmune diseases suggests that their increase in moderate and severe emphysema might be associated with autoimmune features contributing to lung tissue destruction in this subset of patients. ...
Rationale: Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component.
Objective: To characterize the transcriptomic signatures from lymphoid follicles (LFs) in ever-smokers without COPD and COPD patients with varying degrees of emphysema.
Methods: Lung sections from 40 COPD patients and ever-smokers were used for LF proteomic and transcriptomic spatial profiling. Formalin and OCT-fixed lung samples obtained from biopsies or lung explants, were assessed for LF presence. Emphysema measurements were obtained from clinical chest CT scans. High confidence transcriptional (HCT) target intersection analyses were conducted to resolve emphysema-induced transcriptional networks.
Measurements and main results: Overall, 115 LFs from ever-smokers and GOLD 1-2 and GOLD 3-4 patients were analyzed. No LFs were found in never-smokers. Differential gene expression analysis revealed significantly increased expression of LF assembly and B cell markers genes in subjects with severe emphysema. HCT analysis revealed activation of abnormal B cell activity signature in LFs (q-value: 2.56E-111). LFs from GOLD 1-2 COPD patients with emphysema showed significantly increased expression of genes associated with antigen presentation, inflammation, and B cell activation and proliferation. LFs from GOLD 1-2 COPD patients without emphysema showed an anti-inflammatory profile. The extent of centrilobular emphysema was significantly associated with genes involved in B cell maturation and antibody production. Protein-RNA network analysis showed that LFs in emphysema have a unique signature skewed towards chronic B cell activation.
Conclusions: An off-targeted B cell activation within LFs is associated with autoimmune-mediated emphysema pathogenesis.
... These IgG4-AID affect different organ systems and are generally rare with a prevalence of 0.001-5/10.000 individuals [22]. During the last decades in vitro and in vivo studies have directly confirmed the pathogenicity of IgG4 autoantibodies in at least six IgG4-AID, and more are expected to follow [23][24][25][26]. ...
... Involvement of the lacrimal gland is commonly bilateral although simultaneous affection may not occur. Associated salivary gland involvement is common with extra-ophthalmic involvement in 70 to 80 % [12][13][14][15]. ...
... According to the diagnostic criteria, IgG4-ROD accounts for nearly half of the cases that were previously diagnosed as orbital pseudotumors or idiopathic orbital inflammation [15,16]. ...
... The exact etiopathogenesis of IgG4-RD is still unknown. It has been suggested that the fibrotic and inflammatory processes that drive IgG4-RD are attributed to a combination of Th2 cells and regulatory T cells (Treg cells) which is contrary to most autoimmune disorders where the inflammatory process is propagated by T helper 1 (Th1) and/or Th17 subsets [15]. ...
... При САРЗ, в первую очередь РА, особый интерес привлекают аутоантитела, реагирующие с белками с измененной конформационной структурой, индуцированной цитруллинированием и/или другими формами посттрансляционной модификации (карбамилирование, ацетилирование, модифицирование малондиальдегидом) [117,119,120]. Представляют интерес так называемые IgG4-аутоиммунные заболевания (пузырчатка, тромботическая тромбоцитопеническая пурпура, аутоиммунный энцефалит, миастения гравис, воспалительные нейропатии и мембранозная нефропатия), для которых характерен синтез аутоантител, относящихся к IgG4 субклассу молекулы Ig, который отличается по эффекторным функциям Fcфрагмента от IgG1-3 субклассов [121,122]. Следует обратить внимание на принципиальные отличия IgG4-аутоиммунных заболеваний от IgG4-связанных заболеваний, для которых характерно развитие фиброза и увеличение концентрации IgG4 без определенной антительной специфичности. ...
Two fundamental pathologic processes are central to the spectrum of chronic inflammation mechanisms: autoimmunity and autoinflammation. Autoimmunity and autoinflammation are mutually potent pathologic processes; their development is considered within the framework of the “immunoinflammatory” continuum, reflecting the close relationship between innate and acquired types of immune response. Autoimmunity is the leading mechanism of pathogenesis of a large group of chronic inflammatory human diseases, defined as autoimmune diseases, the frequency of which in the population exceeds 10%. Advances in molecular biology, pharmacogenetics and bioinformatics have created prerequisites for individualization of therapy of autoimmune rheumatic diseases within the concept of personalized medicine. The study of immunopathogenesis mechanisms, improvement of diagnostics, deciphering the nature of molecular taxonomy, development of approaches to prevention and personalized therapy of human autoimmune diseases is among the priority directions of medicine of the 21st century.
... IgG4 antibodies can be detected in various medical conditions, including helminth infections, allergies, cancer, and rheumatoid arthritis. They now constitute a newly recognized category of illness characterized by the presence of pathogenic, antigen-specific autoantibodies belonging to the IgG4 subclass [4]. Diagnosing IgG4-related disease (IgG4-RD) is challenging and involves conducting a clinical assessment, radiology, analyzing tissue samples under a microscope, utilizing imaging techniques, and performing blood tests to assess specific antibodies [5]. ...
IgG4-related disease (IgG4-RD) is an immune-mediated disorder that involves multiple organs and is characterized by the infiltration of lymphoplasmacytic cells, including IgG4-positive plasma cells, along with storiform fibrosis and obliterative phlebitis in the inflamed organs. The primary sites affected by this condition include the pancreas, bile ducts, salivary glands, aorta, lungs, kidneys, meninges, lacrimal glands, mediastinal lymph nodes, and retroperitoneum. The pathogenesis is linked to a type 2 T-helper-cell cytokine profile and the involvement of regulatory T cells. However, the exact mechanism is still unknown. Patients with IgG4-related disease are frequently misdiagnosed as having malignancies due to the resemblance of the lesions to infections or other immune-mediated diseases and certain tumors, such as pancreatic cancer and pseudo-renal pelvis tumor. Prompt identification of IgG4-related disease is essential as a delayed diagnosis until advanced stages can result in severe organ damage and potentially fatal outcomes, despite the disease being highly responsive to treatment. This report presents a highly unusual case of IgG4-related disease (IgG4-RD) with an atypical presentation in a 38-year-old female patient. The patient sought medical attention in the emergency department due to nasal septal erosions and an oral-antral fistula. Nasal cultures were conducted and indicated the presence of Klebsiella ozaena. Subsequent investigations, including a nasal biopsy, confirmed the diagnosis of IgG4-related autoimmune disease.
... These affect different organ systems and are generally rare with a prevalence of 0.001-5/10.000 individuals (17). During the last decades in vitro and in vivo studies have directly confirmed the pathogenicity of IgG4 autoantibodies in at least six IgG4-AIDs (18)(19)(20)(21). ...
A subset of autoimmune diseases is characterized by predominant pathogenic IgG4 autoantibodies (IgG4-AIDs). Why IgG4 predominates in these disorders is unknown. We hypothesized that dysregulated B cell maturation or aberrant class switching causes overrepresentation of IgG4 ⁺ B cells and plasma cells. Therefore, we compared the B cell compartment of patients with muscle-specific kinase (MuSK) myasthenia gravis (MG), pemphigus, leucine-rich glioma inactivated (LGI1) encephalitis and contactin-associated protein-like 2 (CASPR2) encephalitis (four IgG4-AIDs) to patients with acetylcholine receptor (AChR) MG, Lambert-Eaton myasthenic syndrome (LEMS) (two IgG1-3-AIDs) and age-matched healthy donors, using flow cytometry. B cell subset relative abundance at all maturation stages was normal, except for a, possibly treatment-related, reduction in immature and naïve CD5 ⁺ cells in IgG4-AIDs. IgG4 ⁺ B cell and plasma cell fractions were normal in IgG4-AID patients, however they had an (sub)class-independent 8-fold increase in circulating mature CD20 ⁻ CD138 ⁺ plasma cells. No autoreactivity was found in this subset after sorting. In conclusion, patients with IgG4-AID do not show increased numbers of IgG4-expressing cells. These results argue against aberrant B cell development in these patients and rather suggest the autoantibody subclass predominance to be antigen-driven. The similarities between B cell subset numbers among these patients suggest that these IgG4-AIDs, despite displaying variable clinical phenotypes, share a similar underlying immune profile.
Graphical abstract
... Its bivalency prevents immune complex formation and cross-linking that signal for endocytosis of transmembrane antigens. It has also been shown to serve an immunoprotective role by competitive binding of antigens that trigger a traditional allergic immune response [5]. ...
... The variance of IgG4 serum concentration within IgG4-RD is still under investigation [7]. The most common target organs for IgG4-mediated autoimmune disease are the central and peripheral nervous systems, including the neuromuscular synapse, mucosa and skin, lungs, kidneys, vasculature, salivary glands, and the pancreato-biliary system [5,8]. Given the subclinical nature and the difficulty of early detection without biopsy or radiologic evidence, IgG4-RD often results in an insidious proinflammatory state that can predispose patients to other autoimmune conditions [8]. ...
... Among the patients with IBD who were included in this study, only 7.7% were categorized to have "low" IgG4 levels, probably because of the very low laboratory value cutoffs that are used for "low" IgG4 at our institution. This contrasts with a previous study that described up to 20% of patients meeting the criteria for "low" IgG4 levels [5]. In this latter study, however, the authors used a reference range of 9-89 mg/dL to identify low IgG4 patients, potentially leading to the higher percentage and to the difference in results [5]. ...
Background:
The etiology of inflammatory bowel disease (IBD) is multifactorial and thought to be influenced by inappropriate activation of the gut mucosal immune system. As the only immunoglobulin G (IgG) subclass unable to activate the classical complement cascade, the role of IgG4 in IBD pathophysiology as an immunomodulator is controversial. This study aimed to determine the association of low, normal and high IgG4 levels with the outcomes of IBD patients.
Methods:
This was a retrospective study of a multisite tertiary care center database evaluating patients with IBD who had an IgG4 level drawn between 2014 and 2021. Subjects were divided into low, normal, and high IgG4 level groups for evaluation of demographic and clinical indicators of IBD activity and severity.
Results:
Of 284 patients with IBD, 22 had low (7.7%), 16 high (5.6%), and 246 (86.6%) normal IgG4 levels. There was no difference in IBD subtype, mean age, age at IBD diagnosis, or smoking between the 3 groups. There was no difference in number of hospitalizations (P=0.20), C-reactive protein levels, need for intestinal resection (P=0.85), or presence of primary sclerosing cholangitis (P=0.15), pancreatitis (P=0.70), or perianal disease (P=0.68) between the groups. Significantly more patients in the low IgG4 group had previous exposure to vedolizumab compared to the other groups and more patients in the low IgG4 group received vedolizumab (P=0.04), azathioprine (P=0.04) and prednisone (P=0.03) during the 5-year follow up.
Conclusion:
In this study, a low serum IgG4 level was associated with higher rates of vedolizumab, azathioprine, and steroid use.
... IgG4-AIDs were first defined as a separate subgroup of antibodymediated autoimmune disorders in 2015 (ref. 10), and a first attempt at their classification based on the level of evidence for a pathogenic role of IgG4 was proposed soon thereafter 11,81 . IgG4-AIDs are characterized by autoantibody responses predominantly of the IgG4 subclass against a known antigen. ...
... Interestingly, evidence for molecular mimicry resulting in an IgG4dominated response to desmogleins in the skin epidermis is found in patients with endemic pemphigus foliaceus from Brazilian and Other diseases that are suspected to be IgG4 autoimmune diseases, but with lower levels of evidence, are described in ref. 81. AChR, acetylcholine receptor; ADAMTS13, a disintegrin and metalloproteinase with thrombospondin motifs 13; CASPR1, contactin-associated protein 1; CNTN1, contactin 1; DSG1, desmoglein 1; LRP4, low-density lipoprotein receptor-related protein 4; MuSK, muscle-specific kinase; ND, not determined; NF155, neurofascin 155; vWF, von Willebrand factor. ...
IgG4 is the least abundant subclass of IgG in human serum and has unique functional features. IgG4 is largely unable to activate antibody-dependent immune effector responses and, furthermore, undergoes Fab (fragment antigen binding)-arm exchange, rendering it bispecific for antigen binding and functionally monovalent. These properties of IgG4 have a blocking effect, either on the immune response or on the target protein of IgG4. In this Review, we discuss the unique structural characteristics of IgG4 and how these contribute to its roles in health and disease. We highlight how, depending on the setting, IgG4 responses can be beneficial (for example, in responses to allergens or parasites) or detrimental (for example, in autoimmune diseases, in antitumour responses and in anti-biologic responses). The development of novel models for studying IgG4 (patho)physiology and understanding how IgG4 responses are regulated could offer insights into novel treatment strategies for these IgG4-associated disease settings.
