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Molecular Immunology Nov 2022Myasthenia gravis is a neuromuscular disease associated with antibodies against components of the neuromuscular junction, most often against the acetylcholine receptor... (Review)
Review
Myasthenia gravis is a neuromuscular disease associated with antibodies against components of the neuromuscular junction, most often against the acetylcholine receptor (AChR). Although several mechanisms have been postulated to explain how these autoantibodies can lead to the pathology of the disease, convincing evidence suggests that destruction of the receptor-bearing postsynaptic membrane by complement membrane attack complex is of central importance. In this review, evidence for the importance of complement, and possible relationships between autoantigen, autoantibodies, complement activation, and the destruction of the membrane are discussed. More recent insights from the results of the complement-inhibiting therapeutic antibody eculizumab are also described, and the mechanisms connecting antibody binding to complement activation are considered from a structural viewpoint.
Topics: Autoantibodies; Autoantigens; Complement Membrane Attack Complex; Complement System Proteins; Humans; Myasthenia Gravis; Receptors, Cholinergic
PubMed: 36063582
DOI: 10.1016/j.molimm.2022.08.018 -
International Journal of Molecular... Nov 2021BP180 is a type II collagenous transmembrane protein and is best known as the major autoantigen in the blistering skin disease bullous pemphigoid (BP). The BP180 trimer... (Review)
Review
BP180 is a type II collagenous transmembrane protein and is best known as the major autoantigen in the blistering skin disease bullous pemphigoid (BP). The BP180 trimer is a central component in type I hemidesmosomes (HD), which cause the adhesion between epidermal keratinocytes and the basal lamina, but BP180 is also expressed in several non-HD locations, where its functions are poorly characterized. The immunological roles of intact and proteolytically processed BP180, relevant in BP, have been subject to intensive research, but novel functions in cell proliferation, differentiation, and aging have also recently been described. To better understand the multiple physiological functions of BP180, the focus should return to the protein itself. Here, we comprehensively review the properties of the BP180 molecule, present new data on the biochemical features of its intracellular domain, and discuss their significance with regard to BP180 folding and protein-protein interactions.
Topics: Autoantigens; Hemidesmosomes; Humans; Keratinocytes; Non-Fibrillar Collagens; Pemphigoid, Bullous; Protein Folding; Collagen Type XVII
PubMed: 34830116
DOI: 10.3390/ijms222212233 -
Frontiers in Immunology 2021Immunoglobin G-related disease (IgG-RD) is one of the newly discovered autoimmune diseases characterized by elevated serum IgG concentrations and multi-organ fibrosis.... (Review)
Review
Immunoglobin G-related disease (IgG-RD) is one of the newly discovered autoimmune diseases characterized by elevated serum IgG concentrations and multi-organ fibrosis. Despite considerable research and recent advances in the identification of underlying immunological processes, the etiology of this disease is still not clear. Adaptive immune cells, including different types of T and B cells, and cytokines secreted by these cells play a vital role in the pathogenesis of IgG-RD. Antigen-presenting cells are stimulated by pathogens and, thus, contribute to the activation of naïve T cells and differentiation of different T cell subtypes, including helper T cells (Th1 and Th2), regulatory T cells, and T follicular helper cells. B cells are activated and transformed to plasma cells by T cell-secreted cytokines. Moreover, macrophages, and some important factors (TGF-β, etc.) promote target organ fibrosis. Understanding the role of these cells and cytokines implicated in the pathogenesis of IgG-RD will aid in developing strategies for future disease treatment and drug development. Here, we review the most recent insights on IgG-RD, focusing on immune dysregulation involved in the pathogenesis of this autoimmune condition.
Topics: Adaptive Immunity; Animals; Antigens, Bacterial; Autoantigens; Autoimmunity; Cytokines; Humans; Immune System; Immunity, Innate; Immunoglobulin G; Immunoglobulin G4-Related Disease; Leukocytes; Macrophages; Signal Transduction
PubMed: 34539675
DOI: 10.3389/fimmu.2021.738540 -
Current Opinion in Immunology Apr 2019B-1 cells represent an innate-like early-developing B cell population, whose existence as an independent lymphocyte subset has been questioned in the past. Recent... (Review)
Review
B-1 cells represent an innate-like early-developing B cell population, whose existence as an independent lymphocyte subset has been questioned in the past. Recent molecular and lineage tracing studies have not only confirmed their unique origins and differentiation paths, they have also provided a rationale for their distinctive functionalities compared to conventional B cells. This review summarizes our current understanding of B-1 cell development, and the activation events that regulate B-1 cell responses to self and foreign antigens. We discuss the unresolved question to what extent BCR engagement, that is, antigen-specificity versus innate signaling contributes to B-1 cell's participation in tissue homeostasis and immune defense as providers of 'natural' and antigen-induced antibody responses, and as cytokine-producing immune regulators.
Topics: Animals; Autoantigens; B-Lymphocyte Subsets; Homeostasis; Humans; Immunity, Cellular; Immunity, Innate; Immunomodulation; Infections; Receptors, Antigen, B-Cell; Signal Transduction
PubMed: 30685692
DOI: 10.1016/j.coi.2018.12.001 -
Best Practice & Research. Clinical... Jun 2022Idiopathic inflammatory myopathies (IIM) are heterogeneous autoimmune diseases. There are distinct subgroups, including antisynthetase syndrome, dermatomyositis,... (Review)
Review
Idiopathic inflammatory myopathies (IIM) are heterogeneous autoimmune diseases. There are distinct subgroups, including antisynthetase syndrome, dermatomyositis, polymyositis, immune-mediated necrotizing myopathy, and sporadic inclusion body myositis. In patients with IIM, autoantibodies are present in up to 80% of the patients. These autoantibodies are often characterized as myositis-specific autoantibodies (MSA) or myositis-associated autoantibodies (MAA). The recognition of the importance of autoantibodies, especially MSA, is increasing in recent years. In this chapter, we provide an overview of the MSAs, including some new autoantibodies of interest as they target mainly muscle-specific autoantigen, in clinical classification, the measurement of the disease activity, and a possible role in the pathogenesis in the patients with IIM.
Topics: Autoantibodies; Autoantigens; Autoimmune Diseases; Dermatomyositis; Humans; Myositis; Myositis, Inclusion Body
PubMed: 35810122
DOI: 10.1016/j.berh.2022.101767 -
Biomolecules Apr 2023Autoimmune bullous diseases (AIBDs), which are a group of tissue-specific autoimmune diseases of the skin, present with various blistering lesions on the skin and mucous... (Review)
Review
Autoimmune bullous diseases (AIBDs), which are a group of tissue-specific autoimmune diseases of the skin, present with various blistering lesions on the skin and mucous membranes, and show autoantibodies of IgG, IgA and IgM against epidermal cell surfaces and basement membrane zone. To date, AIBDs have been classified into a number of distinct subtypes by clinical and histopathological findings, and immunological characteristics. In addition, various biochemical and molecular biological studies have identified various novel autoantigens in AIBDs, which has resulted in proposals of new subtypes of AIBDs. In this article, we summarized various distinct AIBDs, and proposed the latest and most comprehensive classification of AIBDs with their autoantigen molecules.
Topics: Humans; Autoantibodies; Autoantigens; Autoimmune Diseases; Skin; Skin Diseases, Vesiculobullous
PubMed: 37189450
DOI: 10.3390/biom13040703 -
Neurotherapeutics : the Journal of the... Apr 2022In recent years, there has been increasing recognition of the diversity of autoimmune neurological diseases affecting all levels of the nervous system. A growing... (Review)
Review
In recent years, there has been increasing recognition of the diversity of autoimmune neurological diseases affecting all levels of the nervous system. A growing understanding of disease pathogenesis has enabled us to better target specific elements of the immune system responsible for the cell dysfunction and cell destruction seen in these diseases. This is no better demonstrated than in the development of complement directed therapies for the treatment of complement mediated autoimmune neurological conditions. Herein, we describe the basic elements of the complement cascade, provide an overview of select autoimmune neurological diseases whose pathogenesis is mediated by complement, the effector system of autoantigen bound autoantibodies, and discuss the complement directed therapies trialed in the treatment of these diseases. Several complement-directed therapies have demonstrated benefit in the treatment of autoimmune neurological diseases; we also review the trials resulting in the approval of these therapies for the treatment of AChR Ab-positive myasthenia gravis (MG) and neuromyelitis spectrum disorder. Finally, on the heels of the recent successes described, we discuss possibilities for the future, including additional targeted therapies with greater ease of administration, improved risk profiles, and other possible uses for therapeutics targeting elements of the complement cascade.
Topics: Autoantibodies; Autoantigens; Humans; Myasthenia Gravis; Nervous System Diseases; Receptors, Cholinergic
PubMed: 35553024
DOI: 10.1007/s13311-022-01223-w -
Frontiers in Immunology 2022T cell receptors (TCRs) recognize peptide antigens bound to major histocompatibility complex (MHC) molecules (p/MHC) that are expressed on cell surfaces; while B... (Review)
Review
T cell receptors (TCRs) recognize peptide antigens bound to major histocompatibility complex (MHC) molecules (p/MHC) that are expressed on cell surfaces; while B cell-derived antibodies (Abs) recognize soluble or cell surface native antigens of various types (proteins, carbohydrates, etc.). Immune surveillance by T and B cells thus inspects almost all formats of antigens to mount adaptive immune responses against cancer cells, infectious organisms and other foreign insults, while maintaining tolerance to self-tissues. With contributions from environmental triggers, the development of autoimmune disease is thought to be due to the expression of MHC risk alleles by antigen-presenting cells (APCs) presenting self-antigen (autoantigen), breaking through self-tolerance and activating autoreactive T cells, which orchestrate downstream pathologic events. Investigating and treating autoimmune diseases have been challenging, both because of the intrinsic complexity of these diseases and the need for tools targeting T cell epitopes (autoantigen-MHC). Naturally occurring TCRs with relatively low (micromolar) affinities to p/MHC are suboptimal for autoantigen-MHC targeting, whereas the use of engineered TCRs and their derivatives (e.g., TCR multimers and TCR-engineered T cells) are limited by unpredictable cross-reactivity. As Abs generally have nanomolar affinity, recent advances in engineering TCR-like (TCRL) Abs promise advantages over their TCR counterparts for autoantigen-MHC targeting. Here, we compare the p/MHC binding by TCRs and TCRL Abs, review the strategies for generation of TCRL Abs, highlight their application for identification of autoantigen-presenting APCs, and discuss future directions and limitations of TCRL Abs as immunotherapy for autoimmune diseases.
Topics: Antibodies; Autoantigens; Autoimmune Diseases; Histocompatibility Antigens; Humans; Major Histocompatibility Complex; Receptors, Antigen, T-Cell
PubMed: 35967436
DOI: 10.3389/fimmu.2022.968432 -
The Journal of Dermatology Mar 2016Bullous pemphigoid (BP) is an autoimmune subepidermal blistering skin disease mainly affecting older individuals. Pathogenic autoantibodies preferentially target the... (Review)
Review
Bullous pemphigoid (BP) is an autoimmune subepidermal blistering skin disease mainly affecting older individuals. Pathogenic autoantibodies preferentially target the non-collagenous 16A domain of collagen XVII (also called BP antigen 2, BPAG2) present in hemidesmosomes. The pathogenic anti-BPAG2 antibodies cause the dermal-epidermal separation in neonatal and adult mice as well as in cryosections of human skin. These experimental BP models stress a pivotal role for neutrophils and the Fcγ receptor of immunoglobulins. Mice that have been genetically manipulated in the pathogenic domain of BPAG2 spontaneously develop subepidermal blistering with pruritus and eosinophilic infiltration. BPAG2 is physiologically and aberrantly expressed in neuronal tissue and internal malignancies, and the associations of BP with Parkinson's disease, stroke and internal malignancies invites new investigations into the immunological dysregulation behind the comorbidity.
Topics: Animals; Autoantibodies; Autoantigens; Disease Models, Animal; Humans; Mice; Models, Immunological; Non-Fibrillar Collagens; Pemphigoid, Bullous; Collagen Type XVII
PubMed: 26603373
DOI: 10.1111/1346-8138.13207 -
Transactions of the American Clinical... 2022The striking association of specific autoantibodies with distinct disease phenotypes and trajectories in human autoimmune rheumatic diseases provides a powerful...
The striking association of specific autoantibodies with distinct disease phenotypes and trajectories in human autoimmune rheumatic diseases provides a powerful opportunity to interrogate disease mechanism. In scleroderma, a subgroup of patients with autoantibodies to POLR3 have coincident onset of cancer and scleroderma. The majority of these patients have genetic changes (somatic mutations and loss of heterozygosity) in the POLR3A gene in their matched cancers, coupled with immune responses directed against the mutated and wild type autoantigen. In some individuals with scleroderma or dermatomyositis where specific immune responses mark a high risk of emergent cancer, cancer does not emerge. Such patients have a broader immune response that targets additional autoantigens, suggesting that the breadth and magnitude of the immune response regulates cancer, and that the rheumatic diseases provide a unique window into natural immunoediting of cancer in humans. This has implications for prediction and therapy in both autoimmunity and cancer.
Topics: Autoantibodies; Autoantigens; Autoimmune Diseases; Humans; Neoplasms; RNA Polymerase III; Rheumatic Diseases
PubMed: 36196176
DOI: No ID Found