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Experimental Dermatology Dec 2017Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease that clinically demonstrates tense blisters with widespread erythema, histologically... (Review)
Review
Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease that clinically demonstrates tense blisters with widespread erythema, histologically demonstrates subepidermal blistering and immunologically demonstrates the presence of circulating autoantibodies against hemidesmosomal molecules. Complement activation has long been regarded as necessary for the generation of the BP. However, certain evidence has recently come to support non-complemental blistering mechanisms. The story of BP blistering mechanisms is a complicated one. This review mainly focuses on a specific blistering mechanism that highlights the role of complements in BP blistering.
Topics: Animals; Autoantigens; Blister; Complement System Proteins; Humans; Non-Fibrillar Collagens; Pemphigoid, Bullous; Collagen Type XVII
PubMed: 28418613
DOI: 10.1111/exd.13367 -
Frontiers in Immunology 2023Progressive loss of regulatory T cell (Treg)-mediated control over autoreactive effector T cells contributes to the development of systemic lupus erythematosus (SLE)....
INTRODUCTION
Progressive loss of regulatory T cell (Treg)-mediated control over autoreactive effector T cells contributes to the development of systemic lupus erythematosus (SLE). Accordingly, we hypothesized that Treg may also have the capacity to suppress the activation of autoreactive CD4 T cells that are considered to drive autoimmunity.
METHODS
To investigate whether Treg are involved in the control of autoreactive CD4 T cells, we depleted CD25 Treg cells either or , or combined both approaches before antigen-specific stimulation with the SLE-associated autoantigen SmD1(83-119) in the NZB/W F1 mouse model either after immunization against SmD1(83-119) or during spontaneous disease development. Frequencies of autoantigen-specific CD4 T cells were determined by flow cytometry using the activation marker CD154.
RESULTS
Both and depletion of CD25 Treg, respectively, increased the frequencies of detectable autoantigen-specific CD4 T cells by approximately 50%. Notably, the combined and depletion of CD25 Treg led almost to a doubling in their frequencies. Frequencies of autoantigen-specific CD4 T cells were found to be lower in immunized haploidentical non-autoimmune strains and increased frequencies were detectable in unmanipulated NZB/W F1 mice with active disease. re-addition of CD25 Treg after Treg depletion restored suppression of autoantigen-specific CD4 T cell activation.
DISCUSSION
These results suggest that the activation and expansion of autoantigen-specific CD4 T cells are partly controlled by Treg in murine lupus. Depletion of Treg therefore can be a useful approach to increase the detectability of autoantigen-specific CD4 T cells allowing their detailed characterization including lineage determination and epitope mapping and their sufficient isolation for cell culture.
Topics: Animals; Mice; T-Lymphocytes, Regulatory; Autoantigens; Mice, Inbred NZB; Lupus Erythematosus, Systemic; Autoimmunity
PubMed: 38022661
DOI: 10.3389/fimmu.2023.1254176 -
Autoimmunity Reviews Sep 2017Chronic immune-mediated disorders (IMDs) constitute a major health burden. Understanding IMD pathogenesis is facing two major constraints: Missing heritability... (Review)
Review
Chronic immune-mediated disorders (IMDs) constitute a major health burden. Understanding IMD pathogenesis is facing two major constraints: Missing heritability explaining familial clustering, and missing autoantigens. Pinpointing IMD risk genes and autoimmune targets, however, is of fundamental importance for developing novel causal therapies. The strongest association of all IMDs is seen with human leukocyte antigen (HLA) alleles. Using psoriasis as an IMD model this article reviews the pathogenic role HLA molecules may have within the polygenic predisposition of IMDs. It concludes that disease-associated HLA alleles account for both missing heritability and autoimmune mechanisms by facilitating tissue-specific autoimmune responses through autoantigen presentation.
Topics: Animals; Antigen Presentation; Autoantigens; Autoimmunity; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; HLA Antigens; Humans; Psoriasis; Receptors, Antigen, T-Cell
PubMed: 28705779
DOI: 10.1016/j.autrev.2017.07.011 -
Molecular Immunology Dec 2018The CD1 family of glycoproteins are MHC class I-like molecules that present a wide array of self and foreign lipid antigens to T-cell receptors (TCRs) on T-cells. Humans... (Review)
Review
The CD1 family of glycoproteins are MHC class I-like molecules that present a wide array of self and foreign lipid antigens to T-cell receptors (TCRs) on T-cells. Humans express three classes of CD1 molecules, denoted as Group 1 (CD1a, CD1b, and CD1c), Group 2 (CD1d), and Group 3 (CD1e). Of the CD1 family of molecules, CD1b exhibits the largest and most complex antigen binding groove; allowing it the capabilities to present a broad spectrum of lipid antigens. While its role in foreign-lipid presentation in the context of mycobacterial infection are well characterized, understanding the roles of CD1b in autoreactivity are recently being elucidated. While the mechanisms governing proliferation of CD1b-restricted autoreactive T cells, regulation of CD1 gene expression, and the processes controlling CD1+ antigen presenting cell maturation are widely undercharacterized, the exploration of self-lipid antigens in the context of disease have recently come into focus. Furthermore, the recently expanded pool of CD1b crystal structures allow the opportunity to further analyze the molecular mechanisms of T-cell recognition and self-lipid presentation; where the intricacies of the two-compartment system, that accommodate both the presented self-lipid antigen and scaffold lipids, are scrutinized. This review delves into the immunological and molecular mechanisms governing presentation and T-cell recognition of the broad self-lipid repertoire of CD1b; with evidence mounting pointing towards a role in diseases such as microbial infection, autoimmune diseases, and cancer.
Topics: Animals; Antigen Presentation; Antigens, CD1; Autoantigens; Crystallography, X-Ray; Humans; Lipids; Structure-Activity Relationship; T-Lymphocytes
PubMed: 30399491
DOI: 10.1016/j.molimm.2018.09.022 -
Molecular Pharmaceutics Nov 2020Many autoimmune therapies focus on immune suppression to reduce symptom severity and halt disease progression; however, currently approved treatments lack specificity...
Many autoimmune therapies focus on immune suppression to reduce symptom severity and halt disease progression; however, currently approved treatments lack specificity for the autoantigen and rely on more global immune suppression. Multivalent antigen arrays can disarm pathogenic autoimmune B cell populations that specifically recognize the antigen of interest via their B cell receptor (BCR). Disarmament may be achieved by BCR engagement, cross-linking, and sustained receptor occupancy as a result of multivalent, high avidity BCR binding. To engage and explore this mechanism, a tetramer display of the encephalogenic proteolipid peptide (PLP), referred to as 4-arm PLP, was synthesized by copper-catalyzed azide-alkyne cycloaddition chemistry. Subcutaneous administration of 4-arm PLP completely ameliorated symptoms of paralysis in a mouse model of multiple sclerosis known as experimental autoimmune encephalomyelitis. Competitive binding of 4-arm PLP to PLP-specific IgG in the mouse serum demonstrated the enhanced avidity associated with the multivalent array compared to the free peptide. Furthermore, key PLP-reactive B cells were depleted following 4-arm PLP treatment, resulting in significant reduction of proinflammatory cytokines. Together, these data demonstrate the potential of 4-arm PLP to silence autoreactive B cell populations and limit the downstream activation of effector cells.
Topics: Administration, Topical; Animals; Autoantigens; B-Lymphocytes; Encephalomyelitis, Autoimmune, Experimental; Female; Immune Tolerance; Immunoglobulin G; Immunotherapy; Mice; Multiple Sclerosis; Myelin Proteolipid Protein; Paralysis; Peptide Fragments; Receptors, Antigen, B-Cell; Treatment Outcome
PubMed: 32903002
DOI: 10.1021/acs.molpharmaceut.0c00665 -
Laboratory Investigation; a Journal of... Jun 2022Vertebrates exhibit patterned epidermis, exemplified by scales/interscales in mice tails and grooves/ridges on the human skin surface (microtopography). Although the...
Vertebrates exhibit patterned epidermis, exemplified by scales/interscales in mice tails and grooves/ridges on the human skin surface (microtopography). Although the role of spatiotemporal regulation of stem cells (SCs) has been implicated in this process, the mechanism underlying the development of such epidermal patterns is poorly understood. Here, we show that collagen XVII (COL17), a niche for epidermal SCs, helps stabilize epidermal patterns. Gene knockout and rescue experiments revealed that COL17 maintains the width of the murine tail scale epidermis independently of epidermal cell polarity. Skin regeneration after wounding was associated with slender scale epidermis, which was alleviated by overexpression of human COL17. COL17-negative skin in human junctional epidermolysis bullosa showed a distinct epidermal pattern from COL17-positive skin that resulted from revertant mosaicism. These results demonstrate that COL17 contributes to defining mouse tail scale shapes and human skin microtopography. Our study sheds light on the role of the SC niche in tissue pattern formation.
Topics: Animals; Autoantigens; Epidermis; Mice; Non-Fibrillar Collagens; Skin; Collagen Type XVII
PubMed: 35145203
DOI: 10.1038/s41374-022-00738-2 -
Autoimmunity Reviews Jul 2016Autoantigen development is poorly understood at the atomic level. Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by antibodies to an... (Review)
Review
Autoantigen development is poorly understood at the atomic level. Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by antibodies to an antigen composed of platelet factor 4 (PF4) and heparin or cellular glycosaminoglycans (GAGs). In solution, PF4 exists as an equilibrium among monomers, dimers and tetramers. Structural studies of these interacting components helped delineate a multi-step process involved in the pathogenesis of HIT. First, heparin binds to the 'closed' end of the PF4 tetramer and stabilizes its conformation; exposing the 'open' end. Second, PF4 arrays along heparin/GAG chains, which approximate tetramers, form large antigenic complexes that enhance antibody avidity. Third, pathogenic HIT antibodies bind to the 'open' end of stabilized PF4 tetramers to form an IgG/PF4/heparin ternary immune complex and also to propagate the formation of 'ultralarge immune complexes' (ULCs) that contain multiple IgG antibodies. Fourth, ULCs signal through FcγRIIA receptors, activating platelets and monocytes directly and generating thrombin, which transactivates hematopoietic and endothelial cells. A non-pathogenic anti-PF4 antibody prevents tetramer formation, binding of pathogenic antibody, platelet activation and thrombosis, providing a new approach to manage HIT. An improved understanding of the pathogenesis of HIT may lead to novel diagnostics and therapeutics for this autoimmune disease.
Topics: Autoantigens; Heparin; Humans; Thrombocytopenia
PubMed: 26970483
DOI: 10.1016/j.autrev.2016.03.011 -
Frontiers in Immunology 2018B cells are major effector cells in autoimmunity through antibody production, T cell help and pro-inflammatory cytokine production. Major advances have been made in... (Review)
Review
B cells are major effector cells in autoimmunity through antibody production, T cell help and pro-inflammatory cytokine production. Major advances have been made in human B cell biology knowledge using rituximab and type II new anti-CD20 antibodies, anti-CD19 antibodies, anti-CD22 antibodies, autoantigen specific B cell depleting therapy (chimeric antigen receptor T cells), and B cell receptor signaling inhibition (Bruton's tyrosine kinase inhibitors). However, in certain circumstances B cell depleting therapy may lead to the worsening of the autoimmune disease which is in accordance with the existence of a regulatory B cell population. Current concepts and future directions for B cell modulating therapies in autoimmune diseases with a special focus on pemphigus are discussed.
Topics: Animals; Antibodies, Monoclonal; Autoantigens; Autoimmune Diseases; B-Lymphocytes; Humans; Immunomodulation; Immunotherapy; Protein Kinase Inhibitors; Rituximab
PubMed: 29706952
DOI: 10.3389/fimmu.2018.00622 -
The Journal of Investigative Dermatology Oct 2017HLA-C*06:02 is the main psoriasis risk allele. By the unbiased analysis of a Vα3S1/Vβ13S1 T-cell receptor from pathogenic psoriatic CD8 T cells, we had recently proven... (Review)
Review
HLA-C*06:02 is the main psoriasis risk allele. By the unbiased analysis of a Vα3S1/Vβ13S1 T-cell receptor from pathogenic psoriatic CD8 T cells, we had recently proven that HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation in psoriasis and identified ADAMTSL5 as a melanocyte autoantigen. We concluded that psoriasis is based on a melanocyte-specific immune response and that HLA-C*06:02 may predispose to psoriasis via this newly identified autoimmune pathway. Understanding this pathway, however, requires more detailed explanation. It is based on the fact that an HLA class I-restricted autoreactive CD8 T-cell response must be directed against a particular target cell type, because HLA class I molecules present peptide antigens generated from cytoplasmic (i.e., intracellular) proteins. This review summarizes the findings on the melanocyte-specific autoimmune response in the context of the immune mechanisms related to HLA function and T-cell receptor-antigen recognition. Identifying melanocytes as target cells of the psoriatic immune response now explains psoriasis as a primary autoimmune skin disease.
Topics: Autoantigens; Autoimmunity; HLA-C Antigens; Humans; Melanocytes; Psoriasis; T-Lymphocytes
PubMed: 28941475
DOI: 10.1016/j.jid.2017.05.023 -
European Journal of Immunology Nov 2015The diversity among B-cell antigen receptor (BCR) specificities is generated by random rearrangement of gene segments during early B-cell development. While such... (Review)
Review
The diversity among B-cell antigen receptor (BCR) specificities is generated by random rearrangement of gene segments during early B-cell development. While such stochastic recombination of gene segments is important for diversity, it introduces the risk of producing self-reactive BCRs which might lead to the development of autoimmune diseases. Therefore, it has been proposed that negative selection of autoreactive BCR specificities during early B-cell development are required to establish tolerance towards self. In fact, transgenic mouse models have identified a number of "tolerance mechanisms" such as receptor editing, clonal deletion and anergy, all of which prevent the development of autoreactive B cells. Recent data, however, reveal that self-recognition is crucial for the generation of B cells, and that the precursor-BCR (pre-BCR), which is essential for early B-cell development, basically plays the role of an autoreactive BCR. Moreover, although it has become clear that autoreactive B cells are present in the periphery of healthy individuals, the role of autoantigen in their development, persistence and regulation is unclear. This review outlines the important role of autoreactivity in early B-cell development and presents potential models for the regulation of the activation of peripheral B cells by different forms of self or foreign antigens.
Topics: Animals; Autoantigens; Autoimmunity; B-Lymphocytes; Clonal Anergy; Humans; Receptors, Antigen, B-Cell; Self Tolerance
PubMed: 26350303
DOI: 10.1002/eji.201444622