Antigen-presenting cells play a direct role in triggering autoreactivity
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Multiple peer-reviewed scientific studies indicate that antigen-presenting cells play a critical and direct role in driving autoimmune responses, such as by activating autoreactive T cells and contributing to disease pathogenesis in conditions like type 1 diabetes and lupus.
The liver is an important immunological organ that controls systemic tolerance. The liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and maintenance. Orchestrating the immune response in homeostasis depends on a healthy and well-toned immunological liver microenvironment, which is maintained by the crosstalk of liver-resident antigen-presenting cells and intrahepatic and liver-infiltrating leukocytes. In response to pathogens or autoantigens, tolerance is disrupted by unknown mechanisms. Intrahepatic parenchymal and nonparenchymal cells exhibit unique antigen-presenting properties. The presentation of microbial and endogenous lipid-, metabolite- and peptide-derived antigens from the gut via conventional and nonconventional mechanisms can educate intrahepatic immune cells and elicit effector responses or tolerance. Perturbation of this balance results in autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. Although the exact etiologies of these autoimmune liver diseases are unknown, it is thought that the disruption of tolerance towards self-antigens and microbial metabolites and lipids, as well as alterations in bile acid composition, may result in changes in effector cell activation and polarization and may reduce or impair protective anti-inflammatory regulatory T and B cell responses. Additionally, the canonical and noncanonical transmission of antigens and antigen:MHC complexes via trogocytosis or extracellular vesicles between different (non) immune cells in the liver may play a role in the induction of hepatic inflammation and tolerance. Here, we summarize emerging aspects of antigen presentation, autoantibody production, and the application of novel therapeutic approaches in the characterization and treatment of autoimmune liver diseases.
Purpose of review Current therapies for autoimmune disorders often employ broad suppression of the immune system. Antigen-specific immunotherapy (ASI) seeks to overcome the side-effects of immunosuppressive therapy by specifically targeting only disease-related autoreactive T and B cells. Although it has been in development for several decades, ASI still is not in use clinically to treat autoimmunity. Novel ways to deliver antigen may be effective in inducing ASI. Here we review recent innovations in antigen delivery Recent findings New ways to deliver antigen include particle and nonparticle approaches. One main focus has been the targeting of antigen-presenting cells in a tolerogenic context. This technique often results in the induction and/or expansion of regulatory T cells, which has the potential to be effective against a complex, polyclonal immune response. Summary Whether novel delivery approaches can help bring ASI into general clinical use for therapy of autoimmune diseases remains to be seen. However, preclinical work and early results from clinical trials using these new techniques show promising signs.
Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which the immune system attacks pancreatic beta cells, leading to high blood glucose levels and requiring lifelong insulin therapy. There is no cure, and individuals with T1D may face a reduced lifespan of up to 12 years. Defects in regulatory T cells (Tregs) are a key contributor to disease onset and are being explored as a therapeutic avenue. However, the effectiveness of Treg therapy remains uncertain. Research is further limited by the inability to directly observe pancreatic and lymph node activity during the long presymptomatic stage of T1D. In this study, we develop a mathematical model for beta and T cell dynamics. We find both Treg quality and quantity affect disease progression, and that antigen-presenting cell (APC) dynamics play a central role. Notably, Treg therapy combined with APC depletion improves outcomes, especially with strong peptide-induced APC activation.
Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which the immune system attacks pancreatic beta cells, leading to high blood glucose levels and requiring lifelong insulin therapy. There is no cure, and individuals with T1D may face a reduced lifespan of up to 12 years. Defects in regulatory T cells (Tregs) are a key contributor to disease onset and are being explored as a therapeutic avenue. However, the effectiveness of Treg therapy remains uncertain. Research is further limited by the inability to directly observe pancreatic and lymph node activity during the long presymptomatic stage of T1D. In this study, we develop a mathematical model for beta and T cell dynamics. We find both Treg quality and quantity affect disease progression, and that antigen-presenting cell (APC) dynamics play a central role. Notably, Treg therapy combined with APC depletion improves outcomes, especially with strong peptide-induced APC activation.
Antigen presentation by cells of the vessel wall may initiate rapid and localized memory immune responses in peripheral tissues. Peptide antigens displayed on major histocompatibility complex (MHC) molecules on the surface of endothelial cells (ECs) can be recognized by T cell receptors on circulating effector memory T cells (TEM), triggering both transendothelial migration and activation. The array of co-stimulatory receptors, adhesion molecules, and cytokines expressed by ECs serves to modulate T cell activation responses. While the effects of these interactions vary among species, vascular beds, and vascular segments within the same tissue, they are capable of triggering allograft rejection without direct involvement of professional antigen-presenting cells and may play a similar role in host defense against infections and in autoimmunity. Once across the endothelium, extravasating TEM then contact mural cells of the vessel wall, including pericytes or vascular smooth muscle cells, which may also present antigens and provide signals that further regulate T cell responses. Collectively, these interactions provide an unexplored opportunity in which targeting of vascular cells can be used to modulate immune responses. In organ transplantation, targeting ECs with siRNA to reduce expression of MHC molecules may additionally mitigate perioperative injuries by preformed alloantibodies, further reducing the risk of graft rejection. Similarly, genetic manipulation of vascular cells
not only play a helper role in the development of autoimmune disease but also a direct role in tissue inflammation … ferons (Section C). Most of the molecules which play a role in the innate immune system also have functions … involved in activation of antigen presenting cells critical to triggering T lymphocyte responses. Cytokines
Atopic dermatitis (AD) is increasingly interpreted through frameworks emphasizing barrier dysfunction, type 2 cytokine signaling, pruritus pathways, and microbial dysbiosis, often relegating IgE-mediated mechanisms to secondary roles. In this narrative review, we synthesize historical, clinical, immunologic, and histopathologic evidence to propose a conceptual model in which IgE-bearing antigen-presenting cells (APCs)-including Langerhans cells, inflammatory dermal dendritic cells, and inflammatory dendritic epidermal cells (IDECs)-participate in an IgE-dependent amplification loop that may contribute to the chronicity of extrinsic (IgE-associated) AD. Evidence from human studies indicates that FcεRI-expressing APCs can acquire environmental allergens through IgE, enhancing antigen uptake and T-cell activation, while mast cells and basophils further reinforce type 2 inflammation through IgE-dependent and IgE-augmented pathways. Although these mechanisms have been described across distinct experimental and clinical contexts, their integration into a unified pathogenic circuit remains hypothesis-driven. We therefore present an interpretive framework that organizes these partially validated mechanisms into a coherent model linking cutaneous sensitization, allergen capture, APC activation, Th2 polarization, and spongiosis formation. This conceptual synthesis aims to reposition IgE-mediated processes within the broader pathophysiology of extrinsic AD and to highlight potential therapeutic implications for targeting IgE-FcεRI signaling and IgE-dependent APC biology.
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