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Mucosal immunity; T cells; B cells; Secretory IgA (sIgA); Mucosa-associated lymphoid tissues (MALT); Immune tolerance; Inflammatory bowel disease (IBD).

Introduction

Mucosal surfaces are the body's primary interface with the external environment, exposed to a variety of pathogens, environmental antigens, and commensal microorganisms. The immune system at these sites, often referred to as mucosal immunity, is designed to respond efficiently to harmful stimuli while maintaining tolerance to benign or beneficial substances [1]. A balanced immune response is critical in preventing both excessive inflammation, which can lead to tissue damage, and inadequate immunity, which can allow infections or malignancies to arise. The mucosal immune system is composed of various lymphoid tissues, including the tonsils, adenoids, Peyer's patches, and the lamina propria, where immune cells such as T cells and B cells reside. These cells engage in complex interactions to maintain mucosal homeostasis. Both T-cell and B-cell responses are critical for effective mucosal immunity. T cells provide the necessary signals for B-cell activation, while B cells produce antibodies that neutralize pathogens and prevent their invasion across mucosal surfaces. Together, they balance immune defense with tolerance to avoid inflammatory disorders [2,3]. This article reviews the key roles of T-cell and B-cell responsses in mucosal immunity, focusing on the molecular mechanisms underlying their actions in immune defense and tolerance.

Mucosal immune system: structure and function

The mucosal immune system is characterized by its unique anatomical and functional features, designed to cope with the constant antigenic challenges encountered at mucosal surfaces. It consists of This includes organized lymphoid structures like Peyer's patches in the intestines, as well as diffuse lymphoid aggregates in the airways and other mucosal tissues [4]. MALT serves as the site of antigen sampling and initiation of immune responses. These form the first line of defense, consisting of tight junctions between epithelial cells that prevent pathogen entry and maintain tissue integrity. Specialized epithelial cells such as goblet cells produce mucus, while Paneth cells in the gut secrete antimicrobial peptides. The dominant immunoglobulin in mucosal immunity, sIgA is produced by plasma cells in the lamina propria and is secreted into mucus. It functions to neutralize pathogens and toxins and prevent their adherence to epithelial surfaces.

T-cell responses in mucosal immunity

T cells are critical players in the regulation and execution of immune responses at mucosal surfaces. T-cell subsets that are most important in mucosal immunity include Th1, Th2, Th17, and regulatory T cells (Tregs). Th1 and Th2 responses are pivotal in orchestrating protective immunity against different types of pathogens. Th1 cells promote immunity against intracellular pathogens, such as viruses and certain bacteria, by producing interferon-gamma (IFN-γ) and activating macrophages [5]. On the other hand, Th2 cells are important in defending against extracellular parasites and contribute to allergic reactions by producing cytokines like interleukin-4 (IL-4), IL-5, and IL-13, which activate eosinophils and mast cells. In the mucosal environment, the balance between Th1 and Th2 responses is tightly regulated. Inappropriate skewing of this balance, such as an overactive Th2 response, can contribute to allergic diseases, while a Th1-dominant response may lead to chronic inflammation and autoimmune disorders. Th17 cells are a subset of T-helper cells that produce IL-17 and play a crucial role in mucosal immunity, particularly in response to fungal and extracellular bacterial infections. They are also involved in mucosal barrier integrity by promoting the recruitment of neutrophils and enhancing the production of antimicrobial peptides [6]. While Th17 responses are essential for controlling infections, excessive or dysregulated Th17 activity is associated with chronic inflammatory diseases such as inflammatory bowel disease (IBD) and psoriasis. A critical feature of mucosal immunity is the ability to distinguish between harmful and harmless antigens. Tregs, characterized by the expression of the transcription factor Foxp3, are essential for maintaining immune tolerance at mucosal surfaces. Tregs inhibit the activation of effector T cells and prevent inflammatory responses to commensal microbiota and food antigens. The absence or dysfunction of Tregs can result in autoimmune diseases, allergies, or chronic inflammatory conditions.

B-cell responses in mucosal immunity

B cells play a key role in mucosal immunity by producing antibodies, particularly secretory IgA (sIgA), which is crucial for protecting mucosal surfaces from pathogens. B-cell activation in mucosal tissues is initiated by antigen presentation to naïve B cells in MALT, often after the antigen is transported across the epithelium by specialized cells called M cells. B cells can undergo class switching to produce different isotypes of antibodies. In mucosal tissues, IgA is the dominant antibody produced by plasma cells. IgA is transported across epithelial cells into the lumen, where it neutralizes pathogens, prevents their attachment to epithelial cells, and reduces the likelihood of infection. IgA, the most abundant antibody at mucosal surfaces, is synthesized as a dimer and secreted into mucus, where it binds to pathogens and prevents their adhesion to the epithelial lining. Unlike other antibodies, IgA does not induce strong inflammatory responses, which makes it ideal for preventing infection without damaging tissue. Moreover, IgA can also promote immune tolerance by binding and neutralizing non-pathogenic antigens [7]. cells in the mucosa are also involved in promoting tolerance to harmless antigens, such as dietary proteins and commensal bacteria. This process involves the generation of B cells that produce IgA but are not involved in inflammatory responses. Dysregulation of B-cell tolerance can result in allergic reactions, such as food allergies, where inappropriate IgE responses occur to harmless substances.

Mechanisms of immune defense and tolerance

The mucosal immune system is designed to balance immune defense with tolerance. This is achieved through various mechanisms, including Antigen sampling and presentation: Specialized cells, including M cells, dendritic cells, and macrophages, sample antigens from the lumen and present them to T cells and B cells in MALT. This process is essential for initiating both protective immune responses and tolerance.

Tolerance to commensals and food antigens: Mucosal dendritic cells promote the development of Tregs, which suppress inflammatory responses and maintain tolerance to commensal microbiota and non-pathogenic food proteins. While sIgA is produced in response to pathogens, its production is tightly regulated to prevent excessive inflammatory responses [8]. IgA production is influenced by cytokines, including transforming growth factor-beta (TGF-β), which helps to promote tolerance in mucosal tissues.

Microbiome influence: The gut microbiota plays a crucial role in shaping mucosal immune responses, particularly by influencing the differentiation of Tregs and the production of sIgA. Dysbiosis, or an imbalance in the microbiota, has been linked to various inflammatory disorders, including IBD and food allergies.

Implications for health and disease

Dysregulation of mucosal immunity can result in a variety of diseases A breakdown in the immune tolerance to commensal bacteria can lead to chronic inflammation in the gut, as seen in Crohn's disease and ulcerative colitis. Both T-cell and B-cell responses play critical roles in the pathogenesis of IBD. Inappropriate immune responses to harmless antigens, such as food proteins, can lead to allergic diseases. The balance between Th2-mediated immunity and Treg-induced tolerance is disrupted in allergic diseases. Mucosal immune responses are also implicated in autoimmune diseases, where immune tolerance is lost, and the immune system attacks self-tissues. The mucosal immune system's role in maintaining tolerance is therefore crucial in preventing autoimmune reactions. Understanding the mechanisms of mucosal immunity is important for developing vaccines that target mucosal surfaces, as well as immunotherapies aimed at modulating mucosal immune responses in diseases such as allergies, cancer, and autoimmune disorders.

Conclusion

T-cell and B-cell responses are central to the function of the mucosal immune system, ensuring both protection against pathogens and maintenance of tolerance to non-harmful antigens. Understanding the intricate balance between immune defense and tolerance at mucosal surfaces is crucial for advancing therapies for mucosal-associated diseases such as inflammatory bowel disease, allergies, and autoimmune disorders. Further research into the molecular pathways that govern these immune responses will be essential for developing novel therapeutic strategies that modulate mucosal immunity for improved health outcomes.

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