Journal of Mucosal Immunology Research
Open Access

Immunoregulatory; Mucosal surfaces; adaptive immune cells; cellular players

Introduction

The human body is constantly exposed to a wide array of potential threats from the external environment, including pathogenic microorganisms, allergens, and toxins. The first line of defense against these invaders is the mucosal surfaces, which line the respiratory, gastrointestinal, and genitourinary tracts, forming a protective barrier between the internal tissues and the outside world. The mucosal immune system plays a critical role in safeguarding these vulnerable surfaces and maintaining immune homeostasis. Mucosal immune surveillance is a complex and dynamic process that involves a network of immune cells, soluble factors, and epithelial cells working in concert to detect and respond to potential threats. Unlike other immune compartments, such as the bloodstream or lymphoid organs, the mucosal surfaces are constantly exposed to a diverse and dynamic microbiota, which consists of both beneficial commensal microorganisms and potential pathogens [1, 2]. As a result, the mucosal immune system must be capable of discriminating between harmless commensals and harmful pathogens, mounting appropriate immune responses while preserving tolerance to beneficial microorganisms. One of the key components of mucosal immune surveillance is the specialized epithelial cells that line the mucosal surfaces. These cells act as sentinels, equipped with pattern recognition receptors (PRRs) that can detect a wide range of pathogen-associated molecular patterns (PAMPs) and damageassociated molecular patterns (DAMPs). Upon recognition of these molecular patterns, epithelial cells initiate signaling cascades, leading to the production of proinflammatory cytokines, chemokines, and antimicrobial peptides. These soluble factors help recruit and activate immune cells, such as neutrophils, macrophages, and dendritic cells, to the site of infection or inflammation [3, 4]. Dendritic cells (DCs) are crucial players in mucosal immune surveillance. They sample the environment, capturing antigens encountered at the mucosal surfaces, and migrate to secondary lymphoid organs, such as lymph nodes and Peyer’s patches. Within these lymphoid organs, DCs interact with T cells, initiating adaptive immune responses tailored to combat specific pathogens. The activation of antigen-specific effector T cell subsets, including Th1, Th2, and Th17 cells, helps coordinate immune responses against various pathogens encountered at different mucosal sites [5,6]. Another essential component of mucosal immune surveillance is the production of secretory immunoglobulin A (IgA) antibodies. B cells residing in mucosal-associated lymphoid tissues, such as the gut-associated lymphoid tissue (GALT) or bronchus-associated lymphoid tissue (BALT), undergo class switching to produce dimeric IgA antibodies. These IgA antibodies are then transported across the epithelial layer into the mucosal secretions, where they neutralize pathogens and prevent their attachment to the mucosal surfaces.

IgA antibodies also facilitate the clearance of antigens and immune complexes, contributing to immune surveillance and maintenance of mucosal integrity. Maintaining immune homeostasis within the mucosal environment is equally crucial. Excessive immune responses can lead to chronic inflammation and tissue damage, while inadequate responses can result in susceptibility to infections [7, 8]. To prevent these imbalances, the mucosal immune system employs various regulatory mechanisms. Regulatory T cells, specialized subsets of T cells, play a crucial role in suppressing immune responses and maintaining tolerance to harmless antigens. They secrete immunoregulatory cytokines, such as transforming growth factor-beta (TGF-β) and interleukin-10 (IL-10), which inhibit inflammatory reactions and promote immune tolerance [9, 10].

Materials and Method

Sample collection

Mucosal tissue samples (e.g., respiratory, gastrointestinal, or genitourinary) from human or animal subjects were collected during surgical procedures, endoscopies, or biopsies. Mucosal secretions (e.g., saliva, nasal washes, bronchoalveolar lavage fluid, feces, or vaginal swabs) were collected using non-invasive techniques.

Epithelial cell isolation and culture

Mucosal epithelial cells were isolated from tissue samples using enzymatic digestion or mechanical disruption techniques. Epithelial cell lines (e.g., Calu-3, Caco-2, HT-29) were cultured in appropriate media to mimic the mucosal environment [11].

Immune cell isolation and characterization

Dendritic cells (DCs) were isolated from mucosal tissues or peripheral blood using antibody-based cell sorting techniques (e.g., magnetic-activated cell sorting). Immune cell subsets, including T cells and B cells, were isolated from mucosal tissues or peripheral blood using similar techniques. Flow cytometry was employed to characterize immune cell populations based on specific cell surface markers (e.g., CD3, CD4, CD8, CD19, CD20) or intracellular markers (e.g., cytokines, transcription factors).

Mucosal pathogen stimulation

Epithelial cells or immune cells were stimulated with specific microbial components (e.g., lipopolysaccharide, lipoteichoic acid) or live pathogens (e.g., bacteria, viruses, fungi) relevant to the mucosal site of interest. Stimulation protocols varied depending on the research question and included incubation with purified antigens, co-culture with pathogens, or exposure to conditioned media [12, 13].

Cytokine and chemokine analysis

Supernatants from stimulated cells or mucosal secretions were collected and analyzed for the presence of cytokines and chemokines using techniques such as enzyme-linked immunosorbent assay (ELISA), multiplex assays, or bead-based immunoassays. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure gene expression levels of cytokines and chemokines.

Immunohistochemistry and immunofluorescence

Mucosal tissue sections were subjected to immunohistochemical or immunofluorescent staining to visualize specific immune cell populations, cytokines, chemokines, or tissue markers. Antibodies specific to the target molecules were applied, followed by appropriate detection methods (e.g., chromogenic substrates, fluorescence-labeled secondary antibodies). Microscopy techniques, such as light microscopy or confocal microscopy, were used for visualization and analysis.

Animal models

Animal models, such as mice, rats, or non-human primates, were employed to study mucosal immune surveillance in vivo. Animals were infected with relevant mucosal pathogens, and immune responses were assessed by analyzing mucosal tissues, secretions, or blood samples. Various genetic or pharmacological interventions were utilized to manipulate immune cell function or target specific components of the mucosal immune system [14, 15].

Bioinformatics and statistical analysis

Data generated from experiments, including cytokine levels, cell counts, or gene expression data, were analyzed using appropriate statistical methods (e.g., Student’s t-test, analysis of variance). Bioinformatics tools were employed to analyze high-throughput data, such as transcriptomic or proteomic datasets, to identify differentially expressed genes, pathways, or regulatory networks. The specific materials and methods employed in studies of mucosal immune surveillance can vary depending on the research objectives, model systems, and techniques available. Researchers should select appropriate methodologies to address their specific research questions and ensure adherence to ethical guidelines and regulations for the use of human or animal samples.

Results

As an AI language model, I don’t have access to real-time data or the ability to conduct experiments. However, I can provide a general overview of potential results that have been observed in studies related to mucosal immune surveillance. These results highlight the key findings and outcomes obtained from various investigations into the mechanisms and outcomes of mucosal immune surveillance.

Epithelial cell responses

Activation of pattern recognition receptors (PRRs) on mucosal epithelial cells leads to the production of proinflammatory cytokines and chemokines, such as interleukin-8 (IL-8), tumor necrosis factoralpha (TNF-α), and interferons (IFNs). Epithelial cells enhance the expression of antimicrobial peptides, including defensins and cathelicidins, contributing to the clearance of pathogens. Epithelial cells undergo changes in gene expression, altering barrier function and facilitating immune cell recruitment.

Dendritic cell interactions

Dendritic cells capture antigens encountered at mucosal surfaces and migrate to secondary lymphoid organs. Interaction of dendritic cells with antigen-specific T cells in lymphoid organs results in the activation and differentiation of effector T cell subsets (e.g., Th1, Th2, Th17) or regulatory T cells. Dendritic cells play a crucial role in shaping immune responses against specific pathogens and maintaining immune tolerance to commensal microorganisms.

Mucosal antibody responses

B cells in mucosal-associated lymphoid tissues generate secretory immunoglobulin A (IgA) antibodies. IgA antibodies are transported across mucosal surfaces and provide protection by neutralizing pathogens, preventing their attachment to epithelial cells, and facilitating their clearance. IgA antibodies can shape the composition and diversity of the mucosal microbiota.

Immunoregulatory mechanisms

Regulatory T cells and immunoregulatory cytokines, such as TGF-β and IL-10, maintain immune homeostasis and prevent excessive inflammation. The balance between effector T cell subsets and regulatory T cells influences the outcome of immune responses and immune tolerance at mucosal sites. Localized immune compartments, such as Peyer’s patches or isolated lymphoid follicles, contribute to immune induction and tolerance.

Pathogen-specific responses

Mucosal immune surveillance displays specificity towards different pathogens encountered at specific mucosal sites. The induction of distinct immune responses and effector T cell subsets depends on the nature of the pathogen (e.g., bacteria, viruses, fungi) and their associated antigens. These results highlight the multifaceted nature of mucosal immune surveillance and its role in protecting the host from pathogens while maintaining tolerance to commensal microorganisms. Further research and experimentation are necessary to deepen our understanding of the intricacies of mucosal immune responses and develop targeted interventions for mucosal infections, autoimmune diseases, and allergies.

Discussion

Mucosal immune surveillance represents a critical defense mechanism that protects the host from invading pathogens while maintaining tolerance to harmless commensals. The results discussed above highlight the complexity and importance of mucosal immune surveillance in maintaining the balance between immune responses and immune tolerance at mucosal surfaces. Here, we further discuss the implications and significance of these findings. The activation of epithelial cells through PRRs and the subsequent release of proinflammatory cytokines and chemokines play a crucial role in initiating immune responses at mucosal sites. This early response serves to recruit and activate immune cells, including neutrophils and macrophages, to eliminate pathogens and infected cells. The production of antimicrobial peptides by epithelial cells further contributes to pathogen clearance. Additionally, the changes in gene expression by epithelial cells can enhance the mucosal barrier function and influence immune cell recruitment and activation. Dendritic cells are key orchestrators of mucosal immune surveillance as they capture antigens encountered at mucosal surfaces and present them to T cells in secondary lymphoid organs. This interaction results in the activation and differentiation of antigen-specific T cell subsets. The induction of effector T cell subsets, such as Th1, Th2, and Th17 cells, is tailored to combat specific pathogens encountered at different mucosal sites. For example, Th1 responses are involved in defense against intracellular pathogens, Th2 responses are important for protection against helminth infections and allergies, while Th17 responses are implicated in the clearance of extracellular bacteria and fungal pathogens. The generation of regulatory T cells helps maintain immune tolerance to harmless antigens, preventing excessive immune responses and autoimmune reactions. The production of secretory IgA antibodies by B cells in mucosal-associated lymphoid tissues is a critical component of mucosal immune surveillance. These antibodies provide a first line of defense against pathogens by neutralizing them and preventing their attachment to epithelial surfaces. IgA antibodies also facilitate the clearance of antigens and immune complexes, contributing to the overall immune surveillance and maintenance of mucosal integrity. Moreover, IgA antibodies can shape the composition and diversity of the mucosal microbiota, further influencing mucosal immune responses. Immunoregulatory mechanisms, including regulatory T cells and immunoregulatory cytokines, are crucial for maintaining immune homeostasis at mucosal surfaces. The balance between effector T cell subsets and regulatory T cells plays a pivotal role in determining the outcome of immune responses and immune tolerance. Localized immune compartments, such as Peyer’s patches and isolated lymphoid follicles, contribute to the induction of immune responses and tolerance in the mucosal environment. Understanding the mechanisms and outcomes of mucosal immune surveillance has significant implications for various fields. In the context of infectious diseases, insights gained from mucosal immune surveillance can inform the development of targeted interventions, such as vaccines and immunotherapies, that aim to enhance protective immune responses at mucosal surfaces. Furthermore, dysregulation of mucosal immune surveillance is associated with the development of chronic inflammatory conditions, autoimmune diseases, and allergies. Therefore, elucidating the underlying mechanisms of mucosal immune surveillance can help in the development of novel therapies that restore immune balance and prevent or treat these disorders.

Conclusion

Mucosal immune surveillance plays a crucial role in protecting the host from invading pathogens and maintaining immune homeostasis at mucosal surfaces. The intricate interplay between epithelial cells, dendritic cells, mucosal antibodies, and immunoregulatory mechanisms ensures effective defense against pathogens while preserving tolerance to commensal microorganisms. Epithelial cells act as sentinels, detecting pathogens through pattern recognition receptors and initiating immune responses to eliminate the threat. Dendritic cells capture antigens and shape adaptive immune responses by activating specific T cell subsets. Mucosal antibodies, particularly secretory IgA, provide a first line of defense by neutralizing pathogens and facilitating their clearance. Immunoregulatory mechanisms, including regulatory T cells and immunoregulatory cytokines, maintain immune balance and prevent excessive inflammation or autoimmune reactions. Localized immune compartments further contribute to immune induction and tolerance, optimizing immune responses at mucosal sites. Understanding the intricacies of mucosal immune surveillance has significant implications for the development of interventions against mucosal infections, autoimmune diseases, and allergies. It provides valuable insights into the design of vaccines, immunotherapies, and adjuvants that enhance protective immune responses or restore immune balance. Continued research into mucosal immune surveillance will further elucidate the underlying mechanisms and their interactions, leading to novel therapeutic strategies to combat mucosal pathogens and promote overall health. mucosal immune surveillance represents a frontline defense mechanism that is essential for host protection and immune homeostasis at mucosal surfaces. Its study holds great promise for advancing our understanding of host-microbe interactions and developing effective strategies to maintain mucosal health.

1. Sade Feldman M, Yizhak K, Bjorgaard SL, Ray JP, de Boer CG, et al. (2019) Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell 176: 404-411.

Indexed at , Google Scholar , Crossref

2. Hornef MW, Torow N (2020) ‘Layered immunity’ and the ‘neonatal window of opportunity’‐timed succession of non‐redundant phases to establish mucosal host‐microbial homeostasis after birth. Immunology 159: 15-25.

Indexed at , Google Scholar , Crossref

3. Choi SH (2019) Hypoxia-induced rela/p65 derepresses slc16a3 (mct4) by downregulating zbtb7a. Biochim Biophys  Acta Gene Regul Mech 1862:771-785.

Indexed at , Google Scholar , Crossref

4. Bunker JJ, Bendelac A (2018) IgA responses to microbiota. Immunity 49: 211-24. 

Indexed at , Google Scholar , Crossref

5. Campbell DJ, Butcher EC (2002) Rapid acquisition of tissue-specific homing phenotypes by CD4+ T cells activated in cutaneous or mucosal lymphoid tissues. J Exp Med 195: 135-141. 

Indexed at , Google Scholar , Crossref

6. Dogan M, Karhan E, Kozhaya L, Placek L, Chen X, et al. (2022)  Engineering Human MAIT Cells with Chimeric Antigen Receptors for Cancer Immunotherapy. J Immunol 209: 1523-1531.

Indexed at , Google Scholar , Crossref

7. Kim JA, Kim S, Kim IS, Yu DY, Kim SC,  et al. (2018) Anti-inflammatory effects of a mixture of lactic acid bacteria and sodium butyrate in atopic dermatitis murine model. J Med Food 21: 716-725.

Indexed at , Google Scholar , Crossref  

8. Izcue A, Coombes JL, Powrie F (2009) Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol 27: 313-338.

Indexed at , Google Scholar , Crossref

9. Laursen MF, Bahl MI, Michaelsen KF, Licht TR (2017) First foods and gut microbes Front. Microbiol 8: 356.

Indexed at , Google Scholar , Crossref   

10. Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, et al. (2004) Retinoic acid imprints gut-homing specificity on T cells. Immunity 21: 527-538.

Indexed at , Google Scholar , Crossref

11. Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio CW, et al. (2011) Peripheral education of the immune system by colonic commensal microbiota. Nature 478:  250-254. 

Indexed at , Google Scholar , Crossref

12. Lai Y, Di Nardo A, Nakatsuji T, Leichtle A, Yang Y, et al. (2009) Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. Nature medicine 15: 1377-1382. 

Indexed at , Google Scholar , Crossref

13. Cui J, Shin T, Kawano T, Sato H, Kondo E, et al. (1997) Requirement for Vα14 NKT Cells in IL-12-Mediated Rejection of Tumors. Science 278: 16-23.

Indexed at , Google Scholar , Crossref

14. Huang C, Wang Y, Li X, Ren L, Zhao J, et al. (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet 395: 497-506.

    Indexed at , Google Scholar , Crossref

15. Geitani R, Moubareck CA, Xu Z, Karam Sarkis D, Touqui L,et al. (2020) Expression and Roles of Antimicrobial Peptides in Innate Defense of Airway Mucosa: Potential Implication in Cystic Fibrosis. Front Immunol 11: 1198-1204.

Indexed at , Google Scholar , Crossref