Immune System: Skin and Mucosal Surfaces PDF

The skin and mucosal surfaces form barriers against infection  Together, the skin and mucosae form the the barrier immune system, technically considered a component of the innate immune system.  These structures form physical barriers to infection that prevent pathogen...

The skin and mucosal surfaces form barriers against infection  Together, the skin and mucosae form the the barrier immune system, technically considered a component of the innate immune system.  These structures form physical barriers to infection that prevent pathogens from entering the body through a variety of methods. 2 Lymphoid tissues are classified as generative organs, also called primary or central lymphoid organs, where lymphocytes first express antigen receptors and attain phenotypic and functional maturity, and as peripheral organs, also called secondary lymphoid organs, where lymphocyte responses to foreign antigens are initiated and develop (immune response). 3 Features of Regional Immunity 4  The Gastrointestinal Immune System Intestinal epithelial cells lining the small and large bowel are an integral part of the gastrointestinal innate immune system, involved in responses to pathogens and antigen sampling for delivery to the adaptive immune system in the gut. The gastrointestinal system, like other mucosal tissues, is composed of a tube-like structure lined by a continuous epithelial cell layer sitting on a basement membrane that serves as a physical barrier to the external environment. Underlying the epithelium is a layer of loose connective tissue called the lamina propria that contains blood vessels, lymphatic vessels, and MALTs. 5 M cells in the small intestine  M cells are located in regions of the gut epithelium called follicle-associated (or dome) epithelium that overlie the domes of Peyer’s patches and other GALT structures.  Antigen may be delivered from the lumen to the GALT through specialized cells within the gut epithelium called M cells.  Although M cells and the more numerous absorptive epithelial cells likely arise from a common epithelial precursor, the M cells are distinguishable by a thin glycocalyx, relatively short, irregular microvilli (referred to as microfolds), and large fenestrations in their membranes, all features that enhance the uptake of antigens from the gut lumen. 6  Homing Properties of Intestinal Lymphocytes  The gut-homing properties of effector lymphocytes are imprinted in the lymphoid tissues, where they have undergone differentiation by naive precursors.  Dendritic cells in gut-associated lymphoid tissues (GALT), are induced by cytokines.  When naive B or T cells are activated by antigen in GALT, they are exposed to retinoic acid produced by the dendritic cells, and this induces the expression of the chemokine receptor CCR9 and the integrin α4β7 on the plasmablasts and effector T cells that arise from the naive lymphocytes.  The effector lymphocytes enter the circulation and home back into the gut lamina propria. 7  IgA class switching in the gut  Immunoglobulin A (IgA) class switching in the gut occurs by both T-dependent and T-independent mechanisms.  In T-dependent IgA class switching, dendritic cells in the subepithelial dome of Peyer’s patches capture bacterial antigens delivered by microfold (M) cells and migrate to the interfollicular zone, where they present antigen to naive CD4+ T cells.  The activated T cells differentiate into helper T cells with a T follicular helper phenotype and engage in cognate interactions with antigen-presenting IgM+ B cells that have also taken up and processed the bacterial antigen. APRIL, A proliferation-inducing ligand; BAFF, B cell–activating factor; PAMP, pathogen-associated molecular pattern. 8 Transport of IgA across epithelial cells o  IgA is produced by plasma cells in the lamina propria of mucosal tissue and binds to the poly-Ig receptor at the base of an epithelial cell.  The complex is transported across the epithelial cell, and the bound IgA is released into the lumen by proteolytic cleavage.  The process of transport across the cell, from the basolateral to the luminal surface in this case, is called transcytosis. 9 Transport of IgA across epithelial cells  The abundance of immunoglobulin A (IgA)- producing plasma cells (green) in colon mucosa compared with IgG-secreting cells (red) is shown by immunofluorescence staining.  IgA that is being transcytosed by the crypt epithelial cells is visualized in their cytoplasm (green fluorescent stain). 10 Antigen sampling by intestinal dendritic cells  DCs and macrophages are abundant in the gastrointestinal immune system and can participate in stimulating protective effector T cell responses or inducing regulatory T cell responses that suppress immunity to ingested antigens and commensal organisms.  DCs in the lamina propria take up and process protein antigens from microbes that are in the lumen or have breached the epithelial barrier and transport these antigens via lymphatics to mesenteric lymph nodes 11  Effector and regulatory T cells in the intestinal mucosa  In the gastrointestinal tract, different subsets of effector CD4+ T cells are induced by and protect against different microbial species.  Th17 effector T cells and regulatory T cells are abundant in the intestinal mucosa. Bacterial antigen–specific Th17 cells differentiate from naive CD4+ T cells in gut-associated lymphoid tissues in response to antigens presented by dendritic cells (DCs) and cytokines they secrete, including interleukin-6 (IL-6) and IL-23.  Differentiation of bacterial antigen–specific regulatory T cells (Tregs) is promoted by transforming growth factor-β (TGF-β) and retinoic acid produced by intestinal epithelial cells. Thymic Tregs that migrate to the intestine expand in number under the influence of bacterial metabolites. Regulatory T cells require antigen presentation by DCs; the nature of these antigens is unknown. 12 The Cutaneous Immune System  The epidermis provides a physical barrier to microbial invasion. The epidermis consists of multiple layers of stratified squamous epithelium, made up almost entirely of specialized epithelial cells called keratinocytes.  In addition to forming a physical barrier, keratinocytes actively respond to pathogens and injury by producing antimicrobial peptides, which kill microbes, and various cytokines, which promote and regulate immune responses. 13 The Cutaneous Immune System  The skin-homing properties of effector lymphocytes are imprinted in skin-draining lymph nodes, where they have undergone differentiation from naive precursors.  Ultraviolet rays in sunlight (UVB) stimulate production of vitamin D, which induces expression of CCR10; interleukin-12 (IL-12) induces expression of the E-selectin ligand CLA; and other signals induce CCR4, CCR8, and CCR10 expression.  These homing molecules direct migration of the effector T cells into the skin. CLA, Cutaneous lymphocyte antigen. 14 Immune-Privileged Tissues  Immune responses and associated inflammation in certain parts of the body, including brain, eye, testes, placenta, and fetus, carry a high risk for lethal organ dysfunction or reproductive failure.  These tissues, which have evolved to be protected, to a variable degree, from immune responses, are called immune-privileged sites 15 Immune-Privileged Tissues Testis  Immune privilege in the testis serves to limit inflammation that may impair male fertility.  Many self antigens in the adult testis are first expressed at the time of puberty, well after the development of a competent immune system, so it is unlikely that lymphocytes specific for these antigens are deleted during development.  Therefore, immune privilege in the testis may also serve to prevent autoimmunity. 16  Immune-Privileged Tissues  The fetus expresses paternally inherited genes that are foreign to the mother, but fetuses are not normally rejected by the mother.  The mother is exposed to fetal antigens during pregnancy because maternal antibodies against paternal major histocompatibility complex (MHC) molecules are easily detectable.  Many different special molecular and barrier features of the placenta and local immunosuppression may contribute. 17