Mucosal Immunology PDF

Immune Responses against Viruses  Humans are constantly exposed to numerous viruses but the consequences of infection are different in different individuals.  The outcome of host–viral interactions depend on the dose and route of infection, viral virulence properties, as well as several host...

Immune Responses against Viruses  Humans are constantly exposed to numerous viruses but the consequences of infection are different in different individuals.  The outcome of host–viral interactions depend on the dose and route of infection, viral virulence properties, as well as several host factors that mainly involve innate and adaptive immunity.  Host factors that influence the outcome of viral infection include genetic factors, such as polymorphism in MHC alleles, mutations in genes encoding innate receptors, cytokines, chemokine receptors, age, the nature of endogenous and persistent infections and pre-exposure to other infections.  The host has numerous anti-inflammatory activities that limit the extent of tissue damage caused by infections.  Successful pathogens such as HIV, hepatitis B virus (HBV), HCV and herpesviruses persist either as chronic or latent infections in the host with or without causing immediate ill effects; however, they may have lethal consequences when the host is immunocompromised.  Viruses that cause chronic infection influence immune cells to produce predominantly anti-inflammatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor-β (TGFβ). The antiviral immune response generally can be divided into an early, nonspecific phase (typically the first 5 to 7 days of infection) involving innate immune mechanisms, followed by a later, antigen-specific phase involving adaptive immunity by T and B cells.The early phase is critical, because infection may be either successfully contained or disseminated throughout the host. After recognition of pathogens (principally by DCs), mediators such as IFNs, cytokines, chemokines, and surfactant proteins are necessary in signaling the antiviral state within the cell and activating and attracting other immune cells such as neutrophils, macrophages, and NK cells to orchestrate an effective antiviral response at the site of infection. The aim of this early innate response is to either eliminate the pathogen or to avoid spread of the infection until elimination is achieved through the adaptive immune response. Innate cytokines improve the efficiency of antigen- presenting cells and to direct the development of naive T cells into different subtypes expressing distinct immune responses. Following entry into host cells, viruses (cytopathic or non-cytopathic) replicate at the site of infection. Cytopathic viruses kill infected cells, causing the release of cellular contents, including proteases and lysosomal enzymes, which digest the extracellular matrix and create an inflammatory responses. Neutrophils that are rapidly recruited to the site of infection release inflammatory mediators. Innate cells recognize viral replication intermediates and secrete pro-inflammatory cytokines, which, in addition to helping to clear the virus, contribute to tissue damage. Viral antigens are taken up by antigen-presenting cells and carried to local draining lymph nodes. Depending on the cytokines in the draining lymph node, different types of T helper (TH) cell responses are induced. Primed CD8+ cytotoxic T lymphocytes (CTLs) migrate to the site of infection and kill virally infected cells, thereby contributing to tissue damage. After migrating to the site of infection, TH cells also contribute to the tissue damage. In conditions in which the control of aggressive TH cells and CTLs by regulatory T (TReg) cells is impaired and other inhibitory pathways fail to curtail them, tissue damage is the main consequence of viral infection. TH cells also provide help to B cells to secrete antibodies, which form immune complexes that are deposited in certain tissues such as the glomeruli of the kidneys and blood vessels to cause immune complex-mediated disease. DAMP, danger-associated molecular pattern; DC, dendritic cell; HBV, hepatitis B virus; HCV, hepatitis C virus; HSV, herpes simplex virus; IFN, interferon; IL, interleukin; MMP, matrix metalloproteinase; NK, natural killer; PAMP, pathogen-associated molecular pattern; pDC, plasmacytoid DC; RNS, reactive nitrogen species; ROS, reactive oxygen species; RSV, respiratory syncytial virus; TCR, T cell receptor; TFH, T follicular helper; TGFβ, transforming growth factor-β; TMEV, Theiler's murine encephalomyelitis virus; TNF, tumour necrosis factor.  Mucosal Immunity Mucosal immunology is the study of immune system responses that occur at mucosal membranes of the intestines, the urogenital tract, and the respiratory system. The mucous membranes are in constant contact with microorganisms, food, and inhaled antigens. In healthy states, the mucosal immune system protects the organism against infectious pathogens and maintains a tolerance towards non-harmful commensal microbes and benign environmental substances. Disruption of this balance between tolerance and deprivation of pathogens can lead to pathological conditions such as food allergies, irritable bowel syndrome, susceptibility to infections, and more. The mucosal immune system consists of a cellular component, humoral immunity, and defense mechanisms that prevent the invasion of microorganisms and harmful foreign substances into the body. These defense mechanisms can be divided into physical barriers (epithelial lining, mucus, cilia function, intestinal peristalsis, etc.) and chemical factors (pH, antimicrobial peptides, etc.) There are areas of the mucosal epithelium that are heavily colonized with microbes and exposed to exogenous proteins, including the nasopharynx, the lower gastrointestinal tract, and the vaginal vault. In contrast, there are other areas that are largely sterile including the lung, the duodenum, the uterus, the renal collecting system, the breast, and the male genital tract. These differences would appear to dictate major differences in how potential foreign proteins and pathogens are recognized both in terms of innate pathogen-associated molecular pattern recognition and in terms of induction of cellular and humoral immunity. E.g. the presence of microfold or M cells. Such sites include the Peyer’s patches in the gastrointestinal tract, the nasopharyngeal Waldeyer’s ring, and the bronchial- associated lymphoid tissue. In other sites, notably the vagino-cervical area, associated lymphoid tissue is minimal. Waldeyer’s ring has two components, namely the inner and outer rings. The inner ring is constituted by, adenoid (nasopharyngeal vegetations) at the roof of nasopharynx, tubal tonsils (or tonsil of Gerlac) which surrounds the pharyngeal ends of eustachian tube, palatine tonsils (or faucial tonsils) on either side of oropharynx, lingual tonsil in the posterior one third of the tongue and sub epithelial lymphoid tissue found in the posterior pharyngeal wall. A basic assumption about the mucosal immune system is that the effector arm acts through IgA. In this regard, a generalization that does seem valid is that IgA and IgM are actively produced in mucosally associated lymphoid tissue and are actively transported across mucosal cells, achieving relatively high concentrations in mucosal secretions. IgA is regarded as the primary mucosal antibody and has the ability, shared with IgM, to be actively transported across the epithelial barrier. However, the relative concentrations of IgA and IgG and their subclasses vary greatly by mucosal sites. Components of the Mucosal Immune System Mucosal immunity is triggered by the coordinated interaction of multiple cell types within the mucosal tissues. The process involves the initiation of the response at an inductive site, leading to an immune response at multiple effector sites. Components of the mucosal immune system (MALT) include:  Gastrointestinal tract – gut associated lymphoid tissue (GALT); includes tonsil and appendix  Respiratory tract – bronchial associated lymphoid tissue (BALT)  Nasal associated lymphoid tissue (NALT)  Genitourinary tract  Lacrimal glands  Salivary glands  Mammary glands  Function The mucosal immune system provides three main functions: First line of defence from harmful antigenic structures and infection. Prevents systemic immune responses to commensal bacteria and food antigens. Regulates appropriate immune responses to pathogens. Physical barrier The mucosal barrier is formed due to the tight junctions between the epithelial cells of the mucosa and the presence of the mucus on the cell surface. The mucins that form mucus offer protection from components on the mucosa by static shielding and limit the immunogenicity of intestinal antigens by inducing an anti-inflammatory state in dendritic cells.  Active immunity approximately 3/4 of all lymphocytes are found in the mucous membranes. These immune cells reside in secondary lymphoid tissue, largely distributed through the mucosal surfaces. The mucosa-associated lymphoid tissue (MALT), provides the organism with an important first line of defense. Along with the spleen and lymph nodes, the tonsils and MALT are considered to be secondary lymphoid tissue. The MALT's cellular component is composed mostly of dendritic cells, macrophages, innate lymphoid cells, mucosal-associated invariant T cells, intraepithelial T cells, regulatory T cells (Treg), and IgA secreting plasma cells. Basic immune response in the gut In the gut, lymphoid tissue is dispersed in gut-associated lymphoid tissue (GALT). A large number of immune system cells in the intestines are found in dome-like structures called Peyer’s patches and in small mucosal lymphoid aggregates called cryptopatches. Above the Peyer’s patches is a layer of epithelial cells, which together with the mucus form a barrier against microbial invasion into the underlying tissue. Antigen sampling is a key function of Peyer’s patches. Above the Peyer’s patches is a much thinner mucus layer that helps the antigen sampling. Specialized phagocytic cells, called M cells, which are found in the epithelial layer of the Peyer’s patches, can transport antigenic material across the intestinal barrier through the process of transcytosis. The material transported in this way from the intestinal lumen can then be presented by the antigen-presenting cells present in Peyer’s patches Intraepithelial T cells, usually CD8+, reside between mucosal epithelial cells. These cells do not need primary activation like classic T cells. Instead, upon recognition of antigen, these cells initiate their effector functions, resulting in faster removal of pathogens. Tregs are abundant on the mucous membranes and play an important role in maintaining tolerance through various functions, especially through the production of anti-inflammatory cytokines The topology and function of intestinal MALT is shown. Pathogens are taken up by M cells in the intestinal epithelium and excreted into a pocket formed by the inner surface of the cell. The pocket contains antigen-presenting cells such as dendritic cells, which engulf the antigens, then present them with MHC II molecules on the cell surface. The dendritic cells migrate to an underlying tissue called a Peyer’s patch. Antigen-presenting cells, T cells, and B cells aggregate within the Peyer’s patch, forming organized lymphoid follicles. There, some T cells and B cells are activated. Other antigen-loaded dendritic cells migrate through the lymphatic system where they activate B cells, T cells, and plasma cells in the lymph nodes. The activated cells then return to MALT tissue effector sites. IgA and other antibodies are secreted into the intestinal lumen.