Lecture 07 - The Mucosal Immune Response PDF

# The Mucosal Immune Response ## Learning Objectives 1. Describe the difference between inductive and effector sites 2. Understand organisation and regulation of mucosal immunity in the gut 3. Outline how mucosal immune system responds to pathogens 4. Explain how the mucosal immune system can be u...

# The Mucosal Immune Response ## Learning Objectives 1. Describe the difference between inductive and effector sites 2. Understand organisation and regulation of mucosal immunity in the gut 3. Outline how mucosal immune system responds to pathogens 4. Explain how the mucosal immune system can be used for treatments ## Mucosal Immunity - Mucosal surfaces exceed 300 m2 in humans, particularly vulnerable to infection - Evolved distinct mucosal immune system (MIS) for protection against toxic elements - enter body via mucous membranes - MIS - largest immune organ in the human body - Single layer epithelium covered by mucus and antimicrobial proteins - reinforced by aspects of innate and adaptive immunity - **Sites:** - NALT - Intranasal - Oral - Cervical lymph nodes - IgA+ B cell - GALT - Upper respiratory tract - Lower respiratory tract - Gastrointestinal tract - Urogenital organ - Exocrine gland - Secretory IgA - Mesenteric lymph nodes - Common mucosal immune system (CMIS) - IgA producing plasma cells - Inductive site - Effector site - Mucosal immune system induces antigen-specific SIgA ## Areas - Within the MIS, there is a community of commensal, symbiotic and pathogenic microorganisms - microbiota. - Share space with host in gut, skin, nasal and oral cavities as well as the female reproductive tract. - Human large intestine contains the largest amount of microbes at approximately 1012 bacteria/cm3. - This intestinal microbiota varies between individuals, plays key roles in defense against pathogens and digestion. ## Inductive and Effector Sites - MIS can be divided into **inductive** and **effector** sites based on their anatomical and functional properties. - **Inductive** sites are collectively called mucosa-associated lymphoid tissue (MALT) and include gut-associated lymphoid tissues (GALT), nasopharyngeal-associated lymphoid tissue (NALT) and lymphoid sites - MALT provides a continuous source of activated memory B and T cells that then move into effector sites - largest population - **Effector** mucosal effector sites include regions of the gastrointestinal, upper respiratory and reproductive tracts as well as secretory glandular tissues. - These sites contain antigen-specific mucosal effector cells - such as antibody producing cells and naive memory B and T cells. ** Inductive Sites:** - GALT (Peyer’s Patches) - NALT - BALT - MLN **Effector Sites:** - Lamina propria (GI tract, upper respiratory tract, genitourinary tract) - Glandular Tissues (Mammary, Salivary) - DC - Plasma cells - Treg - Th1 - Th2 - B cells (blood stream) - Th17 cells - digA - The mucosal immune system (MIS) is divided into inductive and effector sites. Both sites are interconnected thus enabling the MIS to protect vast surface areas. ## Effector - Effector site are the **lamina propria regions** of the GI tract. - **But how do the invader end up there?** Mucosal immunity is most abundantly expressed in the gut. - DC cells with antigen - go in follical to stimulate naive Bcells - end memory/effector cells. (Class switching) - **Head to lymph node** - Mucosal plasma cells produce **dimeric IgA** which, along with pentameric IgM can be exported by secretory epithelia. - **Efficient immune exclusion depends on plgR/SC** as it is performed mainly by SIgA - stops infection - **Table 1. Antimicrobial effects of secretory immunoglobulin A (SIgA) antibodies.** - SIgA is dimeric/polymeric, therefore exerting efficient microbial agglutination and virus neutralization - SIgA performs non-inflammatory extracellular and intracellular immune exclusion by inhibiting epithelial adherence and invasion - SIgA exhibits cross-reactive (‘innate-like’) activity and provides cross-protection in the herd - SIgA (particularly SIgA2) is quite stable (bound SC stabilizes both isotypes of IgA) - SIgA is endowed with mucophilic and lectin-binding properties (via bound SC in both isotypes and mannose in IgA2) - Receptor transport IgA and IgM to provide secretory antibodies (SIgA and SIgM) at the mucosal surface. - Polymeric Ig receptor (plgR) helps move IgA and IgM aross the membane via the production of J chain versions. - J chain is produced by mucosal IgG plasma cells (70–90%), and is degraded intracellularly. - Locally produced IgG is not subject to plgR-mediated transport, is transmitted paracellularly to the lumen. ## Inductive - Immune-inductive mucosa-associated lymphoid tissue (MALT) resembles lymph nodes, has: - B-cell follicles - T-cell zones - Antigen-presenting cells (APC) Mcells / (macrophages) - Exogenous stimuli come directly from the mucosal surfaces via a follicle-associated epithelium containing epithelial M cells. - Has lots of isolated lymphoid follicles and gut-draining mesenteric lymph nodes. - In region DC samples antigens - shows to B and T cells - develops tolerability - **Inductive site:** - Peyer’s patch (GALT) **Effector site** - Immune exclusion: SIgA/SIgM **Diagram of Peyer’s Patch - Schematic representation of a Peyer's patch:** - M cells - APC - FDC - T cells - B cells - Lymphoid follicle - CD4 - CD8 - γιδ (plgR/mSC) - Oral tolerance (suppression) - Productive stimulation - CD4 - Mesenteric lymph node - Thoracic duct - Endothelial gatekeeper function - IgA - IgG - IgM - IgE - DTH - B cells - Peripheral blood - Other secretory effector tissues - Mucus - Inductive sites for mucosal T and B cells are established by gut-associated lymphoid tissue (GALT) - Made up of M cells - exogenous antigens (Ag) are actively transported to reach antigen-presenting cells (APC), including dendritic cells, macrophages an B cells. - After being primed, naïve T and B cells become memory/effector cells and migrate from GALT to mesenteric lymph nodes - Secretory IgA (SIgA) and secretory IgM (SIgM) are generated via plgR/membrane secretory component (mSC)-mediated epithelial export. ## Mucosal Immunity in the Gut - Microbes beneficial to the host in many ways - Estimated 1014 microbes live within the human lower intestines - Gut mucosa largest immunological environment of the body. - Employs immune cells to maintain immune homeostasis and protect against prolonged inflammation. - **Key roles:** - Provide protection against pathogenic bacteria in the gut - Serve nutritional role - synthesizing key vitamins - Microbes *can also be detrimental* to the host - MIS evolved mechanisms: - Avoid negative responses from food antigens - Detect/destroy pathogenic organisms gaining entry via gut - Harness the beneficial effects of commensal microbes ## Organisation of Gut IS - **Villi** - intestinal surface covered with finger-like projections - Role in nutrient absorption - Host body’s largest population of immune cells - Intestinal mucosa are also dome-like structures - Peyer’s patches. - These are filled with lymphoid tissue, = key sites for coordinating immune responses (T + B cells, dendric cells (DC)). - **Remove pathogens; maintain tolerance to food; commensal bacteria.** - **Villi contain a network of blood vessels** - transport nutrients from food to the rest of the body. - **Within villi are loose connective tissue = lamina propia** - **Base of villi = crypts which contain stem cells** - **The epithelium (+mucus) form protective layer against microbes** ## Regulation of Gut Immune Homeostasis (DCs) - Dendric cells (DCs) critical for maintaining immune homeostasis in gut. - **DCs** - sample antigens, process and present them to T cells. - Results in activation of anti-inflammatory response, aids in the maintenance of immune homeostasis. - **DCs** travel to Peyer’s patches, present antigen to T-cells and stimulate their differentiation to T regulatory cells (Tregs). - Disruption of Treg function is associated with IBD as immune tolerance is changed. - **T cells** then move to the lamina propia of the villi through the lymphatic system - secrete the immunosuppressive cytokine Interleukin (IL)-10. ## Pathogenic Infection - Dysregulation or a breakdown of homeostasis in the gut can lead to intestinal inflammation - Caused - mechanical, chemical or pathogenic factors. - Bacteria activates epithelium = bacterial influx. - Releases inter lukins (IL-25) - activate immune cells. - IL always available/passively secreted due to cellular damage. - **Inflammatory Bowel Disease** - commonly involved sites: - Small intestine - Small intestine - Large intestine ## Innate Lymphoid Cells in Gut Pathogen Defense - Innate immune lymphoid cells (ILCs) critical for immune responses and maintaining homeostasis. - **Three subsets:** - **ILC1** - respond to tissue inflammation, viruses, bacteria, and certain parasites. - Consists of NK cells. - Interleukin (IL)-12, drives activity and causes the group to produce IFN-y. - Innate counterpart of T helper 1 cells - deemed non-cytotoxic, - Although, research shown to have NK-like cytolytic activities. - **ILC2** - Contribute to the response to helminths (parasitic worms). - In response to the IL-25, ILC2s produce proteins that induce mucus production from goblet cells. - Activates DCs that prime effector T cells and recruit mast cells and eosinophils. - Causes muscle contraction and expulsion of the worms. - ILC2s are also involved in tissue repair. - **ILC3** - interact with DCs to maintain the gut epithelial barrier. - Encounter antigen from the gut microbiota cause DCs secrete IL-23 = ILC3s produce IL-22 - IL-22 then activates the epithelium = secretion of anti-microbial peptides kill bacteria. - Interact with macrophages to induce gut immune homeostasis. ## Mucosal Immunity and Treating Disease - MIS critical for protecting the body and maintaining homeostasis. - **Dysregulation = disease.** - Conditions include autoimmune diseases, IBD, allergies, infections. - MIS can be exploited to develop effective therapies for treating these diseases. - **Protein biomarkers** - **Regulatory T cells** - Tr1 cells, IL-10 - FOXP3+ Tregs, TSDR methylation - **Suppressing capacity** - **Phenotype of immune cells (pro/anti-inflammatory)** - Surface markers (e.g. chemokine receptors) - Effector cytokines - Transcription factors - **Antigen specificity** - Numbers of antigen-specific cells - Phenotype of antigen-specific cells - TCR repertoire in combination with antigen specificity - **Biomarkers** - Specific markers of tolerance induction (e.g. IL-10) - Indirect markers of inflammation and tissue damage (e.g. NfL) ## Targeting Immune Cells - **Key diseases = structural damage to bowl wall** - IBD mediated dysregulation of the MIS - Crohn’s disease (CD) and ulcerative colitis (UC). - **Need to understand signalling pathways** - wound healing, intestinal inflammation and barrier function. - **Key gut cell signal receivers:** - Intestinal epithelial cells (IECs) - Goblet cells - **The signals regulated by:** - Cytokines - Toll-like receptor (TLR) ligands - Growth factors - **Signal effect:** - Apoptosis - Proliferation - IBD = characterized by an inflamed mucosa and alterations in barrier functions DUE TO IECs. ## Molecular Targets - **Healing of the inflamed mucosa and restoration of barrier functions goals of therapy** - Structural changes in IECs due to proinflammatory cytokines such as TNF, IFN-y, and IL-13 - all increased. - Therapys that target upstream proteins to reduce applied - **Response is low** - new targets needed. - **New strategies:** - Anti-cytokine agents such as antibodies to IL-13, IL-6R, IL-21 and IL-12/IL23, all linked to IBD inflamation - **Other methods:** - Increasing Tregs and anti-inflammatory cytokines, - JAK inhibition - Inhibition of T cell homing via the integrins. - **No translation to clinical practice - YET!** ## Vaccination - Pathogens enter the body through aerodigestive and reproductive tract. - Vaccines designed to induce both mucosal and systemic immunity - Mucosal vaccines - licensed to treat cholera, Salmonella, poliovirus. **Function:** - M cells in the follicle-associated epithelium (FAE) take up vaccine antigens - Vaccine antigens transferred to antigen presenting cells (APCs) - Processed and presented to CD4 and CD8 T cells. - Mucosal vaccines induce rapid immune responses, typically between 48-72 h - **Negitive** - contain killed micro-organisms with toxin-like molecules = adverse immune responses. - **Future work** - Novel delivery technologies, plant-based vaccines ### Respiratory - Respiratory route of infection - **No approved vaccine** - RSV - >100-150,000 deaths p.a. - >33 million infections p.a. - **Suboptimal vaccine coverage:** - Mycobacterium tuberculosis - >1.5 million deaths p.a. - >10 million infections p.a - SARS-CoV-2 - >2.6 million deaths p.a. - >115 million infections p.a. - Streptococcus pneumoniae - >1.2 million deaths p.a. - >190 million infections p.a. - Bordetella pertussis - >160,000 deaths p.a. - >24 million infections - Haemophilus influenzae - >48,000 deaths p.a. - >40 million infections p.a. - Lung cancer - >1.6 million deaths p.a. ### Enteric - Oral-faecal route of infection - **No approved vaccine** - Shigella - >200,000 deaths p.a. - ETEC - > 50,000 deaths p.a. - Helicobacter pylori - >15,000 deaths p.a. - 50% of world population infected - CRC and stomach cancers - 1 in 100 to 1 in 150 lifetime risk of stomach cancer - 1 in 25 lifetime risk of CRC - Epstein-Barr virus, HHV8 and HTLV1 ### Sexually Transmitted - **No approved vaccines** - HIV - >700,000 related deaths p.a. - >1.7 million new infections p.a. - Hepatitis C virus - >400,000 related deaths p.a. - >1.7 million infections p.a. ### Other Cancers - **Oncogenic viruses including:** - Epstein-Barr virus, HHV8 and HTLV1