19 - Mucosal Immunity Flashcards
Examples of mucosal tissues of immune system
- Respiratory tract
- Gastrointestinal tract
- Urogenital tract
Effector cells activated in mucosal tissue
Drain via lymphatics into circulation, and home back to musoca
NALT
- Nasopharyngeal associated lymphoid tissue
- Equivalent to Waldeyer’s Ring
GALT
Gut associated lymphoid tissues
MALT
Mucosal associated lymphoid tissue
Anatomical features of MALT
- Interactions between mucosal epithelia and lymphoid tissues
- Discrete compartments of diffuse lymphoid tissue and more organised structures (e.g. tonsils)
- Specialised antigen uptake mechanisms
Effector mechanisms of MALT
- Activated/memory T cells predominate
- Multiple activated ‘natural’ effector/regulatory T cells present
- Secretory IgA antibodies
- Presence of distinctive microbiota
Immunoregulatory environment of MALT
- Active down regulation of immune responses
- inhibitory macrophages and tolerance inducing dendritic cells
Weldeyer’s ring
- Consists of Lingual, palatine, tubal, and pharyngeal tonsils
- Organs of immune tolerance
- Generation and maintenance of allergen-specific FOXP3 + Treg cells is controlled by pDCs in the palatine and lingual tonsils
Tonsil crypts
Numerous narrow and deep invaginations of the surface squamous epithelium which grow into tonsillar follicular tissue
Lingual and palatine tonsils
Separated from the microbe-rich oral cavity by multiple layers of squamous epithelial cells, rather than the single columnar epithelial cell layer that separates the intestinal lumen from other GALT.
Immunity in respiratory tract
- The mucosa of the respiratory system lines the nasal passages, nasopharynx, trachea, and bronchial tree
- Alveolar macrophages represent most of the free cells within the alveolar spaces.
Alveolar macrophages
- Functionally distinct from other macrophages (maintain an anti inflammatory phenotype)
- Express IL-10, nitric oxide, and TGF-beta
- Poorly phagocytic compared with resident macrophages in other tissues
- Inhibit T cell responses as well as antigen presentation of airway DCs (IL-10 and TGF-beta)
Goblet cells
Produce airway mucins, the key components of the protective barrier that impedes pathogen entry into the airway epithelium
Three major ways that gut prevents infection
- Presence of thick mucus layer that keeps most organisms in the lumen away from the intestinal epithelium
- Antibiotic peptides produced by
intestinal epithelial cells kill pathogens in the lumen or reduce their entry into the epithelium - IgA transported into lumen and neutralises pathogens before they can enter through epithelium
Main features of immunity in the gastrointestinal tract
- Epithelial barrier covered by secreted mucus
- Dendritic cells (DCs) and microfold
(M) cells that sample antigens - Tuft cells that respond to helminths by secreting cytokines
- Paneth cells that secrete anti microbial peptides
- Goblet cells that secrete mucins
- Lymphocytes in the lamina propria beneath the epithelial layer
- Peyers patches
- Plasma cells beneath epithelium that secrete IgA
- Draining mesenteric lymph nodes
Peyer’s patch
Organised MALT beneath epithelial barrier
M (microfold) cells
- Specialised intestinal epithelial cells found in the small bowel epithelium overlying Peyer’s patches and lamina propria lymphoid follicles
- Shorter villi
- Engage in transport of intact microbes or molecules across the mucosal barrier into GALT,
where they are handed off to dendritic cells
Intestinal glycocalyx
The apical surface of gastrointestinal epithelial cells is coated with membrane-bound mucin proteins, which combine with various glycolipids to form the glycocalyx
Functions of the intestinal glycocalyx
- Physical barrier
- Interaction with microbes
- Chemical barrier
Mesenteric lymph nodes
Collect lymph-borne antigens from the small and large intestines and are sites of differentiation of effector and regulatory lymphocytes that home back to the lamina propria
Functions of mesenteric lymph nodes
- Differentiation of B cells into IgA secreting plasma cells
- Development of effector T cells as well as regulatory T cells
- Key site for tolerance induction to food proteins
IgA class switching in gut
- Occurs by both T dependent and T independent mechanisms
T dependent IgA class switching
- Dc in peyer’s patches capture bacterial antigens delivered by M cells and migrate to the interfollicular zone where they present antigen to CD4 T cells
- Activated T cells differentiate into Tfh cells and engage in cognate interactions with antigen-presenting IgM + B cells that have also taken up and processed the bacterial antigen.
- B cell class switching to IgA is stimulated through T cell CD40L
binding to B cell CD40, together with the action of TGF-β. - Yields high-affinity IgA antibodies
T independent IgA class switching
- Involves DC activation of IgM + B cells, including B-1 cells.
- TLR–activated dendritic cells secrete cytokines that induce IgA class switching ( BAFF, APRIL, and TGF- β)
- Yields relatively low-affinity IgA antibodies.
Transport of IgA
Secreted IgA transported through epithelial cells into the intestinal lumen by the poly-Ig receptor pIgR (via transcytosis and released by proteolytic cleavage)
Functions of IgA
- Immune exclusion
- Intracellular neutralisation
- Antigen excretion
Intraepithelial lymphocytes (IEL)
- Typically express Th1 cell type cytokines and have cytolytic properties
- Long lived resident effector cells that are interspersed between epithelial cells
- Most are CD8+ T cells
Effector and regulatory T cells in the intestinal mucosa
- Th17 effector T cells and regulatory T cells are abundant in the intestinal mucosa
- Th17 cells differentiate from naive CD4 + T cells in GALT in response to antigens presented by DC via IL-6 and IL-23
Gut homing properties of intestinal lymphocytes
- When naive B or T cells are activated by antigen in GALT, they are exposed to retinoic acid produced by the dendritic cells, inducing the expression of the chemokine eceptor 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 because the chemokine CCL25 (the ligand for CCR9) and the mucosal addressin cell adhesion molecule 1 (MAdCAM-1) (the ligand for α4β ) are displayed on lamina propria venular endothelial cells
Clostridium difficile infection
- Treatment with antibiotics causes massive death of commensal bacteria that normally colonise the colon
- This allows pathogenic bacteria to proliferate and occupy that ecological niche
- C. difficile can cause bloody diarrhoea in patients treated with antibiotics
Major components of cutaneous immune system
- Keratinocytes, Langerhans cells, and intraepithelial lymphocytes, all located in the epidermis
- T lymphocytes, innate lympiod cells, DCs and macrophages located in dermis
Homing properties of skin lymphocytes
- Ultraviolet rays in sunlight stimulate production of vitamin D, which induces expression of CCR10
- CCR10 regulates balanced maintenance and function of skin resident regulatory and effector T cells.
- IL-12 mediates lymphocyte rolling on E-selectin, endothelial cell ligand for CLA (cutaneous lymphocyte antigen
- CCL27 and CCL17 required for establishment of resident lymphocytes and immune homeostasis in barrier tissue
- These homing molecules direct migration of the effector T cells into the skin.
- CCL27 mediates homing of memory T cells to skin
Foetal and neonatal immunity
- IgG is transported from maternal blood across the placental syncytial trophoblast cells by the neonatal Fc receptor (FcRn), and is then transported across foetal vessel endothelial cells into the foetal circulation
- Neonate starts making IgG soon after birth
- IgM development begins late in pregnancy, reaching adults levels faster than IgG
- IgA levels take much longer to reach adult levels but can receive IgA from breast milk
Transfer of antibodies to breast milk
- Plasma cells from mucosal tissues home to the mammary gland, following CCL28 chemokines gradient generated by evolving mammary tissue
- Plasma cells produce IgA and IgM, which is passed into breast milk by the polymeric Ig receptor pIgR on the mammary epithelium.
- IgG originating from the blood is transferred into the breast milk via FcRn expressed on the mammary epithelium cells
