L3 Mucosal Immunology PDF

Mucosal immunology Learning Objectives On completion of this session you should be able to 1) Describe the normal function of the mucosa and associated immune tissue 2) Understand how mucosal immunity responds to food antigens, commensals and pathogens within the digestive tract What’s spe...

Mucosal immunology Learning Objectives On completion of this session you should be able to 1) Describe the normal function of the mucosa and associated immune tissue 2) Understand how mucosal immunity responds to food antigens, commensals and pathogens within the digestive tract What’s special about mucosal immunity 1) Most pathogens enter the body via mucosal surfaces 2) Local immunity (specific IgA/IgG, cellular immunity) is an important first line of defence vs pathogens 3) Mucosal immunity may be able to provide sterilizing immunity (influenza) 4) Particularly important for pathogens that evade subsequent immune clearance Physiological Barriers 1) Histological architecture of mucosa, tight junctions 2) Rapid turnover of epithelium from epithelial stem cells 3) Presence of mucus, glycocalyx 4) Ciliated surfaces (movement) 5) Optimal pH 6) Presence of physiological microflora Mucosal Immune System (MALT) 1) Protects mucosal surfaces i.e. those covered by mucous secreting epithelium (GI, GU, respiratory tracts plus associated structures/glands). 2) Largest immune tissue in the body (contains ~75% total lymphocytes) 3) Due to function, mucous membranes are thin and permeable so vulnerable to infection 4) Most pathogens invade via these routes 5) Mucous membranes also contact non-pathogenic/non-harmful antigens e.g. food protein, commensal bacteria, environmental antigens 6) Not only important to distinguish self/non-self but also harmful/non-harmful Mucosal Immune System (MALT) Examples 1) GALT: gut-associated lymphoid tissue 2) NALT: nose-associated lymphoid tissue 3) BALT: bronchus-associated lymphoid tissue 4) Mucosal system of eyes 5) Mucosal system of breast 6) Urogenital mucosal system Organisation of MALT 1) Focus on intestinal mucosa 2) Immune cells (lymphocytes, macrophages and DCs) are found throughout the intestinal tract both in organised tissues (GALT) and scattered throughout the mucosal epithelium and underlying connective tissues 3) Organised tissues – secondary lymphatic tissue of GALT plus mesenteric lymph nodes are sites of immune responses 4) Scattered cell are effector cells of local immune responses Gut-associated lymphoid tissue: GALT Antigen Uptake in the Intestine 1) 1. M cells take up particles from the gut lumen by endocytosis/phagocytosis 2) 2. Particles are transported through the cell interior and released at the basal cell border – transcytosis 3) 3. DCs are recruited to the epithelial border by chemokines released from epithelial cells 4) 4. The basal border of M cells is folded to form a pocket that encases DCs and lymphocytes 5) 5. Once a DC has taken up an antigen, it migrates to the T cell area of the Peyer’s patch and presents to a naïve T cell 6) 6. B cell activation and class switching to IgA then occurs Antigen Uptake in the Intestine Effector Cells in the Intestine 1) In the healthy gut, there are large numbers of effector T cells and plasma cells in the tissue 2) This is unusual for healthy non-lymphoid tissue 3) In the epithelium, lymphocytes (CD8+ T cells) predominate 4) In the lamina propria, CD8+, CD4+ T cells, plasma cells, DCs, macrophages, mast cells & eosinophils can be found 5) Thus, healthy gut resembles a chronic inflammatory state in the absence of infection 6) Requires a balance between effector and regulatory T cells CD4+ T cells in Lamina Propria 1) Effector CD4+ T cells are found scattered throughout the lamina propria and include: 2) 1. Th1 cells – inflammatory T cells involved in anti- bacterial response 3) 2. Th2 cells – helper cells mediating IgE production of anti-parasitic response 4) 3. Th17 cells – found only in ileum and colon; secrete IL-17 that acts on stromal cells -> chemokines (IL-21, IL-22) -> neutrophil recruitment CD4+ T cells in Lamina Propria 1) 4. Induced regulatory T cells (Treg) – CD25+ 2) Express TGFb and IL-10 and are immunosuppressive 3) Thus the proinflammatory Th1, Th2 and Th17 cells are balanced by the actions of Treg cells 4) This state is referred to as physiological inflammation Induction of immune responses 1) The gut is exposed to pathogens, non-pathogenic bacteria (commensals/microbiota) and other innocuous substances (food/pollen etc.) 2) The mucosal immune system must discriminate between harmful (pathogenic) and harmless/innocuous antigens 3) Commensal organisms are found in the mouth, oesophagus, stomach, ileum, colon, conjunctiva, upper and lower respiratory tract, distal urethra, vagina and cervix 4) Look at responses in the GALT Response to Food Antigens 1) Response ensures that tolerance to food antigens is generated 2) Both mucosal and systemic immune systems are effected -> oral tolerance 3) Oral tolerance is - A general immunosuppressive state in the oral mucosa to prevent reaction to harmless antigens such as commensals or foods - The generation of systemic immune unresponsiveness by feeding of antigen 4) Necessary to prevent excess response to normal flora and food antigens 1) Mechanisms include: 1. Anergy and deletion of antigen-specific T cells 2. Generation of antigen-specific Treg cells via activation of naïve T cells in mesenteric lymph nodes by immature DCs 2) Unclear how this leads to systemic tolerance For more details about oral tolerance, refer to: https://www.nature.com/articles/nri 1370 Response to Commensals 1) Gut commensal bacteria perform important functions (metabolism of food and toxins, synthesis of cofactors, vitamins, fatty acids) 2) Gut commensals are important in immune system development (mechanisms unclear) 3) Do not produce virulence factors so cannot invade epithelial layer, if they do they are cleared rapidly by phagocytes 4) Can cause infection if they enter the blood stream in pathological states 5) Commensals are recognised by the immune system but do not induce immune tolerance 6) Intestinal inflammation is limited by several mechanisms (physiological inflammation) Response to Commensals 1) Molecular patterns differ to those on pathogens so different effects produced following binding of TLRs and NODs 2) Commensals cross gut wall through M cells and are taken up by local quiescent DCs 3) DCs can also squeeze between epithelial cells and take up antigen from the gut lumen 4) DCs secrete TGFb & IL-10 and drive activation of Treg cells 5) Treg cells produce TGFb which promotes IgA secretion in activated B cells 6) IgA crosses epithelial barrier to prevent transcytosis of bacteria from the gut lumen -> reduced inflammation Response to Commensals 1) Commensal specific Th1 and Th17 effector cells are also produced but do not initiate an inflammatory response 2) DCs can produce IL-23 that drives Th17 differentiation 3) Th17 cells produce IL-22 that stimulates release of anti- microbial peptides from Paneth cells -> inhibition of bacterial transcytosis -> reduced inflammation 4) Commensals also inhibit expression of pro-inflammatory cytokines by inhibiting NFkB activity 5) Commensals are confined to gut lumen through actions of tight junctions between epithelial cells, mucin production, IgA and defensin secretion Response to Commensals Response to Pathogens Effect of antibiotics on commensal bacteria Summary 1. The mucosa acts as a physical barrier that protects the underlying tissues from pathogens and mechanical damage. 2. The mucosal tissue contains specialised immune cells which work together to detect and respond to potential threats. 3. The immune system learns to tolerate harmless food antigens, preventing unnecessary immune responses. 4. The immune system maintains a symbiotic relationship with commensal bacteria, promoting health while preventing overgrowth. 5. Pathogen-associated molecular patterns (PAMPs) on pathogens are recognised by pattern recognition receptors (PRRs) on immune cells, initiating an immune response. Activated immune cells release cytokines and other mediators to promote inflammation and recruit additional immune cells to eliminate the pathogen.