L23: Mucosal Immunity Flashcards
Mucosal Immunity Tasks (4)
- Anti-infective: protection from pathogens
- Barrier function: prevention of penetration of pathogenic and immunogenic components form mucosa to circulation
- Musocal tolerance: low reactivity to harmless antigens
- Immune regulation: maintenance of mucosal homeostasis
Mucosal immune system features (6)
- Epithelium: physical and chemical barriers, specialised cells, close interactions with immune cells
- Innate immune cells: PRRs, professional antigen-presenting cells for antigen sampling and presentation, innate-like lymphocytes
- Mucosal lymphocytes: Ag-experienced activated/memory T cells even in infection absence; specific phenotype, repertoire, secreted products; sub- and intra-epithelial lymphocytes (IEL), Tregs, Mucosal IgA
- Microbiota
- Immunoregulatory environment
- Oral tolerance
Epithelial barrier
Physical barrier - tight junctions through homotypic adhesion
Cell types: conventional enterocytes and enteroendocrin cells; Goblet cells - mucus, growth factors (renewal, repair); Paneth cells - pathogen recognition, defensins; M cells - antigen uptake
Antimicrobial defence: physical - mucus (sticky), tight junctions; chemical - lysozyme (digests bacterial cell walls), lactoferrin (iron binding), antimicorbial peptides (Defensins); biological - immune cells, resident microbiota
M cells
Specialised epithelial cells (NO digestive enzymes, mucus , glycocalyx), characteristic membrane ruggles, direct exposure to soluble antigens (food, micorbial) in gut lumen, weak spot - pathogen entry
Transcytosis
Antigen uptake and transport by M cells. Close contact with T and B lymphocytes and dendritic cells. M cells take up antigen by endocytosis and phagocytosis; antigen is transported across the M cells in vesicles and released at the basal surface; antigen is bound by dendritic cells, which activate T cells
Means of antigen capture by professional antigen presenting cells in the lamina propria
Nonspecific transport across epithelium
FcRn-dependent transport
Apoptosis-dependent transfer
Antigen capture
Intraepithelial lymphocytes in the gut
T cells (in small intestine all CD8+) alphaE:beta7 integrin (CD103) binds to E-cadherin on epithelial cells Restricted use of V(D)J gene segements - restricted TCR repertoire Surveillance of epithelium (e.g. kill virus infected or stressed cells)
Immune cells in the lamina propria (5)
- T cells: antigen experienced; CD4+ predominate in lamina propria but also some CD8+; Treg immune suppression, IL-10
- Plasma cells: arise from B-cells that are activated in Peyer’s Patches and home via bloodstream back into mucosa (alpha4beta7 integrin, CCR9, CCR10); produce IgA in absence of infection just driven by presence of microbiota
- Innate lymphoid cells: functions in epithelial homeostasis (IL-22), development of lymphoid tissue, inflammatory cytokine receptors
- Mast cells
- Specific subsets of macrophages and DCs, antigen capture and presentation, immune regulation
IgA secretion: transcytosis
Binding of IgA to receptor on basolateral face of epithelial cell
Endocytosis
Transcytosis to apical face of epithelial cell
Release of IgA dimer at atypical face of epithelial cell
Secreted IgA on the gut surface can bind and neutralise pathogens and toxins
IgA is able to bind and neutralise antigens internalised in endosomes
IgA can export toxins and pathogens form the lamina propria while being secreted
Gut Microbiota
‘Good bugs’:
- Vitamin K (coagulation)
- Short-chain fatty acids (epithelial barrier, mucosal immune functions)
- Required for development and maintenance of functional mucosal immune system
- Prevention of colonisation by pathogens (competition, exclusion, anti-microbial defence of mucosa)
Gut Microbiota - Direct
Commensal microbiota competes with pathogens for nutrients, also produce metabolites which suppress virulence factors in pathogenic organisms.
Gut Microbiota - Indirect
Short chain FA produced by commensals upkeep barrier function and mucus production. IL-22 cytokine important to maintain gut barrier functions by inducing antimicrobial peptides, preventing pathogen colonisation. IgA neutralises pathogens and prevents systemic infection.
Mucosal Tolerance
Specific unresponsiveness to systemic challenges after a prior mucosal exposure to the antigen. Tolerance is the natural immune response induced in response to a soluble antigen at mucosal sites, prevents harmful inflammatory responses and important for establishing homeostasis between natural microflora and host at mucosal sites.
Celiac Disease
Inflammatory responses to a food antigen - immunological responsiveness to gluten. Morphological changes to mucosa of upper small intestine (long crypts or flat mucosa, partial or complete atrophy of villi). Genetic link - HLA-DQ2 and HLA-DQ8. 4 components: gluten, tissue Transglutaminase, HLA-DQ, T cells. Peptides produced from gluten don't bind to MHC class 2 molecules; tissue transglutaminase (tTG) enzyme modifies peptides so they bind to MHC class 2 which activates gluten-specific CD4 T cells, kills mucosal epithelial cells by binding Fas. Also secrete IFN-y which activates epithelial cell.
Salmonella
Gram-negative bacterium, foodborne pathogen and cau cause diarrheal diseases and systemic diseases.
Salmonellae enter and kill M cells, infect macrophages and epithelial cells. Invade the luminal surface of epithelial cells, enter dentrites of DCs that sample gut luminal contents
