Gastrointestinal Mucosal Immune System Lecture 3 PDF

week offel uth Gastrointestinal mucosal immune system Lecture 3 CLN 372 Nutritional Immunology Dr. May Alsayb OUTLINE Introduction Gut associated lymphoid tiss...

week offel uth Gastrointestinal mucosal immune system Lecture 3 CLN 372 Nutritional Immunology Dr. May Alsayb OUTLINE Introduction Gut associated lymphoid tissues (GALT) Effector sites in the gut Antigen enter into gut sites Mucosal immune responses The human gut flora Oral tolerance  mucde ligThe Mucosal Immune System a intercon The mucosal immune system protects the internal surfaces of the body all type o - The mucosal immune system COMPOSED OF ㆍGI tract aufigen ㆍRespiratory tract ㆍUrogenital tract ㆍExocrine glands associated with these organs museserveentering ORGANIZATION OF THE MUCOSAL IMMUNE SYSTEM pathogen a are rensom - Mucosal sites represent a large surface area exposed to the environment. The vast majority of infections invade via mucosal surfaces. Microorganisms that live in mucosal tissues are essential to -our health. The mucosa is exposes to a variety of antigens, e.g., food.  FEATURES OF THE MUCOSAL IMMUNE SYSTEM ble they are distribution - barriers patto & organized they work [ 3 3 as cause gate" second lymp organtt think when clla enterToythem I they thateme - to Tall went be x reade -- so they should total testing i Prot for together the be & always found L interio - cas is the (epi (ym) + cell cell Perfee T if that bon't harm > - > near the buty so we trumregelten so we commencele the for Tall activation Jedric combe its Gowngrade reaso &  Gut-associated lymphoid tissues (GALT) station for the defenceAs orquises where the bly and it like ㆍpayer's patches ㆍlymphoid follicles of the intestine ㆍappendix ㆍtonsils ㆍadenoids ㆍmesenteric lymph nodes  its like ring their barrier So tab fitter every ii) enter - The tonsils and adenoids form a ring of lymphoid tissue, Waldeyer’s ring around the entrance of the gut and airway  cell like dentric engoulment to the immune funcioncapture & & give it cell thier - Microfold cells (M cells) : the route by which Ag enters the Peyer’s patch from lumen - Isolated lymphoid follicles in the small and large intestine ⇒ contain mainly B cells - Similar isolated follicles are found in other sites ㆍbronchus-associated lymphoid issues (BALT) Euph have is all ㆍnasal-associated lymphoid tissues (NALT) - The fetal development of intestinal lymphoid tissues is controlled by a specific set of -- cytokines agniast - THE EPITHELIUM OF PP CONTAINS SPECIALIZED CELLS M cells are distinguished by membrane ruffles/microvilli Why do we Need to Understand How the Gut Immune System Works? * - The gut is the major site of contact in the body for foreign antigens Gastrointestinal diseases kill more than 2 million people every year Lack of effective mucosal vaccines  Multiple Factors protect against GI pathogens Saliva Stomach acid & enzymes Bile Water and electrolyte secretion Mucosal products (mucus, defensins) Epithelial barrier Peristalsis Bacterial flora  Diseases of the Intestinal Immune System Caused by: Failure to establish oral tolerance Failure to maintain oral tolerance a & coulde oe a EFFECTOR SITES IN THE GUT  EFFECTOR SITES: EPITHELIUM AND LAMINA PROPRIA C C & & # Containcellthe happens betwae ③ ally immuno ea attach Intentpart the hone Hel inkrake & Het aer a ↳ e ) Generally cells have characteristics of activated cells Lamina propria contains the ⑮ whole range of immune cells Epithelium contains CD8 T cells.  bec INTRAEPITHELIAL LYPMPHOCYTES (IELs) tin monechi l d Imp = - - 10-15% of epithelial cells are IELs. IELs are mostly (90%) CD8 T cells. Tymphocytes - Restricted usage of V regions/limited specificities. und imp [ - Two types: conventional CD8 ab and CD8aa. ① xype & type  ANTIGEN ENTRY INTO MUCOSAL SITES kurl cop - The intestine has distinctive routes and mechanisms of antigen uptake - 1- The M cells in the follicle-associated epithelium are continually taking up molecules and particles from the gut lumen by endocytosis or phagocytosis supturing D 2 ⇒ Released into the extracellular space cell - sentorie ⇒ DC take up the transported material -- ⇒ Presentation to T lymphocytes & 1. M CELLS ARE RESPONSIBLE FOR ANTIGEN UPTAKE · - - sp M cells facilitate antigen entry. THEY ARE NOT An antigen-presenting cell (APC) -D M cell “hands” off intact antigen to lymphocyte or dendritic cell Enteric pathogens know how to exploit M cells use  well to attract other immune used to anc & help & 2- Chemokines released by the epithelial cells: CCL20 (MIP-3a) and CCL9(MIP-1g) - - ⇒ recruitment of Dendritic Cells (DC) jay. T cell areas of the Mesenteric lymph nodes Peyer’s patch ↓ encounter naïve T cells  2. DENDRITIC CELLS FACILITATE ANTIGEN UPTAKE & ⑫and DCs are abundant in the wall of the intestine mainly in lamina propria ⇒ acquire antigens across an intact epithelial barrier without the need for M cells ⇒ transport antigen to the T cell areas of mesenteric lymph nodes MUCOSAL IMMUNE RESPONSES 1- MUCOSAL EPITHELIAL CELLS ARE AN ACTIVE BARRIER D Epithelial cells interact with bacteria via intracellular receptors Toll- ⑪ like receptors (TLRs) and Nod-like receptors(NLRs) (TLR or NODs) are two major forms of innate immune sensors, which provide immediate responses against pathogenic invasion or tissue injury. must importat activate & Activation of these receptors in turn causes activation of NFkB. NF- specific - κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is nah - a protein complex that controls transcription of DNA, cytokine production and cell survival.Signal & - sing - >a Promoters for a wide array of pro-inflammatory mediators are activated by NFkB  2- THE IgA RESPONSE & "enteric bacteria Effective immunization against enteric pathogens is associated with an Immunoglobulin A (IgA) response sarm + precommentnight o we subdass&Lymphot mus Y Ig * monomeric KMost IgA is from the GI tract/PP to & entered when attacked to pathogen of the Pablo & take part Lamin they safe pen it as iteitiya keep  3- FUNCTIONS OF IEL (CONVENTIONAL T CELLS) intracellular effe & Jestroy i & g a Cancer & virusn cell - viral infection & thier best function Y a dais, Nil DO CD8ab cells protect against infection and are similar to peripheral P CD8 cells in their behavior 4- THE ROLE OF COMMENSAL BACTERIA IN TOLERANCE AND IMMUNITY - Commensal bacteria stimulate epithelium to produce cytokines Postglandin and other factors that prevent - dendritic - cell maturation -- Invasive bacteria stimulate dendritic cells to mature - there is another one - Immature dendritic cells induce & T regulatory cells& (TGFb producers) do suppress to the immune zyake Mature T cells induce T helpers & & immunosuppress  a elivThe erinHuman Gut Flora Mat , ↳ Rapidly colonises gut after birth Comprises more than 1014 organisms Weighs 1-2 kg More than 400 species An individuals flora is immunologically distinct Symbiotic relationship with host Probiotics - Commensal bacteria their product are recognized by the adaptive immune system e.g. germ-free animals : marked reduction in the size of all peripheral lymphoid organ, serum Ig and immune response - weakness - Commensal do not posses the virulence factors necessary for penetrating the epithelium and cannot disseminate throughout the body 959 5 , - In the presence of commensal bacteria, gut epithelial cell and mesenchymal cells ⇒ TGF-b, TSLP and PGE2 ⇒ maintain local DC in a quiescent state with low levels of co-stimulatory molecules ⇒ T reg induction  PATHOGEN EXPLOITATION OF MUCOSAL IMMUNITY: SALMONELLA Salmonella enters via M cells, epithelial cells or with the help of dendritic cells  Our Gut Flora Helps Prevent Colonisation by Pathogens becangel will the i c al prevent  Immune Responses in the Gut Initiation Immune Activation Infection APC Activation Foreign Ag T Cells Switched on Inflammation Pathogen erradicated Initiation of Gut Responses  Oral Tolerance Prevents response to normal flora and food antigens Cause of poor or absent immune response to most orally administered antigens? like fat drinks & medication ,  The mucosal immune system must maintain a balance between protective immunity and homeostasis to a large number of different foreign antigens - The majority of antigens encountered by the normal intestinal immune system are not derived from pathogen but come from food and commensal bacteria - The mucosal immune system has developed sophisticated means of discriminating between pathogens and innocuous antigens - The default response to oral administration of a protein antigen ⇒ specific peripheral unresponsiveness (oral tolerance) - A similar phenomenon in the respiratory tract ⇒ mucosal tolerance - Mice were injected with CD4 T cells bearing a transgenic receptor specific for an ovalbumin peptide. - Two days later they were fed ovalbumin or a control protein. - Four days later mice were injected with the relevant ovalbumin peptide. - Eight days later the drainnig lymph node was harvested and the number of ovalbumin-specific transgenic T cells was measured and their proliferative response was assessed to stimulation by ovalbumin peptide in vitro. - Mice fed with ovalbumin demonstrated a small reduction, compared with control-fed mice, in the number of transgenic T cells recovered, showing some deletion of T cells by orally fed antigen. - However, many transgenic T cells remained in the ovalbumin-fed mice and these were refractory to stimulation by antigen in vitro, compared with the control-fed mice, which showed vigorous proliferative responses. - These transgenic T cells had become anergic following oral intake of antigen - A breakdown in oral tolerance ⇒ celiac disease : Interferon gamma(IFNg) producing CD4 T cell ⇒ inflammation in the upper small intestine - The mechanisms of the oral tolerance ㆍanergy or deletion ㆍthe generation of regulatory T cell of different Thank you