Mucosal Immunity and Privilege Organs

Mucosal Immunity & privilege Organs Outline  Mucosal Immune System include √ Oral – Respiratory- Genitourinary √ Gastrointestinal (as a representative) - Innate & Adaptive Immunity Diseases Related to IR in Gut Immunity in Privileged Tissues - Eye ,CNS , Testis , Fetus  Why Mucosal Immunity is so important? The 10 most dangerous killer diseases in the world Apart from Ma, and Ne.Te. 8 remaining rest enters the body through mucus. How much skin surface area do we have?          the human body surface area (BSA) is around 2 m2. In the case of total mucosal area it is about 400 m2 Approximately about 200 fold of skin surface In gastrointestinal system The gut surface area is about 200 m2 The typical length & diameter Small intestine 6mx2.5 cm Colon 160cmx6cm About 1.5 litres volume Two remarkable properties Gastrointestinal Highest the size and complexity The GI immune system is the largest and most complex I.S. in our body. 1- Total surface area of more than 200 m2 (the size of a tennis court)  2-bacterial diversity Who live in there ˃500 species of bacteria ≈ 1014 cells, it is interesting to know number of all the cells in our body is 1013 refer to (P292 Chapter 14) it is 10 times more than our total body cells. we can conclude “ humans are actually only 10% human and 90% bacterial! “  How much do we eat in a year? How much air enters the lung in a day? Other Facts About Mucosal System The amount or volume of air a person breathed The average adult inhales about 10000 L air/day The amount of food a person eat each year lung 1 gr >1000 Ag Epi stomach Along with air A lot of Dust and Plant Pollens The first and most important sign of immune response is inflammation Default is Ignores patience / Intact Ag Pass and leave the body. Obviously, the body should not respond to this huge number of antigens Default & main duty is ejected Ags and dust are trapped in the mucus and ejected by Coughing and sneezing maintains the integrity and impervious barrier Default is barrier Another important issue in regional immunity is the number of lymphocytes as a mane adaptive cells in these areas Dr.Jazayeri Mucosal immunity Oral tolerance • Default response to oral antigens (food) oral tolerance • Immune unresponsivness • Active suppression performed by regulatory T cells producing TGF-β, IL-10 • Tolerogenic dendritic cells (CD103+) • This DCs sampling small and soluble Ags and cause tolerance • to induce tolerogenic response in GI Immunity in GI System Phagocytosis of M.tuberculosis GI as a representative mucosal system - Immunological study of different organ is done in three sections  Innate or natural Immunity in Gastrointestinal Tract - ( AMP - TLR - Epithelial cell in Mucosal surfaces – MALT )  Adaptive or acquired Immunity in Gastrointestinal Tract - ( B-cells class-switching IgA and T cells to T reg )  Diseases Related to Immune Responses in Gut - (Crohn’s disease , Ulcerative colitis , Celiac disease) because of impairment or IR deficiency in GI Innate Immunity in the Gastrointestinal Tract Schematic diagram of the cellular components of the mucosal immune system in the intestine Clear and informative Epithelial Cells Duty : mucus secretion has the largest number M Cells role : antigen sampling DCs with pseudopod extended Paneth cells:Antibiotic factory defensin production AMP- >20 (α S- β C) Goblet cell: Cytokine secretion Mucus is like a swamp trapped & driven out (mucus) ،sticky (mucous) ‫مخاط‬ war trumpet Toll Like Receptor(TLR) Mobilize forces TLRs are another important molecules of Innate immunity in GI. under attack TLR-2, -4 and -9 The first molecules that are aware of the attack very low and hidden to inhibit inflammation I.S. strategy in GI is ignores of Ags and Tolerance All of this condition causing ignores and Toler Simple—one layer of cells cells are present in the Stratified—more than one layer MALT (Mucosal Associated Lymphoid Tissue) Adaptive or acquired Immunity in GI. B B-cell development and class-switching T naive B & T lymphocyte are main actor of adaptive Immunity. If this cytokine pattern does not change IL-2, IL-4, IL5 B Proliferation cytokines IL-2, IL-4, IL5 Diffentiating cytokines IL-4 IgM primary antibody IgE Allergen TGF- IL-10 B IFN- Treg TGF- IgA / IgG2b IgG intracellular infection pIgR = Poly-Ig receptor IgA Immunoglobulin A Do you know how many IgA subclass we have? Dimer IgA or secreted IgA Protected from proteinases By secretory component secretory component Transport of lgA across Epithelial Cells different types of Igs such as IgG, IgE , IgM or IgA monomer Are not present in the lumen Immediately destroyed by intestinal enzyme nFCR in placenta two-sided Diseases related to immune responses in gut Inflammatory bowel disease : IBD IBD Is a group of chronic inflammatory disease of the large and small intestine-IBD fall into autoimmune diseases arising from an abnormal immune response to a normal body part  Reducing normal tolerance to intestinal antigens  - Creates an uncontrolled immune response against intestinal cells  There are three well-known diseases in this group  - Crohn’s disease, - Ulcerative colitis,- Celiac disease Transgenic mice foxp3 knockout gen (Treg Neg) IBD- Animal model IBD & IBS Irritable Bowel Syndrome (IBS)- Faecal Calprotectin Unlike IBD, IBS does not cause inflammation, ulcers, or other damage to the bowel. Barium enema. X-ray exam –Swallow & Meal---Follow Through--Enema Compare Crohn’s disease and Ulcerative colitis chronic inflammatory Crohn’s disease: that may affect any part of the gastrointestinal tract from mouth to anus(diffused). Signs and symptoms often disjointed include abdominal pain, diarrhea fever, and weight loss. The main reason of Crohn’s disease is defensin deficiency in Paneth cells.  Ulcerative colitis is restricted to the colonic mucosa. symptoms include abdominal pain, diarrhea mixed with blood, weight loss and anemia . Ulcer is uniform and monotonic. In order to IBD treatments we usually use anti-inflammatory drugs, such as sulfasalazine, corticosteroids The exact causes of uc is not known, but there are some Risk factors such as Genes, immune disorders & Environmental Complications factors(Smoking) are Effective. - Endoscopy - Colonoscopy  3- Celiac disease: AID Gluten-Sensitive Enteropathy (Celiac Disease) People with celiac disease cannot eat gluten Gluten is a protein found in wheat, , barley, and rye. gluten is such a triggers to active I.R. Mostly in women leading to infertility Abortion - Thin nails- Easy to break complain Treatment : Eating Gluten free food This Damages Occurs inside of small intestine . Microvilli's Damaged Shortened IMMUNE PRIVILEGED TISSUES  The first person who Bring up privileged organs was Peter Medawar (He received Nobel Prize in 1940 Because of the discovery that he had done)  Immune privilege describe the lack of immune responses in the brain or the eye of experimental animals that he surgery them.  Definition of privilege is special right, advantage, or granted that available only to a particular person or group. He knew that any inflammatory reaction after a tissue injury or surgery is routine. But this site have not any inflammation. – Eye ,CNS , Testis , Fetus (Not available for the immunity system) properties of privilege organs 1. tight junctions 2. Apoptotic factorsFasL,TRIL,PD-L1 inhibits any transmission 3. Local soluble inhibition factors : TGF- , IDO, IL10 start the apoptosis cascade in immune cells that wana attack to this organs strong connections Any inflammation in the brain causes shock - coma and ultimately death. Couse suppuration of microglia activation To Control / inhibit the inflammatory response Dr.Jazayeri Inflammation can cause opacity in vision and ultimately blindness Immune Skewing (Deviation) We have a solid barrier BEB around the eyes , To prevent the entry of immune cells into the eye. In this site also we have Apoptotic factors FasL,TRIL,PD-L1 that can start the apoptosis cascade Around the eyes. Induction Blood-Eye-Barrier(BEB) Blood-Ocular-Barrier(BOB) Blood Retinal Barrier(BRB) Induceing immune tolerance in eye Immunological Inflammatory reactions in Testis can cause problems in reproduction and infertility Sertoli Cells leydic cells Rl ·v· eged si es - est·s _une evasion atural kill er ce I S I KIR HLAI E, G HLAJ A B,C oli cell s CD8+ cytotoxic Tc 1. T e rim ry go I of immu o,... su pressive ech nis s in the testis is to circ en di srupti on of s production. Mechanisms k own to operate in the protection of sperm eel s fro m ttack by cytotox ic i mune cel ls such as atur I killer cells nd CD8+ cytotoxic T ce Is involve Jack of expr ssi on class I HLA A, B a d C recep o s a d t e induced expression of class I HLA E and G receptors. Sertoli cells xp.-ess cell surfac lig nds FasL and PD-L 1 ich promote poptosis in activated Tc 11s follow;ng ngagemenl with r sp ctive Fas and P0-1 rec tors. In d • • , S rtor ce Is in ibrl T ceU prolii rafon by mect·at·n d pJ fon of tryp ophan ·t 100 , dol min 2,3-dioxy n s (" .. ... Fetus or Embryo is a privilege site Any immunological inflammatory reaction can cause abortion.    The fetus has got paternal alloantigen of HLA and Can be rejected by the mother's immune system as an Foreign antigen. The trophoblast And placenta play a key role in inhibiting the maternal immune system activation . Role of IDO (Indoleamine 2,3-dioxygenase) –Tryptophan IDO role is consumption of tryptophan Tryptophan is an essential growth factor to T cell Inhabiting abortion process Kynurenine induces TGF-b production and activates Treg Dr.Jazayeri