Immunology: Chapter 12 Flashcards

Question

Dendritic cells in Peyer's patches

Answer 1

In sub-epithelial dome acquire antigen from M cells In resting conditions (beneath epithelium), produce cytokine IL-10 in response to antigen uptake (prevents priming of T cells to become pro-inflammatory) Infection by Salmonella, enter epithelial layer of Peyer's patches Bacterial products activate dendritic cells to express co-stimulatory molecules for activating pathogen-specific T cells

Answer 2

Mostly express integrin CD103: CD103 dendritic cells When loaded with antigen, they leave mucosa and migrate to T-cell areas of mesenteric lymph nodes via afferent lymphatics Interact with naive T cells and induce gut-homing properties Causes T cells to return to intestines as differentiated effector T cells 5-10% of mucosal dendritic cell population emigrates to mesenteric lymph node each day in resting intestine respond poorly to imflammatory stimuli (ex: TLRs) Produce IL-10 Resting conditions, those that arrive in mesenteric lymph nodes induce differentiation of Treg Depends on retinoid acid (from vitamin A) and TGF-beta Constant delivery of antigens from mucosal surface (crucial for tolerance of): Food antigens in small intestine Commensal bacteria in large intestine Anti-inflammatory behavior is reinforced by prostaglandin and product of IL-10 by mucosal macrophages

Answer 3

Produce IL-6, IL-23, TNF-α, NO Drive differentiation of CD4 TH17 cells Promotes class switching to IgA in B cells Do NOT migrate to lymph nodes Do NOT present antigens to T cells Main purpose may be to produce pro-inflammatory mediators in the presence of inflammation NOT to shape T cell responses

Answer 4

Most have cell surface markers associated with effector or memory T cells (antigen-experiences) Secrete large amounts of IFN-γ, IL-5, IL-17, and IL-10 in the normal intestine Colon and ileum are the only locations in the healthy body where CD4 TH17 cells are found (in response to commensal bacteria CD4 TH1 and TH2 cells produce: IL-4, IL-5, IL-, IL-21, and TGF-beta (assisting IgA production) IL-22 (inducing antimicrobial peptide secretion and epithelial repair) Anywhere else, this would lead to inflammation In the intestine, the TH17, TH1, and TH2 cells are balanced bt Treg cells producing IL-10

Answer 5

Occurs with infection by a pathogen (balance tips in favor of effector cell activation) CD4 and CD8 responses are activated Same happens with Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, and celiacs

Answer 6

iNKT cells, restricted by CD2 Mucosal invariant T cells (MAIT) Other cells that produce large amounts of IL-22

Answer 7

Intraepithelial lymphocytes (IELs) 10-15 per 100 enterocyte One of largest opoulations of lymphocytes in body More than 90% T cells, and ~80% of these are CD8 T cells Most have activated appearance, with intracellular granules containing perforin and granzymes Show restricted use of V(D)J segments (indicating that are targeted to a small number of antigens)

Answer 8

``` ~50% Traditional CD8 T cell α:beta receptors Standard cytotoxic T cell responses: Killing virus-infected cells Secreting cytokines such as IFN-gamma ```

Answer 9

Express CD8 α homodimer α:α co-receptor Either have α:beta or a γ:delta TCR α:beta cells do not bind to conventional peptide:MHC ligands Bind to other ligands, including MHC class Ib Expresses NK activating NKG2D receptor, which binds to MIC-A and MIC-B on stressed endothelial cell and kills it. (TCR is not involved) Process is enhanced by production of IL-15 by damaged epithelial cells

Answer 10

γ:δ IELs are particularly active in repairing mucosa after inflammatory damage. Stimulate release of antimicrobial peptides. Release cytokines that promote formation of epithelial barriers. Suppress inflammation by producing TGF-β. γ:δ IELs also promote skin repair Have low affinity for conventional peptide:MHC complexes. (CD8β chain is required for high affinity. These are CD8alpha:alpha.) Never self-reactive & are not eliminated in thymus by negative selection. Selected positively in thymus by relative high-affinity self-ligands, just as natural Treg cells and iNKT cells. Constitutive expression of genes associated with inhibitory and activating functions.Each checks the other. Activating: Cytotoxic molecules, NO, proinflammatory cytokines. Inhibitory: TGF- and inhibitory receptors such as those on NK cells.

Answer 11

``` Breakdown of oral tolerance Gluten in wheat generates IFN-γ-producing CD4 T cell responses in genetically susceptible individuals Immune response to gluten, from wheat ~30 years until diagnosis MIC-A-dependent cytotoxic activity of Type b IELs is enhanced. Associated with: Epithelial damage Increased numbers of IELs ```

Answer 12

IgA monomer: produced in bone marrow from plasma cells IgA dimer: produced in mucosal tissues Class switching to IgA is induced by TGF-β ~3-4 g/day of IgA; most of any antibody Is secreted into lumen of gut as dimers from plasma cells in lamina propria Dimeric IgA is transported to lumen of intestine by transcytosis Cells express polymeric IG receptor (poly-Ig receptor) on basolateral surface Poly-Ig receptor has high affinity for J-chain linked immunoglobulins, like dimeric IgA IgA is released from poly-Ig receptor through cleavage of extracellular portion Result: secretory IgA

Answer 13

Consists of: Two IgA molecules J chain that links them Extracellular portion of poly-Ig receptor Prevents pathogens from adhering to the mucus layer. Neutralizes toxins and enzymes. Does NOT activate complement. Does NOT act as an opsonin. Is therefore not engaged in inflammatory processes. Helps restrict commensal bacteria to the gut lumen. Contains antibodies to commensal bacteria which are found nowhere else, unless the commensal bacteria invade the bloodstream. Individuals who can't produce IgA secrete IgM polymers (which also have J chain) instead

Answer 14

Cause local inflammatory response and development of protective immunity **Gut is most frequent site of infection by pathogens Enterocytes do NOT have TLRs on lumen-exposed surfaces Commensal bacteria live there If pathogen invades an enterocyte, it will be recognized (commensal bacteria never invade enterocytes) If pathogen passes all the way through the enterocyte, TLR-5 receptor on basal membrane allows epithelial cell to recognize it Have TLRs in their intracellular vacuoles Can activate NKkB through NOD1 and NOD2 protein recognition NKkB activation, release of: Cytokines Chemokines Anti-microbial peptides called defensins Neutrophils, monocytes, eosinophils, dendritic cells, and T cells are attracted site of infection + activated. Enterocytes make MIC-A and MIC-B receptors on their basal membranes, making them susceptible to killing by lymphocytes bearing NKG2D receptor

Answer 15

Many invade the host through transcytosis through M cells. Polio HIV Some bacteria secrete protein toxins and never invade the epithelium. Some bacteria invade epithelial cells and produce harmful toxins from the intracellular location. E. coli All viruses must get into the cytosol in order to replicate. Many enteric pathogens gain access through M cells

Answer 16

``` Agent of food poisoning May cause infection by: Invading M cells Invading enterocytes directly Entering dendrites of dendritic cells that extend between epithelial surfaces and sample the gut luminal contents ```

Answer 17

Some work to the advantage of the pathogen. Ex: IL-1β and TNF-α loosen tight junctions between enterocytes, allowing pathogens to enter body. (Bacterial infection can do same to enterocytes lining mammary glands and allow HIV virus to enter breast milk.)

Answer 18

Ex: pathogens have ways of modulating the host immune response in their favor Grows in cytoplasm of epithelial cells Remodels the actin cytoskeleton to spread by direct cell-to-cell contact, thereby avoiding contact with the immune system Host eventually wins

Answer 19

If a purified protein is administered to a experimental animal Animal develops oral tolerance State of permanent unresponsiveness to that protein If animal is later given the antigen with adjuvant, by a non-mucosal route, an immune response can NOT be elicited Systemic immune responses most susceptible to oral tolerance are those associated with tissue inflammation

Answer 20

Antigen: invasive bacteria, viruses, toxins Ig production: Intestinal IgA Specific Ab present in serum T-cell response: local and systemic effector and memory T cells Response to antigen re-exposure: Enhances (memory) response

Answer 21

Anergy or deletion of antigen-specific T cells Generation of Treg cells in mesenteric lymph nodes w/ CD103 dendritic cells bearing food antigens. Treg cells produce TGF-β TGF-β is immunosuppressive & stimulates class switching to IgA (IgA is neutralizing,not pro-inflammatory). IL-10 may be involved. Can prevent/treat autoimmunity in animal models. Antigen: Food proteins, commensal bacteria Ig production: Some local IgA Low or no Ab in serum T-cell response: no local effector T-cell response Response to antigen re-exposure: low or no response

Answer 22

~1,000 species are not a problem unless they get into our blood stream, Can cause a fatal systemic infection. Significant source of vitamin K Digest complex carbohydrates that we can’t. Produce short-chain fatty acids, which helps to reduce chronic inflammation in IBD. Removal of commensal bacteria (through antibiotic administration) may cause opportunistic infections Stimulate local IgA production, along with active suppression of T cell responses Normally confined to gut. Breach the gut, they lack virulence factors and innate immune system will destroy them immediately. If they breach gut in large numbers, they will cause immune response bc the rest of the body has no knowledge of them. (get into blood) In contrast, food antigens illicit tolerance (small amount finds its way to the blood stream) throughout the body (IgA).

Answer 23

In germ-free (gnotobiotic) animals, there is no colonization of gut. These animals have marked reductions in size of all secondary lymphoid organs, and reduced levels of antibodies of all isotypes. Indicates the scale of normal immune response to gut bacteria. Peyer's patches do not develop normally. Isolated lymphoid follicles are absent. Severe reduction in T lymphocytes, especially TH1 and TH17. Reduction in other mediators such as antimicrobial peptides.

Answer 24

Polysaccharide A from Bacteroides fragilis drives several CD4 T cells subsets, including IL-10-producing Treg cells. Segmented filamentous bacteria induce TH1 and TH17 in mice. Some autoimmune diseases are worse in germ-free mouse models. (e.g. Type 1 diabetes from defective Treg development.)

Answer 25

High levels of IgA are directed at commensal bacteria. Fully differentiated TH1 and TH17 cells are kept in check by Treg cells. Balanced state called physiological inflammation.

Answer 26

Commensal bacteria provoke intestinal disease IBDs such as Crohn's disease result Can be mimicked in animal models through defects in IL-10 and TGF-β production, or by disruption of epithelial barrier to allow entry of large numbers into body. Strong systemic immune responses are generated. Strong inflammatory T-cell responses are generated in the mucosa, leading to severe intestinal damage

Answer 27

Intestinal helminths provoke strong TH2-mediated immune Infect ~3 billion people. Debilitating, but rarely fatal. Compete with the host for nutrients. Cause local damage to epithelial cells or blood vessels. Responses can induce much collateral damage. Many different modes of infection. Production of IL-4 and IL-13 result in: High IgE Recruitment of mast cells and eosinophils. Production of mucus. Increased migration and turnover of epithelial cells. Differentiation of alternatively activated macrophages, called M2 type. (Normal are M1)

Answer 28

Produce arginase Works towards increasing contractility of intestinal smooth muscle Promotes tissue remodeling and repair. Makes it difficult for parasite to maintain attachment to epithelial surface.

Answer 29

Activated + recruited by TH2 cells, to sites of worm infection Only a small number of IgE receptors Produce little histamine Better adapted to eliminating worms Secrete large amounts of TNF-alpha (bad for worm, but also damage intestinal lining + cause inflammation)

Answer 30

Harder for worm to maintain infection | Harder for host bc replacement cells are immature and can't absorb nutrients well

Answer 31

Can defend against various immune responses. Persist indefinitely. Reduce host inflammatory response (Treg’s are made, IFN-γ and TNF-α are limited). Good for the parasite. Less collateral damage to host. Host intestine has some function in spite of a large worm load. Chronic infections caused by eukaryotic parasites are associated w/ marked pathology caused by overproduction of: IFN-γ by T cells TNF-alpha by macrophages.

Answer 32

Absence of infection: both inflammatory + regulatory parts of immune system are likely to be operating simultaneously in mucosa. “Physiological inflammation”: appearance of normal intestine, describes presence of large #'s of lymphocytes and other cells that, in non-mucosal tissues, are associated with chronic inflammation. “Inflammation” is driven by commensal bacteria, and to lesser extent food antigens. Probably ensures dendritic cells are in state of high readiness to respond to changes in local environment.

Answer 33

Human immune system has evolved in face of continued exposure to worms. Don’t have worms bc we have hygiene. Our regulatory systems are all out of kilter in absence of worms, which is why we, in industrialized societies, are susceptible to allergies to minute amounts of harmless environmental materials. People in developing countries do not have allergies!

Answer 34

Human colon contains ~10^14 bacteria. None of these bacteria gain access to the blood stream. (1) Outer layer is gelatinous mucous layer in lumen of colon. Layer contains antimicrobial peptides and IgA antibodies that are reactive against commensal bacteria in colon. (2) Bacteria that get through outer mucous layer must travel thick mucous layer that physically prevents access to epithelial cells that line colon. (3) Get to epithelial cells that line colon must deal w/ tight junctions between enterocytes (epithelial cells) and somehow gain entry by crossing layer of epithelial cells. (4) Bacteria that cross epithelial cells are phagocytosed by special class of macrophages that eat bacteria w/o transmitting pro-inflammatory signals. (5) Bacteria that evade macrophages are delivered in lymph through portal vein, into liver, where they're phagocytosed by Kupffer cells w/o transmission of pro-inflammatory signals. Net result: extremely effective series of defenses that prevent beneficial bacteria in colon from gaining access to blood stream.

Answer 35

Small degree of access to blood stream appears in form of LPS Phagocytosed by Kuppfer cells w/o transmitting proinflammatory signals. (Quietly disposed of.) 2-3X higher amounts in blood of obese people 10X normal in blood of heavy drinkers Kuppfer cells in alcoholic liver disease are converted to phagocytic macrophages by general inflammatory state of liver. LPS activates macrophages (through TLR-4) to make NFκB and TNF-α.

Answer 36

Pro-inflammatory Respond to LPS and IFN-γ Produce pro inflammatory cytokines: TNF-α and IL-1beta and reactive oxygen species (ROS) to deal w/ bacterial infection. Rely primarily on glycolysis and pentose phosphate pathway --> produce NADPH and, from that, glutathione to limit damage from ROS. Conditions that favor M1 macrophages also favor development of TH17 cells.

Answer 37

Anti-inflammatory Activated by IL-4 and IL-13 &produce anti-inflammatory cytokines. Involved in long-term tissue repair + defense against extracellular parasites. Rely on oxidative phosphorylation. Favor M2 macrophages also favor development of Treg cells. Kuppfer cells in liver, and macrophages in lamina propria of gut that deal w/ commensal bacteria and bacterial components --> M2 macrophages, or, at least have properties similar

Immunology: Chapter 12 Flashcards

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