EXAM 2

Cytokines

Signaling molecules produced by antigen-presenting cells (APCs) during infection that regulate the differentiation of T cells.

Adaptive immune response

The immune response that occurs after the establishment of infection, characterized by the activation and differentiation of T and B cells.

Innate response

The non-specific immune response that targets pathogens non-specifically, such as through the breakage of skin.

Antigen presenting cells (APCs)

Cells that encounter pathogens, pick them up, and present them to lymphocytes (T or B cells) to stimulate an immune response.

T helper cells

Mature effector cells that differentiate from naive CD4 cells and play a role in the adaptive immune response.

Plasma cells

Mature effector cells that differentiate from B cells and produce antibodies.

Dendritic cells

APCs that produce different cytokines depending on their activation status, such as TGF beta when not fully activated and IL6 and IL-23 when activated.

Naive CD4 T cells

CD4 T cells that have not yet encountered a pathogen and can differentiate into different subsets (TH1, TH2, TH17) depending on the cytokines present.

TH17 cells

Subset of CD4 T cells that differentiate in response to high levels of IL6 and TGF beta during the early phase of infection.

TH1 cells

Subset of CD4 T cells that differentiate in response to IL12 produced by dendritic cells during infection with viruses or bacteria.

TH2 cells

Subset of CD4 T cells that differentiate in response to IL4 produced by NK cells during infection with parasites.

Treg cells

Regulatory T cells that produce TGF beta and inhibit the differentiation of other CD4 T cell subsets.

L-selectin

A molecule that mediates the homing of naive T cells to the lymph nodes.

VLA 4

An integrin molecule that binds to VCAM1 and ICAM-1 on peripheral vascular endothelium.

LFA-1

An integrin molecule that binds to VCAM1 and ICAM-1.

Primary antibody

Antibodies produced by plasma cells that are more general and have relatively low affinity and few somatic mutations.

Secondary antibody

Antibodies produced by memory B cells that are more specific, undergo clonal expansion, and have high affinity for the antigen.

Memory B/T cells

Cells that remember pathogens and provide a quicker and more specific response upon re-infection.

Mucosal immune system

The immune system that protects the internal surfaces of the body, with lymphoid organs associated with various mucosal tissues.

Commensal microorganisms

Microorganisms that reside on the surface of the body or at mucosa without harming human health and provide essential functions like aiding in digestion and educating the immune system.

Gut-Associated Lymphoid Tissues (GALT)

Organized secondary lymphoid tissues in the gut, including Peyer's patches and isolated lymphoid follicles.

Waldeyer's Ring

A ring of lymphoid organs that surround the entrance to the intestine and respiratory tract, including adenoids, palatine tonsils, and lingual tonsils.

Peyer's patches

Lymphoid tissues in the small intestine that contain T cells and B cells and are separated from the intestinal lumen by a single layer of epithelium.

Effector cells

Lymphocytes that are scattered throughout the mucosa and are involved in the immune response, such as effector T cells and antibody-secreting plasma cells.

M cells

Specialized cells found in the follicle associated epithelium of Peyer's patch in the small intestine.

Mechanism of M cell uptake and transport of antigens

M cells take up antigens through endocytosis and phagocytosis, transport them across the cell in vesicles, and release them at the basal surface. The antigens are then bound by dendritic cells, which activate T cells.

Transcytosis

The name of the mechanism by which antigens are transported across cells, specifically referring to the transport of antigens by M cells.

Mononuclear cells

Cells located in the lamina propria of the small intestine that capture antigens from the intestinal lumen.

Enterocytes

Cells in the surface epithelium of the small intestine that capture and internalize antigens through antibody complexes. They transport the antigens across the epithelium by transcytosis.

T-cells in the lamina propria of the small intestine

express the integrin α4:β7 and the chemokine receptor CCR9, which attracts them into the tissue from the bloodstream.

Difference between CD4 T cells and CD 8 T cells:

CD4 T-cells predominate in the lamina propria, whereas CD8 T-cells predominate in the epithelium.

What are the M cells found in the small intestine?

found in the the follicle-associated epithelium of the Peyer’s patch

What’s are the distinct phases of infection

1. establishment of infection

2. induction of adaptive response

3. adaptive immune response

4. immunological memory

describe the course of the immune response

• Innate response- target pathogens non specifically

• Breakage of skin, pathogens come in antigen presenting cells encounter pathogens = pick them up and go to lymphonide to present to lymphocytes (T or B) and stimulated, once becomes stimulated become mature effector cells = T helper cells (no longer naive) B cells (plasma cells)

  
  

Phase 2 of the infection, what is happening in the induction of adaptive response?

• # of pathogens continue to grow

• Growth took off

in the course of the immune response, what happens in phase 4?

• Infection = cleared + dose of antigen falls below threshold- response ceases

• Provide lasting protection against reinfection

What are the cytokines made by the APCs during infection and their effects?

• When dendritic cells not not fully activated = TGF beta

  • activated= IL6, IL-23=produces naive CD4 cells into TH17

• Naive CD4= IL-12 + IFN gamma ≠TH2 but does =TH1

• TLR drives dendritic cells =IL-12 

• Naive CD4+IL4=TH2

Is TGF beta present when there is an infection? Or what is present when infection is present?

• TGF beta when no infection (main cytokine) or early stage of infection = see Treg cells or TH17 cells 

  • T17= 1st to respond/come out

• Treg = suppress activity 

  • When infection doesn’t want inhibition 

TH3

• involved in mucosal immunity and protecting mucosal surfaces in the gut from nonpathogenic non-self antigens.

• mediate this non-inflammatory environment by secreting TGF-beta and IL-10.

What cytokines made in the earliest phase of an infection influenced the differentiation of CD4 T17 subset?

• When infections 

  • High level of IL6 + TGF beta = naive CD4 T cells responds by expressing ROR gamma T= TH17 cells 

• encountering of a pathogen the earliest response of dendritic cells is to synthesize: IL-6 and TGF-, these two cytokines induce naïve CD4 T-cells to differentiate into TH17 which leave the lymph node and migrate to distant sites of infection

Are lymphocytes active when there is no infection? Are they when there is an infection?

When lymphocytes are inactive. Don’t want swelling. When infection comes in want inhibition from Treg to be lyfted= want lymphocytes to do work

What cytokines made in the later stages of an infection influenced the differentiation of CD4 T cells towards the TH1 or TH2?

• Parasite

  • IL4 (interleukin) by NK cells= naive CD4 tells activated= TH2 cells 

• virus/bacteria 

  • Induce IL 12 by dendritic cells= Nk cells=IFN gama= TH1 

how subset of CD4 T cell regulate each other’s differentiation?

• No infection 

  • TGF beta produced by Treg cells=naive T cells

  • Naive T cells inhibit TH17, TH1, or TH2

• During infection 

  • TH17 1st response due to IL6 produced from dendritic cells

  • TH17  develops regulatory t cell (downgraded) + TH 17 (decrease in environment)

  • TH 1 or TH2 ≠ TH17

  • TH2=IL(interleukins) 10 =macrophages 

    • Macrophages ≠ TH 1 

      • By blocking macrophages IL-12 synthesis and TGF beta= acts directly on TH1 cell to inhibit growth 

  • TH1 make IFN gamma=blocks growth of TH2 

  • IL 6 evelated= switch point = produce TH 17

• Tgbeta decreases as T reg isn’t as  high 

• TH1 + 2 inhibit TH17

Distinct subset of CD4 T cells can regulate each others differentiation:

what are L selectin?

• Mediates homing to the lymphnodes

• Expressed in naive T Cells

What’s VLA 4?

• Bind to VCAM1 (vascular cell adhesion molecule 1)  and ICAM-1  on peripheral vascular endothelium 

• Integrin

What’s LFA-1?

• Bind to VCAM 1- and ICAM- 1

• Integrin

Differences between VLA 4 and LFA

• Effector T cells don’t express VLA 4

• Different set of adhesion molecules

Primary Antibody:

• ANTIBODY MADE BY PLASMA CELLS 

• More General - precursor B cells specific for specific different epitopes of antigens and with receptors with range of affinities for the antigen 

• Relatively low affinity

• Few somatic mutations

• initial rapid production of IgM

• Mild IgG

Secondary Antibody:

• More specific- more limited population 

• Undergo significant clonal expansion 

• High affinity for antigen 

• Extensive somatic mutation

• large amounts of IgG

• small amounts of IgA and IgE

Describe the survival requirements for naive t-cells and memory cells.

• Survival naive T-cells + memory B/T cells 

  • Stimulation with: 

    • IL7, I15

  • They don’t need contact with self peptide: self MHC complex but will for proliferation 

• Naive T cells

  • Stimulation with: 

    • IL7, I15

  • Self-peptide: self MHC complex

Describe the original antigeic skin phenomenon

• Make antibodies only against epitopes present on the initial virus 

• Only recognize the 1st antigen 

  • Try one approach and then adapt when it doesn’t work (2… time) 

• Gets reinfected with different variant/ type and memory cells don’t have knowledge 

  • Get more IgM 

  • B cells will be activated 

  • New memory cells will be made

  • responds to epitopes shared with original virus, add the subnormal response to new epitopes is retained

description of mucosal immune system:

• Protect the internal surface of the body 

• Antamically defined compartment and scattered through muscol tissues

• Large # of effector lymphocytes 

• Controlled by tissue-specific adhesion molecules + chemokines receptors

What lymphoid organs is the mucosal immune system associated with?

• Intestines, respiratory tract, urogential tract, oral cavity, pharynx, salivary glands, lachrymal glands, digestive system, lactating breast. 

  • Opening to the outside (similarities ) 

    • Communicating with outside pathogens 

  • Innate immunity 

  • Contain  white blood ____

Facts about the mucosal immune system II

• Priming of Lymphocytes in one mucosal tissue can induce protective immunity at other mucosal surfaces.

• Unique populations of dendritic cells control mucosal immune responses.

• secretory IgA class of antibody associated with mucosal immune system

• IgA deficiency is common in humans but may be compensated for by secretory IgM.

What are commensal microorganisms (microbiota)?

• Reside on the surface of the body or at mucosa without harming human health 

  • (live symbiosis with host) 

• Non pathogenic 

  • Don’t cause problems 

    • Why 

      • Non cell

      • Beneficial as they don’t allow other bacteria to grow 

        • Why? 

          • Competition / fight for resources 

            • Keep suppress bad bacteria 

why are microbiota there?

• supply the host with essential nutrients and defend the host against opportunistic pathogens

where do microbiota live?

• Mouth

• Esophagus 

• Skin

• Stomach 

• Vagina 

• Colon 

Examples of microbiota

• Lactobacillus spp. (Firmicutes), 

• Bifidobacterium spp. (Actinobacteria),

•  Bacteroides fragilis (Bacteroidetes)

•  Escherichia coli (Proteobacteria)

What are Gut-Associated Lymphoid Tissues(GALT) and Walderyer’s Ring?

• Galt

  • Comprises: 

    • the peyer’s patches, isolated lumpoid follicles, palatine tonsils, adenoid and lingual tonsils 

  • Organized secondary lymphoid tissues 

• Waldeyer’s Ring 

  • Ring of lymphoid organs that surround the entrance to the intestine and respiratory tract 

  • Comprises: 

    • Adenoids, palatine tonsils, and lingual tonsils

describe the lymphocyte population distribution in the small intestine

• Found in compartment in the intestine: 

  • Peyer’s patches + isolated lympod follicles (GALT) 

    • Separated from the content fo the intestinal lumen by tsingle layer of epithelium 

• Peyer’s pathes and mesenteirc lymph nodes

  • Contain desciste T cells and isolated follicles comprise mainly B cells 

• Lymphocytes  found scattered throughout the mucosa outside the organized lymphoid tissues: these are effector cells

  • effector T-cells and antibody-secreting plasma cells

• Found in 

  • lamina propria (floating around are effector) 

  • Peyer’s patch 

  • Follicles

what are part of the discrete lymphoid compartment?

• lamina propria

• epithelium

what’s lamina Propria?

• contains a heterogeneous mixture of IgA-producing plasma cells, lymphocytes with a ‘memory' phenotype, conventional CD4 and CD8 effector T-cells, dendritic cells, macrophages, and mast cell

what’s the difference between CD4 T cells and CD 8 T-cells?

CD4 T-cells predominate in the lamina propria, whereas CD8 T-cells predominate in the epithelium.

Describe the mechanism that M cells uptake and transport antigens

• Mechanism 

  • M cells take up antigens 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 

• Transport across cell mechanism name:

  • Transcytosis

How mononuclear cells located in the lamina propria capture antigens from the intestinal lumen? (step 1)

Soluble antigens get transported across or between enterocytes where M cells might be in the surface epithelium outside Peyer’s patches

How mononuclear cells located in the lamina propria capture antigens from the intestinal lumen? (step 2)

• Enterocyctes capture and internalize antigens though antibody complex 

  • FcRn on their surface and transport them across the epithelium by transcytosis 

  • At the basal face of the epithelium, lamina propria dendritic cells expressing FcRn and other Fc receptors pick up and internalize the complexes.

How mononuclear cells located in the lamina propria capture antigens from the intestinal lumen? (step 3)

an enterocyte infected with an intracellular pathogen undergoes apoptosis and its remains are phagocytosed by the dendritic cell

How mononuclear cells located in the lamina propria capture antigens from the intestinal lumen? (step 4)

mononuclear cells have been seen extending processes between the cells of the epithelium without disturbing its integrity. The cell process could pick up and internalize antigen from the gut lumen and then retract

Examples of leukocytes

• NK

• dendritic cells

• monocytes

• leukocytes 

What is the “type a” intraepithelial lymphocyte (IEL)?

• CD8 cryptic T cells

  • Recognize Peptides derived from virus 

• Triggered by MHC I

What is the “type b” intraepithelial lymphocyte (IEL)?

• T cells actives by IEL 

• Stressed epithelial 

How do IgA antibodies get to be sereted into the gut lumen ?

• mediated by polymeric Ig receptor (pIgR)

  

What can IgA do at the epithelial surface?

• Neutralize pathogens + toxins= prevents access to tissues + inhibit their functions 

  • How: 

    • IgA absorbs on the layer of mucus covering the epithelium 

• Neutralize antigens internalized in endosome 

  • How 

    • Antigens internalized by the epithelial cells can meet 

• IgA can export toxins and pathogens form the lamina propria while being secreted 

describe the protective response to intestinal helminths

Induce CD 4 T cells 

• TH2 induce B cells in order to switch to IgE (protective response) 

• TH1 produces inflammatory reaction. Generated when activating dendritic cells express I

what do TH3 cells do?

• Secrete TGF-beta and IL-10

• Inhibit TH1 and TH2 responses 

• Differentiation is enhanced by TGF Beta IL 4, and IL 10

how mucosal dendritic cells regulate the induction of tolerance and immunity in the intestine? (under normal condition)

• dendritic cells present in the mucosa underlying the epithelium and can acquire antigens or commensal organism

• take antigens to the draining lymph node- present them to naive CD 4 T cells

• constitutive production by epithelia cells and mesenchymal cells:

  • TGF beta, TSLP, PGE2

    • maintain the local dendritic cells in quiescent state w/ low levels of co-stimulatory molecules

      • when present antigen to naive CD 4 t cells, reg T cells generated

how mucosal dendritic cells regulate the induction of tolerance and immunity in the intestine? (invasion by pathogen)

• full activation of local dendritic cells and their expression of co-stimulatory molecules and pro-inflammatory cytokines (IL12)

• presentation of antigen to naive CD4 T cells in mesenteric lymph nodes by dendritic cells cause differentiation into effector TH1 and TH2 cells

Protective Immunity with invasive bacteria, virus, toxins:

primary Ig Production:

• Intestinal IgA

• specific Ab present in serum

Primary T cell response

• local and systemic effector and memory T cells

Response to antigen reexposure:

• enhanced memory response

mucosal tolerance w/ food proteins

primary Ig production:

• some local IgA

• low or no antibody in serum

Primary T response:

• no local effector T cell response

Response to antigen reexposure:

• low or no response

what are the three route of entry for Salmonella

1. enters and kills M cells and then infects macrophages and epithelial cells

2. invades the luminal surface of epithelial cells

3. enters phagocytic cells that are sampling the gut luminal contents

Discuss the infections from salmonella

• Enters M cells and causes apoptosis 

• Penetrates the epithelium and infects macrophages and gut epithelial cells 

• Epithelial cells express TLR 5= bind flagellin on the salmonella flagella= activating an inflammatory response via the NFkB pathway

• Induces Caspase 1 activation= promoting production of IL 1 Beta and Il 18 

• CXCL 8 is produced by infected macrophages and recruit and activate neutrophils

Discuss the infections from shigella flexneri

• Binds to M cells and is translocated benearth the gut epithelium 

• Bacteria infects intestinal epithelial cells from their basal surface and are released ino the cytoplasm. 

  • Murmamy tripeptide containing diaminopimelic acid in the cells walls of shigella bind to and oligomerize the protein of NOD1

• Oligomerized NOD1 binds to serine/thronine kinase RIPK2= trigs activation of NFkB pathways= leading to the transportation of genes for chemokines and cytokines

• activated epithelial cells release the chemokine CXCL8= acts a neutrophil chemoattractant.

• IkB inhibitor of NFkB; IkK, IkB kinase

chemokine CXCL8

Acts a neutrophil chemoattractant

Discuss the infections from C. Diff

• colon is colonized by large # of commensal bacteria

• antibiotics kill many of these commensal bacteria

• C.Diff gains a foothold and produces toxins that cause mucosal injury

• neutrophils and red blood cells leak into gut btw injured epithelial cells

• connective tissue degraded lead to colitis and pseudomembranous formation

Describe the crucial role the epithelial cells have in the innate defense against pathogens.

• TLRs +NODs activate the NFkB pathway= generate pro=inflammatory response by epithelial cells

  • production of:

    • CXCL8, CXCL1 (GROalpha), CCL1, CCL2

      • attract neutrophils and macrophages

    • CCL20 + beta defense’s

      • attract immature dendritic cells

• cytokines IL 1 +IL 6

  • activate macrophages

• epithelial cells express MIC-1 + MIC B

NOD1 and NOD2 pattern recognition receptors

• found in the cytoplasm and recognize cell wall peptides from bacteria

TLR 5

recognize flagellin

TLRs

• present in intracellular vesicles or on the basolateral or apical surfaces of epithelial cells, where they recognize different components of invading bacteria

TLRs + NODs activate ____

NFkB pathway

NFkB pathway

lead to the generation of pro-inflammatory responses by epithelial cells

discuss the immediate response in allergic reaction

• IgE-mediated mast cell activation 

• Due to the activity of histamine, prostaglandin = rapid increase in vascular permeability and contraction

  • Mass cells 

  • Prostagladin 

    • Inflammation

discuss the late-phase response in allergic reaction

• Caused  by

  • Induce synthesis and release mediators including prostaglandins, leukotrienes, chemokines, and cytokines such as IL-5 and IL-13 from activated mast cells and basophils. These recruit other leukocytes to the site of inflammation.

• associated with a second phase of smooth muscle contraction mediated by T-cells, with sustained edema and with tissue remodeling such as smooth muscle hypertrophy (an increase in size due to cell growth) and hyperplasia (an increase in the number of cells

  • Fluid leaking = swelling =edema 

    • Histamine increases the permeability of blood vessels= allowing leukocytes to bring to the site and go inside blood tissue 

    • Permeability = allows to escape

    • Allows fluid to escape 

    • Thus allowing fluid to be released into the tissue 

      • Allows lymph drainage to take pathogen to lymphoid

Describe the type I of hypersensitivity reactions

• Mediated:

  • IgE Ab-mediated

• effector mechanism

  • mast cell activation

• antigen

  • soluble antigen

Describe the type II of hypersensitivity reactions

• mediator

  • IgG Ab

• effector mechanism

  • complement

  • phagocytic

• antigen

  • cell surface antigen

  • matrix antigen

Describe the type III of hypersensitivity reactions

• mediated

  • IgG Ab

• effector mechanism

  • complement

  • phagocytic

• antigen

  • soluble antigen

Describe the type IV of hypersensitivity reactions

• mediated

  • T lymphocytes

• effector mechanism

  • Macrophage activation by T H 1

  • Eosinophil activation by T H 2

  • cytotoxicity via CD8 TC

• antigen

  • soluble antigen

  • cell-associated Antigen

Give an overview of the IgE–mediated reactions to extrinsic antigens.

• IgE is produced by plasma cells in lymph nodes

• binds to mast cells via FcERI receptor (high–affinity IgE receptor) which causes mast – cells to release their granules which causes allergic symptoms

• high permeability – things can leave blood vessels to go to tissue

Describe the process of sensitization to an inhaled allergen (respiratory tract)

Antigen invades mucous membrane by breaking down occluding – interacts w/dendritic cells, the dendritic cells pick up the Ag and present it to naïve T cells in lymph nodes

How B–lymphocytes get triggered for class switching to IgE

IgE bound to a high – affinity Fc receptor on mast cell cross–links to Ag express CD40 ligand