Unit 4 - Wk 5 Immunology

Front 1

Step 1 in allergy response?

Back 1

DC* phagocytoses antigens and begins to express costimulatory molecules [B7-1 (CD80); B7-2 (CD86)] and CCR7 which causes it to travel through lymph to LN* paracortex (T cell area). This starts the adaptive immune response. DCs activated in this way (without recognition of microbial products by PRRs* since the antigen is not a microbe) do not produce IL-12.

Front 2

Generic Allergic Response

Step 2?

Back 2

*DCs present peptides from ingested antigens on MHC class II to naïve CD4+ T cells. CD28 on T cells also binds costimulatory molecules (listed above) on DCs. Naïve CD4+ T cells become activated.

Front 3

Generic allergic response

Step 3?

Back 3

*IL-4 from previously activated CD4+ TH2 cells or mast cells causes differentiation of newly activated CD4+ T cells into TH2 effector and long-lived TH2 memory cells. Some TH2 effector cells lose expression of CCR7 (and begin to express some CXCR5), causing them to move out of LN paracortex and toward the LN follicles.

Front 4

Generic Allergic Response

Step 4?

Back 4

Antigens enter LN* via lymph and activate naïve B cells in LN follicles by binding to their BCR (C3d on antigen also binds CR2 on B cell)*. Newly activated B cells begin to lose expression of CXCR5 and begin to express CCR7, causing them to move toward the newly activated CD4+ TH2 cells at the edges of the LN follicles. Bound antigens are taken up by receptor-mediated endocytosis into activated B cells, processed into peptides, and loaded onto class II MHC and presented to these TH2 cells.

Front 5

Generic Allergy Response

Step 5?

Back 5

IL-4 (+ IL-13) produced by TH2 cells, and interactions between CD40L on the TH2 cells and CD40 on the B cells, cause B cells to class switch from IgM to IgE.

Front 6

Step 6?

Back 6

B cells differentiate into plasma cells that secrete IgE antibodies which bind FceRI (high affinity receptor for IgE) on mast cells (also on eosinophils and basophils).

Front 7

Generic Allergic Response

Step 7?

Back 7

Other effector TH2 cells lose expression of CCR7 and travel out of LNs* to other sites where the antigen is present, being presented by local antigen-presenting cells (i.e., macrophages). Cytokines from these TH2 effector cells are responsible for:
IL-5: eosinophil production (by bone marrow) and activation
IL-4: differentiation of newly activated CD4+ T cells into TH2 cells in local LNs
IL-13 (+ IL-4): mucus secretion by epithelial cells
IL-13: stimulation of fibroblasts to synthesize collagen (long-term this can cause tissue fibrosis)
IL-4, IL-13 and IL-10: alternatively activate macrophages, so that they produce IL-10, TGF-b and growth factors. Although alternatively activated macrophages play an important role in wound healing, cytokines produced by these cells (especially TGF-b) may cause pulmonary fibrosis.

Front 8

Generic allergic response

Step 8?

Back 8

Cross-linking of FceRI on mast cells or basophils (not shown) by multivalent antigens* activates these cells which causes them to degranulate*, produce/release lipid mediators, and secrete cytokines (IL-1, TNF-a; IL-4, IL-5 and IL-13). Lipid mediators*, chemotactic factors, PAF* and cytokines released from mast cells recruit and activate eosinophils, basophils, neutrophils and TH2 cells*. Products from these recruited cells amplify the reaction, cause tissue damage and inflammation.
Cytokines from activated mast cells are responsible for:
IL-1 and TNF-a: inflammation
IL-5: eosinophil production (by bone marrow) and activation
IL-4: differentiation of more newly activated CD4+ T cells into TH2 cells in local LNs
IL-13 (+ IL-4): mucus secretion by epithelial cells
IL-13: stimulation of fibroblasts to synthesize collagen (long-term this can cause tissue fibrosis)

Front 9

Generic allergic response

Step 9?

Back 9

Major basic protein and eosinophil cationic protein (both toxic to epithelial cells), and proteases from eosinophils contribute to tissue damage.

Front 10

Development and Migration of B and T cells

Back 10

Front 11

CXCR5

Back 11

Chemokine receptor that binds chemokines produced in LN follicles

Front 12

CXCR5

Back 12

Chemokine receptor that binds chemokines produced in LN follicles

Front 13

CCR7

Back 13

Chemokine receptor that binds chemokines produced in LN paracortex

Front 14

Actiavted T and B cell interaction

Back 14

Front 15

What stimulates class switching to B cell IgE?

Back 15

IL-4 produced by TH2 cells

Front 16

Atopic

Back 16

Genetically predisposed to allergy

CD4+T cells respond to IL-4; this happens more often in people who are atopic

Front 17

IL-4

Back 17

Induce B cells to class switch to IgE

Front 18

IL-5

Back 18

Important in development and activation of eosinophils

Front 19

IL-13

Back 19

Stimulates mucus secretion by epithelial cells (an allergy/asthma symptom)

Front 20

Mast Cells

Back 20

Arise in BM from stem cells;

IL-9 = mast cell production

Front 21

Sensitization phase of immediate hypersensitivity

Back 21

TH@ cells produced to antigen (bee venom); IL-4 from TH2 induces B cells to switch to IgE

Plasma cells produce IgE; IgE binds with high affinity to FCR1s on mast cells, basophils and eosinophils throughout the body

Front 22

What kind of antigen is necessary to cross link bound IgE on FCR1s on mast cells?

Back 22

Multivalent antigens;

cross linking results in mast cell activation and degranulation

Front 23

What kind of antigen is necessary to cross link bound IgE on FCR1s on mast cells?

Back 23

Multivalent antigens;

cross linking results in mast cell activation and degranulation

Front 24

Anaphylaxis

Back 24

Antigen cross links IgE bound on FCR1s on mast cells; mediators released upon degranulation can cause bronchial constriction, massive tissue edema and cardiovascular collapse

Front 25

Products of activated mast cells and anaphylaxis

Back 25

Mast cell granules contain vasoactivate amines (HISTAMINE), lipid mediators and platelet activation factor

Granule contents and lipid mediators are primary cause of immediate or initial reaction (within minutes) of vasodilation, vascular leakage, and smooth muscle spasm

Front 26

Late Phase of Immediate Hypersensitivity Reaction

Back 26

Leukocytes recruited to site;

Front 27

Why do pts receive broad spectrum antiinflammatory drugs (corticosteroids) after severe allergic attacks?

Back 27

Inflammation caused by tissue damage during late phase allergic reactions (leukocyte recruitment)

Front 28

How do basophils contribute to Type I hypersensitivity (and anaphylaxis)

Back 28

basophils are structurally similar to mast cells; are blood granulocytes that express high levels of FC3R1; when recruited to tissues they act like mast cells by producing vasoactivate amines, lipid mediators and cytokines; they thus contribute to type I hypersensitivity reactions

Front 29

Superantigens and shock

Back 29

Exposure to high concentration of superantigen activates large numbers of T cells (eventually leads to anergy)

Activated T cells produce large amounts
of IFN-g (and TNF-a)

IFN-g activates large numbers of macrophages which produce pro-inflammatory cytokines
(IL-1, TNF-a) and nitric oxide (NO)

TNF-a activates endothelial cells

Activated endothelial cells produce NO

This “cytokine storm” (especially TNF-a and NO) can cause shock due to peripheral vasodilation (decreases blood pressure)

Front 30

Toxic Shock Syndrome Toxin

Back 30

TSST-I exotoxin of staph aureus

Front 31

How do PRR cause septic shock?

Back 31

Microbial (or damage) product binds to PRR (i.e., LPS binds TLR4)

Binding causes activation of receptor-bearing cells which produce factors (i.e., TNF-a, IL-1, IL-6, NO for macrophages)

Endothelial cells become activated in response to microbial products or
cytokines (i.e., TNF-a)

Activated endothelial cells produce NO, IL-6 and IL-8*

TNF-a, NO (+many other factors*) cause vasodilation (etc.) resulting in shock

Front 32

Describe the role of C5a and C3 a (called anaphylatoxins) in shock

Back 32

Complement activation (directly by microbes; or indirectly through proteolysis by plasmin (cleaves C3) or kallikrein (cleaves C5), or proteolysis by mast cell proteases causes activation of mast (and endothelial) cells

Mast cells have receptors for C5a and C3a

Because of the ability of C5a and C3a to activate mast cells, they are called anaphylatoxins

Additionally:
- C5a can cause vasodilation directly
- C5a is chemotactic for leukocytes