#6 Inflammation, Apoptosis, Response to Danger Signals

Question 1

How do APCs recognize pathogens?

Answer 1

The PRRs allow APCs to discriminate between self and non-self

They can recognize pathogens and are quiescent until they are activated via a set of PRRs (recognize PAMPs).

Question 2

Danger Theory (Model)

Answer 2

Immune system detects “danger” (damage) signals from injured tissues, rather than by the recognition of non-self→activate APCs

Question 3

Humoral response to danger signals

Answer 3

Soluble inflammatory mediators:

Activation of complement, immune cells (releasing chemokines, PG’s, leucotrienes, ROI, NO etc)

Question 4

Necrosis

Answer 4

Cell gets injured→ necrosis→release danger signals→immune cell is activated→ innate immune response (leukocytes and inflammatory mediators)

Question 5

Danger signals:

HMGB1

Answer 5

“High mobility group box 1”. Receptor=RAGE

Released during necrosis

-Activates NF-κB pathway (in DC)

Question 6

Danger signals:

Uric acid

Answer 6

Activates NF-κB pathway (in DC)

Question 7

Danger signals:

HSPs

Answer 7

Induce NF-κB pathway and release of inflammatory cytokines (TNF-α and IL-1β) (in DC)

Question 8

Acute Inflammatory Response (common signs)

Answer 8

1. ↑ blood supply→redness and heat
2. ↑ capillary permeability→ swelling and pain
3. ↑ neutrophils
4. Arrival of MΦ (16-48 hrs)
5. MΦ phagocytosis of debris, restoring homeostasis

Question 9

Stages of Acute Inflammatory Response

Answer 9

1. Detection of danger/damage signal via PRR
2. Leukocyte Recruitment and Elimination of Stimuli (release of inflamm. mediators)
3. Resolution (Mφ clean up everything via scavenger receptors-type of PRRs)
4. Wound healing (Mφ stimulate fibroblasts by releasing TGF-β. (Tissue repair, angiogenesis, re-epithelialization)

Question 10

Inflammation in Atherosclerosis

Answer 10

1. Monocytes recruited via activated endothelium→Mφ
2. Several microbial molecules recognized by TLRs→activate cells
3. Inflammatory cytokines, chemokines, ROI, NO are released
4. Inflammation/tissue damage
5. Mφ accumulate lipids and become foam cells

Question 11

Apoptosis

Answer 11

Apoptotic cells=removed without tissue inflammation (necrosis can cause damage)

• Doesn’t give off danger signals→no immune response
• HMGB1 is not released during apoptosis
• Can render APCs into a tolerant state
• Anti-inflammatory IL-10, TGF-β and regulatory T cells may contribute to the process

Question 12

What is immunological tolerance?

Answer 12

Process by which the immune system does not respond to Ag (lymph node)

Question 13

Mechanisms of Apoptosis: Fas

Answer 13

Each cell expresses Fas but only activated lyphocytes express Fas ligand (FasL)

Question 14

Caspases in Apoptosis

Answer 14

Major executioners, cysteine proteases, orchestrate changes, latent precursors, destroy key components of cell infrastructure

Question 15

Autoimmune Lymphoproliferative Syndrome (ALPS)

Answer 15

Abnormal lymphocyte survival caused by defective Fas mediated apoptosis

-Majority of patients have heterozygous mutations in gene encoding Fas

Patients have:

• chronic adenopathy and/or splenomegaly in early years of life
• chronic persistence and activation of both T cells that stimulate B-cell maturation (Abs in blood)
• Extended survival of lymphocytes due to defective Fas-mediated apoptosis may allow malignant transformation to occur

Question 16

Intrinsic Mitochondrial Pathway

Answer 16

3 triggers: Bcl-2 (BAK, BAX), Ca 2+, Free radicals

Regulators: Cyt-C

Executioners: Casp 9 → Casp 3

Question 17

Extrinsic Apoptotic Pathway

Answer 17

Fas ligand binds to Fas (belong to TNF)→FADD (death domain) →caspase 8→caspase 3→apoptosis