Innate immunology 1

Question 1

TLRs

Answer 1

group of PRRs that recognize PAMPs

Question 2

TLR4

Answer 2

recognizes LPS on cell surface, signaling causes release of cytokines and cell adhesion molecules = acute inflammatory response.

LPS binds TLR4 —> MyD88 binds TIR domain of TLR4 –> IRAK4 binds MyD88 —> kinase cascade activates IKK —> release of NFKB = transcription of cytokines and adhesion molecules.

Mutation of TLR4 (D299G) causes increased susceptibility to septic shock.
Mutated IKK-gamma (NEMO) causes loss of antibody switching (hyper IgM) and recurrent infections, also conical teeth, skin and hair issues.

Question 3

TLR3

Answer 3

recognizes dsRNA (viral infections, especially important for Herpes simplex 1). Found in endosome of leukocyte.

*Requires UNC-93B endoplasmic reticulum protein for normal signaling

Question 4

TLR7 and TLR8

Answer 4

recognize ssRNA (viral infections), found in endosome of leukocyte.

*Requires UNC-93B endoplasmic reticulum protein for normal signaling

Question 5

TLR9

Answer 5

recognizes unmethylated CpG (bacterial and viral genomes), found in endosome of leukocyte.

*Requires UNC-93B endoplasmic reticulum protein for normal signaling

Question 6

NOD-like receptors (NLRs)

Answer 6

PRRs that are always intracellular and recognize PAMPs that result from intracellular digestion of pathogens. All have a CARD domain (caspase recruiting). Some have a PYD domain (pyrin).

Question 7

NOD1 and NOD2

Answer 7

recognize peptidoglycan

Question 8

NRLP3

Answer 8

NRLP3 gene encodes the NLR cryopyrin which forms an inflammasome. Binds procaspase 1 and cleaves it to caspase 1 upon macrophage activation. Caspase 1 then cleaves pro-IL-1B to IL-1B (cytokine).

Associated with FCAS1 gene variant which causes NRLP3 gain of function mutation = rash/fever/pain following exposure to cold temps.

Question 9

RIG-1-like receptors (RLRs)

Answer 9

detect cytoplasmic viral RNA, activation causes release of type 1 IFNs and cytokines in response to viral infection

Includes RIG-1 and MDA-5

Question 10

3 major functions of Type 1 IFN

Answer 10

1. induce antiviral state to limit spread
2. promotes antigen presentation and natural killer cell functions while restraining pro-inflammatory pathways
3. activates adaptive immune system

Question 11

IL-1B

Answer 11

cytokine produced by NLRP3 pathway in response to macrophage activation, helps in both viral and bacterial infections

Question 12

neutrophil extravasation

Answer 12

1. slow down: Sialyl-Lewis-x on neutrophil weakly binds a selectin on the vascular endothelium.
2. stable arrest: LFA-1 (or CR3) on neutrophil binds tightly to ICAM-1 on vascular endothelium. Enhanced by chemokine CXCL8.
3. diapedesis (squeeeeze)
4. migration into tissue

Question 13

neutrophil phagocytosis

Answer 13

neutrophils can phagocytize and kill pathogens with ROS and hypochlorite (bleach). Requires NADPH oxidase to produce the ROS/bleach.

Mutation in any one of NADPH oxidase’s 4 subunits causes CGD.

Question 14

TLR4 D229G mutation (asp to gly)

Answer 14

causes lower affinity of TLR4 for LPS, thus causing increased susceptibility to septic shock.

Question 15

NEMO mutation

Answer 15

mutated IKK-gamma (NEMO) causes loss of antibody switching (hyper IgM) and recurrent infections, also conical teeth, incontinentia pigmenti.

(assc with TLR4)

Question 16

FCAS1 gene variant

Answer 16

causes NRLP3 gain of function mutation = rash/fever/arthralgias following exposure to cold temps

assc with NLRs

Question 17

Chediak-Higashi syndrome

Answer 17

large cytoplasmic granules in the neutrophil interfere with diapedesis

Question 18

Chronic Granulomatous Disease (CGD)

Answer 18

usually X linked recessive, deficiency of any one of the 4 subunits of NADPH oxidase = inability to produce ROS or hypochlorite = susceptibility to infections/abscesses of certain pathogens that require killing by ROS/bleach. (Test with DHR assay in the lab.)

Question 19

CXCL8

Answer 19

chemokine that enhances the stable arrest of neutrophils’ LFA-1 (or CR3) binding to ICAM-1.

Question 20

UNC-93B

Answer 20

ER protein required for proper signaling by TLR3,7,8,9. Crucial for host response to herpes simplex.