Immunology

Question 1

S100A12 - what is it, evidence in literature?

Answer 1

S100A12 = calgranulin C. Cytoplasmic damage-associated molecular pattern found predominantly in Np & Mp involved in activation of phagocytic cells.
Evidence:
- Faecal [S100A12] associated with disease activity in dogs with IBD.
- Serum [S100A12] increased in dogs with PLE or FRE.
- Serum [S100A12] positively correlated with dogs with higher hepatic necroinflammatory scores on liver bx (congenital PSS, CH, hepatic neoplasia)

Question 2

What are the 5 proposed mechanisms for improved platelet count with vincristine administration in IMTP?

Answer 2

LaQuaglia JVIM 2021
1) Fragmentation of megakaryocytes
2) Inhibition of platelet phagocytosis
3) Interference with formation of anti-platelet antibodies
4) Inhibition of anti-platelet antibody binding
5) Stimulation of thrombopoiesis

Question 3

List mechanisms for predisposition to PTE in IMHA?

Answer 3

1) Platelet dysfunction: dogs with IMHA have been shown to have hyperactive platelets associated with platelet plasma membrane alterations –> activated platelets release vasoactive molecules such as serotonin and thromboxane A2 –> may contribute to a hypercoagulable state.

2) Use of glucocorticoids

Question 4

Adverse effects of cyclosporine use in IMHA?

Answer 4

1) Increases TXA synthesis –> potentially increasing thrombogenic properties of platelets.
2) GI effects (common)

Question 5

Aspirin MOA?

Answer 5

Cyclooxygenase (COX) inhibitor -decreases TXA A2 synthesis & irreversibly inhibits platelet function. (COX enzyme is essential for conversion of arachidonic acid to several biologically
active prostaglandins (TXA A2) necessary for normal hemostasis).

Question 6

What is the difference between autoantibodies & alloantibodies?

Answer 6

Alloantibodies = immune antibodies that are only produced following exposure to foreign RBC antigens. Produced by exposure to non-self RBC antigens but are of the same species. They react only with allogenic cells.

Autoantibodies = antibodies that target **self antigens **present on the patient or donors’ own RBCs.

Question 7

What are eicosanoids & their key function?

Answer 7

Eicosanoids = lipid metabolites of arachidonic acid (AA).
Roles: mediate endothelial function, vascular reactivity & proteinuria. Anti-inflammatory. Also neuroprotective.

Question 8

How do neutrophil extracellular traps (NETs) form & what are their roles?
Which arm of the immune response do they belong?

Answer 8

After activation by LPS/CXCL8, Np release azurophil granule contents & release DNA strands, proteins, lysosomal enzymes into ECF –> collectively form a network of fibres (NETs).
NETs are coated with antimicrobial proteins, granule components; which physically capture bacteria & kill them.

Innate immune response.

Question 9

Name the associated with the following TLRs:
- TLR-2
- TLR-4
- TLR-5

Answer 9

• TLR2 recognizes lipopeptides and lipotechoic acid mainly found in the cell wall of G+ bacteria
• TLR4 recognizes lipopolysaccharide (LPS) present in the cell wall of G- bacteria
• TLR5 recognizes flagellin (main protein of bacterial flagella)

Question 10

What TLRs are upregulated in the duodenal & colonic mucosa of dogs with IBD?
Which breed has TLR polymorphisms associated with IBD, and which TLRs are they?

Answer 10

TLRs 2, 4, 9
GSDs. TLR 4 & 5.

Question 11

What is calprotectin (S100A8/A9) and what is its ligand?

Answer 11

DAMP, marker for neutrophilic inflammation.
Ligand = TLR-4 (type of PRR)

Question 13

What is rheumatoid factor?

Answer 13

Autoantibodies against IgG.

Question 14

Leflunomide
- MOA
- AE

Answer 14

Active metabolite = teriflunomide. Inhibits DHODH = Dihydroorotate dehydrogenase (rate-limiting enzyme in de novo synthesis of pyrimidines)
May induce T reg production.

Mild-moderate GI toxicity
Myelosuppression: neutropenia, anaemia (rare – high doses)
Cutaneous drug reactions (can be severe – TEN, SJS), hepatotoxicity, respiratory signs (dyspnea, cough), pulmonary lesions (interstitial lung dz), lethargy, hyperchol

Question 15

Mycophenolate mofetil
- MOA

Answer 15

Selective & reversibly inhibits IMPDH = inosine monophosphate dehydrogenase (key enzyme in the rate of guanine monophosphate synthesis in de novo purine biosynthesis)
Selectively acts on activated T cells (IMDPH found in activated but not resting cells)
Inhibits B & T cell proliferation > reduces Ab pdtn

Question 16

Cyclosporin
- MOA
- TDM methods

Answer 16

• Binds to cyclophilin A (predominant cyclophilin within T-lymphocytes), forming a complex with high affinity for specific cell receptors on calcineurin –> inhibits calcineurin function –> blocks TCR-activated signal transduction pathway involved in transcription of cytokine genes (esp IL-2).
• Resultant decreased IL-2 expression in CD4+ Th1 cells –> blocks proliferation and activation of both helper and cytotoxic T-lymphocytes
• Overall suppresses cell-mediated immunity.
• Also suppresses IL-3, IL-4, TNF-α production; indirect suppressive effects on granulocytes, macrophages, natural killer cells, eosinophils, and mast cells. Also B cells.

TDM:
- PK – whole blood [ ]
- PD – functional assays analyzing T-cell activation & IL-2 & IFN-g suppression

Question 17

Which cytokine is responsible for eosinophil maturation & release from the BM?

Answer 17

IL-5

Question 18

What is the MOA of oclaticinib?

Answer 18

JAK inhibitor. Canine anti-IL-31 monoclonal Ab.

Question 19

What is calprotectin (S100A8/A9) and what is its ligand?

Answer 19

DAMP, marker for neutrophilic inflammation.
Ligand = TLR-4 (type of PRR)