Immunology Flashcards
S100A12 - what is it, evidence in literature?
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)
What are the 5 proposed mechanisms for improved platelet count with vincristine administration in IMTP?
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
List mechanisms for predisposition to PTE in IMHA?
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
Adverse effects of cyclosporine use in IMHA?
1) Increases TXA synthesis –> potentially increasing thrombogenic properties of platelets.
2) GI effects (common)
Aspirin MOA?
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).
What is the difference between autoantibodies & alloantibodies?
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.
What are eicosanoids & their key function?
Eicosanoids = lipid metabolites of arachidonic acid (AA).
Roles: mediate endothelial function, vascular reactivity & proteinuria. Anti-inflammatory. Also neuroprotective.
How do neutrophil extracellular traps (NETs) form & what are their roles?
Which arm of the immune response do they belong?
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.
Name the associated with the following TLRs:
- TLR-2
- TLR-4
- TLR-5
- 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)
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?
TLRs 2, 4, 9
GSDs. TLR 4 & 5.
What is calprotectin (S100A8/A9) and what is its ligand?
DAMP, marker for neutrophilic inflammation.
Ligand = TLR-4 (type of PRR)
What is calprotectin (S100A8/A9) and what is its ligand?
DAMP, marker for neutrophilic inflammation.
Ligand = TLR-4 (type of PRR)
What is rheumatoid factor?
Autoantibodies against IgG.
Leflunomide
- MOA
- AE
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
Mycophenolate mofetil
- MOA
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
Cyclosporin
- MOA
- TDM methods
- 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
Which cytokine is responsible for eosinophil maturation & release from the BM?
IL-5
What is the MOA of oclaticinib?
JAK inhibitor. Canine anti-IL-31 monoclonal Ab.
Positive vs negative acute phase proteins?
Positive:
- Hepcidin
- SAA
- Ferritin (increased with anemia of inflammation)
Negative:
- Albumin
- Transferrin
Antigen presenting cells - which 3?
MHC-I presents Ag to ….. while MHC-II presents to …..
T cells require which lympohokines?
Dendritic cells (prsent to T cells), dendritic cells, B lymphocytes
Cytotoxic T cells, T helper cells
IL-2 (Tc growth & proliferation)
Almost all ILs esp IL4 to IL6 (B cell activation - Ab response)
GM-CSF, IFN-g
What is Felty’s syndrome?
Triad of rheumatoid (erosive) arthritis, splenomegaly, and neutropenia. Spleen is the site of immune-mediated neutrophil destruction, so splenectomy is a tx (for refractory cases).
DDx for erosive polyarthropathy?
Rheumatoid arthritis (small dogs)
Greyhound erosive PA
Juvenile-onset PA (Akitas)
Shar Pei fever
Chronic progressive PA (cats)
What serological markers can be useful in the diagnosis of SRMA? Are these prognostic?
Paired IgA in serum & CSF.
Older dogs with high CSF IgA levels tend to experience more frequent relapses and require longer duration of tx.
Most common clinical signs in dogs vs cats with SLE?
Dogs: non-erosive PA > pyrexia, renal, skin > lymphaenopathy/splenomegaly > CNS (5%)
Cats: skin (60%), pyrexia > renal, non-erosive PA, CNS (24%), IMHA (24%)
Diagnostic criteria for SLE?
Discuss interpretation of serum ANA titre in diagnosis of SLE.
What diagnostic test finding may support presence of anti-phospholipid antibodies with SLE?
Definitive dx = 2 major signs & positive ANA.
Probable dx = 2 major signs & negative ANA.
Major signs: polyarthritis, glomerulonephritis, haemolytic anaemia, leukopaenia, thrombocytopaenia, characteristic skin lesions, polymyositis
Minor signs: fever, CNS signs, oral ulceration, lymphadenopathy, pericarditis, pleuritis
ANA+ in >90% SLE cases; ANA >1:40 is positive but >1:256 is more supportive of SLE. (NB poor Sp as increased with any multi-systemic inflammatory dz, also 10% healthy animals will be ANA+)
Ab bind to cell-associated phospholipids –> interferes with the function of procoagulant phospholipids in clotting tests in vivo –> causes prolonged APTT (aka lupus anticoagulant) that fails to correct with a 1 : 1 mixture of the patient’s plasma and normal plasma
