Week4 Flashcards
TI Hypersensitivity
Anaphylactic, Allergic, Asthma
IgE
Early: 2-30mins, mast cells mediators (vasoperm + sm contraction)
Late: 2-8hrs-24-72hrs, cellular infiltrate (eosinophils +)
Systemic: mast cells
Local: tissue (URT/LRT, GI, skin)
Rxns: anaphylaxis, rhinitis, asthma, food allergy
[Ag] < picogram range
TII Hypersensitivity
Cytotoxic
Ab (IgM,IgG) —> binds Ag —> complement—> ADCC
Immediate onset w preformed Ab
Cell membrane action
Rxns: transfusion, hemolysis, allograft rejection, drugs, autoimmune
TIII Hypersensitivity
Immune-complex
Ag + IgM/IgG —> soluble Ab-Ag complexes —> tissue deposition
Preformed + Ab induction (6-12d)
Rxns: inflammation, vasculitis, serum sickness (complexes in kidney, joints), Arthus, drugs
Non-blanching capillary damage rash
[Ag] - mg range
TIV Hypersensitivity
DTH
CD4 Th1 cells
Pre-sensitization: Th1 stimulates by APCs
Delayed 24-72hrs rxn: Th1 re-stimulation —> cytokines (IFNy, TNFB, MCF, MIF) —> macrophage (ROI, lytic enzymes)
Skin & organs
Rxns: contact hypersensitivity, tuberculin, granulomatous
Addisons
Primary adrenal insufficiency
Autoimmune/other attack on adrenal cortex
Dec all adrenocorticosteroids
Fatigue, appetite loss, weight loss, dizzy, nausea
Hyperkalemia (via red aldosterone)
Cortisol treatment
Secondary adrenal insufficiency
Hypothalamus, pituitary disorders
Prolonged glucocorticoids
—> reduced ACTH —> reduced cortisol/androgens
Regular aldosterone
Fatigue, appetite loss, weight loss, dizzy, nausea
Cortisol treatment
Cushing’s syndrome
Adrenal, pituitary (“disease”), ectopic tumor
Increased cortisol
Iatrogenic cause most common (drugs)
Adipose distribution, hypertension, osteoporosis, immunosuppression, diabetes)
Glucocorticoid replacement therapy
Adrenal insufficiency Physiological/small doses Oral cortisol (Primary & secondary)
Glucocorticoid anti-inflammatory treatment
Suppress inflammation (asthma, RA) Pharmacological/ high doses (keep effects local, not systemic) Inhaled, topical, depot
Glucocorticoid side effects
Hyperglycaemia/insulin resistance Diabetes Fast twitch muscle atrophy Fat redistribution (central obesity) Inhibited Vit D absorption (hyperparathyroidism) Osteoporosis
Glucocorticoid antagonist
Blocks GR
Treat elevated glucocorticoid levels (ACTH tumor)
Mifepristone: progesterone R antagonist for abortion
Glucocorticoid synthesis inhibitor
Not specific Mitotane Aminoglutethimide Ketoconazole Metyrapone Trilostane
Aldosterone synthesis regulation
- RAA system (inc Ca2+ inc side chain enzyme)
- Inc extracellular K+ (depolarise ZG cells and inc Ca2+)
- ACTH (stimulates, but no feedback)
Aldosterone hypofunction
Reduced synthesis (primary) Dec in renin (diabetic renal insufficiency) Salt wasting, V depletion, hyperkalemia, acidosis
Aldosterone hyperfunction
Inc aldosterone (hyperplasia/adenoma) ECV expansion, renin suppression, potassium wasting, hypokalemia, hypertension
Mineralocorticoid agonist
Can’t use aldosterone, undergoes 1st pass metabolism
Fludrocortisone
Mineralocorticoid antagonist
K+ sparing diuretics
Hyperkalemia
Eplerenone & spironolactone
IGIV
Ig from large donor group
Normalising serum
Low doses: humoral deficiency
High doses: asthma, autoimmune, Kawasaki
Rho Ig
Human IgG w Ab to Rho(D) RBC Ag
Prevents Rh- mother sensitisation
Given 24-72hrs post birth
Hyperimmune Ig
Pools of selected human or animal donors
High titer to particular Ag (CMV, respiratory syncytial virus)
Warburg effect
Tumor cells favor lactate production over ox phos
Tumor genetic instability causes
- Homologous recombination issues (BRCA1/2)
- NER defects (UV light damage: XP)
- MMR deficiencies (DNA insertion/deletion issues —> inc microsatellite DNA variation: Lynch syndrome/HNPCC)
TAMs
Tumor associated macrophages (tumor promoting)
- GF secretion (EGG, FGe, IL6, TNF)
- Angiogenesis (VEGF, PDGF)
- Invasion/metastasis (metalloproteases)
- Immune inhibition via cytokines (TGFB?)
Hematogenous spread
Venous invasion > arterial
Desmoplastic response
Malignant
Local fibroblast response to tumor —> inc collagen
Scirrhous
Malignant tumor
Firm, irregular, gritty texture
Benign mesenchymal tumors
CT and derrivates: Fibroma Lipoma (fibrous capsule surrounds) Chondroma Lieomyoma
Benign epithelial tumors
Papilloma
Adenoma
Cystadenoma
Hamartoma
Benign tumor of cells that belong in a tissue but not arranged properly
Choristoma
Heterotropic rest
Normal cell nest from a different tissue
Teratoma
Cells from diff germ layers
Malignant epithelial tumor
Carcinoma
Spread to regional lymph nodes, then blood
T N M
Skin, glands, respiratory, renal, liver, UT, placenta, testicles, melanocytes
Malignant mesenchymal tumor
Sarcoma
Hematogenous spread —> lungs
CT, endothelial (vessels), mesothelium, muscle
Malignant cell features
Pleomorphism Anisocytosis Dec cell-cell adhesion Polarity loss Mitotic figures Hyperchromatic nuclei Chromatin clumping Large nucleoli Anaplasia Dysplasia
Epithelial progression towards malignancy
Metaplasia
Dysplasia
Carcinoma in situ
Tumor invasion routes
Direct body cavity seeding
Lymphatics (carcinomas)
Hematogenous (sarcomas)
Cutaneous fungi
Infect keratinised layer of skin, hair, nails
Subcutaneous fungi
Infect dermis, subcutaneous tissue, bone, cornea
Systemic/endemic fungi
Dimorphic, confined to specific geographic regions
Infect lung & disseminate
Opportunistic fungi
Human commensals, environmental Affect immunocompromised ppl Not very virulent Conditions: Loss of bacterial flora Iatrogenic immunosuppression Immunodeficiency Diabetes Break in skin Indwelling catheter
SDA
Standard nutrients medium for fungi
Mold growth & spore (conidia) ID
Low pH & antibacterial
1-4wks to grow at 25C
Yeast can be grown at 37C on special media
IDed directly in tissue
Cutaneous forms w KOH treatment
Definitive host
Species in which parasite undergoes sexual reproduction
Intermediate host
Species in which parasite undergoes Asexual reproduction
Incidental host
Unnatural host
Unusual pathology
Dead end host
Vectors
Transmit parasite from one host to another
Trophozite
Binary fission life cycle
Cyst
Dormant life form
Non-replicating
Resists environmental extremes
Frequently transmitted
Herd immunity
Insufficient # of non-immune individuals to sustain transmission of an organism
Live vaccines
Attenuated: no virulence, can grow & elicit response
Antigenically cross-reactive: not human pathogen, shares similarity to produce response (smallpox)
Inactivated / killed vaccine
Whole: structural proteins intact (polio, measles)
Subunit: specific subunit w antigenic determinants
CYP11A1
Side chain cleavage enzyme
Converts cholesterol to pregnenolone
+ StAR
CYP11B1
ZF
Cortisol
Corticosterone
Deficiency: excess aldosterone & androgens
CYP11B2
ZG
Aldosterone synthase
CYP17
ZF/ZR
17a hydroxylase
Androgens & cortisol
ACTH absence
Atrophy if ZF, ZR
ZG
Angiotensin II & Hugh serum K+ tropic factors
Transcortin
Binds cortisol
High affinity
Low capacity
Albumin
Binds cortisol
Low affinity
High capacity
TII GR
Glucocorticoid receptor
Cortisol causes GR-hsp90 dissociation
Nucleus translocation
GRE binding (10% of all genes)
Cortisol metabolic effects
Liver (gluconeogenesis)
Muscle (aa release)
Adispose (HSL activation)
Cortisol anti-inflammatory effects
Annexin I (inhibits PLA2) MAPK phosphatase I (blocks c-Jun & cytokines) Blocks NFkB (anti-cytokine)
Fludrocortisone
Mineralocorticoid agonist
F at C9
Use instead of aldosterone
Prednisolone
Methylprednisolone
Glucocorticoid
Dbl bond
CH3
Dexamethasone
Glucocorticoid > mineralocorticoid
F & CH3
Cortisone / Prednisone
Absorbed better than cortisol (oral) Inactive topically Carbonyl replaces OH Inactive Prodrug activated by liver (11B-HSD1) Inactive form produced by kidney (11B-HSD2)
Inhaled corticosteroids
Extensive 1st pass metabolism, don’t go systemic
Fluticasone, beclomethasone, flunisolide, triamcinolone
Topical corticosteroids
For psoriasis & dermatitis
Can’t use prodrugs
Cortisol, methylprednisolone, dexamethasone
Depot corticosteroids
Intra-articular
RA/gout
Methylprednisolone in polyethylene glycol
Glucocorticoid tapering
<2wks no taper
2-4wks = 1-2wk taper
>4wks = 1-2mo taper
High cortisol suppresses CRH/ACTH —> cortical atrophy
TI GR
MR (mineralocorticoid receptor)
Nucleus translocation
CYP21 deficiency
Most common congenital adrenal hyperplasia
Anti- aldosterone & cortisol
Transplant prep
Immunosuppression drugs
Daclizumab
ATG
Anti-CD3
Hyperacute & chronic rejection
Can’t be stopped
Acute rejection
Calcineurin inhibitor (cyclosporine / tacrolimus) +
Cell cycle inhibitor (mycophenolate mofetil / sirolumus) +-
Steroids
Goodpastures
T II rxn Glomerulonephritis Auto-Ab against basement membrane Alveolar haemorrhage Smooth distribution
Graves’ disease
Auto-Ab against thyroid acinar cells (LATS)
Mimic TSH
Inc thyroid hormone production
IgG Ab mediated (placental transfer)
Anti-TSH receptor Ab
T3/T4 overproduction
TII hypersensitivity
Ag tolerogenic response
IV, oral, inhaled Ag Very large doses Prenatal & neonatal periods Persistence in host No adjuvants (gel, salt) Low costimulation
CD22
On B cells
FcyRIIB receptors
Cows-linkage inhibits activation
Prevents low affinity IgM from being produced if high affinity IgG is already being made
Neuroendocrine regulation
Stress —> corticosteroids & endorphins
IL-1/6 —> inc body temp, slow wave sleep, inc ACTH —> dec Th1 /inc TGF-B
T cell positive selection
Self MHC reaction
Dbl + cells
=> MHC restriction
Others die by apoptosis
T cell negative selection
AIRE (autoimmune regulator) In thymus medulla Tx peripheral organ specific genes Inhibits autoimmunity High affinity cells deleted Self tolerance
Treg cells
Auto reactive T cells in periphery
FoxP3 (absence = IPEX)
Depend on IL-2
Induced by +TGF-B, -IL-6/23 from dendritic cells
Produce IL-10/TGF-B (inhibitory cytokines)
High CTLA-4
Peripheral T cell tolerance
Anergy (only Signal #1) CTLA-4 down regulation Persistence of self-Ag AICD (T cells express Fas, via exhaustion) Treg cells
Central B cell tolerance
Receptor editing:
Self-Ag prompt RAG1/2 rearrangement of VJ LC
Failure = clinal deletion, anergized
Peripheral B cell tolerance
Depends on T cell tolerance
Controls autoreactive B cell proliferation
B vs T cell tolerance
Naive B cells shorter lived
Ig somatic mutation
T cell help from neighbors
Immune privilege
Brain
Testes Ovary
Placenta
Eye
Infections breaking tolerance
- Disruption of barrier exposing sequestered self Ag (eye)
- By-stander effect (inc B7 on self MHC cells)
- Foreign Ag binds to self —> epitope spread
- Molecular mimicry —> cross reactive T/B cells —> effector activation
- Polyclonal activation vs superantigen
Autoimmune progression
Predisposition (genes, hormones)
Stochastic event (environment, mutation, infection)
Propagation (epitope spread)
MS
Relapsing-remitting or chronic progression
IL-17/Th17 cells
Fas on oligodendrocytes
TI Diabetes
CTLs
Th1 cells
Macrophages
TIV hypersensitivity
Pernicious anemia
Auto-Ab against IF
TII hypersensitivity
B12 supplement
SLE
TIII hypersensitivity
Lumpy bumpy glomerulonephritis
High ANA (B cell) + nuclear debris
Histone H1 reactive Th cells can activate anti-histone/anti-DNA B cells
RA
Early: neutrophils, lymphocytes, plasma cells
Late: lymphocytes, plasma cells, macrophages, fibroblasts (calcify)
RF
T cells
MG
Anti-Ach Ab IgG (placental transfer)
TII hypersensitivity
Folding membrane destruction
MLR
Mixed lymphocyte reaction
T cells and foreign MHC II
Donor + recipient: one way (irradiate)
Quantitate 3H thymidine in DNA
PRA rest
Panel reactive Ab Pre-transplant evaluation Recipient serum + pooled WBCs donors Complement + blue dye Inc PRA = inc preformed Ab
Crossmatch
Once ID donor
Recipient serum + donor PBCs
Positive is bad
Serological Ab lysis
Microcytotoxocity
Cells + Ab against specific HLA
+ complement —> lysis
Cr release assay
CTL response test, MHC I
Target cells loaded w Cr51
Donor target (HvG)
Recipient target (GvH)
HSCT HLA match
10 Ag gold standard
HLA A, B, C, DR, DQ
Platelet granulomere
Alpha (PDGF, VWF, Va)
Delta (Ca2+, ADP, ATP, serotonin)
Lambda (lysosomal enzymes)
ATIII
Antitheombin III Liver Inactivates t & Xa & others Serpin Heparin inc activity
Protein C-S Complex
Inactivates VIIIa & Va
Thrombin-thrombomodulin complex
Factor V Leiden
Thrombophilia / hypercoaguability
Resistant to APC
