Exam 1 Flashcards
APECED
Defect in AIRE gene - break in central tolerance - fungal infections, tan skin
ALPS
Mutation in Fas or FasL - failed peripheral tolerance - widespread lymphadenopathy, splenomegaly, autoimmune cytopenias
IPEX
FOXP3 mutation loss of Tregs - hypergammaglobulinemia very high IgE
What three factors contribute to autoimmune diseases?
- HLA - what gets presented 2. SNPs - AIRE, FOXP3, IL-2 (+T reg) 3. Environment - triggered (<60% twins, molecular mimicry, presented at same time as viral particles)
Type I Hypersensitivity
IgE mediated - requires Th2 development e.g. food allergies, asthma, allergic rhinitis
Type II Hypersensitivity
Antibody mediated
Type III Hypersensitivity
Antibody/antigen complexes
What is the mechanism of disease in Type III Hypersensitivity
Failure to clear immune complexes in circulation deposit on vasculature
Type IV Hypersensitivity
Delayed T cell mediated disease CD4 - see self and begin inflammation CD8 - see self and kill
What are some examples of Type IV Hypersensitivity?
T1D, MS, IBS, contact sensitivity, viral hepatitis, superantigen mediated shock syndrome
Neoplasia
New growth
Neoplasm
Abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of normal tissue, and persists in the same excessive manner after cessation of the stimuli that evoked the change.
Benign tumors typically end in ____.
Oma
Malignant tumors end in __________ or ___________.
Carcinoma or sarcoma
Benign tumors are by definition __________ and do not ____________.
- Non-invasive/encapsulated
- Metastasize
Tumors arising from epithelial duct cells are refered to as _________ if benign and __________________ if malignant.
- Adenoma
- Adenocarcinoma
Tumors arising from mesoderm are referred to as a _________.
Sarcoma
What are 4 examples of hematolymphoid tumors?
- Lymphoma
- Leukemia
- Plasmacytoma
- Pseudolymphoma
Tumors of the melanocytes have what origin? What is the term for a benign and malignant tumor?
- Neural crest
- Nevus
- Melanoma
Define: Tumor grade or differentiation. Is this a visible on gross or microscopic analysis?
The degree to which tumor cells morphologically and functionally resemble normal tissue.
Microscopic
Anaplastic
A complete lack of differentiation - ugly
Large nucleoli, hyperchromatic nuclei, high N/C ratios, pleomorphism, loss of polarity, atypical bizarre mitoses
Tumor in situ
Preinvasive lesion - malignant cells do not penetrate beyond BM
Dysplasia
Disordered growth of epithelium
Loss of polarity maturation, architecture/org
Abnormally located mitoses
Is moderate dysplasia reversible?
Yes - may spontaneously resolve
Is severe dysplasia reversible?
No. It is CIS
Are all benign neoplasms encapsulated?
No
Next to the development of __________, _________________ is the most reliable feature that distinguishes malignant from benign tumors.
- Metastases
- Local invasiveness
What are the steps of local invasion?
- Loosening of intercellular junctions
- Attachment
- Degredation - Type IV collagen cleavage
- Migration
What are two examples of highly invasive cancers that don’t metastasize?
- Basal cell carcinomas
- Most primary tumors of the CNS
What are the 3 main ways that malignant neoplasms disseminate?
- Seeding within body cavities
- Lymphatic spread - carcinoma
- Hematogenous - sarcoma
What organs are most frequent secondary sites in hematogenous dissemination?
Lungs and liver
What are 5 barriers to immune elimination of neoplasms?
- Tumors evade recognition - downreg MHC and immune stimulating molecules
- Activate negative regulation pathways of effector T cells
- Secrete immune suppressive enzymes - TGF-beta and IL-10
- Expansion and recruitment of reg. cells - myeloid suppressors
- IDO overexpression
What are 3 main approaches to cancer immunotherapy?
- Antibodies
- Adoptive cellular immunity
- Vaccines
What are 4 examples of antibodies killing off tumor cells via non-cellular mechanisms?
- Bind complement
- Linked to radionucleotide/toxin
- Block survival signal
- Proapoptotic
TILs
Lymphocytes cultured from tumors, removed by surgery, are expanded in culture and given back to patients to provide large numbers of highly activated T cells
What problems are associated with using TILs?
Autoimmunity: vitiligo, uveitis, immune system targets non-mutated self-antigens overexpressed on cancercells
Chimeric antigen receptors (CARs)
Antibody w/ T cell signaling motifs - not MHC restricted
Activate when they bind tumor antigen
What are some limitations of CARs?
- Doesn’t work well for solid tumors
- Can create toxic shock like symptoms (control w/ IL-6)
- Tumor antigen may be lost
- Autoimmunity
Allogneic T cells (HSC transplantation) Graft vs. Tumor Effect
Donor T cells become activated to host alloantigens
Used in leukemias
Can cause GVHD
What are 2 reasons cancer vaccines aren’t very effective?
- Traditionally used to prevent disease
- Traditional targets are smaller
What are 5 main cancer gene targets?
- Protooncogenes/oncogenes
- Tumor suppressor genes
- Anti-apoptosis genes
- Apoptosis genes
- DNA repair genes
Who might benefit from a cancer vaccine?
People with premalignant lesions, or at high risk for a certain type of cancer
What are the 5 main classes of oncogenes?
- Growth factors
- Growth factor receptors
- Signal transducing proteins
- Transcription factors
- Cell cycle regulators
What is an example of a growth factor gene mutation?
SIS gene produces beta-PDGF
Overexpression leads to astrocytoma/osteosarcoma
What are two examples of GFRs that cause cancer?
- ERB B2 (Her2/Neu) - unresponsiveness to estrogen therapy
- C-kit - YK activity - Gleevec inhibits it
What are two examples of signal transducing proteins that cause cancer?
-
Ras (pt mutated in 15-20%) - GTP-binding proteins w/ reduced GRPase activity
- K-Ras in pancreas, colon CA
- H-Ras in bladder, kidney CA
-
C-ABL gene - transient YK, not receptor linked
- t(9;22) Philadelphia Chromsome → bcr-abl fusion
- **CML and ALL **
- Constitutively active - Gleevec
What is an example of a TF that cause cancer?
Burkitt lymphoma t(8;14) co-expressed w/ Ig heavy chain on 14
- C-MYC continuously expressed
**Neuroblastoma - **N-MYC continuously amplified
What is an exmpale of a cell cycle regualtor that causes cancer?
Cyclin D1 - t(11;14) cyclin D1-IgH fusion - mantle cell lymphoma
- Activates CDK4
- Involved in G1:S transition - hyperphos Rb
What is the 2 Hit Hypothesis?
Mutations in both alleles of tumor supressor genes are required for oncogenesis.
What are 3 examples of tumor supressor genes?
- RB
- APC
- p-53
APC Gene
Involved in the destruction and down-regualtion of beta-catenin.
What does beta-catenin accumulation lead to?
Complexes w/ TCF and stimulates transcription of GFs → 100s of adenomas
Familial Adenomatous Polyposis (FAP)
APC gene mutation - 100-1000s of polyps on colon
p53
Cell cycle arrest, initiation of apoptosis following DNA damage
Li-Fraumeni Syndrome
Inheritance of mutated p53 allele
Develop multiple cancers at younger ages
25x risk developing CA by 50
What 2 things are required for repair of tissue?
- Stroma (CT)
- Existing cells - to respond to GFs
Stem cells self-renew and _____________ replicate.
Asymmetrically
What are 4 examples of growth factors involved in tissue repair?
- VEGF - angiogenesis
- FGF - angiogenesis + fibroblast migration
- PDGF - induce fibroblast and sitm production of ECM
- TGF-beta - suppress endothelial prolif/mig stim. stim production of ECM proteins
What are 3 sources involved in tissue repair?
- Leukocytes at site of injury
- Parenchymal cells
- Stroma
ECM provides mechanical support and a scaffold for _________________.
Scarless healing
What are the two main components of the ECM?
- Interstitial matrix - 3D amorphous gel - made by fibroblasts
- Basement membrane - highly organized IM around epi/endothelaia and sm. muscle cells - made by mesenchyme and epithelium
What proteins make up the ECM and what is their function? (4)
- Collagen - tensile strength
- Elastin + fibrillin - recoil
- Proteoglycan and hyaluronon - compression and GF storage
- Fibronectin - major part of interstitial matrix
Ehlers-Danlos Syndrome
Defect in collagen - 6 types
Poor tensile strength, wound healing, hyperextensible
Classic = Type V collagen
Marfan Syndrome
Mutation effecting fibrillin
Degeneration of aorta, lens defects, abnormal vlaves, long arms and legs, hyeprextensible joints
Keloid
Raised scar due to excessive collagen (Inc. TGF-beta and IL-1)
What are the 4 steps to scar formation?
- Angiogenesis
- Fibroblast migration and proliferation
- Deposition of ECM
- Maturation of fibrous tissue
Wound strength is at _____ after 1 week and plateaus by the 3rd month at ______.
10%
70-80%
What are 7 factors that influence healing?
- Nutrition - vitamin c
- Metabolic Status - diabetes - impaired neutrophil fx and macrophage, impaired vessel formation and collagen
- Circulatory Status
- Hormones: Steroids block TGF-beta and dec. fibrosis
- Infection
- Mechanical Factors
- Foreign bodies
Exuberant granulation
Protrudes above surrounding skin, prevents re-epithelialization
Blood exposures to HIV are higher risk than sexual exposures because there is a _______________________________.
Higher average number of HIV particles per mL
Why is there a greater chance of contracting HIV as a receptive partner of anal sex vs. vaginal sex?
Different tissues have different native immune populations. More immune cells/targets to invade in the GI tract than the vaginal canal
What is the mechanism of HIV transmission?
Enter thru epithelial cells
Enter Langerhaans cells
Transport to regional lymph node
Infect CD4 T cells
What are 4 natural defenses against HIV?
- Intact epithelium (vaginal stratified columnar vs. rectal single layer columnar)
- Mucous, pH, SLPI, lactoferrin, Trappin-2
- Adaptive mucosal immunity
- Presence of selective co-infection (Syphillis, HSV II, TB)
Non-circumcised individuals have a _______ chance of acquiring HIV infection.
Higher
What are symptoms of acute HIV?
Rash, diarrhea, fever, no cough, headache
What is on the differential with acute HIV?
- Strep
- Mono (CMV, EBV)
- Influena
Window period (HIV)
Routine HIV antibody tests are negative, but virus can be detected in blood
What two tests must be ordered to cofirm a diagnosis of Acute HIV?
HIV antibody test - low/non-existant
HIV-1 RNA test - high
Antibody/p24 antigen test
Cheaper than RNA test
Positive slightly later than RNA test (14 days post exposure)
Over _______ viral particles are produced daily if untreated.
1 billion
A strong ____ response is associated with _________________.
CTL
slow progression
Why is HIV difficult to cure?
DNA is inserted into genome of T cells - resevoir exists in memory T cells
Immune Reconstitution Inflammatory Syndrome
Deterioration in clinical status ~ 8 weeks after starting ART
In response to some other disease e.g. tB, MAC, p. jiroveci, histo, Hep B/C, Parvo,
Due to CD4+ cells being impacted dramatically in the ____, patients with chronic HIV are more susceptible to ________.
Gut
Bacteremia - meausre plasma LPS levels
Higher immune activation is coorelated with inc. likelihood of AIDS related event
Tumor killing follows ________________: A constant dose of drug kills a constant __________ of tumor cells
First-order kinetics
Fraction
A 2-4 log-kill is need to ________ expected lifespan. To be considered curative a regiment must have 2-4 log-kill efficiency and be repeated for __________ of therapy
Double
4-12 cycles
What are 3 mechanisms of anti-angiogenic therapy?
- Anti-VEGF
- Soulble VEGFR
- Peel off pericytes - toxic
What are 4 mechanisms of resistance to anti-angiogenics?
- Vascular mimicry
- RTKs don’t syndergize well with chemotherapy
- Makes other pro-angiogenic factors
- Fibroblasts in tumor bed are not a genomically stable compartment
What are 4 causes of edema?
- Increased hydrostatic pressure
- Decresaed plasma osmotic pressure
- Lymphatic obstruction
- Na/Water retention
What diseases cause increased hydrostatic pressure?
Venous Obstruction - DVT, mass, inactivity, cirrhosis
Congestive Heart Fialure -hypoperfusion of kidney - 2˚ hyperaldosteronism
Arteriolar dilatation - heat,
What are cuases of decreased plasma osmotic pressure?
Excessive loss of albumin and 2˚ hyperaldosteronism
Nephrotic Syndrome
IBS
Malnutrition
Cirrhosis
What are cuases of lymphatic obstruction?
Inflammatory - parasitic infection
Neoplasms
Post-surgical scarring/removal of LN
Na and Water Retnetion
· Cause inc. hydrostatic pressure and dec. colloid osmotic pressure
Excessive salt intake w/ renal insufficiency
What are two common cuases of subcutaneous edema?
Congestive heart failure/renal failure
What is a common cuase of pulmonary edema?
L ventricular failure
What is the main difference between hyperemia and congestion?
Hyperemia is an active process - inflammation/exercising muslces
Congestion is a passive back up/impaired outflow of venous blood
What factors are involved in primary hemostasis?
Platelet plug formation
Vasculature, blood flow, platelet count and fx, ECM proteins
What are the steps of platelet plug formation?
- Trauma
- Vasoconstriction (endothelin release)
- vWF binds platelet
- Active platelets change shape and recruit more via ADP and TXA2
What are the steps involved in secondary hemostasis
- Tissue factor released (begins extrinsic pathway)
- Phospholipid complex expression
- Thrombin activation
- Fibrin polymerization
What are 4 ways we develop bleeding disorders?
- Vascular integrity - Ehlers-Danlos, Scurvy
- Defects in platelet count/fx - thrombocytopenia, Glanzmann throbasthenia
- vWF deficiency/dysfunction - vWF disease
- Clotting factor deficiencies/inhibition - Vita K def, liver disease, hemophilia (Factor 8 and 9 problems) Anticoagulation (Warfarin)
Hematoma
Accumulation of blood within tissue
Petechial Hemorrhages
1-2mm in skin, mucuos memranes
Associated w/ thrombocytopenia, platelet dysfunction, loss of vascular wall support or local pressure
Purpura
>3 mm
Assoicated with thrombocytopenia, platelet dysfunction, loss of vascular wall support or local pressure
Vasculitis and vascular fragility
Ecchymoses
>1-2 cm
Bruises associated with traume
Factors that inhibit thrombosis
- Tissue factor pathway inhbitor - shuts down extrinsic pathway
- Thrombomodulin - Protein C and Protein S shut down clotting cascade (Va and VIIIa)
- PGI2- inhibit platelets
- Antithrombin III (inactivates thrombin)
Lab screen for anticoagulants?
- Protein C and S activity and antigen
- atIII activity and antigen
- Molecular abnormalities in Factor 5 or Porthrombin gnees
- Lupus anticoagulant and antiphospholipid antibodies
What are factors that put someone at risk for hypercoag?
- Factor 5 Leiden
- Protein C, S, and atIII deficiency
- Malignancy
- Estrogens
- Antiphospholipid antibody syndrome
Factor 5 Leiden
Most common inherited predisposition
Changes cleavage site for protein C
Increased clotting risk - 5-7% of Caucasians are heterozygous
Antiphospholipid antibodies
Acquired autoantibodies that inhibit phospholipids
Important to clot formation
**Arterial and venous thrombosis **
Lupus anticoagulant - in vivo promotes clotting
In vitro prolongs clotting
What three conditions help form thrombi?
Site of endothelial injury
Turbulent flow
Site of blood stasis
What are causes of abnormal blood flow?
Ulcerated atherosclerotic plaques, aneurysms, acute MI
A fib, mitral valve stenosis
What is a classic example of red infarct?
Lung infarct secondary to embolus (hemorrhagic)
Brain - colateral flow
Venous occlusions
What is an example of white (anemic) infarct?
Kidney, spleen
Arterial end arterial circulation
What is the differnece between a hematoma and hemorrhagic infarct?
Hemorrhagic infarct blood is intermixed with necrosis
Hematoma blood is collected and forms a solid mass
DIC
Small vessel clotting - organ ischemia
Bleeding tendencies - consumptive coagulopathy (platelets and clotting factors)
Shock
CV collapse
Systemic hypoperfusion
Cardiogenic Shock
Hypovolemic Shock
Hemorrhage, fluid loss – burns vomiting, diarrhea
Septic Shock
Overwhelming microbial infection à Peripheral VD and pooling of blood, endothelial activation or injury, leukocyte induced damage, cytokine activation and DIC
Neurogenic Shock
Interruption of sympathetic vasomotor input – arteriolar and venous dilation – dec cardiac output
What are the three stages of shock?
- Non-progressive phase - still perfusing organs
- Progressive phase - tissue hypoxia, lactic acidosis, lower pH
- Irreversible phase - multiorgan failure
Hypovolemic and cardiogenic shock patients have skin that is ____________________.
Cool, clammy and cyanotic
