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224 Cards in this Set
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Is HSV-2 unenveloped?
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No
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Where does HSV-2 become lytic vs latent?
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Lytic/productive infection in epithelial cells
Latent infection in neurons |
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What is the #1 cause of genital lesions?
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herpes
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What are the 3 steps of gene transcription in HSV-2?
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Virus DNA goes to nucleus, transcription of immediate early genes (alpha) (temporal)
Transcription of early (beta genes (genome replication) Viral DNA replication (rolling circle replication) Transcription of late (gamma genes (structural proteins) |
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What happens during the lytic portion of HSV-2 infection?
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Transmitted by body fluids
Virus infects, replicates in and kills epithelial cells (1-5 days) 5 days post-exposure (virus is shedding) local symptoms -- pain, itching systemic symptoms -- fever, headache, tender lymph nodes lesions appear 5-15 d. post-exposure Lesions become wet, ulcer |
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What kind of transportation is used for 1. infection of neurons and 2. reactivation?
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1. retrograde
2. anterograde |
high yield
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For HSV, where does transcription and translation occur?
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transcription- nucleus
translation- cytoplasm |
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What are LATs? Latency-associated transcripts (RNAs)
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expression is associated with the downregulation of early HSV genes to prevent virion progeny production, helps establish latency
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What is the Prodrome phase ?
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tingling or burning in original lesion site; involves recurrent infections
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How do newborns get herpes? Where does it infect? What does it cause? Why is it so severe?
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Contracted during passage of infant through birth canal when mother is shedding virus during delivery
HSV disseminated to the liver, lung, CNS Septic, skin lesions CNS infection results in death, mental retardation, neurological disability Neonates have no Cell Mediated Immunity |
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How does HSV-2 evade your immune system?
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Latent in ganglia -- protected from host’s CTL response (nerve cells don’t express MHC I; no viral Ag being produced)
Moving cell-to-cell -- protected from host’s antibodies Replicating in epithelia -- immunevasion proteins (soluble antibody and complement receptors) |
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How does acyclovir become activated? How does it inhibit viral DNA synthesis?
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HSV thymidine kinase
HSV-2 DNA polymerase incorporates acyclovir into viral DNA Viral DNA synthesis inhibited |
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What are the limitations of acyclovir??
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can't clear latent infection
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Why doesn't a condom not protect completely against HSV?
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lesions may not be covered
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Are acyclovir resistant mutants more or less virulent?
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less
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How do you test for HSV?
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antibody band test
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What does HPV infect?
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Infect squamous epithelium of skin (warts) or mucous membranes (genital, oral)
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How does HPV give you cancer?
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E6- binds p53
p53 detects genetic mistakes and makes cells either to correct mistakes or die E7- binds Rb (uncontrollable, constitutive growth) RB binds to E2F to prevent it from being a transcription factor. |
high yield
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Which HPV strains cause cancer?
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16, 18, 31
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How do you diagnose HPV?
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Warts upon visual examination
Microscopic examination of epithelial cells Hyperkeratosis (excess production of keratin) Papanicolaou stain -- gives clear staining of nucleus PCR and/or DNA probes |
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What does the abnormal pap smear look like?
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Abnormal Pap smear
Shows malformed cells, enlarged nuclei (due to transformation of cells) |
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What lowered the rate of death from cervical cancers?
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pap smears
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How do you treat HPV?
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Spontaneous regression
Cryotherapy, chemicals, laser or loop excision Precautions (use of condoms, abstinence) to prevent sexual transmission of HPV HPV vaccine for women |
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What is Dysplasia in terms of HSV cancer?
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40-70% of cases spontaneously regress back to normal
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What can't you use in Lab Diagnosis of HSV?
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No ELISAs or culturing
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Which virus is this: Reverse transcriptase present in virion virally encoded, but not a retrovirus
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Hep B
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What is the lifecycle of hep b?
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Virus binds to liver cell via HBsAg protein
DNA to nucleus; completion of dsDNA in nucleus Virus genome is integrating into liver cells and remains latent in SOME CASES transcription is regulated by host cell transcription factors RNA is packaged into virion (-) DNA is made by RT in core RNA is degraded (+) DNA is made |
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What happens with hepatitis 10% of the time?
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chronic disease
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How do you transmit HBV?
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Transmitted by sexual intercourse, blood, direct injection into bloodstream (needle)
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What are the symptoms of hep b?
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Acute infection -- long incubation period, followed by an insidious onset -- fever, malaise, nausea, abdominal discomfort, jaundice, dark urine, pale stools
Hypersensitivity reactions due to antibody-HBsAg complexes -- rash, fever, glomerulonephritis |
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What are the symptoms of hep b?
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Acute infection -- long incubation period, followed by an insidious onset -- fever, malaise, nausea, abdominal discomfort, jaundice, dark urine, pale stools
Hypersensitivity reactions due to antibody-HBsAg complexes -- rash, fever, glomerulonephritis |
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How do you diagnose hep b?
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Clinical symptoms and elevated liver enzymes
HBsAg, HBcAg are secreted into the blood during virus replication Best way to measure a recent acute infection is to detect anti-HBc IgM. |
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HBV Lab Diagnosis
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Clinical symptoms and elevated liver enzymes
HBsAg, HBcAg are secreted into the blood during virus replication Best way to measure a recent acute infection is to detect anti-HBc IgM. |
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HBV Treatment, Prevention and Control
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No cure-all. IFN and anti-herpes drugs are being tried.
Screen blood or blood products for HBsAg and anti-HBc Vaccination recommended for infants, children and people in high risk groups Subunit vaccine, recombinant HBsAg |
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What are the chances of chronic infection from birth to older children and adults?
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decrease
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Why is it impossible that polio vaccines created AIDS?
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Original vaccines stocks were negative for SIV and HIV
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Where did HIV originate?
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non-human primate host
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What is the difference between p24 and p17 in AIDS?
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P24 proteins make up the capsid
P17 surrounds the capsid |
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What are gp120 and gp41 used for in AIDS virions?
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Gp120 + gp41 are used to attach to host cells
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What kind of cells can be infected by HIV?
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Only cells with CD4 and chemokine receptors can be infected by HIV
(macrophages, CD4+ T cells, microglia) |
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What are the two tropic evens of HIV?
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M-tropic HIV-1 -- infects cells with CCR5 and CD4 (macrophages); tropism of HIV-1 at the beginning of an infection
T-tropic HIV-1 -- infects cells with CXCR4 and CD4 (T cells); tropism of HIV-1 at later stages of infection |
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What mutation gives resistance to HIV and why?
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CCR5-32 mutation -- people are resistant to M-tropic HIV-1
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What are the steps of the HIV lifecycle?
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Viral RNA genome enters cytoplasm
Pre-synthesized Viral RT transcribes RNA to ss cDNA Viral RT transcribed ss CDNA to dsDNA ds DNA goes to host nucleus dsDNA integrates into host DNA with preformed viral integrase |
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Why do gag, pol., and env need to be protelytically processed?
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to generate mature viral proteins
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What are the 3 stages of a HIV infection?
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Acute Retroviral Syndrome (Phase where the host is desparately trying to fight back): Extensive seeding….viremia….infected macrophages and dendritic cells are seeding lymphoid tissues across the body.
A middle chronic phase: Asymptomatic: Clinical latency: Full blown AIDS |
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What 2 tests are done to identify and confirm HIV infection?
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ELISA, Western Blot
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What is the problem with HIV rapid test?
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A negative result does not mean you don't have AIDS
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bDNA = branched DNA test
What is it for? What is the caution? |
Measures the viral load present in the blood
Used for testing donated blood Caution: tests may be negative if patient is on anti-HIV drugs, but virus is not necessarily cleared from the body |
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What is the HAART cocktail?
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Reduces viremia, but, once the medication is stopped, the viremia is back
Generally given once the CD+ T cell count falls below 200 even if patient is asymptomatic Nucleoside Analog Reverse Transcriptase inhibitors AZT ddC ddI Non-nucleoside Reverse Transcriptase inhibitors Nevirapine delaviridine Protease inhibitors Saquinavir ritanavir |
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What are the advantages and disadvantages of HAART?
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proven clinical, virologic and immunologic efficacy
resistance requires multiple mutations targets HIV at two steps of viral replication may be difficult to use and adhere to may have long-term metabolic side effects VERY EXPENSIVE!! Does not clear virus from body |
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How do Nucleoside Analog Reverse Transcriptase inhibitors work?
Example? |
Phosphorylated by cellular enzymes, gets incorporated into viral DNA -- causes chain termination
Prevent chain elongation of DNA because there’s no 3’ hydroxyl on the sugar AZT |
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How do Non-nucleoside Reverse Transcriptase inhibitors work?
Example? |
Binds tightly to RT to prevent viral RNA from being reverse transcribed into DNA
Nevirapine |
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How do Protease inhibitors work? What is the disadvantage? Example?
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Slip into the hydrophobic active site of the HIV protease
Blocks morphogenesis of virion by preventing cleavage of the gag and gag-pol proteins Mutant strains of HIV can arise Saquinavir |
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What is T20/enfuviritide/Fuzeon?
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Blocks Binding/Fusion
Peptide blocks gp41 function to prevent viral entry into host cells |
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How do you manage AIDS?
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Check CD4 counts and viral loads every 3 months
Check CBC, CMP every 6 months Annual vaginal and anal Pap smears Start Antiretrovirals when viremia ensues or when symptoms of immunodeficiency appear and/or when T cell counts drop |
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How is HIV transmitted?
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Semen, vaginal secretions
In utero or at delivery Breast milk Blood |
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How is HIV transmission prevented?
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• Barrier precautions
• No sharing of needles-drug users • Health personnel- no re-capping of needles • Treatment of HIV-infected pregnant women, during pregnancy and immediately after childbirth • Post-exposure treatment to reduce viremia • Circumcision (2 yr Kenyan study-60 percent protection) |
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Which cells are initially infected with HIV upon first exposure?
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Macrophages, DC, Memory T cells
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How do dendritic cells unwittingly aid the virus?
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They pick up virus and home to lymph nodes and T cells. They have a DC sign receptor.
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What are the first symptoms of HIV infection?
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Primary infection- Fever
Generalized lymphadenopathy Sore throat, pharyngitis Rash, mucocutaneous ulcerations Myalgias GI symptoms |
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What type of immune response is elicited against HIV?
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Vigorous, CD8 (cytotoxic) T cell response
HIV neutralizing Antibodies |
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Why is the host immune response against the virus ineffective?
(Note: these are the same challenges to developing an effective HIV vaccine). |
HIV is able to form latent proviral DNA:
occurs early in infection has a long half-life HIV has high variability, difficult target for CTLs: 12 known subtypes intersubtype recombination events high error rate of reverse transcriptase and RNA polymerase HIV is a difficult target for neutralizing antibodies: exposed targets are highly variable (mutation) conserved targets (eg. gp41) are thermostably concealed targets (eg. gp120) are camouflaged by heavy glycosylation |
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What is the typical timeline for the development of AIDS?
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Acute retroviral syndrome- Primary HIV infection (first weeks)
Seroconversion-appearance of anti-HIV Abs (first 6 weeks) Latent phase (years) AIDS (final years) |
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What is best laboratory diagnostic marker for the development of AIDS?
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ELISA (intial) and Western blot (final) to detect serum antibodies
CD4 cell count |
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What types of opportunistic infections do AIDS patients develop? Why?
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Parasites, fungi, intracellular bacteria, and viruses. They require CD4+ T cells
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Why do AIDS patients develop cancer? What types of cancers develop?
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1) HIV disregulates the immune system causing uncontrolled cell proliferation leading to cancer (sometimes autoimmunity).
2) Due to AIDS, oncogenic viruses are unchecked by the immune system 3) Due to AIDS, cancer itself is unchecked by the immune system karposi, nonhodgkins, burkitts, primary lymphoma of brain |
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How does ART work? Why doesn’t it completely clear the virus?
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Antiretroviral agents.
Nucleoside Analog Reverse Transcriptase inhibitors Phosphorylated by cellular enzymes, gets incorporated into viral DNA -- causes chain termination Prevent chain elongation of DNA because there’s no 3’ hydroxyl on the sugar Non-nucleoside Reverse Transcriptase inhibitors Binds tightly to RT to prevent viral RNA from being reverse transcribed into DNA Protease inhibitors work Slip into the hydrophobic active site of the HIV protease Blocks morphogenesis of virion by preventing cleavage of the gag and gag-pol proteins Viral entry inhibitors- Blocks Binding/Fusion Peptide blocks gp41 function to prevent viral entry into host cells Mutation can render all of these drugs ineffective. Also, HIV hides as a latent provirus in the genome of CD4+ T cells. |
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What is the connection between tuberculosis and AIDS?
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Latent Tb becomes reactivated and CD4+ T cell levels drop.
The bacteria is no longer contained in granulomas Many areas of the world in which HIV-AIDS has fueled an increase in the incidence of active Tb! |
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What causes sepsis and who is at risk?
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70 percent of sepsis cases can be attributed to infection (lungs, abdomen, urinary tract, blood)
Systemic response to bacteria or bacterial products or extensive tissue damage TNF-α and IL-1 are major initiators “cytokine storm” Also initiated by superantigens (Staph/Strep) |
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How does sepsis cause hyperdynamic shock?
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Caused by systemic vasodilation and leakage of fluid from capillaries
Loss of blood pressure Maldistribution of body fluids and blood flow Inadequate supply of nutrients and oxygen Lactic acidosis and tissue damage Extreme demands put on the lungs -85% of patients ventilatory support -50% meet criteria for ARDS (lung damage) |
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How is sepsis diagnosed?
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Systemic Inflammatory Response Syndrome
high temp tachycardia tachypnea leukocytosis Severe Sepsis SIRS + organ dysfunction Septic Shock SIRS + hypotension + perfusion problems |
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Which organs are affected by severe sepsis and what symptoms are presented?
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Brain
ischemic encephalopathy Heart coagulation necrosis subendocardial hemorrhage contraction band necrosis Kidneys tubular ischemic injury acute tubular necrosis oliguria, anuria, and electrolyte disturbances Lungs resistant to hypoxic injury but alveolar damage “shock lung”. Adrenal insufficiency-corticol cells deplete lipids needed for synthesis of steroids. Gastrointestinal tract patchy mucosal hemorrhages and necroses “hemorrhagic enteropathy” (this can release bacterial products into blood). Liver fatty change, if more severe-central hemorrhagic necrosis. |
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How is sepsis and septic shock clinically managed?
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Early detection is essential (procalcitonin better than C-reactive protein).
Broad spectum antibiotics right away Cultures to focus antibiotic therapy Fluid replacement therapy Vasopressor therapy Ventilatory support during lung failure Insulin |
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What are the two major reasons I talked about horseshoe crabs?
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Copper based blood system and have hemocytes that coagulates in presence of LPS. They are extremely sensitive to LPS and used as a coagulation assay. All intravenous supplements are tested for LPS.
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How is the coagulation system disregulated in sepsis?
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Procoagulation Pathway --> overactive
Cytokines and pathogens Lack of inhibition by aPC Anticoagulation Pathway --> underactive Inhibited by high PAI-1 Lack of inhibition of PAI-1 by aPC |
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What is DIC and how can patients with DIC continue to bleed?
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Disseminated Intravascular Coagulation
Large amounts of clotting leads to clotting, exhaustion of clotting factors, and subsequent paradoxical bleeding. |
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What is activated protein C and why is it controversial as a treatment for sepsis?
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aPC is inhibits coagulation and increases fibrinolysis. It has not shown clear benefits (very marginal) and dangerous to patients who are bleeding (contraindicated).
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What are the basic responses that occur between infection and final tissue repair?
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Recognition --> inflammation --> [vascular effects, inflammatory cell accumulation, destruction of initial stimulus, removal, and repair]
Inflammation is initiated by INNATE immunity while ADAPTIVE immunity perpetuates it |
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What is the difference between acute and chronic inflammation?
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Acute Inflammation:
-response lasts from minutes to days -often caused by infections that are cleared -hypersensitivity reactions to transient antigens (allergic response) -subsides when pathogen and antigens are cleared Chronic Inflammation: -can last from weeks to entire lifetime -causes persistent infections (Tb) -prolonged exposure to toxic/stimulating agents (silica) -autoimmune disease (self antigen) -in all cases antigen persists -typically involves activated monocytes and T lymphocytes (Th1) (sometimes also neutrophils (Th17)) |
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How do tissue breakdown products and inert particles activate the immune system?
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They are picked up by NLRs and make cytokines.
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What is the inflammasome and what does it do?
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Multiprotein complex that contains NLR and caspace. Produces IL-1B and other cytokines.
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How do glucocorticoids work and what is the problem with their long term use?
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They bind to NF-kb receptors and turn down production. They also are transcription factors for anti-inflammatory agents.
Long term side effects mainly associated with endocrine and metabolic changes are a problem: Dyslipidemia, hypertension, GI bleeding, ulcers, delayed wound healing, muscle atrophy, osteoporosis, retarded long bone growth and delayed puberty (children with inhalers), increased sodium retention, immunosuppresion (activation of latent viruses), mood and behavioral effects, etc. |
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How do NSAIDS work and what is the problem with their long term use?
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-are non-selective COX-1 and COX-2 inhibitors.
-have pain-relieving (analgesic) effects as well as reducing inflammation. -widely used to treat Rheumatoid arthritis, Osteoarthritis, Ankylosing spondylitis and gout -long term use can lead to GI ulcers and renal problems. |
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What drugs directly target TNF-alpha and IL-1beta?
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Etanercept-soluble TNF-receptor analogue
Infliximab (Remicade)- monoclonal antibody that binds TNF-α Anakirna (Kineraet)-IL-1 receptor antagonist |
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What is the pathology of chronic inflammation, especially in the lung and liver?
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Injury --> fibrosis (scarring and loss of function)
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What is the role of T cells, fibroblasts and chondrocytes in rheumatoid arthritis?
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T cells cause inflammation and tissue destruction. Fibroblasts and chondrocytes cause tissue damage and tissue remodeling.
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What is rheumatoid factor and how does it contribute to disease?
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IgM antibody that binds to human IgG, this activates complement
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What drugs are used to treat rheumatoid arthritis?
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TNF-a and IL-1 receptor antagonists (see above). Other treatments include corticosteroid injection and COXIBS (Celebrex).
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What are the symptoms and pathologic signs of Crohn’s disease?
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Symptoms include diarrhea, abdominal pain, fever, clinical signs of bowel obstruction, passage of blood and/or mucus.
More severe involves fever, weight loss, abdominal pain or tenderness, intermittent nausea and vomiting, anemia, obstruction, abscess formation. Signs: Thickened section of intestinal wall, (normal mucosal surfaces on either side), Serosal fat deposits (creeping fat), Inflamed and ulcerated lumen, and Constriction of the lumen (can cause total obstruction). Skip lesions: sections of colon are inflamed. The skip lesions involve granulomas that lead to fissures and ulcerations. |
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What causes inflammatory bowel disease and how is it treated? Venn Diagram
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Luminal microbial and adjuvants, immune response, genetic susceptibility, and environmental triggers.
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Why is atherosclerosis considered a chronic inflammatory disease?
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inflammation, it involves the infiltration of macrophages and T cells.
Statins shut down cholesterol production and have anti-inflammatory effects |
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What is a myocardial infarction and how does it occur?
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Interruption of blood supply to heart (come on). Atherosclerotic plaque breaks off --> occlusion --> MI.
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How is atherosclerosis treated?
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Statins shut down cholesterol production and have anti-inflammatory effects
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What two cell type is commonly involved in all forms of chronic inflammation?
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monocytes and t-cells
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What happened to the first blood transfusion recipients?
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They died horribly. We didn’t know about blood types and transfusion reactions.
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What are the A, B and O blood group antigens?
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A and B blood group antigens are similar to polysaccharides found on the surface of E. coli bacteria present in normal gut flora. They are present on blood cells and other cell types.
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What are natural antibodies or isohemagglutinins, why do we have them?
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Antibodies (usually of IgM isotype) are produced against these polysaccharide antigens (TI antigens) and are called “natural antibodies” or “isohemagglutinins”.
Tolerance prevents production of antibodies to RBC antigens that you possess. |
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What 20th century innovations have made blood transfusion safer?
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Compatibility testing
Anticoagulant solutions Preservative solutions Refrigeration Blood Banks Venous access Plastic blood bags Component administration Infectious disease testing High-risk donor screening |
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What are the blood components that can be transfused? What diseases do each of them treat?
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RED BLOOD CELL IN ADDITIVE SOLUTION (Anemia)
PLATELETS (Thrombocytopenia) FRESH FROZEN PLASMA (Crytalloids are equally good volume expanders) CRYOPRECIPITATE (Clotting disorders) |
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What are the 3 major causes of anemia? How are they treated?
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Hemorrhagic anemia – result of acute or chronic loss of blood (eg. trauma, surgery)
Hemolytic anemia – prematurely ruptured erythrocytes Aplastic anemia – destruction or inhibition of RBC production in red bone marrow |
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What is a transfusion reaction? How can it be prevented?
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Transfusion reactions occur when mismatched blood is infused
Donor’s cells are attacked by the recipient’s plasma agglutinins causing: Diminished oxygen-carrying capacity Clumped cells that impede blood flow Ruptured RBCs that release free hemoglobin into the bloodstream Circulating hemoglobin precipitates in the kidneys and causes renal failure Use a cross match test and double check to watch out for clerical errors. |
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Who are considered universal donors/universal recipients?
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O- universal donors/ AB+ universal recipients
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How does universality change for transfusion of RBCs versus plasma?
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Plasma- don’t have to worry about dilute Rh factor.
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What is an acute hemolytic transfusion reaction (symptoms/cause)?
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Medical emergency
Occurs due to rapid destruction of transfused RBCs by preformed recipients Abs Mostly due to ABO incompatibility (typically type O receiving non O blood due to a clerical or procedural error). IgM mediated complement fixation leading to rapid intra vascular hemolysis The most common symptoms are chills, rigors, fever, dyspnea, light-headedness, urticaria, itching, and flank pain. Complications include DIC, shock, acute renal failure |
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What should be done if an acute hemolytic transfusion reaction is suspected?
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• If suspected, immediately stop the transfusion.
• Recheck the sample and patient identifications. Alert the blood bank; retype and cross type. • Measure serum and urinary hemoglobin; serum LDH, and serum bilirubin to confirm the diagnosis. • Intravascular hemolysis produces free hemaglobin in the plasma and urine-increased bilirubin may follow. • After the acute phase, the degree of acute renal failure determines the prognosis. Diuresis and a decreasing bilirubin usually portend recovery. Permanent renal insufficiency is unusual. • Prolonged oliguria and shock are poor prognostic signs. Organ failure and death can ensue. |
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How is a febrile nonhemolytic transfusion reaction different (symptoms/cause)?
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• Clinically, febrile reactions consist of a temperature increase of ≥ 1° C, chills, and sometimes headache and back pain. Simultaneous symptoms of allergic reaction are common (eg. skin rash, but rarely anaphylaxis).
• Anti-leukocyte or anti-platelet antibodies (This is most common in multitransfused or multiparous patients). Cytokines released from WBCs during storage, particularly in platelet concentrates, is another possible cause. Bottomline: Fever without hemolysis. So no bilirubin and oliguria. |
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What is the origin of spherocytes in a nonhemolytic transfusion reaction?
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Weaker titers of univalent antibodies against non-ABO, non Rh antigens cause stiff RBC membranes.
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What causes hemolytic disease of the newborn and how is it diagnosed and treated?
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Rh antigen. The Rh- mother makes antibodies against the second Rh+ child.
Pathology: Destruction of RBC in spleen, anemia, bilirubin toxicity accumulates in brain Prevention of Hemolytic Disease of the Newborn Diagnosis- Testing for the presence of Rh antibodies (Coombs) Prevention of Hemolytic Disease of the Newborn: -Rhogam at 28 weeks (routine), 72hrs after delivery -Plasmapheresis of mother’s blood (severe) -Transfusion of baby’s blood with Rh- RBCs (severe) -UV light to break down bilirubin (after birth) |
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What is the major barrier to successful organ transplantation?
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Histo-incompatibility
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What 3 genetic factors contribute to MHC diversity?
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Polygenic: There are several MHC class I and several MHC class II genes, encoding proteins with different ranges of peptide-binding specificity.
Co-dominant expression: Both MHC alleles are expressed in any one individual, and the products of all alleles are found on all expressing cells. Polymorphic: A single MHC gene exhibits great diversity in the population. |
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What methods are used to type HLAs?
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microcytoxicity test
Take sample, add antibody and complement. The matching sample to the antibody will lyse and have holes. Dye is added and taken up if antibody matches. mixed lymphocyte reaction Donor and recipient cells are mixed --> lack of donor-recipient match causes recipient T cell proliferation which is measured with thymidine radiation --> donor-recipient match causes no T cell proliferation and resulting radiation HLA immobilized probe typing system DNA Mircoarray |
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What is a mixed lymphocyte reaction and how does it work?
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mixed lymphocyte reaction
Donor and recipient cells are mixed --> lack of donor-recipient match causes recipient T cell proliferation which is measured with thymidine radiation --> donor-recipient match causes no T cell proliferation and resulting radiation |
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What are the reactions that contribute to graft rejection? 3 types
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Acute rejection: takes days to develop; immunosuppressive drugs can help. Graft rejection is usually a delayed-type hypersensitivity reaction: cell-mediated immune response to alloantigens through activation of resident macrophages by TH1 cells cytotoxic CD8 cells than kill the transplant
Hyperacute rejection: rapid rejection of graft. pre-existing antibodies of recipient react with graft antigens complement fixation through of vasculature of graft rapid rejection of graft. can also occur if there are preexisting antibodies against HLA antigens in women who have had multiple births and in patients who have received multiple blood transfusion or previous grafts Chronic rejection: gradual destruction of the vasculature of the graft leading to ischemia and loss of function. Often mediated by antibody-dependent cell-mediated cytoxicity. Helper CD4 T cells help naïve B cells that have BCRs specific for the HLA allotypes of the graft B-cell response alloantibodies specific for HLA class I are produced acute- T cells hyper acute- Antibodies (especially pre-existing), complement Chronic- destruction, T/B cells and antibodies |
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What causes hyperacute rejection and how can it be prevented?
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Due to pre-existing antibodies of recipient that react with graft antigens. Deposition of blood vessel walls and activation of complement.
Most dramatic form of rejection-can be detected during surgery. Will result from ABO blood mismatch (since ABO antigens are also expressed by endothelial cells of graft). Can also result from preexisting antibodies against HLA antigens-multiparous women and patients who have received multiple blood transfusions or previous grafts. Prevented by: Cross match test is done before engraftment. (blood serum of recipient is mixed with white blood cells of donor-look for lysis). |
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What are steps leading to acute and chronic graft rejection?
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Host and donor APC move to lymphoid organs.
APCs activate T cells. Effector cells home to graft via blood. T cells destroy graft. |
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What are the mechanisms by which immunosuppressive drugs prevent graft rejection?
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Cytotoxic Drugs- attach T cells
Azathioprine cyclophosphamide methotrexate mycophenolate Glucocorticoids Shut down NF-kB signaling and activate anti-inflammation genes (SEE ABOVE, Pg. 5) Cyclosporin Tacrolimus Blocks calcineurin (transcription factor of NFAT, which is increased by T cell activation) Soluble CTLA-4 Attaches to T cells (CD28) blocks B7 costimulation and causes premature cell cycle arrest. Anti-IL2Rα Antibody (Rapamycin)- IL-2 is linked to inflammation and T cell proliferation Anti-CD3 Antibody- T cell activation blocking |
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How is a bone marrow transplant different from transplants of other tissues?
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Major problem is not graft rejection but donor cells attacking recipient (Graft vs Host Disease)
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What are the steps leading to a successful bone marrow transplant?
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1. Myoablative therapy (cytotoxic drugs and irradiation)
2. Reconstitution with donor blood cells (must also be HLA matched) 3. T cells generated from donor cells need to be selected in thymus 4. T cells generated from donor cells also need to interact with donor DCs |
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What are the benefits of cord blood over bone marrow?
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More easily available
Lack of risk to donor Higher frequency of rare haplotypes Greater tolerance of mismatches Extension of donor pool Lower incidence and severity of GVHD Lower risk of transmitting viruses |
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What the cause, symptoms and treatments for graft vs host disease?
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T cells from the donor home to lymph, interact with DC, and proliferate. T cells then cause damage. Cytokines are involved. GVDH usually involves the skin, liver and intestine
Treatment involves correctly matching transplants and corticosteroids. |
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What is mixed chimerism and how is it achieved?
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All organ graft recipients retain donor leukocytes, and all bone marrow recipients retain some of their own leukocytes
Successful engraftment requires “responses of coexisting donor and recipient cells, each to the other, causing reciprocal clonal exhaustion, followed by peripheral clonal deletion.” |
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Define each type of hypersensitivity?
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•Type I, Immediate: IgE antibody triggering mast cells and eosinophils
•Type II, Antibody Mediated: IgG antibody reacting with cell surface or matrix antigens •Type III, Immune Complex Mediated: antigen-antibody complexes •Type IV: T cell mediated |
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Role of FcR
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• Opsonization, phagocytosis mediated by Fc receptors
• Activation of Complement • Antibody-Dependent cell-mediated cytotoxicity (ADCC) by Fc receptors on NK cells • Transcytosis (across epithelium) • Allows passive immunization of fetus and neonate via breast milk • Activation of mast cells and eosinophils by IgE |
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Characteristics of IgE
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Eliminate parasites, like helminths (worms), histamine granules, induces mast cell degranulation and eosinophil activation
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Phases in development of allergy:
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• Sensitization phase: CD4 TH2 T cells’ cytokine profile leads to isotype switching to IgE
• CD40L and IL-4 from TH2 cell trigger Activation Induced Deamidase in B cell (DNA repair enzyme that is required for isotype switching) • Effector phase: IgE triggers Mast cell degranulation when cross-linking with mast cell FceRI. • Immediate actions from granules and delayed and chronic effects from lipid effectors and cytokines |
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What is the point of Mast cell proteases?
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act on fibrinogen (reducing clotting) and the products of fibrinogen breakdown stimulate macrophages to release chemokines.
Other proteases create molecules that attract neutrophils. Another protease causes T cells to secrete IL-13, which increases production of mucin. The proteases CAUSE tissue damage, and late phase leukotrienes and cytokines cause more T cell influx, eusinophiles and basophils, and MORE tissue destruction (so 3 things that damage tissue). |
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What is the effect of inflammation on the GI?
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increased fluid secretion, peristalsis, diarrhea & vomiting
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What is the effect of inflammation on airways and blood vessels?
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Airways leads to decreased airway diameter, increased mucus secretion, increased congestion.
Blood vessels leads to increased blood flow, increased permeability to increase flow to lymph nodes. |
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Food allergy and anaphylaxis
What kind of response? What type of antibody? How is it systemic? What are the components of anaphylaxis? |
Can produce local or systemic response.
IgE. Systemic response of IgE cross linking receptors on connective tissue mast cells and circulating basophils. Components to anaphylaxis: laryngeal edema, bronchoconstriction, hypotension, vascular leakage. |
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Treatment of anaphylaxis
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epinephrine
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Role of platelet activating factor in anaphylaxis
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Platelet activating factor (PAF) enhances sensitivity to histamine and increases vascular leakage. PAF serum levels controlled by PAF acetylhydrolase. PAF receptors on platelets, monocytes, macrophages, and neutrophils. Failure of PAF acetylhydrolase to clear PAF may be responsible for fatal anaphylaxis.
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What is the effect of Th2 and Th1 on allergies?
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• Helper T cells (TH2) that secrete IL-4, IL-5, and IL-13 are responsible for inducing allergen specific IgE production
• Non-atopic people activate TH1 helper T cells and make IgG antibodies to same antigens • Non-atopic individuals also have T cells that recognize allergens after sensitization, but in normal individuals the T cells are kept in check by Tregs (IL-10 and TGFb) |
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What in baby skin cream gives babies allergies?
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peanut proteins
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Why are some people more prone to atopy?
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1) Variants of IL-4 promoter, IgE receptor, MHC II, beta-adrenergic receptor.
2) gene-environment interactions. Ie endotoxin exposure: endotoxin acts via TLR-4 and CD14 (binds LPS and LPS binding protein). Polymorphisms in promoter for CD14 gene related to asthma: if you have low endotoxin levels in your house, CD14 is protective. If your house has high endotoxin levels, CD14 induces asthma. 3) Maternal factors: transplacental and lactating exchange of antibodies |
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Allergy therapies:
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avoidance, cromolyn reduces mast cell degranulation, desentitization, anti-IgE antibodies.
Symptomatic treatments: antihistamine, adrenaline, corticosteroid, anti-leukotrienene, cromolyn. |
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What 2 treatments that cause allergen desensitization?
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new adjuvants like CpG DNA (TLR9 ligand) promote TH1 response. Induces Tregs and IgG secreting B cells r/t IgE.
use peanut peptide epitopes to target to induce TH1 response. |
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What is the anti-IgE treatment?
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bind IgE CH3 (aka C3) region, masking FcR (FceRI) binding site for mast cells. Allergen responsiveness returns after discontinued treatment however. Oral tolerance with TGFbeta, or cytokine antagonists may work.
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What is the acute and chronic response to inhaled antigen?
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acute response: inflammatory mediators produce mucus secretion and smooth muscle constriction. Circulating cell recruitment.
Chronic response is caused by cytokines and eosinophil products. Eosinophils are involved with the CHRONIC response! Add on neutrophils and remodeling of lamina reticularis in airway. Unspecific responses develop to smoke, etc (airway hypersensitivity). |
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What is the effect of inflammation on Skin exposure?
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Urticaria (hives, can also be induced by systemic exposure). Chronic: eczema. Urticaria is NOT necessarily caused by Type I, it is only one of many reasons that urticaria develops. Skin allergic reaction: DC, keratinocytes secrete cytokines, mast cells. Pruritus: itch.
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What is the significance of T-bet?
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transcription factor necessary for differentiation of TH1 helper T cells. When knocked out they can’t make TH1 but can make TH2 but get a lot of airway breakdown and inflammation. Increased IgE, collagen deposition.
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What is difference between type II and III hypersensitivity reactions?
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1. Difference between Type II and III- Whether or not the antigen is soluble (opsonization and attack of cells or matrix would be Type II, circulating antigen-antibody that deposits is most typical Type III). Non-IgE Antibody Related Diseases. Antigen-antibody complexes can deposit in any tissue
a. Type II- tissue antigen- If reacting with tissue antigen (cellular or extracellular matrix or red blood cells, disease is usually related to specific tissue (Type II) b. Type III- soluble antigen (immune complexes)- Other diseases (Type III) arise from deposition of antigen-antibody complexes in vessels at sites of high turbulence (branching points) or high pressure (kidney glomeruli and synovium) c. Therefore, immune complex diseases (Type III) tend to be systemic and often manifest as vasculitis, arthritis, and nephritis (not always) |
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Type II antibody
Where are the antibodies? What type of antibodies? What handles the effector function? What are examples of complement mediated and ADCC mediated type II hypersensitivity? |
Type II - Ab Cytotoxic Hypersensitivity
a. Ag present on surface of cells or matrix b. May be part of cell or exogenous Ag deposited on cell c. IgG mostly, occasionally IgM d. Effector function through FcR (ADCC) or complement (C3a and C5a recruit neutrophils) e. Complement mediated: Hemolytic anemia, ABO transfusion reaction f. Complement attraction of neutrophils: Vasculitides (vascular autoimmune disorders such as Wegener’s granulomatosis, with anti-neutrophil cytoplasmic antibodies) g. ADCC mediated: hemolytic disease of the newborn |
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What is Goodpasture's Syndrome?
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attack of basement membrane components in lung and kidney (type II)
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Alloantigens
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Antibodies against antigens that are polymorphic among individuals
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Hemolytic disease of newborn
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A mother who is Rh- is pregnant with an Rh+ child. During the first pregnancy the Rh+ child’s blood mixes with the mother’s. The Rh antigen causes the mothers blood to make IgG anti-Rh antibodies that will cross the placenta and attack subsequent fetuses that are Rh+ causing erythroblastosis fetalis. This can be prevented by administering Rhogam which prevents Bcell activation and memory cell formation.
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Autoimmune Hemolytic Anemia
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a. Antibodies are formed to red blood cell antigens
b. Often occurs in association with other diseases such as lymphoma, or can occur in response to administration of certain drugs such as penicillin c. Hemolysis of red blood cells results in anemia characterized by fatigue, dyspnea on exertion, and pallor. d. Diagnosis is made by the findings of decreased hematocrit (and hemoglobin), destroyed red blood cells on blood smear, and a positive Coombs antiglobulin test which detects the autoantibodies. e. Treatment is directed at the underlying problem or removal of the drug and may also include steroids |
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Pemphigus vulgaris
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is a rare group of blistering autoimmune diseases that affect the skin and mucous membranes. In pemphigus, autoantibodies form against desmoglein. Desmoglein forms the "glue" that attaches adjacent epidermal cells via attachment points called desmosomes. When autoantibodies attack desmogleins, the cells become separated from each other and the epidermis becomes "unglued", a phenomenon called acantholysis. This causes blisters that slough off and turn into sores. In some cases, these blisters can cover a significant area of the skin.
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Graves' Disease
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i. Autoantibodies (called thyroid stimulating immunoglobulins) bind to receptors in the thyroid gland.
ii. Stimulate the gland to grow and produce more thyroid hormone iii. Hyperthyroidism results with the clinical manifestations of weight loss, tremor, heat intolerance, muscle weakness iv. Autoantibodies also cause infiltrative changes that swell the front of the lower leg (pretibial myxedema) and behind the eyeball causing it to protrude from the socket (exophthalmus) due to T cell-mediated stimulation of fibroblasts. v. Diagnosis is confirmed by measuring increased thyroid hormone and thyroid stimulating immunoglobulins vi. Treatment consists of thyroid ablation – monoclonal Ab are being studied vii. Patients with graves disease make anti-TSHR antibodies that cross the placenta into the fetus. Newborn infant also suffers from Graves disease. Plasmapheresis removes maternal anti-TSHR antibodies and cures the disease. |
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Myasthenia Gravis
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an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability. It is an autoimmune disorder, in which weakness is caused by circulating antibodies that block acetylcholine receptors at the post-synaptic neuromuscular junction, inhibiting the stimulative effect of the neurotransmitter acetylcholine. Myasthenia is treated medically with cholinesterase inhibitors or immunosuppressants, and, in selected cases, thymectomy.
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arthus reaction
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a. Localized immune-complex mediated vasculitis- Activates complement C5a binds to and sensitizes the mast cell to respond to immune complexes. Activation of FcR on mast cells induces degranulation and causes local inflammation, increased fluid and protein release, phagocytosis and blood vessel occlusion.
b. Subcutaneous antigen to someone who has antibodies against the antigen c. Immune complexes deposit in walls of small vessels at site of injection d. Edema, hemorrhage, necrosis e. Occasionally seen after tetanus re-vaccination f. Pneumonitis is a form of Arthus reaction- Farmer’s lung |
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What are the different effect of T cell types on hypersensitivity type IV?
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b. CD4 (TH1): Delayed Type Hypersensitivity, T cells activate macrophages, which produce damage
c. CD4 (TH2): chronic allergy and asthma, production of IgE and activation of eosinophils, which produce damage |
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Macrophage inhibitory factor
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a. Secreted by T cells, anterior pituitary, skin, macrophages in liver
b. Localizes macrophages at sites of inflammation and activates them c. MIF and TNFa enhance each other d. Counters cortisol’s inhibitory effects |
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Describe metal contact dermatitis
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Molecules complex with skin proteins (may be covalent). Proteins processed into hapten-peptides. Presented on MHC II or MHC I
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What modifies gluten peptides so they can bind to MHC II peptides?
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tissue transglutaminase
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What can Mycobacterium tuberculosis granuloma result from?
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T cell hypersensitivity
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How does T cell hypersensitivity contribute to tuberculosis granuloma formation?
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a. Phagosomal maturation is promoted by activation with interferon-γ(IFN-γ),which stimulates anti-mycobacterial mechanisms in macrophages,notably reactive oxygen intermediates(ROI) and reactive nitrogen intermediates (RNI)
b. Several types of T cells are important in containing tuberculosis: CD4 TH1 helper T cells, CD8 CTLs, dg T cells and T cells recognizing lipids presented by CD1 c. IFNg is critical in controlling tuberculosis, but TNFa and lymphotoxin-3 are other cytokines that contribute |
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What 3 factors are important for graft tolerance?
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a. Both central and peripheral tolerance are elicited in successful transplantation
b. Donor APCs migrate to recipient thymus and eliminate donor reactive T cells c. Peripherally, regulatory T cells specific for donor antigens limit alloreactive T cells |
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Mixed leukocyte chimerism
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Leukocytes survive from both donor and recipient
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Micro-Chimerism
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Mother has blood cells of fetus for years after birth (and off-spring has maternal cells circulating)
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The mother does see the fetus as foreign, and makes antibodies against paternal MHC, so how is the fetus protected? What does failure of tolerance lead to?
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Physical barriers, systemic factors, and local immunosuppression
infertility and preeclampsia |
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What is the purpose of HLA-G and HLA-E?
what is the purpose of HLA-G? What increases HLA-G expression? |
protect against Natural Killer-mediated cell lysis
Suppression of allo-reactive cytotoxic T cells progesterone |
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What is the purpose of IDO? What makes them? What does a blockage of IDO do?
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catalyze tryptophan and prevents T cell proliferation and induces apoptosis
trophoblasts miscarriage of allogeneic fetuses but not syngeneic fetuses |
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What is the point of Fas-FasL?
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Trophoblast restricts free access of T cells to fetus and kills infiltrating T cells by expressing Fas-L
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How do trophoblasts help fetus tolerance? What induces Th2 cytokines? What is the danger and purpose of Type I cytokines (IFNg, IL-12)?
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Trophoblasts secrete cytokines (TGFbeta, IL-10, IL-4) that prevent TH1 helper type and enhance TH2 and regulatory T cell function
progesterone in high levels will lead to fetal resorption (miscarriage), but low levels are needed for angiogenesis |
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How do gonadal hormones (estrogen, progesterone, and human chorionic gonadotropin) affect pregnancy and autoimmunity?
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i. During pregnancy, autoimmunity diseases often less severe
ii. Anti-pathogen immunity usually not affected iii. Direct effects of hormones on immune cells iv. Steroid receptors that respond directly |
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What genetic contributions contribute to autoimmunity?
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HLA association for each disease, gender, polymorphisms in immune regulatory molecules (MHC, inflammatory molecules, regulatory molecules involving apoptosis, CTLA-4, cytokines).
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What happens with mutations in AIRE, CTLA4, FoxP4, Fas, and C1q?
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AIRE, you get a decreased expression of self antigens in the thymus, resulting in defective negative selection of self-reactive T cells (APECED disease). You get associated diseases with CTLA4 and FoxP4 – NO TREGS! (ask Dr Roy about this stuff). Fas error leads to failure of apoptosis. C1q error in lupus leads to defect in immune complex clearing.
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Narcolepsy
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loss of orexin (hypocretin) neurons, with specific HLA propensity, subtle differences in binding groove. Pocket for P4 amino acid blocks binding of the hypocretin peptide. Peptide association makes it a risk factor rather than a GENERAL INFLAMMATORY CONDITION.
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APEX versus IPEX?
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APEX is a mutation in AIRE: autoimmune regulator / transcription factor responsible for protein diversity in the thymus – central tolerance becomes shot (defective negative selection of T cells).
IPEX is involving FoxP3 and peripheral tolerance, necessary for Treg development. |
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Aryl Hydrocarbon receptor
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directly modifies TH17 pro helper T cells leading to Encephalitis. Point: same receptor that binds toxin can either increase or decrease susceptibility to Multiple Sclerosis.
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Define:
Bystander activation Molecular mimicry Cryptic antigens Superantigens |
Bystander activation: you have enhanced processing of self antigen, cell necrosis, cytokine release. Slightly divergent may be more effective because they are tolerized less well.
Molecular mimicry: part of pathogen resembles self antigen. Cryptic antigens: things not normally exposed to the immune system become available because of tissue damage. Superantigens: activate T cells, linking them to MHC but NOT through a peptide. |
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Epitope spreading:
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T cells react against other epitopes on the same protein. Ie if you attack myelin, the T cells will then attack other similar myelin’s.
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Rheumatoid Arthritis
Where is the antigen? Where is the immune attack? Why is autoimmune CD4 an issue? Do you require inflammation of joints? What is the original trigger? What is the purpose of CD8 in diabetes What is the role of rotavirus peptides in diabetes? If your CD8 cells recognize self, are they destructive? |
antigen is widely spread but immune attack is localized. The autoimmune CD4’s have been shown to not be eliminated by central tolerance. Prior inflammation of joints is not required for Ab against GPI to localize in joints. Original trigger in synovial membranes is unknown. In diabetes, CD8’s infiltrate the pancreas and kill beta cells. Rotavirus peptides produce mimicry that leads to tissue destruction of the pancreas. IMPORTANT RULE: just because your CD8 T cells recognize self, they are not destructive until they are activated by the PATHOGEN invading.
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How does HLA and latitude affect MS?
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HLA
HLA-DR2 has 4-fold greater. Heritable but polygenic – no single genetic locus contributes enough susceptibility. CD4 TH1 inflammatory response. Further activation of TH17 T cells and IL-10 secreting cells (regulatory) these inflammatory molecules are all in skewed populations in MS patients. Latitude Has an effect on MS severity, based on where you grew up before Age 15. The closer you are to UV radiation and Vit.D, the less severe the symptoms. The US and Canada have it worst for incidence. |
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Role of adjuvants in EAE?
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Adjuvant produces danger signals.
Role of adjuvant T cells don’t normally migrate through to the brain. They have to usually do extravasation, interacting with integrins, -1 integrin that allows T cells to squeeze through. Microglia or dendritic cells are antigen presenting to the T cells in this case to activate inflammation. You can target the 4:1 integrins with antibody. Adjuvant is something that stimulates TLRs on antigen presenting cell, so that when it is presented it is an active signal. Adjuvant stimulates APC to express B7. |
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What is Freund Adjuvant?
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is killed mycobacterium tb cells, if you inject spinal cord homogenate with this adjuvant, you get EAE. If you just use spinal cord homogenate the mouse doesn’t get EAE. You can take T cells from the tolerized mouse, transfer them to another mouse, give him EAE, and that mouse will be protected! It’s the Tregs that the first mouse produced that protect the second mouse! Protection transfer.
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What are the 2 theories on why EBV gives you MS?
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one is that EBV molecularly mimics MYELIN BASIC PROTEIN, the second is that viral antibody to IL-10, shuts down the Treg regulator product and leads to TH1 activity.
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What is Tysabri?
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Anti-VLA antibody (anti 4-integrin), design based on EAE studies, blocks extravasation of T cells, preventing entry into the brain. Twice as effective as IFN-B.
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How does IFN-B affect MS?
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decreases MHC II expression on antigen presenting cells, mechanism not clear. Maybe inhibits entry of T cells by outcompeting endothelial VCAM with soluble VCAM (T cells use their VLA to bind VCAM).
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What is DEFERVESCENCE?
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shutting off of inflammation
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What are the elements of active resolution, split into intra, intercellular and systemic?
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intracellular: signaling pathway changes.
Intercellular: lipid mediators and lipid binding proteins (prostoglandins). Systemic: glucocorticoids and parasympathetic influences. |
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How does TNFa act as antiinflammatory indirectly?
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activates transcription factor IkBa, which shuttles NFKb back to the cytoplasm
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What are the actions of Intercellular Regulators, Lipid Pro-Resolution Mediators (Resolvin)?
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1) decrease vascular permeability
2) stimulate non-phlogistic uptake of effete neutrophils by macrophages 3) block NFKb activation. |
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What is made of omega 3 PFAs?
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Lipoxins, resolvins, protectins
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What induced by glucocorticoids induces apoptosis? What makes them? What else do they do? What does it block?
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annexin-1
neutrophils blocks inflammation by interfering with neutrophil adhesion and extravasation Blocks synthesis of prostoglandins |
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What is the HPA axis?
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The hypothalamo-pituitary-adrenal pathway involves cortisol/ACTH effect on immunosuppression.
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What releases MIF? What does it do? What enhances it?
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Macrophage Migration Inhibitory Factor is released by T cells and suppresses the effects of cortisol. It localizes macrophages at sites of inflammation and activates them. MIF and TNFa enhance each other, countering cortisol’s effects. MIF is released from the PITUITARY, and its release from macrophages is induced by cortisol. It goes in between and blocks cortisol from suppressing inflammatory cytokines.
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What is the effect of acute and chronic stress on antibody production to vaccine?
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acute: more
chronic: less |
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What is the effect of mechanical damage on inflammation?
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Bradykinin is produced from damaged blood vessels, stimulating pain nerve terminals,bradykinin stimulation then releases endocannabinoids that act on VR1 receptors on pain afferent neurons. The following NTs are then released:CRH, glutamate, substance P. Inflammation spreads to neighboring branches, and NTs cause local vasodilation, vascular leakage, and stimulate inflammatory cells. NTs also activate mast cell degranulation, increase platelet aggregation, permeability, and attract neutrophils and macrophages. This can all be centrally induced because pain fibers are afferent. That’s why you get CNS and efferent sympathetic activation of mast cells (arthritis, asthma, colitis).
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What mediates the Neural anti-inflammatory reflex?
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vagus
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What are the ways to activate neural anti-inflammation?
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pain
cytokines to vagal nerve endings in the liver epinephrine/adrenergic receptors on leukocytes |
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What NT is anti-inflammatory and part of the anti-inflammatory reflex?
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ACh
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What is the effect of long term usage of non-steroidal anti-inflammatory drugs and cyclooxegynase-2 inhibitors on cancer incidence?
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reduces
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What are Immune mechanisms that directly promote cancer?
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free radical production destroys DNA,NFKb does paracrine regulation of intracellular pathways and disrupts them
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How does the immune system indirectly promote cancer?
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angiogenesis and tissue remodeling by release of growth factors, cytokines, chemokines, matrix proteinases; cyclooxygenase-2 upregulation (converts arachadonic acid to prostoglandins), promotes tolerance by suppressing anti-tumor immune responses
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Tumor surveillance hypothesis
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immune system actively protects the host from tumor cells that have undergone transformation. So if tumor antigens exist, then tumors should develop more when immune surveillance decreases, which is the case with RAG mic, HIV/AIDS, and Aging
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How can Damage to DNA repair mechanisms can act as antigen?
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oncogene products, tumor suppressor gene products (p53), viral cancer proteins (ie HPV proteins), AND overly expressed NORMAL proteins
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Why does the immune response fail with cancer?
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Tolerance and immune evasion suppression by tumor
Tumor cells can respond to antibody by endocytosizing their antigen and modifying it, appearing similar to self, create physical barriers, release their own IL-10 and TGF-B, as well as induce Tregs, immune suppression factors/cytokines (cytokines contribute to differentiation of Tregs), and maintain low immunogenicity by downregulating their MHC I, becoming less visible to T cells. It also may lack costimulatory signals. |
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Presence of CTLs in tumor better or worse prognosis than absence of CTLs?
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better
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What happens with breast cancer and paraneoplastically?
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Breat cancer is similar to neurons, there is molecular mimicry/ cross reaction
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Whatis the effect of IDO on tumors?
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suppressor, just like T cells, tumors need tryptophan
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What are Mabs and how do you use them to fight cancer?
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monoclonal antibodies (passive immune treatment). Most likely you are using mabs to neutralize the antigen, but you can even introduce radiation with the antibodies to attack stuff even. You can also attach toxin (diphtheria) to the antibody and to the antigen to make your body attack.
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How does Vaccination prophylactic against cancer work?
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(vaccinate against viral antigens such as HPV): vaccine elicits a T cell response
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How do you make a tumor into an APC?
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By transfecting B7 costimulatory signal to it, attracting APCsto the tumor and expanding APCs (recall that B7 binds CD28 or you’re in trouble for Monday!)
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Adoptive transfer of APCs or T cells
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modify them ex vivo and expand the cells; Dendritic cells and T cells. You take the dendritic cell out, expand and modify, then mix dendritic cells with the patient’s tumor cells, then implant them back into the patient. “Take T cells out, expand them, put them back in and they will kill melanoma” You irradiate the patient to wipe out all of his nonspecific T cells, then take the expanded tumor specific ones and inundate their system with it to irradicate the tumor, and this is VERY effective…but costs $93,000.
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Myeloid vs lymphoid
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a. Myeloid- RBC, Platelets, macrophages/monocytes, granulocytes (neutrophils, basophils, eosinophils)
i. any disease that arises from the myeloid elements is a myeloid disease b. Lymphoid- B cells&T cells i. any disease that arises from the lymphoid elements is a lymphoid disease |
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Acute vs chronic leukemia
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a. Acute Leukemia- young, immature, blast cells, more fulminant presentation, more aggressive course
i. Lymphoid- ALL - (acute lymphoblastic leukemia) lymphoblasts ii. Myeloid- AML – (acute myeloid leukemia) myeloblasts b. Chronic Leukemia- accumulation of mature,differentiated cells, often subclinical or incidental presentation, |
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chronic lymphoid vs myeloid
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i. Lymphoid- CLL – (chronic lymphocytic leukemia) mature appearing lymphocytes
ii. Myeloid- CML – (chronic myeloid leukemia) mature appearing neutrophils |
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Leukemia vs lymphoma
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a. Leukemia- increased WBC in blood and marrow. Presents in blood and marrow
b. Lymphoma- always of a lymphoid origin: B cell lymphoma (85%), T and NK cell lymphoma (15%). You have 2 |
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Types of lymphoma
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i. Hodgkin’s lymphoma: B cell origin, Reed-Sternberg cells
ii. Non-Hodgkin’s lymphoma: all others, mostly B, but some T and NK lymphomas |
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How do lymphoid and leukemic diseases overlap?
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c. most lymphoid diseases can enter a leukemic phase if advanced enough BUT myeloid diseases very rarely present in lymph nodes
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Myelo vs myeloid
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Myelo generally refers to bone marrow (talking about the marrow itself), Myeloid is more specific means derived from bone marrow(talking about things that come from the marrow)
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Hodgkin’s vs non-Hodgkin’s lymphomas
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a. Hodgkin’s- Most common usually arises in the lymph nodes of young adults. Characterized by Reed-Sternberg cells, germinal center B cell. Cure rates of more than 80% can be achieved with present therapies.
i. Reed- Sternberg Cells are diagnostic of Hodgkin’s Lymphoma- They are malignant germinal center Bcells. Have mutated IkBgene. b. Non- Hodgkins i. Diffuse large B-cell lymphoma- Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL 20% of cases have translocations of BCL2. DLBCLs are clinically, morphologically and molecularly heterogeneous. 40% of patients with DLBCL can be cured by conventional chemotherapy. ii. follicular lymphoma- indolent B-cell lymphoma with a follicular growth pattern. Most are characterized by the overexpression of BCL-2. They cannot be cured by conventional chemotherapy and the survival rate is 73% at 10 years iii. Burkitt’s lymphoma- aggressive B-cell lymphoma of children and young adults that is associated invariably with translocations of c-MYC. The endemic form involves Epstein–Barr virus (EBV) infection of malignant cells, whereas the sporadic form is EBV independent. These lymphomas can be cured in more than 80% of cases. Rituximab-humanized antibody against CD20 (B cell marker) now used to treat patients with low-grade B-cell lymphoma |
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Multiple myeloma
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An incurable malignancy of plasma cells with a median survival of three years. Multiple myelomaconstitutes 10% of all hematological malignancies,with a median age at diagnosis of 65. Neoplastic cells are located in the bone marrow, and osteolytic bone lesions are characteristic.
a. Criteria for Diagnosis- Paraprotein in serum or urin, Increased numbers of abnormal cells in the bone marrow, Osteolytic lesions in the bones |
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Cancer homing properties
Where do mature naive cells go? Where do activated T cells go? |
Each type of tumor cell has a normal B-cell equivalent, homes to similar sites, and has behavior similar to that cell. Thus, myeloma cells look much like the plasma cells from which they derive, they secrete immunoglobulin, and they are found predominantly in the bone marrow. Similar to cells of origin.
a. Mature naïve cells go to lymph nodes (lymphomas such as Hodgkin’s lymphoma, follicular lymphoma, b. Activated T cells home to skin |
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How do translocations lead ton cancer?
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a. E.g. #1: Philadelphia Chromosome in Chronic Myeloid Leukemia
b. BCR-ABL fusion gene c. ABL tyrosine kinase d. Gleevec (imatinib) inhibits this unique kinase, 90% effective but not usually curative (kinase mutates) e. Allogeneic bone marrow transplant can be curative, but 30% treatment associated mortality |
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What are the 2 forms of immune suppression?
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• Nonspecific immunosuppression includes broad-antinflammatory corticosteroids and NSAIDs, and non-specific blocking with cytotoxic drugs and T cell signaling pathways.
• Specific immunosuppression includes shifting TH1 to TH2 response (unskewing proliferaton), blocking specific HLAs, blocking cell types and cytokines. |
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How does TNFa cause autoimmune damage and how do you block it?
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• TNFa destroys collagen and bone by activating IL-1. You can block it with an antibody to TNFa, or with a fusion protein to TNF-R. Infliximab is a Mab (monoclonal) for TNFa.
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How does the most common adjuvant activate APCs?
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• ALUM is most common, it increases uric acid levels by killing cells
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Why didn't MABs work in the past?
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• Problem: immunogenicity of mouse Ig…human anti-mouse antibodies (HAMAs) attack the monoclonals quickly and make them useless.
• Human effector systems rarely associate with mouse Fc. • Now we improve the Fc portion by making everything HUMAN except for the CDR (complementarity determining region). • Also, we genetically engineer antibodies now, then check which works best by binding specificity. |
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RITUXIMAB
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• You must know what RITUXIMAB is for the exam. It is used to treat Non-Hodgkin Lymphoma (NHL), it is a genetically engineered chimericmurine/human antibody, which binds specifically to CD20 on normal and malignant Pre-B and mature B lymphocytes.
• The benefit of this CD20 attack is that it is cancer specific, and CD20 is also not found on human stem cells or normal plasma cells, so after the antibody rips away at the cancer, you can still effectively repopulate your immune B cells. • But it only cures 6% of patients… |
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What technique can read the Phenotypic Markers (CD markers) associated with cancer?
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flow cytometry
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What is a myeloma? Is it myeloid or lymphoid?
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Plasma cell neoplasm that homes to bone
lymphoid |
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Holy trio of early inflammation
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TNFa, IL-1 and IL-6
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