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PNB 4400 > Exam1 > Flashcards

Exam1 Flashcards

1
Q

Three pathological hallmarks of MS

A

Inflammatory reaction, scarring of tissue, at least two neurologic problems separate in space and time

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2
Q

Pathogenesis

A

The biological mechanism that leads to a diseased state

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3
Q

Calcitriol

A

Active hormone in Vitamin D

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4
Q

7-dehydrocholesterol

A

Circulating precursor in Vitamin D

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5
Q

Mendelian inheritance

A

The manner by which genes and traits are passed from parents to their children

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6
Q

Autosomal dominant

A

One mutated copy of the gene in each cell is sufficient for a person to be affected

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7
Q

Autosomal recessive

A

Both copies of the gene in each cell have mutations

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8
Q

Complex genetic disorder

A

Multiple polymorphic genes influence susceptibility and interact with environmental factors

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9
Q

Polymorphism of a gene

A

The occurrence of two or more genetically determined phenotypes in a certain population

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10
Q

Single nucleotide polymorphism (SNP)

A

Genomic variant in which a single base in the DNA differs from the usual base at that position

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11
Q

Gene

A

A portion of DNA that determines a certain trait; expression of traits

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12
Q

Allele

A

Specific form of a gene

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13
Q

HLA-DRB1 gene

A

Provides instructions for making a protein that plays a critical role in the immune system; helps the immune system distinguish the body’s own proteins from proteins made by foreign invaders such as viruses and bacterias

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14
Q

HLA-DRB1*1501 allele

A

Different version of the HLA-DRBA1 gene; most strongly linked genetic factor for the risk of MS

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15
Q

What was the main gene identified by GWAS screens?

A

HLA-DRB1 locus

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16
Q

MHC locus

A

Plays an important role in discriminating between self and non-self

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17
Q

What is the function of MHC I?

A

Antigen presentation

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18
Q

What is the function of MHC II?

A

Initiation of antigen-specific immune response

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19
Q

HLA-DRB1*1401

A

Gene associated with a lower risk of MS

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20
Q

HLA-DRB1*0801

A

Gene associated with a higher risk of MS

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21
Q

HLA-A*0301

A

Gene that predisposes to MS

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22
Q

HLA-A0201, HLA-C05

A

Genes that have a protective effect

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23
Q

A mutation in which gene makes African Americans more at risk of the secondary progressive form of MS?

A

HLA-DRB5 null mutation

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24
Q

Less CYP27B1 results in ….?

A

Less vitamin D

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25
Q

What part of the HLA-DRB gene product has the most variable amino acid sequence?

A

Beta chain

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26
Q

Innate immunity

A

Antigen-nonspecific defense mechanisms that come into play immediately or within hours of an antigen’s appearance in the body; rapid response at the site of infection; physical barriers such as skin, chemicals in the blood, immune system cells that attack foreign cells in the body

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27
Q

Adaptive immunity

A

Antigen-specific defense mechanisms; protection from an infectious disease agent that is mediated by B- and T-lymphocytes following exposure to a specific antigen, and characterized by immunological memory

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28
Q

Humoral immune response

A

Production of antibody molecules in response to an antigen; B lymphocytes

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29
Q

Cell-mediated immune response

A

Production of cytotoxic and helper T lymphocytes; activation of macrophages, NK cells; cytokine secretion

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30
Q

Function of Th-1 cells

A

Pro inflammatory

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31
Q

Function of Th-2 cells

A

Stimulate B cells

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32
Q

Function of CD4 cells

A

Helper T cells

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33
Q

Function of CD8 cells

A

Cytotoxic T cells; kills target cell by inducing apoptosis

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34
Q

What happens when MOG is injected?

A

A T cell response in the periphery is activated

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35
Q

Classical view of MS, regarding immunity?

A

CD4+ Th1 and Th17 pro-inflammatory T cells recognize myelin antigens on antigen-presenting cells in the context of MHC II and become activated and secrete cytokines which promote disease in the CNS

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36
Q

Intrathecal IgG

A

Key biological feature of MS

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37
Q

Evidence for the role of B cells in MS

A

Oligoclonal bands in CSF of 80-90% of MS patients, intrathecal IgG present; CD20 expressed on all stages of B cell development except the first and last

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38
Q

Myelin

A

A mixture of proteins and phospholipids forming a whitish insulating sheath around many nerve fibers, increasing the speed at which impulses are conducted; formed by oligodendrocytes in the CNS

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39
Q

Which cell types express MHC class I molecule?

A

All nucleated cells in the body

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40
Q

Which cells types express MHC class II molecules?

A

Antigen-presenting cells

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41
Q

What is the function of deactivating a4-integrin (VLA-4)?

A

Stops T cells from attaching to endothelial cells and prevents them from breaking through the BBB

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42
Q

Natalizumab

A

Reduces the amount of T cells that come into the brain; effective for relapses

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43
Q

EAE

A

An animal model of brain inflammation

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44
Q

Difference between EAE and MS

A

Most EAE models show focused inflammation in the spinal cord, whereas MS is usually dominated by brain inflammation

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45
Q

How are rodents immunized to elicit EAE?

A

Active immunization, adoptive transfer

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46
Q

Evidence that Th1 T cells cause demyelination

A

Th1 cells secrete cytokines known to cause tissue damage

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47
Q

Which type of cell is more likely to cause demyelination? Why?

A

CD8+ because it’s more abundant in tissue near lesions

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48
Q

How can the EAE model be used to elucidate the immunological mechanism of MS?

A

Can help us determine how T cells that are activated in the periphery enter the CNS

49
Q

What are some questions about MS pathogenesis that cannot be answered by the EAE model?

A

How T cells cause demyelination, how myelin-reactive T cells become activated

50
Q

Why has MS not been classified as an autoimmune disease?

A

No precise autoantigen has been identified in all patients with MS

51
Q

Blood-brain barrier

A

A filtering mechanism of the capillaries that carry blood to the brain and spinal cord tissue, blocking the passage of certain substances

52
Q

Paresthesia

A

An abnormal sensation, typically tingling or pricking, caused by pressure on or damage to peripheral nerves

53
Q

Ataxia

A

The loss of full control of bodily movements

54
Q

Diplopia

A

Double vision

55
Q

Safety factor for action potential generation

A

Amount of current available relative to the minimum amount of current needed to elicit an AP; 3-7 in normal axon; close to 1 in MS

56
Q

Where are action potentials generated?

A

Node of Ranvier, axon initial segment

57
Q

Uhthoff phenomenon

A

The effects of temperature on conduction in demyelinated axons; demyelinated axons fail to conduct at body temperature; temperature coefficient for Na+ channel inactivation > activation

58
Q

B cells play an important role in pathogenesis of what form of MS?

A

Primary progressive MS

59
Q

Why are action potentials generated at the Node of Ranvier and the axonal initial segment?

A

These places have a lot of Na channels which increases conductance for sodium

60
Q

What is the evidence that axons are damaged in MS?

A

Cortical lesions on MRI that are severely damaged; brain becomes atrophied because of significant axonal loss and neuronal degeneration; enlargement of ventricles

61
Q

What are some ways to prevent axonal damage in chronic MS?

A

Potassium channel blocking agent 4-aminopyridine can be effective in restoring conduction to demyelinated axons

62
Q

Would Na+ channel blockers be an effective treatment?

A

Might be effective in treating the positive symptoms of MS

63
Q

Would K+ channel blockers be an effective treatment?

A

Could be effective in restoring conduction to demyelinated axons

64
Q

What was the hypothesis of the Akiyama MS paper?

A

Bone marrow stromal cells can form myelin when expanded and injected into demyelinated lesions in the CNS and improve conduction velocity

65
Q

How did Akiyama et al test their hypothesis?

A

They created a demyelinated injury in the dorsal column of rats and transplanted marrow stromal cells into them

66
Q

What did Akiyama et al discover?

A

At least a subpopulation of remyelinated axons in the bone marrow stromal cell-injected rats showed increased conduction velocity

67
Q

What was the goal of the clinical trial in the Montalban paper?

A

Determine if depleting CD20-expressing B cells is useful for the treatment of MS; determine if ocrelizumab helps to slow down disability progression in the primary progressive form of MS

68
Q

What does Ocrelizumab target?

A

CD20-expressing B cells while preserving the capacity for B-cell reconstitution and preexisting humoral immunity

69
Q

What is the difference between ocrelizumab and rituximab?

A

Ocrelizumab is humanized and rituximab is not; ocrelizumab is better for targeting human B cells

70
Q

What were the major findings in the Ocrelizumab clinical trial?

A

Total volume of brain lesions decreased; disability progression decreased in patients who had taken the drug

71
Q

What are the two criteria for classifying a cell as a stem cell?

A

Cell can differentiate into other types of cells; cell can divide in self-renewal to produce more of the same types of cells

72
Q

WHO grading of glioma

A

Grade I (pilocytic astrocytoma); Grade II (astrocytoma); Grade III (anaplastic astrocytoma); Grade IV (glioblastoma multiforme)

73
Q

What is the median survival for patients diagnosed with glioblastoma multiforme?

A

5 months

74
Q

Primary brain tumors

A

Tumors that originate within the cranial vault - above the brain tissue

75
Q

Why do cancers of other organs metastasize to the brain:

A

Hematogenous spread; tumors invade blood vessels, get in the circulation, and metastasize throughout the body

76
Q

Cell of origin in meningioma

A

Fibroblasts in the mesodermal layer

77
Q

Cell of origin in schwannoma

A

Schwann cells of nerve roots

78
Q

Where are neurinomas found?

A

They arise from the nerve sheath of cranial nerves alongside the cerebellum & brainstem

79
Q

Neurofibromatosis

A

Disease in which neurofibromas form throughout the body; mutation in NF1 (tumor suppressor gene)

80
Q

What embryonic germ layer does the central nervous system arise from?

A

Ectoderm

81
Q

What four cell types arise from the neural tube?

A

Astrocytes, neurons, oligodendrocytes, ependymal cells

82
Q

What kind of behavior do GBM cells exhibit that is not frequently seen in benign tumor cells?

A

Abnormal activity around tumor which suggests that cells are moving outward

83
Q

What are the characteristics of GBMS on a CT/MRI scan?

A

Low-density spots that could be hemorrhage, calcification; dark area around tumor that suggests edema

84
Q

What are the histological characteristics of GBMs?

A

Necrosis, atypical cellular appearance, neovascularization

85
Q

How do glioma cells survive in a hypoxic environment?

A

They migrate along CD31+ endothelial cells for oxygen

86
Q

What structures do GBM cells migrate along?

A

White matter tracts, blood vessels

87
Q

What is the hypothesis that explains why glioma cells can squeeze through tight extracellular space?

A

Calcium / chloride hypothesis; when calcium increases in cells, it activates calcium chloride channel, initates efflux of chloride and water; cell shrinks due to efflux; cell changes morphology and slips through tight matrixes in CNS

88
Q

What neuroectodermally derived cell type does not contribute to glioma? Why?

A

Neurons, they have apoptosis and do not divide

89
Q

Neural stem cells

A

Cells found in the nervous system that can differentiate into other types of cells

90
Q

Where are neural stem cells found in the adult CNS?

A

Subventricular zone

91
Q

Cancer stem cell

A

Cancer propagating cell; stem-cell like population in tumor responsible for constantly generating glioma stem cells

92
Q

Glioma cell of origin

A

Cancer initiating cell

93
Q

Oncogene

A

Slight variation of normal cellular gene that causes controlled cell growth; gain-of-function

94
Q

Tumor suppressor gene

A

Gene that normally acts to inhibit uncontrolled cell growth

95
Q

Is a gain-of-function mutation dominant or recessive?

A

Dominant mutation, only one copy of mutated allele needed to produce effect

96
Q

Is a loss-of-function mutation dominant or recessive?

A

Recessive, two copies of mutation are required to produce effect

97
Q

Loss of heterozygosity

A

Loss of normal allele in a heterozygous cell

98
Q

Missegregation

A

When a cell divides and the chromosomes don’t segregate properly; results in one daughter cell with the same heterozygous compliment with mutant, other daughter cell has two mutant copies; how you can get from heterozygous to homozygous mutant

99
Q

Mitotic recomibnation

A

Translocation of tips of chromosomes; results in 1 daughter cell that’s homozygous for the normal allele and one that’s homozygous for mutant allele

100
Q

What are the two most likely candidate cell types that can generate gliomas?

A

Neural stem cells, astrocytes

101
Q

What are the characteristics of glioma stem cells?

A

Express CD133+ which acts like stem cells and allows the ability to continuously generate rapidly proliferating cells

102
Q

Molecular classification of glioblastoma multiforme

A

Classification based on genes that are mutated or overexpressed; classical, mesenchymal, neural, proneural

103
Q

Molecular signature of classical GBM

A

EGFR amplification and loss of PTEN

104
Q

Molecular signature of mesenchymal GBM

A

Deletion of NF1, also PTEN mutation

105
Q

Molecular signature of proneural GBM

A

PDGFRA and p53 mutations

106
Q

Molecular signature of neural GBM

A

Expression of neuronal genes as well as astrocyte and oligodendrocyte genes

107
Q

Which GBM class resembles astrocytes?

A

Classical, neural

108
Q

Which GBM class resembles oligodendrocytes?

A

Proneural, neural

109
Q

What are the three main signaling pathways that are commonly altered in glioma?

A

Receptor tyroskine kinase pathway, P53 pathway, Retinoblastoma pathway

110
Q

What is the EGFRvIII mutation?

A

Oncogenic mutation, deletion of exon 207; gain the function of EGFR, constantly “on”; activates downstream signaling effectors which leads to amplification, overexpression, mutation

111
Q

Are oncogenes gain-of-function or loss-of-function?

A

Gain-of-function

112
Q

Are tumor suppressor genes gain-of-function or loss-of-function?

A

Loss-of-function

113
Q

How is a receptor tyrosine kinase activated?

A

EGFR binds and makes it active; causes cross-phosphorylation of the receptor; recruits signaling molecules downstream which lead to increased cell proliferation

114
Q

How does p53 inhibit cell proliferation?

A

Tumor suppressor gene that causes apoptosis in mutated cells; upregulates p21 when there’s DNA damage, which inhibits CDK and stops at either G1 or G2 phases of cell cycle to prevent uncontrolled proliferation

115
Q

How does Rb inhibit cell proliferation?

A

Tumor suppressor gene that inhibits cell cycle progression in cell cycle; binds to E2F, inactivating E2F and not allowing it to activate CDK complexes which would initiate progression through cell cycle

116
Q

If someone is born with a mutation in the Rb gene in one allele, what event must occur in order for this person to develop a retinoblastoma?

A

Loss of heterozygosity

117
Q

Why does loss of heterozygosity in the NF1 gene contribute to tumor formation?

A

NF1 is a tumor suppressor gene; need two copies of mutant allele for uncontrolled cell proliferation that leads to tumor formation; loss of heterozygosity gives rise to cells with two mutant alleles

118
Q

Why does loss of heterozygosity in the PTEN gene contribute to glioma formation?

A

PTEN is a tumor suppressor gene; need two copies of the mutant allele for uncontrolled cell proliferation that leads to tumor formation; loss of heterozygosity causes production of a cell with two mutant PTEN alleles

PNB 4400 (1 decks)

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