Exam1 Flashcards
Three pathological hallmarks of MS
Inflammatory reaction, scarring of tissue, at least two neurologic problems separate in space and time
Pathogenesis
The biological mechanism that leads to a diseased state
Calcitriol
Active hormone in Vitamin D
7-dehydrocholesterol
Circulating precursor in Vitamin D
Mendelian inheritance
The manner by which genes and traits are passed from parents to their children
Autosomal dominant
One mutated copy of the gene in each cell is sufficient for a person to be affected
Autosomal recessive
Both copies of the gene in each cell have mutations
Complex genetic disorder
Multiple polymorphic genes influence susceptibility and interact with environmental factors
Polymorphism of a gene
The occurrence of two or more genetically determined phenotypes in a certain population
Single nucleotide polymorphism (SNP)
Genomic variant in which a single base in the DNA differs from the usual base at that position
Gene
A portion of DNA that determines a certain trait; expression of traits
Allele
Specific form of a gene
HLA-DRB1 gene
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
HLA-DRB1*1501 allele
Different version of the HLA-DRBA1 gene; most strongly linked genetic factor for the risk of MS
What was the main gene identified by GWAS screens?
HLA-DRB1 locus
MHC locus
Plays an important role in discriminating between self and non-self
What is the function of MHC I?
Antigen presentation
What is the function of MHC II?
Initiation of antigen-specific immune response
HLA-DRB1*1401
Gene associated with a lower risk of MS
HLA-DRB1*0801
Gene associated with a higher risk of MS
HLA-A*0301
Gene that predisposes to MS
HLA-A0201, HLA-C05
Genes that have a protective effect
A mutation in which gene makes African Americans more at risk of the secondary progressive form of MS?
HLA-DRB5 null mutation
Less CYP27B1 results in ….?
Less vitamin D
What part of the HLA-DRB gene product has the most variable amino acid sequence?
Beta chain
Innate immunity
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
Adaptive immunity
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
Humoral immune response
Production of antibody molecules in response to an antigen; B lymphocytes
Cell-mediated immune response
Production of cytotoxic and helper T lymphocytes; activation of macrophages, NK cells; cytokine secretion
Function of Th-1 cells
Pro inflammatory
Function of Th-2 cells
Stimulate B cells
Function of CD4 cells
Helper T cells
Function of CD8 cells
Cytotoxic T cells; kills target cell by inducing apoptosis
What happens when MOG is injected?
A T cell response in the periphery is activated
Classical view of MS, regarding immunity?
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
Intrathecal IgG
Key biological feature of MS
Evidence for the role of B cells in MS
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
Myelin
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
Which cell types express MHC class I molecule?
All nucleated cells in the body
Which cells types express MHC class II molecules?
Antigen-presenting cells
What is the function of deactivating a4-integrin (VLA-4)?
Stops T cells from attaching to endothelial cells and prevents them from breaking through the BBB
Natalizumab
Reduces the amount of T cells that come into the brain; effective for relapses
EAE
An animal model of brain inflammation
Difference between EAE and MS
Most EAE models show focused inflammation in the spinal cord, whereas MS is usually dominated by brain inflammation
How are rodents immunized to elicit EAE?
Active immunization, adoptive transfer
Evidence that Th1 T cells cause demyelination
Th1 cells secrete cytokines known to cause tissue damage
Which type of cell is more likely to cause demyelination? Why?
CD8+ because it’s more abundant in tissue near lesions
How can the EAE model be used to elucidate the immunological mechanism of MS?
Can help us determine how T cells that are activated in the periphery enter the CNS
What are some questions about MS pathogenesis that cannot be answered by the EAE model?
How T cells cause demyelination, how myelin-reactive T cells become activated
Why has MS not been classified as an autoimmune disease?
No precise autoantigen has been identified in all patients with MS
Blood-brain barrier
A filtering mechanism of the capillaries that carry blood to the brain and spinal cord tissue, blocking the passage of certain substances
Paresthesia
An abnormal sensation, typically tingling or pricking, caused by pressure on or damage to peripheral nerves
Ataxia
The loss of full control of bodily movements
Diplopia
Double vision
Safety factor for action potential generation
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
Where are action potentials generated?
Node of Ranvier, axon initial segment
Uhthoff phenomenon
The effects of temperature on conduction in demyelinated axons; demyelinated axons fail to conduct at body temperature; temperature coefficient for Na+ channel inactivation > activation
B cells play an important role in pathogenesis of what form of MS?
Primary progressive MS
Why are action potentials generated at the Node of Ranvier and the axonal initial segment?
These places have a lot of Na channels which increases conductance for sodium
What is the evidence that axons are damaged in MS?
Cortical lesions on MRI that are severely damaged; brain becomes atrophied because of significant axonal loss and neuronal degeneration; enlargement of ventricles
What are some ways to prevent axonal damage in chronic MS?
Potassium channel blocking agent 4-aminopyridine can be effective in restoring conduction to demyelinated axons
Would Na+ channel blockers be an effective treatment?
Might be effective in treating the positive symptoms of MS
Would K+ channel blockers be an effective treatment?
Could be effective in restoring conduction to demyelinated axons
What was the hypothesis of the Akiyama MS paper?
Bone marrow stromal cells can form myelin when expanded and injected into demyelinated lesions in the CNS and improve conduction velocity
How did Akiyama et al test their hypothesis?
They created a demyelinated injury in the dorsal column of rats and transplanted marrow stromal cells into them
What did Akiyama et al discover?
At least a subpopulation of remyelinated axons in the bone marrow stromal cell-injected rats showed increased conduction velocity
What was the goal of the clinical trial in the Montalban paper?
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
What does Ocrelizumab target?
CD20-expressing B cells while preserving the capacity for B-cell reconstitution and preexisting humoral immunity
What is the difference between ocrelizumab and rituximab?
Ocrelizumab is humanized and rituximab is not; ocrelizumab is better for targeting human B cells
What were the major findings in the Ocrelizumab clinical trial?
Total volume of brain lesions decreased; disability progression decreased in patients who had taken the drug
What are the two criteria for classifying a cell as a stem cell?
Cell can differentiate into other types of cells; cell can divide in self-renewal to produce more of the same types of cells
WHO grading of glioma
Grade I (pilocytic astrocytoma); Grade II (astrocytoma); Grade III (anaplastic astrocytoma); Grade IV (glioblastoma multiforme)
What is the median survival for patients diagnosed with glioblastoma multiforme?
5 months
Primary brain tumors
Tumors that originate within the cranial vault - above the brain tissue
Why do cancers of other organs metastasize to the brain:
Hematogenous spread; tumors invade blood vessels, get in the circulation, and metastasize throughout the body
Cell of origin in meningioma
Fibroblasts in the mesodermal layer
Cell of origin in schwannoma
Schwann cells of nerve roots
Where are neurinomas found?
They arise from the nerve sheath of cranial nerves alongside the cerebellum & brainstem
Neurofibromatosis
Disease in which neurofibromas form throughout the body; mutation in NF1 (tumor suppressor gene)
What embryonic germ layer does the central nervous system arise from?
Ectoderm
What four cell types arise from the neural tube?
Astrocytes, neurons, oligodendrocytes, ependymal cells
What kind of behavior do GBM cells exhibit that is not frequently seen in benign tumor cells?
Abnormal activity around tumor which suggests that cells are moving outward
What are the characteristics of GBMS on a CT/MRI scan?
Low-density spots that could be hemorrhage, calcification; dark area around tumor that suggests edema
What are the histological characteristics of GBMs?
Necrosis, atypical cellular appearance, neovascularization
How do glioma cells survive in a hypoxic environment?
They migrate along CD31+ endothelial cells for oxygen
What structures do GBM cells migrate along?
White matter tracts, blood vessels
What is the hypothesis that explains why glioma cells can squeeze through tight extracellular space?
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
What neuroectodermally derived cell type does not contribute to glioma? Why?
Neurons, they have apoptosis and do not divide
Neural stem cells
Cells found in the nervous system that can differentiate into other types of cells
Where are neural stem cells found in the adult CNS?
Subventricular zone
Cancer stem cell
Cancer propagating cell; stem-cell like population in tumor responsible for constantly generating glioma stem cells
Glioma cell of origin
Cancer initiating cell
Oncogene
Slight variation of normal cellular gene that causes controlled cell growth; gain-of-function
Tumor suppressor gene
Gene that normally acts to inhibit uncontrolled cell growth
Is a gain-of-function mutation dominant or recessive?
Dominant mutation, only one copy of mutated allele needed to produce effect
Is a loss-of-function mutation dominant or recessive?
Recessive, two copies of mutation are required to produce effect
Loss of heterozygosity
Loss of normal allele in a heterozygous cell
Missegregation
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
Mitotic recomibnation
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
What are the two most likely candidate cell types that can generate gliomas?
Neural stem cells, astrocytes
What are the characteristics of glioma stem cells?
Express CD133+ which acts like stem cells and allows the ability to continuously generate rapidly proliferating cells
Molecular classification of glioblastoma multiforme
Classification based on genes that are mutated or overexpressed; classical, mesenchymal, neural, proneural
Molecular signature of classical GBM
EGFR amplification and loss of PTEN
Molecular signature of mesenchymal GBM
Deletion of NF1, also PTEN mutation
Molecular signature of proneural GBM
PDGFRA and p53 mutations
Molecular signature of neural GBM
Expression of neuronal genes as well as astrocyte and oligodendrocyte genes
Which GBM class resembles astrocytes?
Classical, neural
Which GBM class resembles oligodendrocytes?
Proneural, neural
What are the three main signaling pathways that are commonly altered in glioma?
Receptor tyroskine kinase pathway, P53 pathway, Retinoblastoma pathway
What is the EGFRvIII mutation?
Oncogenic mutation, deletion of exon 207; gain the function of EGFR, constantly “on”; activates downstream signaling effectors which leads to amplification, overexpression, mutation
Are oncogenes gain-of-function or loss-of-function?
Gain-of-function
Are tumor suppressor genes gain-of-function or loss-of-function?
Loss-of-function
How is a receptor tyrosine kinase activated?
EGFR binds and makes it active; causes cross-phosphorylation of the receptor; recruits signaling molecules downstream which lead to increased cell proliferation
How does p53 inhibit cell proliferation?
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
How does Rb inhibit cell proliferation?
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
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?
Loss of heterozygosity
Why does loss of heterozygosity in the NF1 gene contribute to tumor formation?
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
Why does loss of heterozygosity in the PTEN gene contribute to glioma formation?
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
