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Mechanisms of Disease > Week 1 Lecture (Intro) > Flashcards

Week 1 Lecture (Intro) Flashcards

1
Q

What is etiology?

A

Cause of a disease
(we may not know exactly what the cause is)

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2
Q

What is pathogenesis?

A

Biochemical and molecular mechanisms of disease development

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3
Q

What is morphology?

A

Appearance of cells/tissues/organs

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4
Q

What are clinical features (manifestation)?

A

Functional consequences of morphological changes

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5
Q

Name the 4 reasons cells die.

A
  1. Lack of resources (hypoxia, nutrient deficiency, growth factor withdrawal)
  2. Exposure to toxins (toxins kill cells)
  3. Removal of aging/ineffective cells (specific targeting)
  4. Attack by immune system (infection, autoimmunity)
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6
Q

List 3 types of intracellular accumulations that could be signs of injury.

A
  1. Fatty deposits
  2. Lipofuscin
  3. Protein
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7
Q

List the modes of cell death.

A
  1. Unregulated (pathological)- necrosis
  2. Regulated (physiological)- apoptosis
  3. Alternatives- necroptosis, anoikis, autophagy
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8
Q

Explain necrosis

A

The cell breaks down/explodes and contents are released into the surrounding area. Enzymes from those cells can start chewing up other cells, damaging their neighbors.

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9
Q

What do necrotic cells look like?

A
  1. Loss of nuclei or pyknotic nuclei
  2. Breakdown of membranes (more debris present)
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10
Q

What are the 4 types of necrosis?

A
  1. Coagulative- loss of cell architecture, but not tissue architecture
  2. Liquefactive- digestion of cells results in viscous mass
  3. Caseous- (cheese-like) fragmented cells and granular debris surrounded by inflammation
  4. Fibrinoid- immune complexes and fibrin in walls of blood vessels
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11
Q

What is an infarction?

A

Blockage caused limited blood flow, which causes necrotic cell death.

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12
Q

What are the causes of necrosis?

A

Overwhelming damage due to…
- toxins
- excessive calcium
- damage to ER and mitochondria
- reactive oxygen species (ROS)–> cause oxidative damage to plasma membrane that makes it leaky and fall apart
- ischemia–> loss of blood flow/nutrients
- membrane damage–> ROS, ethanol
- nutrient withdrawal

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13
Q

What are the 4 specific instances of physiological cell death (apoptosis)?

A
  1. Embryogenesis- origin of the term ‘programmed cell death’
    - death of specific cells at specific times (ex: digit development)
  2. Tissues that produce new cells as part of their function- maintenance of homeostasis
    - immature lymphocytes in bone marrow/thymus that fail to express useful antigen receptors
    - epithelial cells in intestinal crypts
  3. Loss of hormone-dependent tissues when hormone levels fall
    - endometrial cell breakdown during menstrual cycle
    - ovarian follicular atresia in menopause
  4. Immune function
    - destruction of self-reactive lymphocytes to prevent autoimmunity
    - death of cells that have served their purpose–> neutrophils/lymphocytes at the end of inflammatory/immune responses
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14
Q

List the apoptotic initiators

A
  • viral infections
  • ionizing radiation
  • chemical damage to cells
  • cytokines (TNF, Fas ligand)
  • mitochondrial damage
  • UPR (unfolded protein response)
  • calcium influx
  • unresolved stress
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15
Q

What are the major morphological features of apoptosis?

A
  • cell rounding/condensation
  • nuclear condensation(pyknotic) /fragmentation–> visible with DAPI staining
  • membrane blebbing–> small blebs form apoptotic bodies; visible with light microscopy
  • formation of apoptotic bodies–> packaging of cell contents into vesicles
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16
Q

What are the 2 different starting points of apoptotic signaling?

A
  1. Extrinsic
  2. Intrinsic
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17
Q

Define extrinsic apoptotic signaling.

A
  • signal coming from outside the cell
  • death receptors on the plasma membrane are activated and transduce a signal through intracellular signaling pathways to activate caspases
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18
Q

Define intrinsic apoptotic signaling.

A
  • mitochondrial signals induce release of pro-apoptotic proteins that activate caspases
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19
Q

What are caspases?

A
  • specific proteases that disassemble the cell
  • biochemical markers of apoptosis
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20
Q

Name some caspases.

A
  • cysteine aspartases
  • consensus sequences–> cleave after aspartic acid residue
  • inflammatory–> involved in NFKB signaling
  • apoptotic–> initiator caspases (activate executioner caspases), executioner caspases
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21
Q

What are the 4 subfamilies of the death domain superfamily and what do they do?

A
  1. Death Domain (DD)
  2. Death Effector Domain (DED)
  3. Caspase Recruitment Domain (CARD)
  4. Pyrin Domain (PYD)–> not included in cell death, actually an immune pathway

All 4 subfamilies are involved in assembly of protein complexes through homotypic binding
- ex: DD of a protein binds to DD of another protein, etc.

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22
Q

What is the advantage of having many proteins involved in the TNF extrinsic pathway?

A

You can use the same signal and have different effects in different cells based on which proteins are associated to form the complex.
TNF is involved in cell signaling and immune signaling; which one happens depends on what proteins are expressed by that cell.
- ex: Cell death is initiated through activation of caspase 8 or caspase 10.

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23
Q

What proteins have 2 domains and how is this beneficial?

A

Adaptor proteins
They can bind to 2 different domains and help form complexes.

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24
Q

How do caspases become active?

A

All caspases are expressed as pro-caspases.
- They undergo proteolytic cleavage of the pro- domain to form the active caspase.

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25
Q

Why are initiator caspases called autocatalytic?

A

Binding to the associated complex induces a conformational change that allows these caspases to catalyze the cleavage themselves.

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26
Q

How do the pro- domains of executioner caspases become cleaved?

A

Initiator caspase is released from the complex and cleave the pro- domains off the executioner caspases.

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27
Q

Where does intrinsic apoptotic signaling typically take place?

A

Mitochondria
- the damage can be direct to mitochondria or it can be transduced through BCL2 family members–> DNA damage or lack of survival signals

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28
Q

What is the Bcl-2 protein family?

A
  • Bcl-2 stands for B cell lymphoma 2
  • It is anti-apoptotic and contains 4 conserved domains (BH 1-4).
  • Pro-apoptotic members members will not have BH4 domain.
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29
Q

Why is balance important for p53 expression?

A
  • Lack of p53 increases cancer susceptibility
  • Overexpression promotes aging
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30
Q

What is PUMA?

A

p53 upregulated modulator of apoptosis

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31
Q

When talking about p53 and genotoxic stress, If the protein, PIDD, has RAIDD available to it, what will this activate?

A

Intrinsic pathway

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32
Q

When talking about p53 and genotoxic stress, If the protein, PIDD, has RIP available to it, what will this activate?

A

Cell survival pathway through NF-KB

33
Q

What is ER stress?

A

Accumulation of misfolded proteins

34
Q

What is the unfolded protein response?

A

A stress response that promotes degradation of proteins and increased chaperone production to improve folding.

35
Q

What happens if a cell cannot resolve ER stress?

A

Cell death will be induced

36
Q

What happens if a scientist overexpresses a protein?

A

They can overwhelm the cell’s ability to properly fold the protein
- inducing ER stress and killing the cells

37
Q

How does the endoplasmic reticulum participate in death signaling?

A
  • Stressed ER releases calcium that can stress the mitochondria, priming the mitochondria to induce an intrinsic pathway.
  • ER propagates death-inducing stress signals through Bcl-2 family members (Bcl-2 family members help the ER manage calcium levels)
  • Contributes to Fas-induced cell death and p53-induced cell death
38
Q

What are the different ways that mishandled calcium in the cell can be toxic?

A
  1. ER calcium depletion induces UPR (unfolded protein response)- a lot of chaperones responsible for protein folding require Ca2+ as a cofactor
  2. ER calcium release may activate specific enzymes in cytosol if calcium is not taken up by mitochondria
  3. Excessive mitochondrial calcium if ER is not maintaining its Ca2+
39
Q

What 2 enzymes did we mention that may be activated by ER calcium release?

A
  1. Calpain (protease)- Bid/Bax/Bcl-2 cleavage; Caspase 12 activation
  2. Calcineurin (phosphatase)- Bad dephosphorylation

Both appear to act through Bcl-2 family members

40
Q

What happens when there is excessive mitochondrial calcium?

A
  • Impairs mitochondrial function (causing depolarization)
  • Increased ROS generation (oxidative stress happening in the cell)
  • induces release of proapoptotic factors through mitochondrial permeability transition (Smac/DIABLO, AIF, cyt c, OMI/HtrA2)
41
Q

List some ways of detecting apoptotic cell death.

A
  1. Morphological methods
  2. DNA ladder formation
  3. Externalization of Phosphatidylserine
  4. Cleavage of specific proteins
  5. Activation of caspases
42
Q

Name some clinical signs of inflammation.

A
  • Redness
  • Swelling
  • Pain
43
Q

Name the histological signs of inflammation.

A
  • Edema (swelling)- unusual accumulation of fluid in the tissue
    *Edema is mediated by mast cells (immediate response) and eosinophils (later response)
  • WBC’s
44
Q

What do mast cells do during an immune response?

A

Mast cells degranulate and some of their products will increase permeability of blood vessels, which allows plasma to flow out of the blood vessels and you get edema/swelling.

45
Q

What is a pyogenic reaction?

A

Puss production- dead bacteria and dead WBC’s (typically neutrophils)

46
Q

What is a granuloma?

A

Macrophages surrounded by T cells- it is the body’s attempt to wall off the antigen it is reacting to

47
Q

How does an immune response end?

A
  • Ends when phagocytes clear all antigen; lack of T cell stimulation results in apoptosis
  • If this does not happen, you go into a chronic inflammatory response
48
Q

Compare and contrast acute vs chronic inflammation

A

ACUTE
- Dilation of small blood vessels
- Increased microvasculature permeability
- Migration and activation of immune cells (basophils, eosinophils, neutrophils, lymphocytes moving into the tissue and becoming activated)
CHRONIC
- Infiltration by macrophages, lymphocytes, plasma cells
- Tissue destruction- secondary to immune response
- Attempts at healing- collagen deposits or scar formation

49
Q

DON’T FORGET TO REVIEW IMAGES IN LECTURES

A

REVIEW THE IMAGES

50
Q

What causes meningitis?

A

Bacterial or viral infection

51
Q

What are the symptoms of meningitis?

A
  • Acute (rapid) onset high fever
  • Headache and stiff neck- due to inflammation in meninges
  • Photophobia
  • Confusion- because of the pressure on the brain
52
Q

Describe neuronal injury

A
  • Inflammation in subarachnoid space because of presence of bacteria or viral infected cells
  • Substantial infiltration by neutrophils
  • May breach blood-brain barrier and cause localized inflammation in neural tissue
  • Damage to blood vessels can cause hemorrhage into the brain- increasing pressure further in brain or spinal cord
  • Most damage is due to pressure
53
Q

Describe meningitis pathogenesis.

A
  • Colonization of the nasopharynx after inhalation- bind to cells of nasopharynx, cross into them and get into bloodstream
  • Evade opsonization in the bloodstream
  • CSF access through endothelium of blood-brain barrier
    *CSF does not have immune cells normally
    *Once there, bacteria have rich source of glucose and nothing attacking them (bacterial eden)
54
Q

What is one of the first lines of defense besides epithelium?

A

Immunoglobulin A (IgA)

55
Q

What is IgA produced by?

A

Plasma cells associated with mucosa
- epithelial cells lining oral cavity, nasopharynx, bronchial tubes, GI system

56
Q

How does IgA act?

A
  • Primarily acts through exclusion, binding and cross-linking
  • Not an inflammatory Ig; opsonization
  • Either soak up bacteria or help target bacterial destruction through other systems
  • Extensive glycosylation to prevent degradation by proteases that can cleave things like IgA
57
Q

What is opsonization?

A

Something infectious has something attached to it that allows the immune system to recognize it (compliment system)

58
Q

What is ciliostasis?

A
  • Prevents movement of bacteria out of bronchial tubes- cilia not functional
  • Attachment of bacteria to cilia impedes movements
  • Toxins- may damage axoneme; may deplete ATP
59
Q

What are adhesive pili?

A
  • Projections on some bacteria that can bind to non-ciliated mucosal cells
  • Once bound, they can cross the epithelium
  • Must also be able to cross the basement membrane
  • Infection occurs most easily in simple epithelia (single cell layer)- nasopharynx and intestines
60
Q

Compare and contrast bacterial toxins.

A

EXOTOXINS (excreted by the cell)
- Highly antigenic (antitoxin neutralizes)
- Highly toxic (fatal in microgram quantities)
- Usually do NOT induce fever
- Usually bind to specific receptors
- Ex: Botulinum toxin
ENDOTOXINS (part of the cell wall)
- As long as the bacteria are alive, these are not being released
- Weakly immunogenic- typically cannot produce antitoxins to them
- Induce fever
- No specific receptors

61
Q

What causes parasitic diseases?

A
  • Single-celled and multicellular organisms
    - Consumption by parasite- ex: hookworms consume blood, causing anemia
    - Damage may result from immune response- the body trying to rid you of the parasitic infection
62
Q

What is Trichinella Spiralis and what does it do?

A
  • Nematode obtained by ingestion of undercooked meat, usually pork
  • Infects skeletal muscle
63
Q

What are the symptoms of Trichinella Spiralis?

A
  • Fever
  • Myalgia (muscle pain)
  • Periorbital edema
64
Q

Describe the life cycle of Trichinella Spiralis.

A
  1. Larvae ingested by eating skeletal muscle (meat)
  2. Larvae released from nurse cells in stomach
  3. Larvae enter small intestine
  4. Adults mature and live in small intestine
  5. New larvae infiltrate blood
  6. Larvae exit blood vessels in skeletal muscle and infect skeletal muscle fibers
  7. Adults die and muscle fiber calcifies
  8. Nurse cell-larva complex formed
65
Q

Describe the enteric phase of Trichinella spiralis infection.

A
  • Strong immune response to larvae
    *T helper cells produce cytokines
    *Eosinophil and mast cell activation- inflammation, pain, increased permeability of mucosal epithelium
  • Increased intestinal mobility (diarrhea)
    *T helper cytokines
    *Mast cell granules
    *Expel larvae from gut in animal models
  • As larvae travel elsewhere, inflammatory response can cause widespread destruction
66
Q

Describe the muscle phase of Trichinella spiralis.

A
  • Muscle cell is co-opted as a nurse
  • Disruption of myofibrils
  • Enlarged/central nuclei
  • Collagen capsule formation
    Note: this phase can persist for years
67
Q

Describe the clinical presentation of Trichinella spiralis.

A

ENTERIC STAGE
- Typical of enteric disease
- Diarrhea and nausea
- Vomiting, pain, low grade fever
MUSCLE STAGE
- Typical of infection/muscle damage
- Myalgia and paralysis
- Fever, headache, skin rash
- Edema and conjunctivitis

68
Q

Name the 2 types of skin disorders.

A
  1. Growths
  2. Dermatitis
69
Q

What is psoriasis?

A
  • Inflammatory skin condition
  • Scaling skin condition characterized by silvery scaly plaques on the skin
70
Q

Describe the pathology of psoriasis.

A
  • Thickened epidermis- elongated rete ridges; more space for more cells in stratum basale
  • Neutrophil infiltration- in dermis and some in epidermis
  • Excessive epidermal proliferation- shortened cell cycle; 2X proliferative population
    *Cells of strat. basale have shortened cycle, producing new cells faster, increasing # of basale cells
    *Epidermis thicker because more cells being produced as part of epidermis
  • Accumulation of nucleated cells at stratum corneum (parakeratosis)
  • Endothelial cell proliferation in blood vessels in the dermis
71
Q

What is angiogenesis and what does it have to do with psoriasis?

A
  • Production of new blood vessels, specifically usually associated with something like cancer
  • Angiogenic factors found in poriatic lesions- TNFalpha, TGFbeta, IL8, VEGF
72
Q

What is VEGF and what does it do?

A
  • Vascular endothelial growth factor
  • Released from keratinocytes
  • Stimulate epidermal hyperplasia, vascular growth, leukocyte infiltration
  • Regulates psoriatic keratinocyte activity
73
Q

What is verrucae?

A
  • Warts
  • Squamoproliferative- proliferation of squamous cells
  • Caused by human papillomaviruses- certain variants
  • Generally regress (self-limited)
  • Virus transmitted by contact
  • Viral typing can confirm if problematic infection (poor prognosis/cancer)
74
Q

Describe verrucae pathology.

A
  • Epidermal hyperplasia is uneven
  • Lots of stratum corneum
  • Cytoplasmic vacuolization (halos)
  • Increased keratinohyalin granules
  • Eosinophilic keratin aggregates in cells
75
Q

Explain the development of verrucae.

A
  • IHC reveals HPV viral proteins in keratinocytes
  • E6 of HPV may interfere with maturation of keratinocytes
    * cells growing more rapidly because they are not differentiating as quickly as they should (higher number of proliferative cells)
76
Q

What is pemphigus?

A
  • Autoimmune formation of blisters
  • Autoantibodies attack intercellular junctions or cell basement membrane junctions
    *In epidermis
    *In mucosa (mouth or throat)
77
Q

What is acantholysis?

A
  • Dissolution of intercellular bridges
  • Which ones determine where blister forms
78
Q

Describe the 3 types of pemphigus.

A
  1. Subcorneal (foliaceus)- between stratum corneum and stratum granulosum; separation close to stratum corneum
  2. Subrabasal (vulgaris)- between stratum spinosum and stratum basale
  3. Subepidermal (bullous pemphigoid)- between dermis and epidermis in basement membrane; attack on things like hemidesmosomes

Mechanisms of Disease (10 decks)

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