Pathology AB_1202 Part I
Rya Riedweg
2021/22
VU Amsterdam
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, Contents
Cell and tissue adaption and damage ..................................................................................................................................... 4
What is disease ................................................................................................................................................................ 4
Cell damage, stress & stressors ........................................................................................................................................... 4
Adaption vs cell death ..................................................................................................................................................... 4
Necrosis ........................................................................................................................................................................... 5
Apoptosis ......................................................................................................................................................................... 5
Necroptosis...................................................................................................................................................................... 7
Storage of molecules ....................................................................................................................................................... 7
Cellular aging ................................................................................................................................................................... 7
Inflammation and repair.......................................................................................................................................................... 8
Mainplayers ..................................................................................................................................................................... 8
Migration of leukocytes through the blood vessel wall ...................................................................................................... 9
Inflammatory reaction..................................................................................................................................................... 9
Migration of leukocytes through the blood vessel wall = Diapedesis ........................................................................... 10
Chemotaxis .................................................................................................................................................................... 10
Phagocytosis and destruction of microorganisms ........................................................................................................ 11
Morphological patterns of acute inflammation ............................................................................................................ 12
Effects of inflammation ................................................................................................................................................. 12
Chronic inflammation .................................................................................................................................................... 12
Edema, hemostasis, thrombosis, embolism and shock......................................................................................................... 13
Edema ............................................................................................................................................................................ 13
Hemorrage and hemostasis........................................................................................................................................... 14
Tissue repair .................................................................................................................................................................. 17
Shock ............................................................................................................................................................................. 18
Immunopathology: Immune mediated tissue damage and hypersensitivity ....................................................................... 19
Hypersensitivity reactions ................................................................................................................................................. 20
Type I ............................................................................................................................................................................. 20
Type II ............................................................................................................................................................................ 21
Type III ........................................................................................................................................................................... 22
Type IV ........................................................................................................................................................................... 22
Autoimmunity.................................................................................................................................................................... 23
Immunologic tolerance.................................................................................................................................................. 23
Pathogenesis ................................................................................................................................................................. 23
Antinuclear Antibodies in autoimmune diseases .......................................................................................................... 23
Systemic sclerosis .......................................................................................................................................................... 24
Immunodefficiencies ......................................................................................................................................................... 24
Secondary (acquired) immunodeficiencies ................................................................................................................... 24
Primary (congenital) human immunodeficiencies ........................................................................................................ 25
Transplant rejection & Tumor immunology .......................................................................................................................... 27
Immune system ................................................................................................................................................................. 27
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, Two main arms .............................................................................................................................................................. 27
Organ Transplantations ..................................................................................................................................................... 27
Types of Transplantations ............................................................................................................................................. 27
Rejection of Transplants ................................................................................................................................................ 28
Hematopoietic Stem Cell (HSC) Transplantation........................................................................................................... 29
Tumor Immunology ........................................................................................................................................................... 29
Interactions between the Immune System and Tumor Cells ........................................................................................ 29
Neoplasia ............................................................................................................................................................................... 31
Benign vs malignant ...................................................................................................................................................... 31
Cancer causing factors ................................................................................................................................................... 31
Hallmarks of cancer ....................................................................................................................................................... 35
Clinical aspects of tumors.............................................................................................................................................. 36
Laboratory diagnosis of cancer ..................................................................................................................................... 36
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,Cell and tissue adaption and damage
What is disease
Dysfunction of an organ or tissue, because of damage to the cells.
The damage can be of many causes, chemical, thermal, radiation, DNA damage, microbacterial, etc.
The damaging agent is the etiology, the influence on and the changes in cellular processes reflect the
pathogenesis
o Etiology is eg radiation -> leads to missense mutation -> incorrect amino acid -> malfunctioning protein
Pathogenesis is often a sequence
Problems in multicellular individuals: internal milieu is optimized and thus also attractive for intruders ->
infectious disease + organization and division of task is mandatory (also with regards to proliferation) ->
otherwise leads to cancer
o Human body is made up out of 3720 billion cells
HeLa cells derived from a cervical cancer, Nicolo Paganini described Marfan’s syndrome)
Cells and cellular pathologies were described by Schleiden, Schwann and Virchow
Cell damage, stress & stressors
Disease is caused by damage to (part of) a cell or group of cells (etiology)
The initial damage can cause further damage (pathogenesis)
The cell/organ reacts to minimize impact of damage (adaptation)
Damage can be reversible, lead to adaptation or, ultimately to death of the cell
Adaption vs cell death
Increased load on myocyte
o Adaption: respond to increased load -> hypertrophy
o Cell injury -> cell death
Adaption
Hypertrophy = Increase in the size of cells, NO increase in
number of cells
o During pregnancy
o Production of more heart muscle proteins -> able
to perform more work
o Is reversable
o In cells that show little mitotic activity -> in cells
that are incapable of cell division
o Induced by growth factors produced in response
to mechanical stress or other stimuli
Hyperplasia = Increase in the number of cells (not in the size of the cells)
o In response to hormones or other growth factors
o In tissue whose cells can divide or have tissue stem cells
Atrophy = decrease of tissue by decrease of cell size and/or number
o Result of decreased nutrient supply or disuse (decrease of activity)
Eg pressure atrophy in the surrounding tissue of a growing tumor due to ischemia
o Happens by protein degradation in living cells through proteasomal degradation, autophagy or
apoptosis
Autophagy
cell gets rid of organells -> when cell is under-nutritioned -> cell gets smaller
if too severe then it results in apoptosis
Metaplasia = replacement of one tissue by a (normal) other tissue
o Response to chronic irritation -> to withstand the stress better
o Usually induced by altered differentiation pathway of tissue stem cells
o Can result in reduced function or increased probability for malignant transformation
o Most common form: metaplasia of grandular epithelium into stratified squamous
epithelium
Eg squamous metaplasia of bronchial epithelium -> epithelium is not ciliated
anymore
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, During smoking, reversable when stop smoking
Gathering of mucus in the respiratory tract + carcinogens from smoke are not
removed
o Barrett’s metaplasia: When gastric juces get into oesophagus -> intestinal type of epithelium in the
oesophagus instead of squamous epithelia
Exception: CNS -> cell division and hypertrophy remains absent even during increased activity
o Bc brain only has limited space in the skull -> would lead to brain stem compression -> ischemia
Cell damage
Hypoxia and ischemia lead to ATP depletion -> failure of energy dependent functions -> first reversible injury
and if not corrected necrosis
o Reversible cell injury: cell swelling, fatty change, plasma membrane blebbing, loss of microvilli,
mitochondrial swelling, dilation of the ER, eosinophilia (resulting from decreased cytoplasmic RNA)
o eg Failure of Na+-K+-ATPase -> cell damage -> cell swells
Water can enter when pump is not working, but is reversable when there is oxygen again,
but has to happen fast otherwise cell explodes
Ischemic-reperfusion injury: restoration of blood flow to an ischemic tissue -> worsens damage bc of
increased production of ROS and inflammation
o Oxidative stress can damage cellular lipids, proteins, DNA
Protein misfolding -> apoptosis
DNA damage (radiation) -> apoptosis
cell dies if it is too stressed -> Cell damage leads to necrosis or
apoptosis
o They have different effect on inflammation, different number
of involved cells, different role in physiology and different
initiation
o But in diseases they play the same role, which is cell death
Necrosis
Accidental death, increased cytoplasmic eosinophilia
Nuclear shrinkage, fragmentation and dissolution, breakdown of
plasma membrane and organellar membranes, leakage and enzymatic digestion of cellular content
gives inflammatory response -> further damage
cells stain less bc they get a lor of water in
several cells are affected
Coagulation necrosis
o Tissue coagulated, common for infarcts (in eg kidney or
heart)
Colliquative necrosis (liquefactive necrosis)
o when shortage of oxygen in the brain -> macrophages and a
hole is left -> liquid from the interstitium replaces the cells
Caseous necrosis (TBC)
o caused by tuberculosis, bacteria causes damage in tissue
Fat necrosis
o When pancrease is inflammed enzymes for digestion are released to surrounding ->
fat is digested by lipase -> fat into fatty acids -> take up ca -> white spots of calcium
Fibrinoid necrosis (arterial wall)
o Fibrinoid only in blood vessels, pink is necrotic tissue in the vessel wall that
looks like fibirin
Apoptosis
Belongs to the regulated elimination, compensatory cell division for replacement -> serves to eliminate
unwanted and irreparable damaged cells
Is darker staining
Everything is fragmented into globules -> taken up by neighbouring cells (by phygocytes)
only one isolated cell does apoptosis
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, Embryonal development (‘programmed cell death’) -> eg development of the hand
Normal tissue homeostasis (cell death and formation of new cells)
Selection of early maturational stages of lymphocytes by antigen receptors
Involution or atrophy (endometrium during periods; breasts after lactation, &c.)
Termination of inflammatory response or immune reaction
Elimination of virus-infected cells or cells with (oncogenic and other) mutations, by CTL
Eliminaton of stressed cells by NK cell
Elimination of damaged cells
Mechanism
executioner caspases activate lytic
enzymes
Extrinsic apoptosis-induction
A lethal signal from outside the cell (FasL, TNF) triggers, through receptor activation, a cascade that leads to
apoptosis
o -> death receptors are members of the TNF receptor family
o Extrinsic pathway is responsible for elimination of self-reactive lymphocytes and damage by CTLs
Mitochondrial (intrinsic) pathway of apoptosis-induction
Process triggered from the inside
Lack of survival signals, or damage or stress of the cell itself, induces apoptosis
o Stress: ER stress -> leads to misfolded proteins
Through mitocondria -> changes in mitocrondia -> formation of apoptosome which triggers caspases -> cell
death
Associated with leakage of proapoptotic proteins from mitochondrial membrane into the cytoplasm -> there
they trigger caspase activation
BCL-2 family manage the balance between suicide or not -> some member of
the family hold off apoptosis, some are apoptopic
o Anti apoptopic members are induced by survival signals or growth
factors
o BCL-2 and B-cell (follicular) lymphoma:
BCL2-geen is translocated (is not mutated!!) -> brought under
control of the promotor of the heavy chain of the
immuunglobulin -> overexpression -> loss of apoptosis
response -> accumulation of cells -> tumor
No starry sky macrophages -> no apoptosis (otherwise
only reactive hyperplasia due to infection
BCL-2 is antiapoptotic bc it interferes with the apoptosome
Cytochrome C:
o Protein of appr. 100 AA, with a heme group
o Present in many unicellular organisms, in plants and animals
o Two functions:
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