General and
Systemic Pathology
Pathology: Study of structural, biochemical, and
functional changes in the body that underlie disease.
•Logos: study
•Pathos: suffering
General Pathology
•Common reactions of cells and
tissues and how they respond to
injurious stimuli.
Systemic Pathology
•System-based
•Alterations and underlying
mechanisms of particular organ
system.
4 Aspects of a
Disease
Process
1. Etiology
•Initiating cause
•Genetic and
Environmental factors
2. Pathogenesis
•Sequence of events
that lead to the
development of the
disease.
•Central focus of
pathology
3. Morphologic Changes
•Structural changes
seen in tissues and
cells
•Pathognomonic signs
or characteristics of a
disease.
4. Clinical Manifestations
•Signs and symptoms
manifested by the
patient based on
etiology, pathogenesis,
and morphologic
changes.
Rudolf
Virchow
Pioneer of pathology
Asserted that diseases
originated at
cellular
level.
THE CELL
Most fundamental
unit of our body
Fertilization —> Blastocyst
—> Inner cell mass
Embryonic Stem Cells
Adult/Tissue Stem Cells
Mesenchymal Stem Cells
•Most undifferentiated cells (TOTIPOTENT)
•From the inner cell mass
•Form any cells in germ cell layers— ectoderm,
mesoderm, endoderm
•Intimate association with differentiated cells
of a given tissue
•Limited capacity to differentiate (only follow
their mature forms)
•Protected within stem cell niches (special tissue
microenvironment)
•Specific form of adult stem cell
•Differentiates into stromal cells (important
for tissue regeneration)
Chondrocytes
Osteocytes
Adipocytes
Myocytes
CELL DIVISION
Asymmetric
Differentiated cell (mature cell) +
Undifferentiated cell (stem cell pool)
Symmetric
2 Differentiated cells (mature cell) OR
2 Undifferentiated cells (stem cell pool)
Cellular Housekeeping
•Maintenance of intracellular homeostasis
•Compartmentalized within membrane-bound
organelles.
Cell Organelles
Endosomal Vesicles
•Shuttle internalized
materials
Mitochondria
•Provides ATP (Anabolic
metabolism)
•Powerhouse of the cell
•Apoptotic function
Plasma Membrane
•Contains protein and
glycoprotein
•Receptor-mediated uptake
and cell-to-cell interaction
Cytoskeleton
•Stabilize organelles
•Important for movement of cell
•3 COMPONENTS:
-Microfilaments
-Microtubules
-Intermediate filaments
Intermediate Filaments
For identifying undifferentiated
tumors through IHC.
Vimentin
Mesenchymal cells
Fibroblasts
Endothelium
Desmin
Muscle
Neurofilaments
Neuronal Axon Structure
Glial Fibrillary Acidic Protein
Glial Cells
Cytokeratins
Epithelial Cells
Lamins
Nuclear Lamina
Nuclear Shape
Regulate Transcri ption
Rough ER/Ribosomes
•Site of translation of mRNA
into proteins
Smooth ER
•Carries newly synthesized protein
into golgi apparatus.
•More conspicuous in fatty structures
(gonads, adrenal gland, and liver)
Golgi Apparatus
•Protein and lipid shuttle for
other organelles or extracellular
export
Proteosomes
•Degrades denatured or tagged
cytosolic proteins
Lys osome s
•Autophagy (breakdown of
senescent intracellular
organelles)
Peroxisomes
•Breakdown of very long fatty
acids
Growth Factors &
Receptors
•Stimulate the activity of signaling
pathways or genes that promote cell
survival, growth or division
•Proto-oncogenes and oncogenes:
mutations in growth factors (cells affected
can serve as precursors to malignancy)
Other Functions:
•Promote entry of certain
components into the cell cycle.
•Relieve blocks in the cell cycle
to promote replication
•Prevent apoptosis
•Enhance synthesis of CHONS,
CHO, lipids and nucleic acids
•Regulate cellular proliferation
in response to injury.
Epidermal Growth Factor/ TGF-ą
•Promote mitosis of hepatocytes, fibroblasts, and
other epithelial cells (keratinocytes).
•Stimulates formation of granulation tissue and
keratinocyte migration
•ERB-B1/EGFR1 Mutation: indicative of cancer
(lung, head and neck, breast, brain)
•ERB-B2/HER2: Breast cancer (treated with
Herceptin/Trastuzumab)
SOURCES:
•Activated macrophages
•Salivary glands
•Keratinocytes
Transforming Growth Factor/ TGF -ß
•Belongs to a larger family which includes: BMPs, Activins,
Inhibins, and Mullerian-inhibiting substance
•TGF-ß1: most widespread distribution
•Stimulates production of collagen, fibronectin, and
proteoglycans
•Inhibits collagen degradation by:
-Decreasing metalloproteinase activity
-Increasing the activity of tissue inhibitor metalloproteinase
•Scar formation
•Anti-inflammatory cytokine (supresses acute inflammation)
•Inhibits lymphocyte proliferation
SOURCES:
•Platelets
•T Lymphocytes
•Macrophages (inflammatory cells)
•Endothelial cells
•Keratinocytes (epithelial cells)
•Smooth Muscle cells
•Fibroblasts
Hepatocyte Growth Factor/
Scatter Factor
•Important for liver cells
•Has mitogenic effects on hepatocytes, biliary
epithelium, lung, kidney, breast, and skin
•Increases cell motility
•Receptor: MET (w/ intrinsic tyrosine kinase activity)
-MET Mutation: Renal and Thyroid Papillary
Carcinoma
SOURCES:
•Fibroblasts
•Mesenchymal cell
•Epithelial cell
•Nonhepatocyte liver cell (stromal
cells)
•Endothelial cells
Platelet-Derived Growth Factor
•Stored in cytoplasmic granules and released by
activated platelets.
•Binds to: PDGF ą and ß
•Induces fibroblast, endothelial, and smooth
muscle cell proliferation and chemotaxis
(including inflammatory cells)
•Stimulates ECM protein synthesis
SOURCES:
•Platelets
•Macrophages (activated)
•Endothelial cells
•Smooth muscle cells
•Keratinocytes
•Tumors
Vascular Endothelial Growth Factor
•Maintenance of normal endothelium
•Angiogenesis (Capillary sprouting)
•Promote formation of vascular lamina and vascular dilation
(increases vascular permeability)
•Actions are seen in kidney podocytes, retinal pigment
epithelium, choroid plexus
•Overexpression:
-Renal and Colon Cancers
-Ophthalmic Disorders (“Wet” age-related macular
degeneration, Retinopathy of prematurity, Diabetic macular
edema)
-Preeclampsia
SOURCE:
•Mesenchymal cells
Fibroblast Growth Factor
•Contributes to wound healing responses,
hematopoiesis and development
•Chemotactic and mitogenic for fibroblasts and
keratinocytes
•Stimulates angiogenesis (basic FGF/ FGF-2) and
ECM protein synthesis
•Acidic FGF: aFGF/FGF-1
•Basic FGF: bFGF/FGF-2
•Keratinocyte growth factor: FGF-7
SOURCES:
•FGF 1 and 2
-Macrophages
-Mast cells
-Endothelial cells
•FGF-7
-Fibroblasts
Cell Cycle
G1: Cellular contents (exc. chromosomes) are duplicated
S: Each of the 46 chromosomes are duplicated
G2: Cell double checks for errors and areas needing repairs.
M: Mitotic phases
G0: Quiescent cells that are not actively cycling.
Checkpoints
Quality Control
G1/S Checkpoint: Monitors DNA integrity
G2/M Checkpoint: Accurate genetic replication
G0/G1 Checkpoint: Checks for nutrients, growth
factors and DNA damage
Cell Cycle Activators/
Inhibitors
•Regulates check points
•Driven by cyclins and cyclin-dependent
kinases (pairs)
Activators
(Induces cell cycle
progression)
Inhibitors
(Enforce/moderate cyclin-
CDK complex activity)
Cyclin D- CDK4
Cyclin D- CDK6
Cyclin E- CDK2
G1-S Transition
S Phase
Cyclin A- CDK2
Cyclin A- CDK1
G2-M Transition
Cyclin B- CDK1
1st Family
(Selective on CDK 4 & 6)
P16- CDKN2A
P15- CDKN2B
P18- CDKN2C
P19- CDKN2D
2nd Family
(Act on multiple CDK;
works at any phase of the
cycle)
P21- CDKN1A
P27- CDKN1B
P27- CDKN1C
DNA
REGIONS
OF DNA
CODING/EXONS
(1.5%)
DNA—> RNA —> Proteins
NON-CODING/INTRONS
(98.5%)
Source of most materials that is produced in
the body
99% of polymorphism cases occurs in this area
5 Classes of
Functional Non-Protein
Coding Regions
1. Promoter and enhancer
regions
2. Binding sites for
proteins (to maintain higher
order chromatin structures)
3. Noncoding regulatory
RNAs
4. Mobile genetic
elements (Transposons)
5. Te lo me re s (Chr ends)
and Centromeres (Chr
tethers)
DNA
Variation
Single
Nucleotide
Polymorphism
Copy Number
Variation
•Variants at a
single nucleotide
position (biallelic)
•Can occur in
coding regions
(1%) and in
regulatory
elements in non-
coding regions
•Consists of
different
numbers of
large continuous
stretch of DNA.
•Biallelic,
duplicated, or
deleted
Epigenetic Factors
(Genetic modifications or heritable
changes)
Chromatin
Organization
Factors
•Bind to noncoding regions
•Long-range looping of DNA
•Regulates spatial relationships
between enhancers and
promoters of gene expression
DNA Methylation
Factors
•Gene regulatory elements
(recognized by transcription
factors)
•High levels of DNA methylation =
Transcriptional Silencing
•Tightly regulated by:
-Methyltransferases
-Demethylating enzymes
-Methylated-DNA-Binding
Proteins
Histone and Histone-
Modifying Factors
•Nucleosomes are 147 bp long
-Wrapped around a central
core of highly conserved low
molecular weight proteins
called histones.
•Coiled DNA structure allows
DNA to be packed inside the
cell.
Heterochromatic
Euchromatic
•Vesicular
(nucleus and
nucleolus become
clearer)
•Transcriptionally/
mitotically active
•Chromatin
material disperses
in the periphery
•Also seen in
CANCER
•Dense (nucleus
and nucleolus
are
inconspicuous)
•Largely
basophilic
•Transcriptionall
y/mitotically
INactive
•Seen in ADULT
CELLS
RNA
Micro-RNA (miRNA)
Long Non-Coding RNA
(lncRNA)
•DO NOT encode proteins
•ONLY MODULATE
translation of target
mRNAs (coregulation)
•Posttranscriptional
silencing of gene
expression
•Almost 6000 miRNA
genes
•MODULATION of GENE
EXPRESSION
•Binds to chromatin and
restrict RNA
polymerase
•May exceed coding
mRNAs by 10 to 20-fold
•E.g., Physiologic X
Chromosome
inactivation in females
FUTURE OF MEDICINE
(Gene Editing)
CRISPRs and CRISPR-
associated Genes
Regenerative
Medicine
Ta rg et ed T he ra pi e s
of Growth Factors
•Insertion of specific
mutations to model
cancers and other
diseases.
•Selectively edit
mutations
•Identify, isolate,
expand, and
transplant stem cell
from stem cell niches.
•Targets receptors
•MET Mutation (Renal Cancer):
Crizotinib
•Her-2 neu inhibitor (Breast
cancer): Trastuzumab or
Lapatinib
•EGFR Mutation (Lung cancer):
Cetuximab, Erlotinib,
Panitumumab, Rociletinib
•ALK: Crizotinib or Lorlatinib
•PD-1/PD-L1: Pembrolizumab or
Nivolimab
Membrane-
Bound
Plasma membrane
Nucleus
RER
SER
Golgi apparatus
Lyso som es
Endosomes
Peroxisomes
Mitochondria
Non-Membrane-
Bound
Ribosomes
Proteosome
Microtubules
Actin Filaments
Intermediate Filaments
Centrioles and Basal
Bodies
Cilia
Flagella
Inclusions
