General Pathology

Pathology of Organels I.

– Introduction

The Secretory

Process

and

Its DisordersInst. Pathol. ,1st Med. Faculty, Charles Univ. Prague

Jaroslava Dušková

http://pau.lf1.cuni.cz/en/texts-from-the-lectures-and-seminars-presentations

Jaroslava Dusko

va

Pathology of Organels I - table of contents

Cell components & their function

Pathomorphology of the cell nucleus

quantitative

qualitative

Pathomorphology of the cytoplasm

cytosol

organelles

intracellular accumulations

water

proteins

lipids

glycogen

pigments,foreign bodies

Cellular secretion

types

organelles involved

sense

Jaroslava Dusko

va

The Cell Components &Their Function

1. nucleus (incl. nucleolus and

nuclear envelope)

2. cytoplasm

cytoplasmic matrix

cytoplasmic organelles

3. plasma membranes

Jaroslava Dusko

va

Main Cell

Organelles

Jaroslava Dusko

va

The Cell Components &Their Function

The nucleus(incl. nucleolus and nuclear

envelope)

chromosomes

DNA, RNA, histones

Jaroslava Dusko

va

Nuclear envelope

with pores

Jaroslava Dusko

va

The Cell Components &Their Function

The nucleus functions

– cell division

– genetic information

transcription & controlJaroslava Dusko

va

Cell Nucleus Pathology (1)

Related to genom changes

quantitative:

– binucleation, multinucleation – regular

polyploidy (4n, 8n… 2nn) - reactive change eg.

in inflammation –adaptation

qualitative:

– translocations, deletions, amplifications –

aneuploidy – often in neoplasms

(DNA densitometry, FISH, CGH, NGS…)

Jaroslava Dusko

va

Neoplasia (Tumour)

DNA disease

Stepwise accumulation

of genetic abnormalities

Escape of immunological

clearing systems

Jaroslava Dusko

va

Neoplasia (Tumour)

DNA disease Stepwise accumulation of genetic abnormalities

self sufficiency in growth signals

insensitivity to anti-growth signals

limitless replicative potential

sustained angiogenesis

tissue invasion and metastasis

Escape of immunological clearing systems

evading apoptosis

Jaroslava Dusko

va

L SIL

HR HPV stimulates loss of tumour supressor genes,

activates cyclins, inhibits apoptosis, combats celular

senescence

Jaroslava Dusko

va

p16INK4a protein

inhibitor of cyclin

dependent kinase

controled in healthy

cells – undetectable

overexpressed as a

result of HPV E7

protein

MARKER OF

DYSPLASTIC CELLSJarosla

va Duskova

Jaroslava Dusko

va

Jaroslava Dusko

va

Jaroslava Dusko

va

Apoptotic bodies

Jaroslava Dusko

va

ATM/p53 Signaling Pathway

Jaroslava Dusko

va

Ca ovarii p53

Jaroslava Dusko

va

Ca ovarii MIB1 (Ki67)

Ki-67 is an excellent marker to determine the growth

fraction of a given cell population.

The fraction of Ki-67-positive tumor cells (the Ki-67

labelling index) is often correlated with the clinical course

of cancer.

The best-studied examples in this context are carcinomas

of the prostate, brain and the breast. For these types of tumors, the

prognostic value for survival and tumor recurrence have repeatedly been proven in uni-

and multivariate analysis.

Jaroslava Dusko

va

Lymphocyti &

mesothelia

Carcinosis

peritonei

AgNORs

Jaroslava Dusko

va

Pleuritis

carcinomatosa

Alc. Blue pH2,5

AgNORs

Jaroslava Dusko

va

Jaroslava Dusko

va

Jaroslava Dusko

va

CSF carcinosis

Jaroslava Dusko

va

Cell Nucleus Pathology (2)

Related to nucleolemma

quantitative:

– invaginations - pseudoinclusions

qualitative:

– thickening (irregular)

– chromatin margination

Nuclear inclusions (real)

– viral, lipids, glycogen

Jaroslava Dusko

va

Cytoplasmic nuclear pseudoinclusions

Jaroslava Dusko

va

papillary ca of thyroid

Jaroslava Dusko

va

Jaroslava Dusko

va

grooves

Jaroslava Dusko

va

CytomegalovirusJarosla

va Duskova

Cowdry A inclusion – herpetic encephalitis

Jaroslava Dusko

va

glycogen nuclei

Jaroslava Dusko

va

The Cell Components &Their Function

ribosomes

endoplasmic

reticulum

Golgi complex

lysosomes

peroxisomes

mitochondria

cytoskeleton

caveolae

The cytoplasm (cytosol)cytoplasmic matrix

cytoplasmic organelles

Jaroslava Dusko

va

The Cell Components &Their Function

The cytoplasm (cytosol)aqueous solution with enzymes

Jaroslava Dusko

va

The Cell Components &Their Function

The cytoplasm function

– proteosynthesis (in coop. with organelles)

– storage unit (fat, carbohydrates and

secretory vesicles)Jaroslava Dusko

va

Intracellular Accumulations

water –hydropic degeneration

proteins – hyaline droplets

lipids – steatosis

glycogen – glycogenosis

pigments – melanin, ceroid, lipofuscin,

hemosiderin

foreign bodies, crystals

microorganisms

Jaroslava Dusko

va

Hydropic Degeneration

intoxications

sepsis

anoxia

starvation

functional overload

autolysis

ENERGY DEFICIENCY

Jaroslava Dusko

va

Jaroslava Dusko

va

Jaroslava Dusko

va

Intracellular Accumulations

water –hydropic degeneration

proteins – hyaline droplets

lipids – steatosis

glycogen – glycogenosis

pigments – melanin, ceroid, lipofuscin,

hemosiderin

foreign bodies, crystals

microorganisms

Jaroslava Dusko

va

Jaroslava Dusko

va

Intracellular Accumulations

water –hydropic degeneration

proteins – hyaline droplets

lipids – steatosis

glycogen – glycogenosis

pigments – melanin, ceroid, lipofuscin,

hemosiderin

foreign bodies, crystals

microorganisms

Jaroslava Dusko

va

Steatosis myocardii (oil red)

Jaroslava Dusko

va

Adenoma corticis glandulae suprarenalis

Jaroslava Dusko

va

Jaroslava Dusko

va

Intracellular Accumulations

water –hydropic degeneration

proteins – hyaline droplets

lipids – steatosis

glycogen – glycogenosis

pigments – melanin, ceroid, lipofuscin,

hemosiderin

foreign bodies, crystals

microorganisms

Jaroslava Dusko

va

PAS

Jaroslava Dusko

va

Intracellular Accumulations

water –hydropic degeneration

proteins – hyaline droplets

lipids – steatosis

glycogen – glycogenosis

pigments – melanin, ceroid, lipofuscin,

hemosiderin

foreign bodies, crystals

microorganisms

Jaroslava Dusko

va

Melanoma

Jaroslava Dusko

va

Ceroid - pseudomelanosis intestini crassi

Jaroslava Dusko

va

HEHS

Jaroslava Dusko

va

Jaroslava Dusko

va

Haemosiderosis hepatis

Jaroslava Dusko

va

Intracellular Accumulations

water –hydropic degeneration

proteins – hyaline droplets

lipids – steatosis

glycogen – glycogenosis

pigments – melanin, ceroid, lipofuscin,

hemosiderin

foreign bodies, crystals

microorganisms

Jaroslava Dusko

va

Asbestosis

Jaroslava Dusko

va

Sinus pilonides

Jaroslava Dusko

va

Intracellular Accumulations

water –hydropic degeneration

proteins – hyaline droplets

lipids – steatosis

glycogen – glycogenosis

pigments – melanin, ceroid, lipofuscin,

hemosiderin

foreign bodies, crystals

microorganisms

Jaroslava Dusko

va

Cytomegalovirus inclusions in the GER

Jaroslava Dusko

va

Chlamydia

Jaroslava Dusko

va

The Cell Components &Their Function

ribosomes

endoplasmic

reticulum

Golgi complex

lysosomes

peroxisomes

mitochondria

cytoskeleton

caveolae

vaults

The cytoplasm -cytoplasmic organelles

Jaroslava Dusko

va

The Cytoplasmic Organelles Functions (1)

Organelle Composition Function

ribosomes RNA –protein

complexes

proteosynthesis

endoplasmic

reticulum

cisternae,tubular

channels

proteosynthesis

& transport

Golgi complex

(GC)

smooth

membranes &

vesicles

processing and

packaging

lysosomes sacklike GC

derived

digestion

Jaroslava Dusko

va

GC

ER

N

Jaroslava Dusko

va

Autophagosomes

Jaroslava Dusko

va

2016

Jaroslava Dusko

va

The Cytoplasmic Organelles Functions (2)

Organelle Composition Function

peroxisomes lysosomes like

producing or

using H2O2

detoxication

mitochondria membrane

bound energy

production

Oxydative

fosforylation, cell

signaling, pH

control, Ca

homeostasis

Jaroslava Dusko

va

Oncocytus

Jaroslava Dusko

va

MGG

HE

Oncocytes

Jaroslava Dusko

va

The Biology and the Genetics of Hürthle Cell Tumors of the Thyroid

Máximo V et al, Endocrine-Related Cancer, 2012, 19, R131-R147

• Hürthle cell appearance - a phenotype superimposed on the

genotypic and conventional histopathologic features of the

tumors.

• large deletions of mitochondrial DNA (mtDNA), mutations of

mtDNA genes and nuclear genes coding for OXPHOS proteins

• energy production defects in Hürthle cell tumors;

• the increased proliferation of mitochondria a compensatory

mechanism

• predisposition for necrosis instead of apoptosis which seems to

be blocked in most Hürthle cell tumors.

Jaroslava Dusko

va

The biology and the genetics of Hürthle cell tumors of the thyroid

Máximo V et al, Endocrine-Related Cancer, 2012, 19, R131-R147

Hypoxia Inducible Factor 1α

Jaroslava Dusko

va

Peroxisomes - microbodiesup to 2 microns - catalase

FunctionDegradation: substrate oxidation

(etanol)

Anabolism: synthesis of

prostaglandin , cholesterol,

billiary acids, plasmalogens,

gluconeogenesis,

transamination

Jaroslava Dusko

va

The Cytoplasmic Organelles Functions (3)

Organelle Composition Function

Cytoskeleton Microtubules & actin

microfilaments

Microvilli, cilia,

flagella

Caveolae Membrane

indentationsShuttling

material

Vaults Octagonal barrrels

like

ribonucleoproteins

Shuttling

molecules

Jaroslava Dusko

va

Jaroslava Dusko

va

Trichomonas vaginalis

Jaroslava Dusko

va

carcinoma

Mesothelioma

Mesothelioma

Jaroslava Dusko

va

Cilia

Jaroslava Dusko

va

The Cell Components &Their Function

The plasma membranes– cell surrounding

– organelles enclosing

– bilayer of lipids and proteinsJaroslava Dusko

va

Cell

mechanismMembrane function

Structure Compartmentalization, cytoskeleton & ER

contacts, fluid & electrolyte balance

Protection Barrier to toxins & foreign organisms/cells

Activation of

cell

Hormones, mitogens, antigens, growth

&proliferation factors

Storage Receptors, transport, diffusion, exocytosis,

endocytosis

Cell to cell

interaction

Communication & attachment –junctional

complexes, nutritive relationship, enzymes

and antibody release

Jaroslava Dusko

va

Tasuku HonjoJ.P. Allison

Nobel Prize 2018

Antibodies blocking the brake molecules CTLA-4 and PD-1

enhance the immune response to cancer

Jaroslava Dusko

va

Estrogen

receptors

Jaroslava Dusko

va

Carcinoma mammae ductale invasivum IDC

HE PRER

MIB1 e-cadherin c-erbB2 / Her2-neu

Jaroslava Dusko

va

Secretion

– exocrine (apical pole of the cell lumen, duct)

– endocrine (basal pole of the cell blood)

– paracrine influencing neighbouring cells

– autocrine self influencing

Jaroslava Dusko

va

Organelles Involved in Secretion

membrane type

maternal origin (ovum cytoplasm)

autoreplicative

– granular (rough) endoplasmic reticulum

– Golgi apparatus

– lysosomesJarosla

va Duskova

Exocytosis and Its Disorders

protein secretion on the granular

endoplasmic reticulum

cis Golgi network

trans Golgi network (signal molecules

attachment)

Golgi Endoplasmic Reticulum

Lysosomes

Jaroslava Dusko

va

Jaroslava Dusko

va

Secretion

continual - permanent -unregulated

pulsatory - regulatedJarosla

va Duskova

Secretion

continual - permanent– unregulated vesicle transport

– protocollagen, proteoglycans, viral

particles

Targetting:immunoglobulins without and after stimulation

Jaroslava Dusko

va

C

o

ll

a

g

e

n

p

r

o

d

u

c

ti

o

n

Jaroslava Dusko

va

Secretion pulsatory - regulated

– exocrine mucin or zymogen granules secretion

– endocrine cells– neurons– T-lymphocytes– heparinocytes– thrombocytes– granulocytes

– endothelia

membrane budding

coating proteinsJarosla

va Duskova

Jaroslava Dusko

va

Secretion Disordersdefects of synthesis product itself

auxilliary proteins

retention in GER(inborn endoplasmic reticulum storage

diseases)

hyaline droplets (Russel bodies)

Jaroslava Dusko

va

Sinusitis chronica

Jaroslava Dusko

va

Autophagosomes

Jaroslava Dusko

va

Neuroendocrine

Secretion Disorders

defects of synthesis product itself

auxilliary proteins

regulation disorders on the receptor level

Jaroslava Dusko

va

Neuroendocrine Secretion

dense core granules

secretory vesicles

(small synaptic vesicles)Jaroslava Dusko

va

Membrane Componentsof Secretory Granules and Vesicles

– Synaptophysin (synaptic vesicle protein)

– Neuron Specific Enolase

– S-100 protein

– chromogranin

identification of neuroendocrine

neoplasms

Jaroslava Dusko

va

Juxtacrine Secretion (?) /Signaling

contact (- dependent) signalling

cell adhesion (inflammatory cells… neoplastic cells…

transmitted via oligosaccharide, lipid, or protein

components of a cell membrane

Unlike other types of cell signaling (such as paracrine

and endocrine), juxtacrine signaling requires physical

contact between the two cells involved.

Juxtacrine signaling has been observed for some

growth factors, cytokine and chemokine cellular

signals.

pathology of INFLAMMATION,

TUMOURS

Jaroslava Dusko

va

Jaroslava Dusko

va