Pathology of extracellular

matrix

Amyloidosis

Extracellular matrix = ECM

Function:

- Mechanical support of cells

- Basement membrane – „ground“ for epithelium

- Separation of different tissues, compartments

- Intercellular communication

- Role in embryogenesis, tumorigenesis, inflammation

Components:

- Filamentous component (fibrilar matrix)

- Basic substance (interfibrilar matrix)

- Water

Colagens

- heterogenous group of proteins with similar chemical composition – triplet of

filaments containing glycin, prolin and hydroxyprolin and form three helical chains

that twist in a fascicle

- cca. 28 types of colagens

- formed in cells as procolagens and deffinitive shape acquire out of cell

Types:

- Fibrilar – type I, II, III, V, XI

- FACIT (Fibril Associated Collagens with Interrupted Triple helices) – type IX,XII,XIV

- Short chain – type VIII,X

- Basement membrane – type IV

- Other – type VI,VII, XIII

Most important types:

Type I – skin, tendons, vessels, ligaments, organs, bone (90%) – strong firm

filaments

Type II – cartilage

Type III = reticulin, usually accompanies col. type I. – fine, elastic filaments

Type IV – basement membrane

Inborn defects of colagens

Osteogenesis imperfecta

- colagen type I.– insufficient quality and/or quantity –leading to different forms of

the disease:

Type 1 – multiple fractures, loose joints, discoloration of scleres

Type 2 – perinatal death or shortly after birth, serious fractures, hemorrhagies

Type 3 – normal life span, mutiple deformities of bones after frequent fractures

Type 4 – 8 – infrequent, variable variants of the disease

AD type of inheritance

Normal bone Osteogenesis imperfecta typ 1

Inborn defects of colagens

Alport syndrome

- colagen type IV. (basement membranes)

- glomerulonephritis with hematuria (to end-stage kidney), deafness, defective vision

- on X-chromosome linked disease or AR inheritance

Ehlers – Danlos syndrome

- colagen type III. (sometimes with defects also in other colagens)

- different types of disease, usually AD inheritance

Skeletal system – hyperflexibility of joints (with frequent luxations), flat feet, muscle

weakness, scoliosis

CVS – aneurysms, medionecrosis, prolaps of mitral valve

Skin – thin, translucent, loose

Other defects of colagen

Scurvy (avitaminosis C)

– vitamin C is important in collagen synthesis

– skin defects, gingiva, slow wound healing (defective scaring), loss of teeth (weak

suspensory aparatus)

Autoimmune process/ chronic inflammation

- repeated, continuous degradation of collagens by inflammatory process

- Systemic lupus erythematosus, Rheumatoid arthritis, Epidermolysis bulosa

Excessive scar formation, fibrosis

- accumulation of collagens (usually col. type I.)

in tissues with repair

- fibrosis of liver, keloid, stiffening of vessels...

Elastin

- protein with high content of glycin, valin, alanin and prolin; with high level of

sretchability and elasticity

- formed as tropoelastin and final form acquires out of cell by cross-linked elastic

filaments (elastic net)

- vessels (aorta, smaller arteries), lung, ligaments, skin, urinary bladder, elastic

cartilage, intervertebral disc...

Disorders of elastin

Inborn defects

Supravalvular stenosis of aorta

- Segmental stricture of aorta above the valve

- frequently in Williams syndrome (deletion of 26 gens on 7. chromosome)

Cutis laxa

- different types of inheritance (AD, AR, X-linked)

- lose, hanging skin, wrinkeled, nonelastic, sometimes darker

- instability of joints (frequent luxations, hypermobility)

- defects of internal organs – emphysema, aneurysm of aorta

Acquired defects

Lung emphysema

- smoking (and other environmental effects) - decreased alfa1-antitrypsin -> loss of

inhibitory activity on matrix metalloproteinses (collagenase, elastase) -> increased

degradation of elastin and collagens -> rupture of alveolar septae

Other fibrilar proteins

Fibrillin

= glycoprotein forming micro fibrils surrounding elastin

- Marfan syndrome:

- AD inheritance

- long extremities, long fingers, defects of heart valves, aneurysm of aorta,

affection of lungs (spontaneous pneumothorax), pectus carinatus, luxation of

lenses

Fibronectin

- Glycoprotein interconnecting cell membranes (integrins) and extracellular matrix

(collagen, elastin) – significant role in mutual interaction between cells and cells with

ECM

- chemotaxia for monocytes, granulocytes, fibroblasts, endothelium, important factor

in wound healing, binds microorganisms (important immunological function)

- loss of fibronectin on neoplastic cells enables metastatic process

Fibrin

- glycoprotein of blood plasma, polymerization of fibrinogen in coagulation

- may accumulate in tissues by bleeding, in inflammation

- (fibrinoid = like fibrin ...staining properties)

Basement membrane

Thin layer of filaments, with mountin epithelium or endothelium:

- lamina densa – colagen type IV., heparan sulfate, colagen type VII.

- lamina lucida – laminin, integrins, entaktins

- lamina reticularis - colagen type III. Interconnected with fibrillin and colagen VII.

Functions:

- connection with epithelium

- limitation of malignant process in epithelium (in situ)

- angiogenesis

- glomerular filtration, alveolar walls

Defects:

Alport syndrome, epidermolysis bulosa

Laminin = glycoprotein interconnecting colagen IV., heparan sulfate and cell surface

Integrins = transmembrane receptors on cell surface connecting with fibronectin and

laminin, responsible for cellular interactions

Basal membrane

Epidermolysis bullosa

IgG anti-BM autoantibodies

Bullous pemphigoid

Basic substance (nonfibrilar component)

Glykosaminoglycans/ mucopolysaccharides

- polysaccharides composed by repeating units of disaccharides – on protein core

molecule – proteoglycans

- bind water, able to bind various proteins, also growth factors

- heparan sulphate – binds protein ligands, regulates angiogenesis, coagulation,

metastatic process

- chondroitin sulphate – participates on elastic strength of cartilage, tendons,

ligaments, aorta

- dermatan sulphate, keratan sulphate

Hyaluronic acid

- Polysaccharide not forming proteoglycan

- adsorbs water – firmness of tissue, incompressibility and resistance

- especially in joint cartilages

- role in inflammation, migration of cells, metastatic process

AMYLOIDOSIS

Amyloidosis – denotes a group of diseases characterized by deposition of

extracellular fibrillar proteinaceous material – amyloid

Virchow chose term „amyloid“ thinking about material similar to starch

chemicaly heterogenic substances:

I. Fibrillar proteins represent cca 95 % of amyloid.

II. Nonfibrillar components include especially P-component and other proteins

that form remaining 5 % of amyloid .

Staining: Congo red – greenish birefringence in polarized light.

Congo red

HE

Congo red polarized light

Fibrillar proteins I. AL (light chain amyloid) protein, most frequently lambda (λ), less

frequently kappa (κ) light chains (primary systemic A)

II. AA (amyloid associated) protein, derived from precursor protein in serum

called SAA (serum amyloid associated protein, from liver – chronic

inflammations, trauma... secondary A)

III. Other proteins (TTR, Aβ2M, Aβ, AH, Acal, Ains, PrP, Alys, Afib...)

Nonfibrillar components

1. Amyloid P: synthetized in liver (AP)

2. Apolipoprotein E (apoE)

3. Sulfated glykosaminoglycans (GAG)

4. α-1 anti-chymotrypsin

5. Protein X (in prion diseases)

6. Other components (complement, proteases...)

Classification of amyloidosis Cause: -primary

-secondary

Deposites: -systemic (generalized)

-local

Clinicaly: -form I (tongue, heart, intestine, muscle, skin, nerves)

-form II (liver, spleen, kidney, adrenals)

Tissue: -mesenchyme

-parenchyme

Biochemical precursors

Clinico-patological classification

A. Systemic (generalized) amyloidosis:

1. Primary (AL)

2. Secondary/reactive/inflammatory (AA)

3. Associated with hemodialysis (Aβ2M)

4. Inherited familial (ATTR, AA, other)

B. Localized amyloidosis:

1. Senile cardiac (ATTR)

2. Senile brain (Aβ, APrP)

3. Endocrine (hormonal precursors)

4. Tumor associated (AL)

A. Systemic (generalized) amyloidosis:

1. Primary (AL)

30 % cases of AL amyloid are related to some form of plasmocytic

dyscrasia, 70 % cases of AL amyloid evidently not related to B-cell

proliferation (heart, kidney, intestine, skin...)

2. Secondary/reactive/inflammatory (AA)

Tbc, bronchiectasia, lepra, osteomyelitis, neoplasm....decomposition of

tumor

(kidney, liver, spleen, adrenals)

3. Associated with hemodialysis (Aβ2M)

dialysis for over 10 y. (vessels, synovia)

4. Inherited familial (ATTR, AA, other)

I. Hereditary polyneuropatic (ATTR) amyloidosis

II. Amyloid in familial Mediteranian fever (AA) (fever, polyserositis)

B. Localized amyloidosis:

1.Senile cardiac (ATTR)

over 70 y., heart, Ao

2. Senile brain (Aβ, APrP)

familial/sporadic (Alzheimer, Down, CJ, kuru)

3. Endocrine (hormonal precursors)

MCT, pancreas (amylin, proinsulin...)

4. Tumor (AL)