MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

nemoci-sympt/OCNI/makularni-degenerace/rizikove-faktory-priciny-zhorseni

Apolipoprotein E (Apo E)

  • Associated with the development of ARMD
  • Codes plasma protein participating in the metabolism of cholesterol and other lipids
    • Also found in drusen

Apo E2 (Cys 112, Cys 158) epsilon 2

  • Linked with the greater risk of developing ARMD.
  • Apo E 2 allele is considered a protective factor for ischemic heart disease

Apo E3 (Cys 112, Arg 158)epsilon 3

Apo E4 (Arg 112, Arg 158)epsilon 4

  • (19 chromosome)
  • Protective variant of gene - diminishing the risk to develop ARMD
  • Reducing the risk of developing the disorder in individuals with a family history of ARMD
  • Apo E4, in contrast to Apo E 2 and 3
    • Does not contain disulfide bridges
    • Therefore, being smaller
    • May be more effectively transported through Bruch’s membrane
  • Apo E 4 has a positive charge
    • Diminishes hydrophobicity of the Bruch’s membrane
    • Thus contributes to better clearance of the debris
  • Apo E 4 allele is associated with hypercholesterolemia and greater risk of ischemic heart disease

C5b-9 komplement

  • Majority of drusen in all eyes examined (of both genotypes)
    • Regions of intense immunoreactivity for C5b-9
  • Some C5b-9 deposition is also observed in “normal” choroidal regions far from drusen in both CFH genotypes.

Caucasians

  • More often diagnosed with ARMD than black people.

Chronic local inflammation



Clusterin deficit

    • Associated with protection from apoptotic retinal cell death.
    • Effectively inhibited vascular endothelial growth factor–induced hyperpermeability
      • In human retinal microvascular endothelial cells
      • In retinal vessels from streptozotocin-induced diabetic mice.
    • Essential role in restoring tight junctions
    • Limiting the inflammatory response after injury
  • Clusterin deficit


Complement factor H (CFH)

  • Allotypic variants of a key complement fluid-phase regulatory protein
  • Strongly associated with age-related macular degeneration (AMD)
  • Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H
    • Elevated levels of CRP in the choroid
  • Polymorphisms in the complement factor H gene (CFH)
    • Associated with a significantly increased risk for, or protection against AMD

CFH polymorphism that segregates most significantly with AMD

  • Associated with a T to C substitution
  • At nucleotide 1277 in exon 9 of the CFH gene
  • Change results in a tyrosine-to-histidine substitution at amino acid position 402 (Y402H) of the CFH protein.
  • Through binding to specific polyanions found on most vertebrate cell surfaces
    • CFH protects host cells from complement-mediated damage
      • Binding to the activated complement component C3b
      • Accelerating the decay of the C3 convertase (C3bBb)
      • Serving as a cofactor for complement factor I
        • A serine protease that inactivates C3b on host cell surfaces
  • At-risk individuals have significantly higher
    • CFH-binding protein
    • C-reactive protein (CRP)(2.5-fold higher) in the choroidal stroma

Homozygous for the 402HH CFH isoform

  • The interaction of CFH with heparin
    • Also mediated at least in part by the SCR7 domain
    • Reported to be enhanced by this amino acid substitution
  • A similar increase in the affinity of CFH for CRP
    • Could explain our observation of elevated choroidal CRP levels in individuals homozygous for the 402HH CFH isoform.
  • www.pnas.org/content/103/46/17456.long

Complement components and immunoglobulins

Acute-phase inflammatory proteins

Amyloid component P

Alfa 1-antitrypsin

Proteins modulating the immune response

Major histocompatibility complex class II antigens

Multinucleated giant cells and leukocytes

Probable relationship between

Lens nuclear sclerosis and ARMD




Cumulative light exposure

  • Associated with progression of age-related macular degeneration (AMD)
  • Light exposure decreased cell viability
  • Increased expression and secretion of VEGF-A, PDGF-BB and PlGF

HUS / MPGNII

  • Organ damage from alternative pathway dysregulation is a prominent feature of
    • Atypical hemolytic uremic syndrome (aHUS)
    • Membrano-proliferative glomerulonephritis type II (MPGNII)
      • (two rare kidney diseases that culminate in acute renal failure)
  • 70+ mutations in the CFH gene
    • Have been linked to aHUS and MPGNII
  • Je u těchto onemocnění prokázana i asociace s AMD?
  • Most of these mutations occur in the C-terminal region of CFH
    • Significant consequences for CFH function

Mutations in N-terminal CFH domains

  • Including the domain where the Y402H variant is located.
  • Binding sites for sialic acid and C3b are far removed from this locus
  • Bind to CFH in this region
    • C-reactive protein (CRP)
    • Heparin
    • Microbial surface molecules

HbA1c

  • Correlations to elevated HbA1c by both types of DM and to further clinical characteristics of case series.
  • Takže při AMD v případě již jen porušené glukozové tolerance - ještě trochu dříve než je definitivně diagnostikována cukrovka 2. tpyu
    • Již může být ochranné pro oči zahájit terapii metforminem nebo jinými léky na snížení hladin glykémií
      • V.s. oddálí poškození retiny, včetně pozdější ev. diabetické retinopatie, která má některé společné rysy AMD

Hemopexin abundance

  • Significantly increased in the vitreous fluid of patients with DME in comparison with PDR and control subjects.
  • Seem to be more directly related to the development of DME
  • Hemopexin
    • The best-characterized permeability factor in steroid-sensitive nephrotic syndrome
    • T-cell–associated cytokines like tumor necrosis factor-a
      • Able to enhance hemopexin production in mesangial cells in vitro
      • Prevented by corticosteroids
  • Proinflammatory cytokines

Inability of tissues to clear apoptotic and necrotic cellular debris properly

  • Linked to the progression of autoimmune diseases and their inflammatory sequelae
  • Drusen contain cell fragments and membranous debris
    • Thought to be derived from degenerate RPE cells
  • CRP is a known constituent of drusen
  • Accumulation of drusen and other sub-RPE deposits in early AMD
    • Regarded as a biomarker of chronic local inflammation at the RPE–choroid interface
  • Elevated levels of CRP in CFH 402HH individuals
    • May be interpreted as evidence for chronic local inflammation and cellular injury in the RPE–choroid
      • Perhaps as a consequence of aberrant regulation of complement by risk-conferring CFH variants
  • Similar disease-associated CRP deposition identified within
    • Atherosclerotic lesions
    • Alzheimer's disease plaques
      • Je u těchto onemocnění vyšší incidence AMD nebo infekce chlamydia pneumonia ?
  • Drusen represent residual debris from degenerating (RPE) retinal pigmented epithelium cells
    • Targets of complement attack
  • It is likely that retinal pigmented epithelium cell debris entrapped between the RPE monolayer and Bruch's membrane
    • Serves as a chronic inflammatory stimulus
    • Potential nucleation site for drusen formation
  • Process of drusen biogenesis may be envisaged as a secondary manifestation of primary RPE pathology
    • Exacerbated by consequences of local inflammatory processes.
  • www.ncbi.nlm.nih.gov/pubmed/11846519

Inhibition of intracellular GSH synthesis


Light–dark transitions and circadian rhythms

  • Modulate the RPE transport of nutrients, metabolic waste products, ions and fluid
    • Between the choroidal blood supply and the subretinal space surrounding the photoreceptor outer segments

High metabolic activity and ongoing exposure to light

  • Makes the RPE particularly vulnerable to oxidative damage

Abnormalities in RPE phagocytosis of rods and cones

  • Can lead to retinal degeneration and photoreceptor cell death

Abnormalities in maintenance of the visual cycle

  • Can lead to retinal degeneration and photoreceptor cell death

Signature genes - unique profile of RPE functions

  • Vision, perception of light and vitamin A metabolism
    • CRX, EFEMP1, RPE65, SFRP5, SIX3, TIMP3, BEST1, RDH11, RBP1
  • Response to stimulus and sensory perception
    • AHR, CDH3, GJA1, ENPP2, PITPNA
  • Oxidoreductase activity
    • PCYOX1, STCH, ALDH1A3, CDO1, BDH2, FADS1);
  • Pigment biosynthesis and melanin biosynthesis
    • GPR143, TYRP1, dopachrome tautomerase (DCT), SILV
  • Phagocytic activity
    • LAMP2, VDP, GULP1
  • Transporter activity
    • SLC39A6, SLC4A2, SLC16A1, SLC16A4
  • Signature gene set can be used to monitor the development to RPE phenotype
  • hmg.oxfordjournals.org/content/19/12/2468.full

Lipofuscin

  • Fotosenzibilizační vlastnosti
    • Dále zvyšuje ox. stres v retině
  • Nutrition and the Eye, Basic and clinical research, Albert J. Augustin, vyd. Krager
  • Increased accumulation in the posterior pole of the eye and the macula
  • Reverse link between the concentrations of lipofuscin and melanin in the retinal pigment epithelium.
    • Stronger in eyes of Caucasian than in eyes of black population
  • ARMD begins earlier and occurs more frequently in less pigmented eyes


Lysozomy - kumulace

  • In ARMD patients, lysosomes of the retinal pigment epithelium
    • Believed to accumulate phototoxic pro-oxidative melanin oligomers of low molecular weight
      • That may be partly responsible for the “digestive” speed reduction in the external photoreceptor layer of the retinal pigment epithelium

Decreased “digestive” speed

  • Associated with the formation of lipofuscin and ARMD

MAC

  • Immunoreactivity in the choroid is observed proximal to most drusen

MCP1, sICAM-1, sVCAM-1

  • Concentrations are significantly associated with exudative AMD
    • Even in the presence of normal VEGF concentrations
  • Could potentially be additional target molecules in therapy for exudative AMD.
  • Intraocular MCP-1 concentrations
    • Correlated with the subfoveal neovascular membrane type and the amount of macular edema.
  • www.ncbi.nlm.nih.gov/pubmed/20937997

MMPs proteolytic zinc-containing enzymes

  • Responsible for degrading extracellular matrix components
  • Important role in the physiological and pathological remodeling of tissues

MMP-9 - gelatinase B

    • Degrade components of the basement membrane
      • Type IV collagen
  • ARMD patients, elevated plasma MMP-9 levels influence the development of choroidal neovascularization
  • Increase in MMP-9 expression is characteristic of ARMD
  • Number of MMP-9 cytosineadenine(CA) sequences in the promoter region
    • Determine the transcription activity - gene expression rate
  • 24 repeats of CA sequence in the MMP-9 promoter region
    • Resulted in up to 20 times higher MMP-9 expression
      • Compared with 20 repeats of CA sequence
  • Relationship between the length of MMP-9 promoter microsatellites and choroidal neovascularization in ARMD patients.
  • Alleles with 22 or more repeats
    • More often found in ARMD patients
    • Carriers of one allele with 22 repeats have more than doubled risk of being an ARMD patient
    • Does not cause the disease but increases the MMP-9 expression leading to increased vascular permeability and choroidal neovascularization.

MMP-2 - gelatinase A

  • Ability to cleave gelatin in vitro
    • Heterogeneous compound of soluble proteins, obtained during partial hydrolysis of collagen

Porucha retinálního pigmentu

  • Snížená pigmetnová ochrana retiny, která je zvýšeně poškozována světlem ?
    • Podobně jako u retinopatia myopica ?
  • Mmají světlí lidé se světlýma očima vyšší riziko retinopatií včetně AMD ?


R102G polymorphism of the complement component (C3) gene

  • In a French population
  • In a case-control study shows C3 to be a moderate susceptibility gene for exudative AMD in the French population.

C/C

  • Ochranná

C/G individuals

  • Odds Ratio compared to C/C individuals was 1.4 (95% CI 1.1-1.8)
  • Dominant model, the adjusted Odds Ratio for carriers of the G allele is 1.4 (95% CI 1.0-1.9; p=0.03)

G/G individuals


Sorafenib

  • Oral multikinase inhibitor
  • Might have beneficial effects on exudative AMD
  • Light-induced overexpression of growth factors in human retinal pigment epithelial (RPE) cells were significantly reduced


TGF-beta

  • Induced VEGF expression by fibroblasts derived from human choroid of eye
  • TGF-beta induction of VEGF secretion by RPE and choroid cells
    • May play a significant role in choroidal neovascularization (CNV) in AMD.

VEGF isoformy 121, 165, and 189

  • Up regulated by TGF-beta1
  • TGF-beta1, beta2, and beta3
    • Potent inducers of VEGF secretion by HRPE cells

Women

  • At higher ARMD risk than men

Aging changes + drusen formation

  • Metabolism of the pigment epithelium
    • Normal structure of Bruch's membrane is destroyed.
  • Associated with lipid accumulation
    • Development of drusen
  • The lipids deposited are predominantly:
    • Phospholipids
    • Neutral lipids
  • Takže takový malý ateromový plát ale exsudát
    • Co když je v také pozadí infekce chlamydií nebo jinou podobnou potvorou ?

Activation of the complement cascade in AMD pathogenesis

  • Complement system proteins,
  • Complement activators,
  • Complement regulatory proteins
  • Identified as molecular constituents of drusen, the hallmark extracellular deposits associated with early AMD

Associations between AMD and variants of several complement pathway-associated genes

  • Complement factor H (CFH)
  • Complement factor H-related 1 and 3 (CFHR1 and CFHR3)
  • Complement factor B (CFB)
  • Complement component 2 (C2)
  • Complement component 3 (C3)

ARMD is associated with

  • Elevated levels of white blood cells,
  • Fibrinogen,
  • Oxidized low-density lipoproteins,
  • cholesterol,
  • C-reactive protein
  • Characteristic of ARMD increase in blood:

Higher total cholesterol and LDL


Increased levels of CRP in the choroid

  • May reflect a state of chronic inflammation
    • By-product of attenuated CFH complement-inhibitory activity in those who possess the CFH at-risk allele
  • CRP-binding site in CFH
    • Lies within the domain containing the Y402H polymorphism
      • AMD risk-conferring allele may alter the binding properties of CFH
        • Thereby leading to choroidal CRP deposition, contributing to AMD pathogenesis
    • (jako že se nenalepí na buňky, ale uloží se někde v okolí)

CRP funkce

  • Activation of the classical complement pathway
  • Inactivation of the alternative pathway
  • CRP bound to the cell surface
    • May target CFH to injured “self” cells
      • Thus protecting them from complement attack
  • CRP binds phosphocholine on the pathogen surface
    • Elicits a complement response
    • Resulting in MAC generation
    • Membrane insertion
    • Pathogen lysis
  • In the host, CRP is hypothesized to mark damaged tissues
    • By binding cell membrane and nuclear constituents such as
      • Phosphocholine,
      • Histones,
      • DNA that may be exposed in injured cells
  • CRP can up-regulate the expression of
    • Proinflammatory molecules
    • Matrix metalloproteinases in cells in vitro
  • Significant CRP deposition within the choroid

The drusen found in Bruch's membrane

  • Represent precursors for the development of age-related macular degeneration.

The factor B (BF)

  • One of the more important factors in the alternative stimulation pathway of the complement system.
  • Tight link between the genetic injuries of the complement factor B (BF), C2, and C3, and the risk of developing ARMD

Variant L9H of the BF gene



Factor C2

  • Initial factor in the pathway of the classical stimulation of the complement system
  • Tight link between the genetic injuries of the complement factor B (BF), C2, and C3, and the risk of developing ARMD

C2 variant in the 10 intron and the R32Q variant of the BF(H7)

  • Lower risk of ARMD (odds ratio is 0.36 )
  • Tight link between the genetic injuries of the complement factor B (BF), C2, and C3, and the risk of developing ARMD

Variant E318D of the C2 (H10)

  • Lower risk of ARMD (odds ratio is 0.45)
  • Tight link between the genetic injuries of the complement factor B (BF), C2, and C3, and the risk of developing ARMD


Focal hyperpigmentation in the macula and systemic hypertension



High arterial blood pressure

  • Increased the risk of developing exudative ARMD by 1.5 times


Hypoxia of the retina

  • Neovascularization is mainly induced by retinal hypoxia
  • Tissue ischemia
    • Increased secretion of the VEGF
    • Higher expression of the VEGF R2

Calcification and fragmentation of Bruch's membrane

  • Soft, diffuse, and large drusen;
  • And basal laminar deposit, but not hard drusen
    • Strongly correlate with the histologic presence of AMD.
  • The degree of calcification and fragmentation of Bruch's membrane
    • Is prominent in eyes with exudative AMD.
  • Formation of choroidal neovascular membranes
    • Represents a stereotypic, nonspecific wound repair response independent of the underlying disease
  • www.ncbi.nlm.nih.gov/pubmed/11587915


Kontkatní čočky (?)

  • Je používání kontaktních čoček spojeno s vyšším mechanickým a prozánětlivým stresem oka ?
  • Vyšší množství volných radikálů vlivem cizího tělesa na sojivkách ?
  • Už to někdo zkoumal ve vztahu k AMD ?

Cigarette smoking

  • Increases ARMD risk 2 times
  • A direct relationship has been found
    • Likelihood of developing the disease and both the smoking duration and number of cigarettes smoked
  • Smoking increasing the risk of ARMD by:
    • Decrease antioxidant levels in the serum
    • Compromise choroidal circulation
    • Increase oxidative injury to the macula


Low plasma lycopene


Low levels of vitamins C, E, carotenoids, zinc, and other

  • In blood and nutrition may influence ARMD

Modré světlo

  • Omezit modré spektrum
  • Raději žlutá teplá žárovka než denní tvrdé denní světlo



Obese individuals

  • Have ARMD twice as frequent

Platelet-derived growth factor (PDGF)




Pigment retiny

  • Absorbing blue-light
    • Macular pigment protects the underlying photoreceptor cell layer from light damage
      • Formation of reactive oxygen species during a photosensitized reaction.
  • Amount of macular pigment is inversely associated with the incidence of age-related macular degeneration
    • An irreversible process that is the major cause of blindness in the elderly.
  • www.ncbi.nlm.nih.gov/pubmed/12626691

Placenta growth factor (PlGF)

  • Substantial impact on development of AMD


Včas léčit všechna zánětlivá onemocnění

  • Hlavně v oblasti hlavy, nosu a očí
    • Chronické rýmy, kašle aj.,

Stimulace cévní novotvorby




High-energy visible light

  • Influenced its development as it has been found in another research


High intake of fats, particularly animal

  • Related to increased risk of ARMD for both men and women


VEGF



Vascular endothelial growth factor (VEGF)

  • Major agent in choroidal and retinal neovascularization events associated with
    • Age-related macular degeneration (AMD)
    • Diabetic retinopathy
  • Causes vasodilatation
  • Increases vascular permeability
  • Protease activity+
  • Expansion of vascular network in the surrounding tissues and its remodeling.
  • The fragmentation of the basilar membrane and intracellular connective tissue
    • Essential for the formation of new capillaries.
    • Activated endothelial cells release matrix metalloproteinase (MMP)
      • Degrading the basilar membrane
        • Allows capillaries to grow beneath the retina and between retinal layers.
  • Such capillaries
    • Often bleed
    • More liquids are filtered through the walls
    • Fibrous tissue grows within
  • Retina swelling and impaired vision occur

Age

Gender

Color of the iris

Nutrition, body mass index

Oxidative stress

Complement factor H gene, Apo E gene

Hypoxia

Inflammatory process

Proteolytic enzymes play a determinant role

  • Genetic polymorphism of matrix metalloproteinases
  • Especially to matrix metalloproteinases 2 and 9
  • Gelatinases A and B
  • Matrix metalloproteinase 9
  • www.ncbi.nlm.nih.gov/pubmed/20440081

Na sítnici zaostřené brýle a bez UV filtru (?)

  • Sbíhající se ohnisko světelných paprsků na sítnici = dobře zaostřený zrak může být vyšším rizikem při práci u PC, monitoru, na slunci, svícením i večer a v noci,...
    • Co když někdo, kdo je krátkozraký profituje z toho, že na makulu nepadá tolik koncentrovaného světla ?
    • Co když je vznik stařecké dalekozrakosti protektivní forma adaptace stárnoucího oka před vznikem makulární degenerace a před zvýšeným poškozením sítnice světlem ?
  • Už to někdo zkoumal ve vztahu k AMD ?

O úroveň výše

Poslední aktualizace: 1. 2. 2024 0:37:56