Cell Response to Injury: Endogenous injury 1 Flashcards
what can be classified as endogenous injury?
can be primarily genetic but can still be influenced by exogenous factors e.g. phenylketonuria (PKU) and diet
what are examples of exogenous injury?
- Something from the external environment – e.g. Ebola
- Primarily environmental causes but may be a genetic influence on persons resistance
- The environment may act via genes
what cell injuries can cause disease?
The cause of disease is multifactorial and often includes both endogenous and exogenous injury
what are some examples of how genes can influence a persons response to the environment?
- schizophrenia
- neoplasia
- breast cancer
- Major Histocompatibility complex (MHC)
- MHC - ankylosing spondylitis
- MHC - Multiple sclerosis
what is schizophrenia?
Breakdown in relationship between thought, emotion and behaviour leading to a faulty perception about reality
what is the genetic factor linked to schizophrenia?
- 20-70% in monozygotic twins
- Genetic role - DISC1, dysbindin, neuregulin, G72 amongst others
- BUT environmental stimuli are important too - Rubella, grief, CNS damage
what is neoplasia?
New and abnormal growth of tissue – rapid division of cells that have acquired a mutation
what is the genetic factor linked to neoplasia?
- Familial adenomatous polyposis of the colon
- Benign and cancerous polyps in the colon and rectum
- Autosomal dominant (APC) or autosomal recessive (MUTYH)
- Diet and lifestyle can influence the disease
what is MHC?
MHC = set of genes encoding cell surface molecules that determine histocompatibility
• Present pathogen peptide fragments for T cells
• Recognition of self
what is the genetic factor linked to MHC?
- HLA genes highly polymorphic (~1500 alleles)
* Graft rejection – donor HLA on cell surface elicits immune response in recipient
what is ankylosing spondylitis?
- Spinal arthritis primarily affecting young males, causing ankylosis of vertebral and sacroiliac joints
- Arthritic fusion of sacroiliac and vertebral joints
- Ossification of spinal ligaments leading to spinal rigidity
what is the genetic factor linked to ankylosing spondylitis?
- HLA-B27 variant
- 95% of AS patients
- 9% of general population
- Only 1:15 HLA-B27 +ve people develop AS
what is multiple sclerosis?
- Progressive disease of the spinal cord and brain
* Patches of demyelination: Loss of nerve conductance and muscle control leads to paralysis and death
what is the genetic factor linked to multiple sclerosis?
- HLA-DW2 variant
- 5x more likely to develop MS
- Viruses, location, vitamins, smoking
- Only 2% chance of passing on to offspring
what are examples of major chromosomal abnormalities?
- neoplastic cells
- turner syndrome
- Down’s syndrome
what are the chromosomal abnormalities of neoplastic cells?
rapid division of cells that have acquired a mutation. often have increased number of chromosomes
what causes turner syndrome?
45 chromosomes – loss of an X chromosome
Random genetic event occurring at conception
what are the clinical features of turner syndrome?
Short stature, underdeveloped ovaries
what is the treatment for Turner syndrome?
Incurable but treatment with growth hormone, HRT, IVF
what causes down’s syndrome?
47 chromosomes – trisomy of chromosome 21
Random genetic event occurring at conception
Child of Down’s parent = 1:2
what are the clinical features of Down’s syndrome?
Reduced muscle tone, facial characteristics, learning problems
what is the treatment for Down’s syndrome?
Incurable, treatment based around social care and support
what are the outcomes of minor chromosomal abnormalities?
invisible - single gene defect
what is sickle cell anaemia?
Hereditary anaemia caused by mutation in haemoglobin. Red blood cells become crescent shaped in low O2
what is the genetic cause of sickle cell anaemia?
Single base substitution in haemoglobin beta chain
Rare recessive – need two copies
One copy = sickle cell trait
what is sickle cell anaemia protective against?
malaria
what is phenylketonuria?
The inability to metabolise phenylalanine (Phe)
what is phenylalanine used for?
- Amino acid synthesis e.g. tyrosine
- Neurotransmitters – dopamine, adrenalin
- Skin biology – melanin
what causes the lack of phenylalanine metabolism?
A lack of phenylalanine hydroxylase so Phe cannot be broken down, but also dietary factors.
what is the outcome of reduced phenylalanine metabolism?
15-100x increase of phenylalanine in the blood and the CSF which leads to myelination in developing brain and can result in severe mental retardation
how can phenylketonuria be treated?
- Restricted diet
* Guthrie test at birth
what are signs of ageing?
- Greying and/or loss of hair
- Muscle weakness/atrophy
- Skin thinning
what are some disorders linked to ageing?
- Cancer
- Glaucoma
- Alzheimer’s disease/ dementia
- Cardiovascular disease
- Type 2 Diabetes Mellitus
what are telomeres?
Long stretches of DNA that cap the end of chromosomes
what happens to telomeres during cell division?
Part of telomere lost at each cell division which leads to protect coding DNA from decay
what does telomere shortening lead to?
Gradually leads to ageing and the loss of ability to divide
what is telomerase?
Reverse transcriptase enzyme that elongates telomeres
what is the Hayflick limit?
The number of times a cell will divide until cell division stops
what is senescence?
Cells stop dividing and undergo phenotypic alteration
why do we get more senescent cells with age?
There is an imbalance between damaging stimuli and cell clearance which leads to:
• Accumulation in aged humans, primates and rodents
• Accumulation in age-related disease – e.g. CV disease and Alzheimer’s disease
what are the factors that affect ageing?
- Telomere length
- Telomerase activity
- DNA damage/repair mechanisms
- Dietary factors
what are examples of premature ageing?
CV disease - abdominal aortic aneurysm
progeria
Werner syndrome
what is abdominal aortic aneurysm?
- Dilation of the aorta
- Rupture = 90% mortality
- Inflammation
- Loss of smooth muscle cells
what is progeria?
Hutchinson-Gilford Progeria Syndrome = mutation in Lamin A, nuclei become unstable leading to premature ageing
what are the features of progeria?
- Rapid ageing from 18-24 months
* Children die aged ~14 from cardiovascular disease
what is Werner syndrome?
Rare progressive disorder characterised by premature ageing
what are the features of Werner syndrome?
- Growth halted at puberty, visible ageing ~25 years
* Life expectancy 40-50 years, mortality from cardiovascular disease
