PBL 1- Multiple Sclerosis Flashcards
Different Types of Inheritance patterns
Mendelian traits:
controlled by a single locus and show simple patterns of inheritance
Also have a dominant/recessive relationship
Incomplete Dominance:
Phenotype is intermediate between the two homozygous phenotype eg dark purple and white become Light purple
Incomplete Penetrnace: Not all genotype express the expected Phenotype
Co-Dominance:
The phenotype of a heterozygote shows the phenotype of BOTH the two homozygotes eg: AB blood group (A and B are co-dominant)
Lethal Alleles:
Cause 100% mortality, If recessive then will be non viable if homozygous. Heterozygotes can be carriers. Dominant lethal alleles are very rare Eg: Huntingtons
Gene Interactions:
The effect of a gene at one locus depends on the effect at another locus
Multifactorial Genetic conditions:
Can be preventable if certain environments are avoided ie Xeroderma pigmentosum should avoid sunlight however huntingtons is unavoidable
Variable expressivity:
not all genotype show phenotype to same level- can be more/ less severe
What is the difference between Qualitative and Quantitative traits?
Qualitative Traits:
Involve discontinuous variables having only a few possible values (red/yellow)= these are typically analysed using basic Mendelian principles
Quantitative traits:
traits that vary continuously along a scale ie height, blood pressure
- Can have overlapping phenotype – usually cannot tell genotype by phenotype
Each must be described with a quantitative measure
1 Are polygenic- ie influenced by many genes
2 Arise when environmental factors modify the effects of a gene (a single genotype can then give rise to a range of phenotype)
Ie except for extreme phenotype it is impossible to infer the genotype from the phenotype
Most are both polygenic AND influenced by environment therefore are multifactorial
= many genes and many environmental factors
What are single gene versus multifactorial disorders?
What are gene- gene interactions?
Single Gene Disorders:
usually autosomal dominant, recessive, sex-linked or related patterns
Polygenic, complex, Multifactorial:
depend on gene-gene interactions, gene-environment interaction, inheritance often complex and/or uncertain- may be unclear if it occurred spontaneously or if it was inherited
- Strongly influence by effects of other genes or the environment (gene gene interactions or environment interactions)
- Depending on other genetic or environmental factors having a mutation does not always result in disease (incomplete penetrance)
- Inheritance patterns often obscured by variation in lifestyle and environmental factors
- Diet, Drugs, Other
Gene-Gene Interactions:
traits not controlled by a. Single gene, usually polygenic- influenced by genes at multiple locus. Alleles of each gene interact not only with each other but with alleles of genes at other loci.
What is familial inheritance?
How can you determine non-mendelian Inheritance
Familial Inheritance
- Family history is a clear risk factor
- Mutant genes are usually rare in the general population
- Usually have a single gene mutation which has strong effects that over-ride other factors
- Having mutation is associated with high disease risk(high penetrance)
- Gene Environment interactions usually relatively unimportant due to strong effect of mutant gene
Determining if a non-mendelian characteristic is Genetic
o Twin
o Family
o Adoption studies
What is:
- Complementary gene action?
- Duplicate Gene Action?
- Epistasis?
Complementary gene action: Functional copies of two genes are required to produce a dominant phenotype . A defect in either of the two genes results in a mutant phenotype eg Hb
Duplicate Gene Action:
A functional copy of either one of two genes is required to produce a dominant phenotype
- A defect in one of the genes does not result in a mutant phenotype
- A defect in both genes will result in a mutant phenotype’
- The genes have similar functions
Epistasis:
alleles of one gene block the phenotypic expression of a second gene
- Not the same as dominance: dominant alleles mask expression of recessive allele of the same gene
- In Epistasis alleles of one gene effect the alleles of a different gene
Complementary gene action: Functional copies of two genes are required to produce a dominant phenotype . A defect in either of the two genes results in a mutant phenotype eg Hb
Duplicate Gene Action:
A functional copy of either one of two genes is required to produce a dominant phenotype
- A defect in one of the genes does not result in a mutant phenotype
- A defect in both genes will result in a mutant phenotype’
- The genes have similar functions
Epistasis:
alleles of one gene block the phenotypic expression of a second gene
- Not the same as dominance: dominant alleles mask expression of recessive allele of the same gene
- In Epistasis alleles of one gene effect the alleles of a different gene
Environment interactions:
- Environment influences each individuals phenotype, individuals with the same genes may look different
- Genes can influence the individuals susceptibility to environmental factors: different genes can respond differently to the same environmental conditions
Multi-factorial disorders
- Most human diseases
- Influences by the effect of other genes and the environment
- Depending on the environment or other genes the mutation does not always result in disease
- Inheritance patterns are often obscure with variation depending on lifestyle
What is: Autoimmunity? Tolerance? Self Tolerance? Self reactivity?
What factors influence tolerance?
Autoimmunity
- Misdirected immune response that occurs when the immune system attacks itself
- Is present to some extent in everyone and is usually harmless (ie RBCs)
- Associated with breakdown in immune tolerance
Tolerance:
State of unresponsiveness that is specific for a particular antigen (protects against autoimmunity)
Self Tolerance:
mechanisms by which the body is prevented from mounting an immune response against its own tissues
Self reactivity:
prevented by processes during development rather than being programmed
Factors influencing tolerance:
- Molecule structure, stage of differentiation when lymphocyte first encounter the epitopes
- The site of the encounter
The nature of the cell presenting the epitopes and the number of responding lymphocytes
What are immunologically privelleged sites
What cells are involved?
What cytokines are involved?
Immunologically privileged sites (Antigen segregation)
- Sites in the body where foreign antigens or tissue grafts do not elicit immune response
- These antigens do interact with T cells but instead of destructive Immune response they induce tolerance or a response innocent to the tissue
- Immunosuppressive cytokines such as TGF-beta seem to be responsible for the response
Sites include:
Brain, eye, testis, uterus
- The sites have specific barrier exclude the immune system (BBB)
- Extracellular fluid does not pass through conventional lymphatics
- Surrounded by tissue barriers that exclude naïve T cells
- Cytokines (TGF-beta) are produced and leave the site together with antigens = tolerance
Expression of apoptosis inducing ligands on tissue cells lead to (FAS-L) induction of apoptosis in FAS expressing auto-reactive t cells
What is ignorance of self antigens?
What is “release of sequestered antigen?”
Ignorance of self Antigens is a
Passive form of immunological tolerance that occurs when:
- T cells can not contact with self-antigens
- If self antigen is present in too low an amount to be detected
- If it is present on cells with few or no MHC molecules
- If there are not enough T cells to respond
- If there is the absence of co-stimulation
Release of Sequestered Antigen
o Trauma or infection can allow the immune system to access these tissues resulting in autoimmune disease
Trauma can cause compromise of the barrier that usually protects the system from auto-immune response
What are the features of Central tolerance?
- Occurs during lymphocyte development
- Occurs in the thymus (T cells) and bone marrow (b cells)
- The immune system generates a large amount of TCRs
- T cells are effector and regulator cells that become “educated” in the thymus
- They become dependent on self MHC for survival
Non-self T cell selection in the thymus (90% of t cells die in the thymus due to errors) - T cells are positively and negatively selected in the thymus
- Positive= selects for t cells capable of interacting with MHC
Negative = removes thymocytes that are capable of strongly binding with SELF MHC
Peripheral tolerance:
What are the aspects of it?
Peripheral Anergy”
is the lack of reaction by the immune system to foreign substances a- direct induction of peripheral lymphocyte tolerance. Immune system is unable to mount a normal immune response against a specific antigen
Regulatory T cells:
- T suppressor cells suppress the immune response through cytokines and intercellular signals. (IL 10 and TGF-B)
- They Recognize self-antigens and inhibit activation of CD + tcells in the lymph notes that recognize the same self antigen
Clonal Deletion:
During B cell development the complete antigen receptor IgM is first expressed on immature B cells.
If those cells encounter their target antigen in a form which can cross link their IgM then those cells are programmed to die.
The requirement for crosslinking means that the antigen is polyvalent.
Ie if activated by self antigen then they apoptose.
What is X-Linked Immunodeficiency Syndrome
Multiple autoimmune diseases such as o Type 1 Diabetes o Thyroiditis o IBD o Atopic dermatitis Can cause Fatal infections in infancy Caused by a mutation in the human FOXP3 gene – controls T-Reg cell function
What are T- Regulatory Cells?
o Suppress autoreactive T Cells
o Mediated by specialized T cells that develop in the thymus
o Secrete IL-10 and TGF-Beta when encountering antigen
o Suppress all surrounding autoreactive T –Cells regardless of their antigen specificity
What are the mechanisms for breakdown in Self Tolerance?
o Failure to present peripheral antigens in the thymus
o Failure to delete autoreactive lymphocytes (clonal deletion apoptosis)
o Release of sequestered antigen (ie damage to the privellaged areas that results in the self antigen not being recognised by the rest of the immune system
o Cross-reactive antigens
o Abnormal antigen presentation
o Reduced suppressor activity (T-Regs, TH2)
o TH1 and TH17 cells are crucial in the effector pahse of autoimmune disease
Summary of the layers of self tolerance
Central tolerance:
deletion and editing in the thymus or bone marrow
Antigen segregation:
physical barrier such as BBB- no lymphoid access in peripheral orgeans
Peripheral anergy:
cellular inactivation by weak signaling without co-stimulation- occurs in secondary lymphoid tissue
Regulatory cells:
suppression by cytokines, intercellular signals in secondary lymphoid tissue and sites of inflammation
Clonal deviation:
apoptosis post activation of cells- secondary lymphoid tissue and sites of inflammation
Types of Hypersensitivity
- Anaphylaxis- Allergy (IgE)
- Antibody mediated (IgG)
- Immune complex (IgG)
( The antibody reacts with antigen, complex is so small it does not get cleared and hangs around in the vascular system, Causes more and more antibodies bind to it) - Cell mediated- (cytotoxic T cell) or delayed sensitivity (Th1 and Th2 cell mediated)
Pathophysiology of MS- autoimmunity
o T cell mediated
Destructive immune response against brain antigens (usually an immune privellaged zone)
o Unknown trigger sets up initial focus of inflammation in brain (possible infection producing cross reactivity when there is a secondary traumatic event)
o Blood brain barrier becomes locally permeable to leukocytes and blood proteins
o T- cells specific for CNS antigen and activated in peripheral tissues reencounter antigen presented on microglia or dendritic cells in the brain
o Inflammatory reaction in brain due to:
• mast cell-activation
• complement activation
• cytokines
Demyelination of neurons = no more insulation = short circuiting = abnormal neuronal response
What is involved in Abnormal Antigen Presentation?
- IN normal people only Macrophages, dendritic cells and B cells can express MHC II antigens
- In some diabetic patients MHC II molecules are expressed on pancreatic islet cells
- MHC expressing pancreatic cells can reactivate microbe specific helper t cells
Polymyositis
Neurological features: - Weakness - Muscle wasting - Muscle tenderness- moderate Laboratory Findings: - Creatine Kinase elevation - ESR elevation - EMG- characteristic myopathic pain
Myasthenia Gravis
Myasthenia Gravis- Cardinal Features
Neurological Features
- Fatiguable weakness ie may see ptosis
- Circadian pattern of weakness
- NO muscle wasting
Laboratory Features
- EMG response- decremental
- Tensilon (edrophonim) test is positive
- Anti-Acetylcholine receptor AB positive
Pathophysiology:
In Myasthenia Gravis: the AcH receptors are blocked by ach antibody or internalized and degraded. This results in impaired muscle contraction
What is the Neuromuscular Junction?
Also How do you test its function?
Neuromuscular junction:
- The area that a motor neuron transmits a signal to a muscle fibre causing contraction
- Vesicles near the border contain AcH- the neurotransmitter that sends the signal that activates muscle contraction
- When nerve is stimulated the vesicles attach to the plasma membrane
- Release the NT into the synaptic cleft (narrow point between peripheral nerve and muscle)
- AcH activates receptors on the muscle side of the neuromuscular junction
- Activation causes Sodium influx and Potassium Efflux- resulting in an Action Potential
Tests for Neuromuscular junction: Repetitive nerve stimulation. In MG= there is a lesser and lesser response to repetitive stimulus
Signs of peripheral Neuropahty
Motor and sensory
Motor Features: - Weakness (distal> proximal) If weakness was more proximal you should suspect a myopathic cause - Atrophy - HypOreflexia
Sensory Features
- Hypaesthesia/anaesthesia
- Hyporeflexia/Areflexia
- Sensory Ataxia/Imbalance
Will have feet wide apart to
balance
- Trophic Changes
Skin atrophy, lose hair growth, dry and fragile skin
Features of Guillain-Barre Syndrome
Autoimmune disorder that Causes peripheral nervous system demyelination
Sometimes causes long term neurodegenerative changes
Features:
- Predominantly a motor neuropathy
- Sub acute ascending paralysis (onset is days to weeks)
- Hyporeflexia/Areflexia
Autonomic Features
- Cardiac arrhythmias
- CP instability
Sensory features (uncommon)
- Parasthesiae
- Back pain
Diagnositic features of Guillain-Barre Syndrome
Guillain-Barre Diagnostic features
- Cerebrospinal fluid = Cyto-albuminemic dissociation
(rise in protein but not in
cells in the CSF) - Nerve conduction studies = Motor conduction slowing
Causative organism = campylobacter jejuni (50% of people)
Immune response causes Mimicry to myelin
