Introduction Flashcards
What is Autoimmunity?
Immune response against self-antigens
What is an immunogen
Substance elicits immune response
What is a Tolerogen
Antigens induce tolerance rather than immune response
What are the three ways that the body achieves self tolerance?
Segregate antigens (eyes)
Central tolerance - limits development of autoreactive B & T cells
Peripheral tolerance - regulates autoreactive cells in circulation
Why do we need central and peripheral tolerance of self- antigens?
Not all self antigens expressed in central lymphoid organs where negative selection occurs.
Explain what happens to immature T-lymphocytes when they bind differently to self-antigens during development in the thymus?
Binding: peptide bound to self MHC molecule:
Strong- -ve selection (apoptosis)
Intermediate - T reg. cell
weak - +ve selection
non - apoptosis
Explain what happens to immature B-lymphocytes when they bind differently to self-antigens during development in the Bone marrow?
High avidity - Leads to receptor editing, express new light chain and if still high avidity then apoptosis
Low avidity - Reduce receptor expression and become anergic ( wont respond to self antigen)
What happens during peripheral tolerance to T lymphocytes?
Normal response - (non self) T cell bins to Antigen Presenting Cell by a MHC + antigen complex ( co-stimulation) forming effector and memory T cells.
Self antigen response - T cell binds to Self antigen by MHC causing
anergy (functional unresponsiveness), suppression (block in activation by Treg cells)
or deletion (apoptosis)
what happens during peripheral tolerance to B lymphocytes?
Normal response (non self) binds and activates forming plasma cell and antibodies
Self antigen - BCR binds to self antigen and t cell isn’t active -> anergy, apoptosis or regulation by inhibitory receptors.
Central tolerance mechanism (short)
Deletion editing
Peripheral tolerance mechanism (short)
Cellular inactivation by weak signalling without co-stimulus
What is an Auto-Immune disease
High levels of auto-antibodies
Self tolerance fails
What genes are associated with autoimmunity?
MHC class 2 genes
What causes tissue injury in autoimmunity?
Activation of self-reactive lymphocytes
How do infections affect autoimmunity?
TRIGGERS autoimmunity usually:
Microbe causes activation of APC ( b7 and cd28 costimulatory molecules)
APC which has been activated has self-antigen on and T-cell becomes activated to target self antigen causing damage in self tissues.
May also have APC which is activated by a microbe where the antigen presented is a microbial antigen however looks like self.
Autoimmunity only when infection occurs- self tolerance without microbe as APC will be ‘resting’.
What are common systemic autoimmune diseases?
Rheumatoid artheritis
What are common organ specific autoimmune diseases?
Myasthenia Gravis
Graves disease
Autoimmune diabetes
What is autoimmune diabetes?
Autoantibodies against acetylcholine receptor.
Antibodies mimic ligand and cause stimulation of thyroid cells.
Autoantibodies directed against receptor for TSH and prevent binding of acetylcholine.
Causes cell mediated attack on islets of Langerhans in pancreas = death of beta cells (insulin) and severe muscle weakness!
Conventional therapies for autoimmunity diseases
Anti-inflammatory drugs (aspirin, ibuprofen, corticosteroids (blocks TNF and IL-1 production)
Immunosuppressive drugs: inhibits lymphocyte proliferation (ciclosporin)
For autoimmune disease:
Organ specific - insulin for diabetes
Acetylcholinesterase inhibitor in myasthenia gravis.
What does IL-1 do
Travels to hypothalamus to the pituitary gland, causing release of prostaglandins causing fever.
Explain the inflammatory response
Trauma/ pathogen
Platelet adhesion & vasoconstriction of efferent vessels
Cytokine induced vasodilation of afferent vessels ( inc. blood flow)
Complement, coagulation, fibrinolytic and kinin systems activated
Leukocyte adhesion
Inc. vascular permeability and tissue swelling from leukocytes
Phagocytosis of material and pus
Wound healing
Bacteria triggers macrophages to release TNFa , IL1 and 6 causing vasodilation and increased vascular permeability causing redness and swelling
Inflammatory mediators released into cells causing pain.
What are Acute Phase Proteins (APPs)
Response to tissue injury and infections
made by hepatocytes
Made in response to proinflammatory cytokines
eg: C reactive protein and fibrinogen
Proinflammatory mediators are…
Acute Phase Proteins
Kinins
Cytokines
Adhesion molecules
Matrix Metalloproteinases
Prostaglandins
What cytokines are proinflammatory?
TNFalpha
IL1
IL6
IL12
IFN a and b
What is NF-kB
a family of transcription factors that regulate hundreds of proinflammatory mediators
Phosphorylation of IkB bound to NF and kB causes transcription
In the second stage of inflammation what are phagocytes attracted by?
Chemokines and chemotaxis
What are released during resolution of inflammation?
Anti-inflammatory mediators
Give examples of anti-inflammatory mediators
Cytokines - IL10
TIMPs- inhibit MMPs
Resolvins / protectins
Opioid peptides - counteract pain
What is chronic inflammation
Sustained inflammation- anti-inflammatory mediators aren’t released as should be.
Can lead to tissue damage, autoimmune diseases
What are the 3 DMARD’s for inflammatory diseases (disease modifying Anti-Rheumatic Drugs)
and what do they do (in short)
Methotrexate
Ciclosporin
Leflunomide
They halt or reverse underlying disease.
How does ciclosporin work?
Immunosuppressive- no anti-inflammatory effect.
Decreases clonal proliferation of T cells, inhibits IL-2 synthesis and may decrease expression of IL-2 receptors.
Decrease clonal proliferation of cytotoxic T cells from CD8+ T cells.
3-4x conc. of what’s in plasma
Can causes HT, nephrotoxicity and hepatotoxicity
How does Leflunomide work?
Inhibitory effect on activated T cells.
Inhibits synthesis of pyrimidines (dihydro-orotate dehydrogenase)
What does COX do
Combines arachidonic acids with oxygen to form prostanoids
Where is COX1 found
Most cells- produces prostanoids.
Homeostasis
Where is COX2 found
Not normally present and induced by inflammation
What do prostanoids do?
Modifies release of hormones
Bronchoconstrictor effect
Inhibition of platelet aggregation
Vasodilation
Renin release
What prostanoid is predominant in inflammation?
PGE2
Unwanted side effects of COX inhibitors
Usually from inhibiting COX1:
GI Effects
CV effects
Bronchospasm
Skin reactions
How to treat paracetamol overdose
Increase glutathione:
Acetlcystine and methionine
