autoimmunity Flashcards
what is autoimmunity
- works to defend the body and eliminate infections caused by bacteria, viruses and other invading microbes
- in an autoimmune disease, the immune system mistakenly attacks self, targeting the cells, tissue, and organs of a person own body
multifactorial reasons of autoimmune diseases
- genetic factors
- infection and environmental exposure
= immune regulation= autoimmunity
features of autoimmune disease
- imbalance between immune activation and control
- underlying causative factors- susceptibility genes + environmental influences
- immune response is inappropriately directed or controlled, effector mechanisms of injury are the same as in normal responses to microbes
- nature of disease is determined by the type of dominant immune response
- many immunological disease are chronic and self- perpetuating
causes
Immune regulatory failure
Loss of central tolerance
Loss of peripheral tolerance
Molecular mimicry
Inappropriate activation
regulation of the immune system
- Central (thymic)
Positive selection
Negative selection - Peripheral
regulatory T & B cells
dendritic cells & ‘danger’
co-stimulation
ignorance
privilege
genetics of autoimmune disease
Human autoimmune diseases are complex polygenic traits
Identified by genome-wide association mapping
Single gene mutations are useful for pathway analysis
Some polymorphisms are associated with multiple diseases
May control general mechanisms of tolerance and immune regulation
Other genetic associations are disease-specific
May influence end-organ damage
environmental factors
- smoking
- air pollution
- drugs
-infectious agents
infections
Infections trigger autoimmune reactions
Clinical prodromes, animal models
Autoimmunity develops after infection is eradicated (i.e. the autoimmune disease is precipitated by infection but is not directly caused by the infection)
infections and autoimmune disease
Some autoimmune diseases are prevented by infections (type 1 diabetes, multiple sclerosis, others? – increasing incidence in developed countries): mechanism unknown
The “hygiene hypothesis”
pathogenesis of autoimmune disease
susceptibility genes—> failure of self- tolerance—> persistence of functional self- reactive lymphocytes+ environmental triggers —-> activation of self-reactive lymphocytes= immune response against self tissues
immune-mediated inflammatory disease
Chronic diseases with prominent inflammation, often caused by failure of tolerance or regulation
RA, IBD, MS, psoriasis, many others
Affect 2-5% of people, incidence increasing
May result from immune responses against self antigens (autoimmunity) or microbial antigens (Crohn’s disease?)
May be caused by T cells and antibodies
May be systemic or organ-specific
auto- antibodies
Often present
May or may not be pathogenic
Specific examples apparently significant
May be associated with specific disease states
auto- antibodies: specific target and immune complexes
Graves disease – TSH receptor
Myasthenia Gravis – acetyl choline receptor
Idiopathic thrombocytopenic purpura (ITP) – platelets
Guillain–Barré syndrome (GBS) - gangliosides
Immune complexes
Tissue antigens
Soluble antigens
graves disease
Thyroid hormones regulated by thyroid-stimulating hormones (TSH)
TSH bind to receptor & stimulates synthesis of thyroid hormones
Grave’s Disease results in non-regulated “activating” auto-antibodies that bind to the TSH receptor, leading to overstimulation of the thyroid hormones
The auto-antibodies are called long-acting thyroid stimulating hormones
cellular mechanisms
T cell specific for auto-antigens may ‘help’ to generate anti-host response
Graves disease – T cells to thyroid follicular epithelial cells
Myasthenia Gravis – T cells to acetyl choline receptor
Propose:
Aberrant effector T cells – Th1 vs Th17 vs Th2
Deficiency of Treg cells
Macrophage / Neutrophils / NK cells / Dendritic cells all implicated via
Cytokine release
Effector pathways e.g. MMPs / ROIs / RNIs
organ specific autoimmune disease
Autoimmune attack vs. self-antigens of given organ
It results in a damage of organ structure and function
- Hashimoto thyroiditis
- addison’s disease
- juvenile diabetes mellitus
non-organ specific
Widespread self-antigens are targets for autoimmune attack
Damage affects such structures as blood vessels, cell nuclei etc.
- systemic lupus
- rheumatoid arthiritis
- mixed connective tissue disease
Guillain-Barré syndrome
Auto-antibody mediated autoimmune disease of the peripheral nerves
Triggered by infections including Campylobacter jejuni
Common cause of acute paralysis
rheumatoid arthritis and evolving pathogenesis
pre-articular/lymphoid phase- autoimmunity, CCP-specific antibody, rheumatoid factor, collagen-specific response, GP39- specific response
transition phase- microbial insult?, bio-mechanical events, neurological events, microvascular dysfunction
articular phase- articular localisation, cardiovascular disease, osteoporosis, functional decline
