Autoimmunity Flashcards
What is the definition of autoimmunity and autoimmune disease?
Immune response against a self-antigen or antigens
Autoimmune disease - tissue damage or disturbed function due to autoimmune response
Describe rheumatoid factor
Autoantibodies, usually of the IgM class, directed against the Fc portion of the IgG
Around 5% of healthy people have a positive test but no autoimmune disease
Not all autoimmunity leads to tissue damage
How is autoimmune disease classified?
Organ specific - affects single organs and autoimmune response against multiple antigens within that organ
Non-organ specific - affects multiple organs and autoimmune response against self-antigens widely distributed in the body
What is the epidemiology of autoimmune disease?
3-5% of population
Peaks at 15-65 years
More common in women apart from ankylosing spondylitis
Tendency for autoimmune disorders to occur in same individual happens in the same type (1,2 or 3)
Why does every individual harbour autoreactive cells?
T cells have a central role in controlling nearly all immune responses, process of T-cell autoreactivity seems to be of greater importance in autoimmunity since B-cells need CD4+ T-cells to give a full IgG antibody response
How does B-cells and T-cells harbour autoreactive cells?
B-cells - somatic hypermutation occurs and theoretical risk of making B-cells reactive against one of our cells
T-cells - deletion of self-reactive cells within thalamus but some manage to escape
What is tolerance?
Non-responsiveness of immune system
Describe antigen specific tolerance
Once induced by an antigen, future immune response to same antigen is ablated
Avoid autoimmune disease, the T and B cells bearing self-reactive molecules must be eliminated or downregulated
Describe self-tolerance
Tolerance to self antigens is a fundamental property of the normal immune system
Failure results in immune reactions against self antigens
Autoimmunity is breakdown of immune self-tolerance
What is central tolerance?
Occurs during lymphocyte development
T and B lymphocytes that recognise self-antigens are eliminated before they differentiate
Most active in foetal life
What is peripheral tolerance?
Inevitably some autoreactive cells evade deletion and reach the peripheral tissues, where they are controlled by mechanisms
What are the central tolerance mechanisms?
Thymus selects the useful, neglects the useless and destroys the harmful
Mature T cells have TCRs with low self affinity
Can’t cover everything - antigens not expressed in thymus, harmless foreign antigens, foetal antigens and transplantation
Describe ignorance mechanism of peripheral tolerance
Self-antigen is effectively invisible to the immune system
Ex. antigen sequestered in a avascular organ and limited amounts escape due to inflammation, this will break down
What are the 2 signals for T-cell activation and proliferate (and produce cytokines)?
Naive CD4+ T-cells
1 - antigen specific signal through the T-cell antigen receptor
2 - non-specific co-stimulatory signal, usually by CD8+ binding to one of the B7 family on dendritic or specialised B cell
Describe deletion and anergy in peripheral tolerance mechanisms
Lack of co-stimulation
Stimulation through T cell receptor alone leads to longstanding anergy or death of the T cell by apoptosis
Describe regulation in peripheral tolerance mechanisms
Active suppression of self reactive T cells by regulatory population of T-cells (Tregs)
Generally defined by markers CD4, CD25 and FoxP3
Secretion of immunosuppressive cytokines or through contact dependant mechanisms
What causes autoimmune disease?
Genes - strongest genetic association is HLA inhuman linked to MHC
Infections
Environmental factors - hormones, physical agents + diet and drugs
Lead to breakdown of tolerance
Why is HLA so strongly associated with autoimmunity?
Defect in immunological tolerance, ability of the cell to recognise between self and non-self antigenic peptides
What physical agents and diet can cause autoimmune disease?
UV exposure can trigger skin lesions of SLE
Cigarette smoking increases RA, Hashimoto’s and Grave’s
How can infection contribute to autoimmune disease?
Molecular mimicry
Adjuvant effect - stimulation
Describe failure of peripheral tolerance
Lack of anergy
Inappropriate or increased local expression of co-stimulatory molecules
Self antigen changes - De novo expression of self-antigen epitope that immune system has not become tolerant to
Alteration in ways which self-molecules are presented to the immune system
Describe molecular mimicry
Structural similarity between self-proteins and those from microorganisms may also trigger an autoimmune response
A self-peptide in low conc. with no access to appropriate APCs may cross react with a structurally similar microbial peptide
Describe post translational modification
Modified Ag may be recognised as foreign
Tolerance established to modified Ag
Ex. RA several autoantigens in joint are citrullinated
How can tissue damage occur?
Antibody mediated - type II (antibody mediated) and III (immune complex mediated)
Cell mediated - type IV (T-cell mediated)
Describe the processes of tissue damage in hypersensitivity reactions
Receptor agonist, receptor antagonist, ligand antagonist, cytotoxicity, neutrophil activation and acantholytic
What are the stages of autoimmune disease?
Immune disturbance
Autoantibodies
Signs and symptoms
How is autoimmune diseases treated?
Replace what is missing - insulin in T1DM and levothyroxine in Hashimoto’s
Controlling the immune response - steroids and immunosuppressive
No cures
What is HLA-B27 a risk factor for?
Ankylosing spondylitis
