32. Specific Immune Response 💢 COPY Flashcards
What type of immune response is involved in autoimmunity?
Adaptive immune response
Which cell type is always involved in autoimmunity?
Lymphocytes
What proportion of people has lymphocytes with the capability of recognising self-antigens?
ALL of us – this is normal autoimmunity
What are the three main factors that affect the transition from normal autoimmunity to autoimmune disease?
Genetic susceptibility Infections Environmental factors
Why are autoimmune conditions chronic?
Because self-tissue is always present
The effector mechanisms in autoimmunity resemble those of which type of immune reaction?
Hypersensitivity reactions (types 2, 3 and 4)
What proportion of people affected by autoimmune disease isfemale?
75% overall (this changes between diseases)
What is a possible reason for the increase in incidence of autoimmune disease?
Hygiene hypothesis
Describe the pathophysiology of autoimmune haemolytic anaemia.
There are autoantibodies against red blood cells, which bind to red blood cells and activate complement This results in clearance and complement-mediated lysis of the autologous erythrocytes
What is a type II hypersensitivity reaction?
Antibody response against cellular or ECM antigens (insoluble antigens)
What is a type III hypersensitivity reaction?
Immune complex formation by antibody against soluble antigen
What is a type IV hypersensitivity reaction?
T cell mediated disease – delayed type hypersensitivity
What is Goodpasture’s syndrome?
Type 2 hypersensitivity reaction in which there are IgG antibodies against a type IV collagen found on the basement membrane in the glomerulus This results in deposition of autoantibodies in the renal corpuscle and activation of complement leading to infiltration of inflammatory cells and kidney damage NOTE: the inflammatory cells (e.g. neutrophils) bind to the Fc portion of antibodies via their own Fc receptors
How do type II and type III immune reactions recruit inflammatory cells?
Inflammatory cells are recruited via the binding of inflammatory cells to the Fc portion of antibodies via their Fc receptors
What is the main difference between type II and type III hypersensitivity reactions?
Type II – insoluble antigens Type III – soluble antigens
What is the autoantigen in multiple sclerosis?
Myelin basic protein
Other than antigen-TCR binding, what else is required for the activation of naïve T cells?
Costimulation
What is the dominant genetic factor affecting susceptibility to autoimmune disease?
HLA (class II in particular)
What did the freemartin cattle experiment show about tolerance?
It showed that early exposure to foreign antigens allows the development of tolerance to those antigens
Define immunological tolerance.
The acquired inability to respond to an antigenic stimulus
What are the main features of immunological tolerance?
It is acquired It is antigen specific It is an active process in neonates
What are the two types of immunological tolerance?
Central Tolerance = happens during lymphocyte development Peripheral Tolerance = once we’ve developed mature lymphocytes, there are mechanisms to develop tolerance
What are the three main mechanisms of peripheral tolerance?
Anergy Ignorance Regulation
What are the three outcomes for T cells based on how stronglythey bind to MHC in the thymus?
Useless –don’t recognise MHC at all – die by apoptosis Useful – associate weakly with MHC Dangerous – associate too strongly with MHC – die by apoptosis
What percentage of thymocytes survives selection?
5%
What class of immunoglobulin are the B cell surface receptors?
IgD and IgM
What happens to B cells that recognise soluble autoantigens?
They will migrate to the periphery but they do not express normal levels of IgM and they are anergic (they are not very responsive)
What is the role of the AIRE transcription factor?
It is important for the low-level expression of a large variety of self-peptides in the thymus, against which the T cells are selected
What is APECED caused by?
Autoimmune polyendocrinolpathy candidiasis ectodermal dystrophy Mutation in the AIRE transcription factor This mutation means that the T cells can’t be selected against a wide range of self-peptides so lots of self-reactive T cells get released into the circulation and can cause autoimmune disease
What is anergy caused by?
The presentation of an antigen in the absence of costimulation – this makes the lymphocytes enter a refractory state
What is immunological ignorance caused by?
Occurs when the antigen concentration is too low It can be due to the absence of antigen presenting molecules It occurs at immunologically privileged sites where the immune cells don’t normally penetrate This is ignorance – the T cells never see their antigen
Give an example of a failure of ignorance.
Sympathetic ophthalmia Damage to the eye can release eye antigens into the lymphatics and lymph nodes These antigens are recognised by T cells, which become activated against the eye antigens The T cells then go back to both eyes and cause damage
What are the main receptors expressed by Tregs?
CD4 CD25 –IL-2 receptor, which is an important growth factor for T cells CTLA-4 – binds to B7 and sends a negative signal FOXP3 – essential transcription factor for Treg development
What is IPEX caused by?
Mutation in FOXP3 FOXP3 encodes a transcription factor that is critical for the development of T regs A mutation in FOXP3 leads to the accumulation of autoreactive T cells
What are the two types of Treg?
Natural Tregs (nTregs) – these are generated in the thymus Inducible Tregs (iTregs) – these are produced as part of the normal T cell response as a mechanism of dampening down an immune response after it has happened
How can infections affect tolerant states?
Molecular mimicry of self-molecules Induction of costimulatory molecules or inappropriate MHC class II expression: pro-inflammatory environment Failure of regulation: effects on Tregs Immune deviation: shift in type of immune response Activation of APCs by pathogens leads to upregulation of costimulatory molecules
Define Rheumatoid Arthritis
Chronic autoimmune disease characterised by pain, stiffness and SYMMETIRCAL SYNOVITIS of synovial (diarthrial) joints
When is the stiffness in the joints particularly bad in rheumatoid arthritis and what can make it better?
In the morning It gets better with exercise
What is a relatively common extra-articular manifestation of rheumatoid arthritis?
Rheumatoid nodules
What causes the extra-articular manifestations?
Rheumatoid factor produces immune complexes that can go anywhere
What type of antibody is the rheumatoid factor?
IgM antibody that binds to the Fc portion of IgG
Is rheumatoid arthritis more common in males or females?
More common in females (3:1)
What is the important genetic component that predisposes toRheumatoid Arthritis?
The genetic component comes down to a specific set of amino acids within the beta chain of the DR molecule (amino acids 70-74 of the DR Beta1-chain) This set of amino acids is conserved among all HLA subtypes that are associated with rheumatoid arthritis – it is called the shared epitope
What important environmental factor can affect the susceptibility and severity of Rheumatoid Arthritis?
Smoking
State some joints that are commonly affected in Rheumatoid Arthritis.
Metacarpophalangeal joint (MCP) Proximal interphalangeal joint (PIP) Wrists Knees Ankles Metatarsophalangeal joint (MTP)
Name and describe two deformities that are indicative of Rheumatoid Arthritis.
Swan-neck deformity ï‚· Hyperextension of PIP ï‚· Hyperflexion of DIP Boutonniere deformity (button-like) ï‚· Hyperflexion at PIP
What is the term given to fingers that are completely swollen, notjust around the joints?
Dactylitis – this can’t be explained by Rheumatoid Arthritis because it is not just the joints that are inflame