32. Specific Immune Response 💢 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
Describe the appearance of extensor tenosynovitis.
There will be swelling around the extensor tendon that is inflamed When the fingers are extended, the swelling will move showing that the inflammation is around the tendon and not the joint
Other that joints and around tendons, where else can synovium become inflamed?
Bursae –> Bursitis
What are sub-cutaneous nodules?
Central area of fibrinoid necrosis surrounded by histiocytes and a peripheral layer of connective tissue
Why are rheumatoid nodules an important clinical finding?
Patients with rheumatoid nodules are always rheumatoid factor positive
Where are rheumatoid nodules commonly seen?
Along the ulnar border
What proportion of cases of Rheumatoid Arthritis is rheumatoid factor negative?
1/3
Name another autoantibody that is very specific for Rheumatoid Arthritis.
Anti-cyclic citrullinated peptide antibody
Which enzymes are responsible for the citrullination of peptides?
Peptidyl arginine deaminases (PADs
Why do citrullinated peptide antigens develop in rheumatoid arthritis?
PADs are present in high concentrations in neutrophils and monocytes so there is increased citrullination of autologous peptides in inflamed synovium Citrulline binds much better than arginine to the shared epitope (specific peptide sequence that is conserved in all MHC molecules that are associated with Rheumatoid Arthritis) So Anti-CCP antibodies are more likely to develop in individuals with citrullinated autoantigens and those that have the shared epitope
State some common extra-articular manifestations of Rheumatoid Arthritis.
Rheumatoid nodules Fever Weight loss
State some rare extra-articular manifestations of Rheumatoid Arthritis.
Vasculitis Episcleritis Neuropathies Amyloidosis Lung disease (nodules, fibrosis, pleuritis) Felty’s syndrome (triad of splenomegaly, leukopenia and rheumatoid arthritis)
What is an early radiographic abnormality in Rheumatoid Arthritis?
Juxta-articular osteopenia
What are some later radiographic abnormalities in Rheumatoid Arthritis?
Joint erosion and, subsequently, joint destruction and deformity
What is the name given to the thickened, chronically inflamed synovial tissue in Rheumatoid Arthritis?
Pannus
Which area of bone tends to be eroded first in Rheumatoid Arthritis?
Bare area of bone – this is within the synovial membrane but is not covered by articular cartilage (periarticular erosion)
How thick is the normal synovial membrane?
It is normally almost a single cell lining
Which cells are responsible for producing synovial fluid?
Synovial fibroblasts NOTE: macrophages are also found within the lining
Why is synovial fluid viscous?
It contains hyaluronic acid
What type of collagen is present in articular cartilage?
Type 2 collagen
What is the main proteoglycan in articular cartilage?
Aggrecan
What three main things are responsible for the synovium becoming a proliferated mass (pannus)?
Neovascularisation Lymphangiogenesis Inflammatory cell recruitment: ï‚· Activated T and B cells ï‚· Plasma cells ï‚· Mast cells ï‚· Activated macrophages
What are the three main cytokines involved in this disease process?
IL-1 IL-6 TNF-alpha
What is the dominant cytokine and which cells produce it?
TNF-alpha Produced by activated macrophages
What is the main treatment goal for Rheumatoid Arthritis?
Prevent joint damage
What class of drugs are commonly used in Rheumatoid Arthritis to modify the natural history of the disease?
Disease-modifying anti-rheumatic drugs (DMARDs)
When are glucocorticoids used and why are they not used long term?
They are used in the short-term to control, for example, exacerbation of the disease They are not used long-term because of their large side effect profile
Describe the onset of action of DMARDs.
Slow onset and complex action
Give some examples of DMARDs.
Methotrexate Sulphasalazine Hydroxychloroquine Leflunomide Gold Penicillamine
What are the shortcomings of DMARDs?
They have significant adverse effects and require regular blood test monitoring
What are the major risks with biological therapy?
EXPENSIVE All biological therapies are associated with an increase infection risk TNF-alpha inhibition is associated with increased susceptibility to mycobacterial infections (TUBERCULOSIS) So all patients must be screened for TB before starting treatment B cell depletion is associated with HEPATITIS B activation so patients need to be screened for this as well B cell depletion is also associated with JC virus infection and progressive multifocal leukoencephalopathy (PML) – RARE
What is the general structure of a T Cell Receptor?
It consists of an alpha and beta chain Both chains have a variable region and a constant region
What other receptor are TCRs associated with and how does it transmit signals?
CD3 is present on all T lymphocytes and they have a longer cytoplasmic tail than the TCR Signals from the TCR are transmitted to the internal compartment of the cell via the CD3 receptors The tails of CD3 have tyrosine residues When antigen binds to the TCR, phosphorylation of tyrosine occurs in the tails, which leads to many chemical cascades.
What class of MHC do CD4+ T cells bind to?
MHC Class II
What class of MHC do CD8+ T cells bind to?
MHC Class I
What type of cells are CD4+ T cells? What do they do?
T helper cells – T helper 1 cells are involved in inflammatory responses (activate macrophages) whereas T helper 2 cells are involved in B cell activation
What type of cells are CD8+ T cells? What do they do?
Cytotoxic T lymphocytes – kills virus infected cells
Where are immature thymocytes found in the thymus?
In the cortex – mature thymocytes are found in the medulla
Describe, in full, T cell development in the thymus.
T cells initially have no TCR or CD4/CD8 receptors The beta chain of the TCR assembles first followed by the alpha chain If the TCR is functional, the T cell goes on to express both CD4 and CD8 receptors Depending on which MHC class it binds to it eventually ends up being only CD4+ or CD8+
What do CD4 and CD8 bind to?
They bind to the side of the MHC molecule
In what order does gene rearrangement take place?
Beta chain is rearranged first (VDJ recombination) and then the alpha chain (VJ recombination)
What percentage of thymocytes survive selection?
5%
Describe, in full, the structure of MHC Class I.
MHC Class I consists of a heavy alpha chain which is polymorphic and a beta-2 microglobulin chain which is the same in everyone Only the alpha chain has a transmembrane domain
How does the light polypeptide associate to the heavy polypeptide in MHC Class I?
Non-covalent bonding
What part of MHC Class I is transmembrane?
Alpha chain
Describe, in full, the structure of MHC Class II.
MHC Class II consists of two polypeptides of a similar size, an alpha and a beta chain Both chains have a transmembrane domain
What part of MHC Class II is transmembrane?
Both the alpha and beta chains have transmembrane domains
What is the difference between the types of peptides presented by Class I and Class II?
Class I presents peptides that are smaller than the MHC molecule Class II presents peptides that are longer than the MHC molecule so it often has bits protruding out of the MHC molecule
Describe how the structure of MHC allows it to bind to a broad variety of peptides.
It has a binding motif that consists of binding pockets where you get particular amino acids binding in those positions – this is a feature that is conserved in most peptides
What is the name for the Human MHC region in the genome?
Human Leukocyte Antigen
What are the types of MHC Class I genes?
A, B and C
What are the types of MHC Class II genes?
DP, DQ, DR
How many types of MHC molecule can one person produce?
12 – 6 class I and 6 class II
What is an MHC haplotype?
Group of MHC alleles linked together on a single chromosome
Describe the process of antigen presentation via MHC Class I.
MHC Class I present endogenous antigens Viral proteins are processed by a proteasome and move through TAP protein into the ER In the ER, the MHC Class I molecule assembles and a chaperone protein aids its folding Once it has fully assembled, it can move to the cell surface via the golgi apparatus
Describe antigen presentation via MHC Class II.
Antigens are endocytosed and move into the endocytic pathway. Newly formed MHC Class II molecules enter the ER using a signal sequence In the ER, the MHC Class II associates with an invariant chain (blocks the binding site to make sure molecules that are meant to be loaded onto MHC Class I aren’t loaded onto class II.) The invariant chain has a signal sequence that directs the MHC towards the endocytic pathway. As it moves into the endocytic pathway, the invariant chain is digested leaving only a clip protein. The final step is the replacing of the clip protein by the antigen.
What are the three secondary effector functions of antibodies once bound to antigens?
Opsonisation Complement activation Cell activation (e.g. mast cells)
Which immunoglobulin category do antibodies fall into?
Gamma immunoglobulins
What type of bond holds together the chains in the immunoglobulin?
Disulphide bonds
What is an immunoglobulin domain?
Internal intrachain disulphide bond
What did scientists find when sequencing the amino acid sequence of the variable region on antibodies?
There are three hypervariable regions called the complementarity determining regions
What part of the variable region of the antibody binds to the antigen?
The complementarity determining regions are found at the end of the variable regions and interact with antigens
What forces are involved in antibody-antigen binding?
THEY ARE ALL NON-COVALENT Hydrogen bonding, ionic bonding, van der waals, hydrophobic interactions
Define affinity.
The strength of the total non-covalent interactions between a single antigen-binding site and a single epitope
What equation shows affinity mathematically?
K = [Ab-Ag]/[free Ab][free Ag]
Define avidity.
The overall strength of the multiple interactions between an antibody with multiple binding sites and a complex antigen with multiple epitopes
What is antibody cross-reactivity? Give an example.
Antibodies that are produced in response to one antigen can cross-react and bind to a different antigen with a similar structure. E.g. cow pox and small pox
What are isotypes and allotypes of antibodies?
Isotypes vary in the constant regions – everyone has isotypes Allotypes – polymorphic variables – some people have them others don’t
How do the different classes of antibodies (GAMED) differ?
They vary in the constant region of their heavy chain
What are the two classes of light chain?
Kappa and lambda
Which immunoglobulin classes have subclasses and how many subclasses do they have?
IgG = 4 (in order of abundance – 1 is the most abundant) IgA = 2
How do the different subclasses vary?
They vary in the hinge region
Describe the formation of secretory IgA.
Dimeric IgA is produced by plasma cells It binds to the Poly-Ig receptor on the basolateral surface of the epithelia This binding stimulates endocytosis Once inside the cell, the poly-Ig receptor is cleaved and the dimeric IgA is secreted with the secretory component The secretory component is derived from the poly-Ig receptor
How can IgE activate cells?
It binds to the Fc (Fc-epsilon-RI) receptor on mast cells When antigens bind to the IgE, which is attached to the mast cell, it stimulates degranulation
Which two Ig classes are mainly responsible for activating complement?
IgM and IgG
