013 Autoimmune disease and the musculo-skeletal system Flashcards
1
Q
what is the definition of immune tolerance?
A
- state of specific immune unresponsiveness to antigens that have the ability to induce an immune response
2
Q
what are immunogens?
A
- substances with antigens that can cause an immune response
3
Q
what are the 2 main cell types in adaptive immunity?
A
- T and B lymphocytes
4
Q
what is the difference between T and B cells in terms of MHC/APC?
A
- T cells are MHC restricted, need APCs
- B cells are not MHC restricted
5
Q
what are the 2 main parts of B cell development?
A
- 1st part in bone marrow from hematopoietic stem cell –> immature B cell, BCR and IgM (VDJ recombination) and then central tolerance
- 2nd part = In peripheral lymphoid tissue, B cell activation from naive B cell into plasma cells and memory B cells, peripheral tolerance
6
Q
what is immune tolerance?
A
- mechanisms in the immune system to control self-reactivity
7
Q
what are the 2 tolerance mechanisms?
A
- central and peripheral tolerance
8
Q
what is autoimmunity?
A
- hypersensitivity reaction to your body’s own antigens
9
Q
when does autoimmunity occur?
A
- when 1 or more of the tolerance mechanisms to self-antigens break down
10
Q
what is central tolerance?
A
- occurs in the thymus for T cells and bone marrow for B cells
- removes all cells that react with self antigens
- clonal deletion / apoptosis
- when cells are still immature
- negative selection
11
Q
describe central tolerance for T cells
A
- in thymus (thymic cortex)
- immature T cells are double negative ( lack both CD4, CD8 receptors)
- then become double positive immature T cells (have both CD4 AND CD8)
- once selected the T cell downregulates 1 of the receptors to become CD4 or CD8
- weak binding affinity to MHC antigens = positively selected
- no recognition/binding = die, apoptosis
- strong binding affinity to MHC = negatively selected, most die by apoptosis, but some escape (autoimmunity)
12
Q
describe central tolerance for B cells
A
- in bone marrow
- immature B cells activate by binding to an antigen receptor
- if a B cell binds to a functional receptor = activates
- if B cell binds to a self-antigen = either negatively selected (apoptosis) or it can change its receptor (VDJ recombination)
- if a
13
Q
what happens if there is failure of positive selection in central tolerance?
A
- immunodeficiency
14
Q
what happens if there is failure of negative selection in central tolerance?
A
- autoimmunity
15
Q
name the 5 different ways of peripheral tolerance
A
- anergy
- ignorance
- AICD /apoptosis
- Tregs/Bregs
- phenotypic skewing
16
Q
what is anergy in peripheral tolerance?
A
- lymphocytes are unresponsive until they recieve costimulatory signals from activated APCs
17
Q
what is ignorance in peripheral tolerance?
A
- where antigens are ignored in areas of lots of receptors (sites of immune privilege e.g. eye, testes)
18
Q
What is the role of Bregs and Tregs in peripheral tolerance?
A
- inhibit the immune response
- downregulate induction and proliferation of B and T cells if they are self reacting
19
Q
What is the role of AICD/apoptosis in peripheral tolerance?
A
- AICD = antigen induced cell death
- if a cell encounters an antigen that is strongly activated = cell death
- activated T cells with Fas ligand may kill Fas-expressing B and T cells
20
Q
what is the role of phenotypic skewing in peripheral tolerance?
A
- when self reactive cells will activate through a different pathway to avoid autoimmunity
21
Q
what is the definition of an autoimmune disease?
A
- a pathophysiological state where immune responses are directed against self and cause tissue damage
22
Q
what factors can cause autoimmune disease?
A
- genetics
- environment e.g. infection, tissue injury
23
Q
what is rheumatoid arthritis (overview)
A
- chronic systemic autoimmune disease
- causes inflammation of the joints leading to joint destruction = deformity and disability
- stiffness, pain and swelling at joints
24
Q
what is the epidemiology of rheumatoid arthritis?
A
- 1% of population
- more common in females
- family history increases risk
25
what is a common genetic pre-disposition to rheumatoid arthritis?
- single nucleotide pleomorphisms
- susepctibility epitope HLA-DR beta chain (MHC class 2)
CTLA-4 gene polymorphisms = no longer downregulates T-cell activation when self reacting
PTPN22 gene polymorphisms = T cell signalling goes wrong
26
Give some examples of environmental risk factors for rheumatoid arthritis
- smoking
- silica (dust inhalation)
- textile dust
- periodontal disease (P.gingivalis can express PAD - peptidylarginine deiminase = generate citrullinated peptides = RA)
- vit D deficiency
- infectious agents
- obesity
- gut microboime
27
what does ACPA and RF stand for in rheumatoid arthritis?
- Anti-citrullinated protein antibodies
- rheumatoid factor
28
what are the names of the 2 autoantibodies in rheumatoid arthritis?
ACPA (anti-citrullinated protein antibodies)
- RF (rheumatoid factor)
29
describe what is rheumatoid factor and its role in rheumatoid arthritis
- IgM or IgA antibodies that bind to the Fc portion of IgG
- around 80% of RA patients have RF
- high levels of RF = worst prognosis
- however, it is also in other diseases and in up to 10% of healthy people
30
how do we detect rheumatoid factor?
- latex bead agglutination
- take serum sample from patients
- incubate with latex beads coated with human IgG
- if Rf is present (positive) = agglutination
31
what is citrulline and how is it made?
- a non-standard amino acid
- created by deamination of arginine residues by peptidylarginine deiminase (PAD)
32
what are citrullinated proteins and what do they do?
- where arginine is converted to citrulline by PAD
- citrullinated proteins fit better in the HLA-DR4 antigen binding groove than arginine containing peptides
- often found in sites of inflammation and tissue stress
33
what antibody isotopes are ACPAs?
- IgG, IgM, IgA
34
give some examples of self proteins ACPAs may bind to
- fibrinogen, histones, type 2 collagen
35
where do B cells produce ACPAs?
- synovium and circulation
36
why are ACPAs important markers
- more sensitive and specific than RF is early and established disease
- may detect early onset in healthy individuals of RA
- however 40% of patients do not develop ACPAs
37
name a factor that increases the citrullination of proteins
- smoking = promotes citrullination = increase risk of developing RA
38
what are the 3 stages of developing ACPA-positive RA?
1 = loss of tolerance at mucosal site / immune response
2 = ACPA-associated disease / inflammatory response
3 = symptomatic /chronic RA
39
describe the stage 1 of developing ACPA-positive RA
- infection/injury to mucosal surface e.g. smoking on lungs
- immune cell recruitment/activation
- expression of PAD
- citrullination of proteins
- HLA-DR binding
- T cell activation
- ACPA production (systemic and then becomes localised)
40
describe the stage 2 of developing ACPA-positive RA
- unknown/unspecific stimuli at localised area e.g. knee joint
- recruitment/activation of immune cells
- activation of PAD
- citrullination of proteins e.g. of enzymes of osteoclast precursors
- influx of ACPAs
- ACPAs bind to mature osteoclasts which induces them to secrete IL-8
- IL-8 triggers osteoclast proliferation (osteoclastogenesis = RANK/RANKL) = bone loss/destruction
41
describe the stage 3 of developing ACPA-positive RA
- diffusion of soluble molecules between bone and synovium
- osteoclast erosion of trabecular bone leading to cortical lesions = diffusion of soluble molecules to the synovium
= immune and stromal activation
= increased inflammation at joint (stromal cells of synovium)
42
what are the 3 types of RA classified based on cell type invading synovium?
- myeloid-dominant
- lymphocyte dominant
- fibroid dominant
43
what are ACPAs against?
- IgG / rheumatoid factor
44
what cells are commonly found in rheumatoid arthritic synovium?
- T cells, macrophages, neutrophils, monocytes, mast cells, B cells, dendrtitic cells, plasma cells, osteoclasts
- complement
45
what cytokines are commonly found in rheumatoid arthritic synovium?
- TNF, IL1,6,17
46
name some treatments for Rheumatoid arthritis
- NSAIDs = non-steroidal anti-inflammatory drugs ( do not reduce joint damage, interfere with pain and stiffness) e.g. ibuprofen
- DMARDs = disease-modifying antirheumatic drugs - reduce joint damage (biological or synthetic)
- cytokine inhibitors e.g. TNFa/IL1,6 inhibitors
- JAK inhibitors = suppress immune response
- glucocorticoids = immune suppressing and anti-inflammatory (regulate genes) = long term effects, but quick response
47
what are the different mechanisms that DMARDs work by?
- TNF blockade e.g. etanercept, adalimumab
- T-cell co-stimulation blockade = abatacept
- IL-6 blockade = tocilizumab
- B cell depletion = rituximab
48
what is myasthenia gravis?
- a prototypical, antibody-mediated autoimmune disorder of the neuromuscular junction
= causes weakness of skeletal muscles
49
what is the prevalence of myasthenia gravis?
1 in 5000
50
why is myasthenia gravis an antibody mediated disease?
- the disease is purely carried in antibodies
- if you injected antibodies into a healthy mouse, it would develop MG
51
what are some symptoms of myasthenia gravis?
- weakness and fatigue of skeletal muscles
- ocular muscles affected = diplopia (double vision), ptosis(droopy eyelid)
- bulbar muscles affected = dysphagia (difficulty swallowing), dysarthria (difficulty speaking)
- limb weakness = may be asymmetrical
52
what is the pathophysiology of myasthenia gravis?
- autoantibodies target the post synaptic membrane, usually AcH receptors
- the receptors get degraded and no longer can receive AcH and then release Na to cause a muscle contraction = muscle weakness and fatigue
- also complement is activated which damages muscle fibre = weaker muscles
53
what are the common and rare myasthenia gravis autoantibodies?
- common = Anti-AChR (IgG1,3)
- rare = Anti-MuSK (IgG4)
= Anti-LRP4 (low density lipoprotien receptor
54
what are the clinical subtypes of myasthenia gravis (6)?
- early onset = before 50yr (ACh), mostly women
- late-onset = after 50yr (ACh, ryanodine receptor), mostly men
- thymoma - tumour of thymus (ACh, rayondine receptor)
- MUSK
- seronegative (generalised)
-Ocular (mostly ACh)
55
what is the EPP/end plate potential and what is it in Myasthenia gravis patients?
- depolarisation potential after the release of ACh
- a decrease of EPPs that reach threshold to induce contraction
56
what is the genetic cause of early onset myasthenia gravis?
- HLA-B (class 1), PTPN22, TNIP1
57
what is the genetic cause of early and late onset of myasthenia gravis?
- HLA class 2, CTLA-4 = both
- just late onset = TNFRFSF11A = Involved in T-B cell interactions
58
name 5 treatments for myasthenia gravis
- cholinesterase inhibitors = first line treatment =e.g. pyridostigmine (decrease breakdown of ACh)
- immunosuppressive agents e.g. corticosteroids, azathioprine
- thymectomy (remove thymus)
- plasma exchange / plasmapheresis (removes and replaces some of auto-antibodies) = short-life = in crisis
- IV Ig = safer alternative to plasma exchange
59
what are idiopathic myopathies and give some examples
- rare group of acquired autoimmune muscle disorders, characterised by muscle weakness and inflammatory cell infiltrates in muscle
- e.g. dermatomyositis (also get rash), polymyositis (weakness of muscles on both sides of body)
- don't know cause
