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Movement and Musculoskeletal Biology Emily > 013 Autoimmune disease and the musculo-skeletal system > Flashcards

013 Autoimmune disease and the musculo-skeletal system Flashcards

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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
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2
Q

what are immunogens?

A
  • substances with antigens that can cause an immune response
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3
Q

what are the 2 main cell types in adaptive immunity?

A
  • T and B lymphocytes
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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
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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
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6
Q

what is immune tolerance?

A
  • mechanisms in the immune system to control self-reactivity
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7
Q

what are the 2 tolerance mechanisms?

A
  • central and peripheral tolerance
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8
Q

what is autoimmunity?

A
  • hypersensitivity reaction to your body’s own antigens
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9
Q

when does autoimmunity occur?

A
  • when 1 or more of the tolerance mechanisms to self-antigens break down
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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
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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)
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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
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13
Q

what happens if there is failure of positive selection in central tolerance?

A
  • immunodeficiency
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14
Q

what happens if there is failure of negative selection in central tolerance?

A
  • autoimmunity
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15
Q

name the 5 different ways of peripheral tolerance

A
  • anergy
  • ignorance
  • AICD /apoptosis
  • Tregs/Bregs
  • phenotypic skewing
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16
Q

what is anergy in peripheral tolerance?

A
  • lymphocytes are unresponsive until they recieve costimulatory signals from activated APCs
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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)
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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
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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
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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
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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
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22
Q

what factors can cause autoimmune disease?

A
  • genetics
  • environment e.g. infection, tissue injury
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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
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24
Q

what is the epidemiology of rheumatoid arthritis?

A
  • 1% of population
  • more common in females
  • family history increases risk
25
Q

what is a common genetic pre-disposition to rheumatoid arthritis?

A
  • 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
Q

Give some examples of environmental risk factors for rheumatoid arthritis

A
  • 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
Q

what does ACPA and RF stand for in rheumatoid arthritis?

A
  • Anti-citrullinated protein antibodies
  • rheumatoid factor
28
Q

what are the names of the 2 autoantibodies in rheumatoid arthritis?

A

ACPA (anti-citrullinated protein antibodies)
- RF (rheumatoid factor)

29
Q

describe what is rheumatoid factor and its role in rheumatoid arthritis

A
  • 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
Q

how do we detect rheumatoid factor?

A
  • latex bead agglutination
  • take serum sample from patients
  • incubate with latex beads coated with human IgG
  • if Rf is present (positive) = agglutination
31
Q

what is citrulline and how is it made?

A
  • a non-standard amino acid
  • created by deamination of arginine residues by peptidylarginine deiminase (PAD)
32
Q

what are citrullinated proteins and what do they do?

A
  • 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
Q

what antibody isotopes are ACPAs?

A
  • IgG, IgM, IgA
34
Q

give some examples of self proteins ACPAs may bind to

A
  • fibrinogen, histones, type 2 collagen
35
Q

where do B cells produce ACPAs?

A
  • synovium and circulation
36
Q

why are ACPAs important markers

A
  • 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
Q

name a factor that increases the citrullination of proteins

A
  • smoking = promotes citrullination = increase risk of developing RA
38
Q

what are the 3 stages of developing ACPA-positive RA?

A

1 = loss of tolerance at mucosal site / immune response
2 = ACPA-associated disease / inflammatory response
3 = symptomatic /chronic RA

39
Q

describe the stage 1 of developing ACPA-positive RA

A
  • 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
Q

describe the stage 2 of developing ACPA-positive RA

A
  • 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
Q

describe the stage 3 of developing ACPA-positive RA

A
  • 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
Q

what are the 3 types of RA classified based on cell type invading synovium?

A
  • myeloid-dominant
  • lymphocyte dominant
  • fibroid dominant
43
Q

what are ACPAs against?

A
  • IgG / rheumatoid factor
44
Q

what cells are commonly found in rheumatoid arthritic synovium?

A
  • T cells, macrophages, neutrophils, monocytes, mast cells, B cells, dendrtitic cells, plasma cells, osteoclasts
  • complement
45
Q

what cytokines are commonly found in rheumatoid arthritic synovium?

A
  • TNF, IL1,6,17
46
Q

name some treatments for Rheumatoid arthritis

A
  • 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
Q

what are the different mechanisms that DMARDs work by?

A
  • TNF blockade e.g. etanercept, adalimumab
  • T-cell co-stimulation blockade = abatacept
  • IL-6 blockade = tocilizumab
  • B cell depletion = rituximab
48
Q

what is myasthenia gravis?

A
  • a prototypical, antibody-mediated autoimmune disorder of the neuromuscular junction
    = causes weakness of skeletal muscles
49
Q

what is the prevalence of myasthenia gravis?

A

1 in 5000

50
Q

why is myasthenia gravis an antibody mediated disease?

A
  • the disease is purely carried in antibodies
  • if you injected antibodies into a healthy mouse, it would develop MG
51
Q

what are some symptoms of myasthenia gravis?

A
  • 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
Q

what is the pathophysiology of myasthenia gravis?

A
  • 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
Q

what are the common and rare myasthenia gravis autoantibodies?

A
  • common = Anti-AChR (IgG1,3)
  • rare = Anti-MuSK (IgG4)
    = Anti-LRP4 (low density lipoprotien receptor
54
Q

what are the clinical subtypes of myasthenia gravis (6)?

A
  • 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
Q

what is the EPP/end plate potential and what is it in Myasthenia gravis patients?

A
  • depolarisation potential after the release of ACh
  • a decrease of EPPs that reach threshold to induce contraction
56
Q

what is the genetic cause of early onset myasthenia gravis?

A
  • HLA-B (class 1), PTPN22, TNIP1
57
Q

what is the genetic cause of early and late onset of myasthenia gravis?

A
  • HLA class 2, CTLA-4 = both
  • just late onset = TNFRFSF11A = Involved in T-B cell interactions
58
Q

name 5 treatments for myasthenia gravis

A
  • 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
Q

what are idiopathic myopathies and give some examples

A
  • 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

Movement and Musculoskeletal Biology Emily (23 decks)

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