Pathology of autoimmune disease Flashcards
(30 cards)
what is rheumatoid arthritis *
chronic inflammation that can result in joint damage - the site of inflammation is the synovium - this is synovitis
it is associated with auto-Ab
- rheumatoid factor - this is an IgM Ab against IgG
- anti-cyclic citrulinated peptide (CCP) Abs
affects the cervical spine - ie the synovial lining between C1 and 2
describe ankylosing spondylitis *
chronic spinal inflammation that can result in spinal fusion and deformity
the site of inflammation is the enthesis
there are no Ab - it is a seronegative spondyloarthropathy
there is inflammation of the spine - lumbar and cervical
there is bony fusion between the vertebrae:
the vertbral bodies are connected by an intervertebral disk - the nucleus pulposes of the intervertebral disk is surrounded by a fibrous band (anulus fibrosis) - the anulus fibrosis inserts into the bone above and below - this insertion is an enthesis - the inflammation is in the enthesis so is called enthesitis = pain, bone destruction, calcification = fusion between vertebrae
describe SLE *
chronic tissue inflammation in the presence of ab directed against self-ag
there is inflammation in many sites - particularly in the joints, skin and kidney
associated with auto-ab:
- anti-nuclear Ab - against ag in nucleus
- anti-dsDNA ab - dsDNA is a key antigen in the nucleus
it is a connective tissue disease
as a result of abnormal production of immune complexes against self
describe the HLA molecules and rheumatology *
it is the major histocompatibility complex
HLA has dominant associations with rheumatoid disease - it is a suseptibility factor
just because have the HLA molecules - doenst mean have condition; but if condition you have very high chance of having yhe HLA molecules
the genes in MHC class 1 and 2 regions encode cell surface proteins = 1st recognised on human white cells so called human leukocyte ag (HLAs)
class 1 are HLA-DR DQ or DP and class 2 are HLA-A B or C
T cells recognise the ag when it is in peptide binding group of HLA
what HLA serotype is associated with rheumatoid arth *
HLA-DR4
what HLA serotype is associated with SLE *
HLA - DR3
what HLA serotype is associated with ankylosing spondylitis *
HLA-B27
what is teh function of HLA molcules *
to present antigens to T cells
describe class 1 MHC *
HLA-A B or C
on all nucleated cells
recognise endogenous (intracellular) antigens eg viral peptides, tumour ag and self peptides
recognised by CD8+ T cells - cytotoxic T cells = cell killing
describe class 2 MHC *
HLA-DR DP DQ
on APCs eg B cells, DC, monocytic/macrophages
recognise exogenous (extracellular) ag eg - bacterial/self-peptides
CD4+ t cell - helper = Ab response
how do HLA molecules fit into the pathology of rheumatoid diseases *
HLA associated disease is due to a peptide ag that is able to bind to HLA molecules and trigger disease - ‘arthritogenic ag’
eg ag and HLA-B27 trigger CD8 T cell in ankylosing spondylitis
ag and HLA-DR4 triggers CD4 t cell in rheumatoid arth
how COULD HLA molecules fit into treatment of rheumatoid disease
perhaps we could find the petide that fits in the HLA molecule taht triggers the T cell response
however there was no arthritogenic peptide identified that binds to HLA-B27
but in rats given HLA-B27 with no T cells - there was still development of ankylosing spondylitis
therefore currently we think that the disease is due to HLA-B27 and the interleukin-23 pathway:
- HLA-B27 commonly misfolds = cellular stress = release of IL-23 and IL-17 production by adaptive immune cells ie cd4+ Th17 cells, and innate immune cells eg CD4-ve CD8-ve (double -ve) T cells
- these double -ve t cells that are suseptibleto cellular stress have been found in enthesis
- perhaps explaining why enthesopathy occurs in ankylosing spondylitis
targeting the Il-23 and 17 is used in treatment
Ab in rheumatoid arthritis *
rheumatoid factor
anti-cyclic citrulinated peptide Ab
ab in SLE *
ANA
anti-dsDNA
anti-cardiolipin - also called anti-phospholipid Ab and associated with risk of arterial and venous thrombosis in SLE - may also occur in absence of SLE in primary anti-phospholipid ab syndrome
ab in osteoarthritis, reactive arthritis, gout, ankylosing spondylitis *
none - they are seronegative
ab in systemic vasculitis
Antinuclear cytoplasmic antibodies (ANCA)
other than SLE - what are connective tissue disorders and the Abs involved
diffuse systemic sclerosis - anti-Scl-70 (also termed ab to topoisomerase 1)
limited systemic sclerosis (fibrosis and inflammation in skin) - anti-centromere ab
dermato-polymyositis (inflammation in muscle) - anti-tRNA transferase ab eg histidyl transferase also called anti-Jo-1 ab
Sjogren’s syndrome (the inflammation targets exocrine glands) - no unique ab but typically see anti-Ro and anti-La (ANA) and rheumatoid factor
describe the ab in SLE *
ANA - seen in all SLE cases - not specific for SLE
anti-dsDNA - specific for SLE, serum level of ab correlates with disease activity
anti-cardolipin ab
anti-sm ab (ag is ribonuceloprotein) - specific for SLE - level does NOT correlate with disease activity
anti-Ro and anti-La ab (ag is ribonucleoprotein) - neonatal lupus syndrome (transient rash in neonate, permenant heart block) and secondary sjogren’s syndrome
anti-ribosomal P ab - in cerebral lupus
describe anti-nuclear Ab *
if ANA positive - teh lab will perform further tests to determine which type of ANA it is
this includes screening for anti-dsDNA and anti-Sm ab
both of these are specific for SLE
describe how you can monitor disease activity in SLE *
when active - immune complex is made that makes people unwell - therefore anti-dsDNA levels increase when disease is active
when disease is treated - anti-dsDNA ab get lower
the immune compex cause tissue damage in 2 ways
- activate inflammatory mechanisms - Fc part of Ig bind to Fc receptors - triggers inflammatory cascade,
- complement recognises the immune complex and triggers a proteolytic cascade = activation
therefore when disease is active - complement levels are low
describe the pathogenesis of lupus *
apoptosis leads to translocation of nuclear ag to membrane surface - normally they are recognised and phagocytosed - in lupus the suseptibility factors interfere with apoptosis
there is impaired clearance of apoptotic cells = enhanced presentation of nuclear ag to immune cells (these are the ag commonly seen in lupus pts eg sm, ro, and la)
this causes B cell autoimmunity
this causes tissue damage by ab effector mechanisms eg by complement/ Fc receoptor engagement
what is teh role of different cytokines in mediating inflammation *
y-IFN - from T cells - activate macrophages
IL-1 - from macrophages - actuvate T cells, fever and pro-inflam
il-2 - from T cells - activate t and b cells
il-6 - from t cells - activate b cells, acute phase response
tnf-a - from macrophages - similiar to Il1 but more destructive
describe the immunological process of production and action of cytokines *
CD4 t helper cells include Th1 2 and 17
Th1 secrete il-2 and y-ifn and response is important in CD8 cytotoxicity and macrophage stim
Th2 cells secrete il-4 (IgE responses) il-5 (eosinophils) IL-6 (B cells to plasma cells) and il-10 - inhibit the macrophage response
th17 cells develop in response to IL-23 and secrete il17 - a potent cytokine that triggers il-6, il8 and tnf -a, MMP, and RANKL in target cells - important in mucosal immunity, arthritis, psoriasis, IBD and MS
what is the key cytokine in rheumatoid arthritis *
TNF-a
