Pathology of autoimmune disease

Question 1

what is rheumatoid arthritis *

Answer 1

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

Question 2

describe ankylosing spondylitis *

Answer 2

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

Question 3

describe SLE *

Answer 3

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

Question 4

describe the HLA molecules and rheumatology *

Answer 4

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

Question 5

what HLA serotype is associated with rheumatoid arth *

Answer 5

HLA-DR4

Question 6

what HLA serotype is associated with SLE *

Answer 6

HLA - DR3

Question 7

what HLA serotype is associated with ankylosing spondylitis *

Answer 7

HLA-B27

Question 8

what is teh function of HLA molcules *

Answer 8

to present antigens to T cells

Question 9

describe class 1 MHC *

Answer 9

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

Question 10

describe class 2 MHC *

Answer 10

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

Question 11

how do HLA molecules fit into the pathology of rheumatoid diseases *

Answer 11

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

Question 12

how COULD HLA molecules fit into treatment of rheumatoid disease

Answer 12

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

Question 13

Ab in rheumatoid arthritis *

Answer 13

rheumatoid factor

anti-cyclic citrulinated peptide Ab

Question 14

ab in SLE *

Answer 14

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

Question 15

ab in osteoarthritis, reactive arthritis, gout, ankylosing spondylitis *

Answer 15

none - they are seronegative

Question 16

ab in systemic vasculitis

Answer 16

Antinuclear cytoplasmic antibodies (ANCA)

Question 17

other than SLE - what are connective tissue disorders and the Abs involved

Answer 17

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

Question 18

describe the ab in SLE *

Answer 18

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

Question 19

describe anti-nuclear Ab *

Answer 19

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

Question 20

describe how you can monitor disease activity in SLE *

Answer 20

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

Question 21

describe the pathogenesis of lupus *

Answer 21

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

Question 22

what is teh role of different cytokines in mediating inflammation *

Answer 22

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

Question 23

describe the immunological process of production and action of cytokines *

Answer 23

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

Question 24

what is the key cytokine in rheumatoid arthritis *

Answer 24

TNF-a

Question 25

what was the worry of inhibiting TNF-a *

Answer 25

that other cytokines would just take over

however as TNFa is dominant - the treatment is effective

Question 26

describe RANKL in rheumatoid arthritis *

Answer 26

it is important in bine destruction in RA

(receptor activator of nuclear factor kB ligand)

it is produced by T cells and synovial fibroblasts

upregulated by IL1, TNF-a, IL-17 (this has potent action on osteogenesis via RANKL-RANK pathway), PTH related peptide

binds to ligand on osteoclast receptors (RANK)

action is antagonised by the decoy receptor - osteoprotegrin (OPG)

denosumab is a monoclonal ab against RANKL - indicated for treatment of osteoporosis, bone metastises, multiple myeloma and giant cell tumours - it slows down bone turnover

Question 27

how do we use the fact that B cell hyperactivity is a key feature of lupus *

Answer 27

biological therapies that target B cells

rituximab is a chimeric anti-CD20 ab used to deplete B cells

belimumab - a recombinant fully human IgG monoclonal Ab against B cell survival factor BLYS = impaired B cell survival and reduced B cell numbers - BLYS is important for autoimmune reactive B cells - belimumab is effective at reducing the symptoms of lupus

Question 28

what are the targets of biological therapy for Lupus *

Answer 28

mainly B cells, but also complement

Question 29

describe the role of prostaglandins in inflammation and how they are produced *

Answer 29

they are lipid mediators of inflammation that act on platelets, endothelium and uterine tissue and mast cells

tehy are synthesised from essential fatty acids - phospholipase A2 generates arachodonic acid from diacylglycerol in membranes

arachodonic acid enters 2 pathways

• COX - makes prostaglandins which mediate vasodilation (PGI2 via IP receptor), inhibit platelet aggregation (PGI2), bronchodilation (PGE2 acting via EP2 receptor, and PGI2), uterine contraction (PGF_2alpha)
• lipooxygenase pathway - makes leukotrienes - they mediate leucocyte chemotaxis (LTB₄) and sm contraction, bronchoconstriction and mucus secretion (LTC₄, LTD₄, LTE₄ via cysLT1 receptors)

Question 30

describe how we can target prostaglandins *

Answer 30

glucocorticoids inhibit phospholiase A₂

NSAIDs inhibit COX

• benefits - analgesic, anti-pyretic, anti-inflammatory, and anti-platelet (thrombxane A2)
• unwanted effects - astham exacerbation, GI ulcer, liver and renal problems
• aim was to target COX2 to reduce SE - but they increased CV events

these are used for symptom management but dont modify disease, so are instead we use cytokine disease modifying therapies and use these as adjuvant to address the symptpms