Mechanisms of autoimmunity Flashcards Preview

Yr 3 - December lectures 2018 > Mechanisms of autoimmunity > Flashcards

Flashcards in Mechanisms of autoimmunity Deck (31)
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1

Why does T cell tolerance occur?

thymic deletion of auto reactive T cells
- A(uto)I(mmune)RE(gulator)

Treg cells
- thymic origin but also from peripheral T cells
- FoxP3
- new evidence that Tregs have antigen specificity and survive as memory CD4 cells
- protect from the development of autoimmune disease

2

Why does B cell tolerance occur?

deletion in the bone marrow
receptor editing
deletion and anergy in the periphery
b cell tolerance to circulating proteins and cells is very important

3

What factors contribute to coeliac disease?

genetics
- HLA DQ2, DQ8
- MZ=75%
- F:M 2:1
- GWAS = 5%
environment
- gluten (rich in glutamine)
autoantibody
- transglumatinase 2 (ttg)
disease
- enteropathy and malabsorption
- dermatitis herpetiformis

4

What factors contribute to rheumatoid arthritis?

Genetics
- HLA DR4.1 (35%) - key enzyme linked to RA
- MZ =60%
- F:M 5:1
- GWAS = 5%
Environment
- smoking 12/13 MZ
- lung infection
- periodontal disease
Autoantibody
- RF, CCP
Disease
- erosive inflammatory arthritis

5

What post translational modifications of peptides occur in RA?

Arginine => citraline = citralinatod peptide forms

6

What can happen to TH17 cells in RA?

Th17 release IL-17 = stimulate release of chemokine which facilitate lymphocyte attraction to site of inflammation/infection
TH17 can convert to TH1 which releases interferon gamma

7

What does necroptyosis?

programmed necrosis

8

Case 1:
F, 34, 3/12hx pains in small joints of hands
stiff hands, esp in the morning, no swelling
excessively tired and lethargic
thinning of hair and dry mouth- difficult to swallow

What are the differential diagnoses?
What other symptoms would you ask about?
What initial investigations would you carry out?

hypothyroidism
RA
SLE
Sjorgen's syndrome (features of RA and autoantibodies in lupus)

dry eyes (+dry mouth) = sicca syndrome
rashes, sunlight sensitivity, mouth ulcers or hair loss (SLE)
neurological symptoms (cerebral SLE)

blood pressure (renal involvement), urinalysis (renal involvement), FBC, CRP/ESR (good discriminator as no inflammatory response in SLE, therefore CRP normal but ESR raised)
ANA, RF, CCP, thyroid function tests, thyroid abs

9

Why would you check for autoantibodies?

diagnostically useful
Sensitive
- most pts have the antibody
- good screening test
- ANA >95% in SLE

Specific
- only patients with the disease have it
- high titre dsDNA 40% SLE +

10

What is SLE?

Systemic lupus erythematosus
- immune complex disease
- multisystem - renal, skin, neurological
- ANA screen >95% sensitive, not specific
- specific autoantibodies => double stranded DNA, histones, extractable nuclear antigens sm, snRNP and anti-cardiolipins (recurrent abortions, headaches, CVA, low platelets)
- non-specific autoantibodies => ENA SS-A (Ro), SS-B (La)

other tests
- CRP only raised in there is an infection
- complement C4 reduced
- Igs raised

11

If you suspected nephrotic syndrome, SLE renal disease what investigations would you order?

urine and blood for proteins
renal function tests and serum albumin (can be negative in nephrotic syndrome)
24 hr urinary protein, selective proteinuria, renal biopsy
immunoglobulins can also decline in nephrotic syndrome which can be due to hyper-catabolism

12

What treatment is required for nephrotic syndrome?

cytotoxic chemotherapy, glucocorticoids
rituximab- anti-B cell therapy
risk of neurological disease in the choroid plexus which can lead to psychiatric symptoms

13

What are the common features of RA?

F
acute pain and swelling of joints (e.g. wrists and elbow)
feel like getting the flu, fever, loss of appetite
hot swollen joints that are tender and painful to touch

14

What investigations would you carry out if you suspected RA and how would you differentials differ if it was just one painful swollen joint?

X-rays
FBC, ESR, CRP, RF, CCP (more sensitive and specific), ANA
if it was one joint exclude infection and consider gout

15

What lab investigations are carried out for RA?

Rheumatoid factor
- antibodies to Fc of immunoglobin
- 70% sensitive but NOT specific
Anti-citrullinated peptides (CCP)
- 90% sensitive
- up to 99% specific
CRP raised
Acute phase proteins raised (C3,4)

16

Other than C3 and C4 what else raises in RA?

Platelet count

17

What is the treatment for RA?

Immunosuppression
NSAIDs
Anti-TNF-alpha
Anti-B cell therapy
long term consequence of the above treatments is development of secondary antibody deficiency

18

How do you distinguish between RA and SLE?

RA
- CRP raised
- RF and CCP
- ANA low titre
- ENA: variable
- no dsDNA Abs
- C3 and C4 raised

SLE
- CRP low, normal
- ANA high titre
- dsDNA
- ENA: Sm, sn RNPs
- C4 low

19

What is the underlying physiology of RA treatment?

blocking IL-6 signalling
- effective but blocking inflammatory response means when you pick up an infection the immune response isn't strong so they don't have raised CRP or fever

20

What investigations are key for arthritis?

CRP
RF, CCP, ANA
if ANA +VE then...
- dsDNA
- ENA (Sm, RNP, Ro, La, Scl 70, Jo-1)
- cardiolipin screen
- Igs, C3 and C4

21

What are the differences in treating RA and SLE?

RA
- anti-TNF better
- anti-B cell better
- glucocorticoids suppress disease
- immunosuppression

SLE
- Anti-TNF worse
- Anti-B cell better
- glucocorticoids suppress disease
- immunosuppression

22

What are the results of the different investigations in RA and SLE?
- CRP
- C3, C4
- RF, CCP
- ANA
- dsDNA

RA
- CRP = raised
- C3, C4 = raised
- RF, CCP = positive
- ANA = +/-
- dsDNA = -

SLE
- CRP = normal
- C3, C4 = low
- RF, CCP = +/-
- ANA = high titre +
- dsDNA = +

23

What are the causes of vasculitis?

autoantibodies to enzymes in neutrophils
- intravascular neutrophil activation = causes small vessel vasculitis
- damage to small blood vessels
- acute renal syndrome
genetics linked with autoantibody
wegener's granulomatosus = linked with development of cytoplasmic antibodies
- cytoplasmic anti-neutrophil cytoplasmic antibodies (cANCA), proteinase 3
microscopic polyarteritis
- pANCA, myeloperioxidase

24

case 2:
intravenous drug user presents abnormal LFTs and a rash over his lower limbs
What infections are top of your list of diagnostic priorities?

Hep B and C and HIV

25

case 2:
intravenous drug user presents abnormal LFTs and a rash over his lower limbs
rash is characteristically seen in hep c infections
What non-immunoglobulin tests would you perform?
What immunological tests would you carry out ?

FBC, ESR, CRP, renal function, CXR

immunological: RF, Cryoglobins (blood needs to clot at 37 degrees), C4

Vasculitis due to immune complexes of antibody and virus
these patients are RF +ve which augments immune complex formation
C4 levels are reduced due to intravascular complement activation

Requires antiviral chemo

26

What is the vasculitis screen?

CRP
ANCA
differential:
- goodpasteurs disease (anti-GBM ab)
- ANA-exlude SLE
- Cryoglobulins (RF, Low C4) hepatitis C

27

What are the treatments for vasculitis?

glucocorticoids
cyclophosphamide
anti-b cell therapy

28

What is antiphospholipid syndrome?
- clinical presentation
- antibodies
- treatment

recurrent abortion, pre-eclampsia, arterial/venous thromboses, venous thromboembolism, migraine, stroke, lived reticular
associated with SLE
thrombocytopenia
antibodies to phospholipid
- anti-cardiolipin abs
- anti-beta-2- glycoprotein

Rx = thromboprophylaxis (anticoagulation)

29

What is scleroderma/CREST?

CREST= less pathogenic form of scleroderma
diffuse scleroderma
- skin, renal, oesophagus, lung
- scl 70 aa (DNA topoisomerase 1) 70%
CREST (better prognosis)
- calcinosis, raynauds, eosophageal reflux, sclerodactylyl, telangiectasia
- centromere aa (kinetochore plates) 70-90%

30

Case 3:
26 yr old F
4/52 h painful fingers and knees
very susceptible to the cold in winter, blotchy skin rash over cheeks when cold
O/E skin rash, painful joints, BP 150/110, Trace protein in urine
What is the syndrome called?
What would you look for on her hands?
What is the differential diagnosis?
What non-immunological tests would you perform?
What immunological tests would you perform?

Raynaud's and livedo reticularis
loss of fingertips, nail bed infarcts (vasculitis)
SLE, CREST, scleroderma, phospholipids
FBC, CRP, ESR, renal function, CXR

RF - cryoglobulinaemia
ANA - SLE
Scl70 - scleroderma
Centromere- CREST
cardiolipins - antiphospholipid syndrome