Mechanisms of autoimmunity Flashcards
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
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
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
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
What post translational modifications of peptides occur in RA?
Arginine => citraline = citralinatod peptide forms
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
What does necroptyosis?
programmed necrosis
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
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 +
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
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
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
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
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
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)
