Autoimmune and Autoinflammatory Disease 2 Flashcards
What is the pathophysiology of polygenic auto-immune diseases?
Mutations in genes encoding proteins involved in pathways a/w adaptive immune cell function.
HLA associations are common.
Aberrant B + T cell responses in primary + secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity towards self-antigens.
Auto-antibodies are found.
What are the 2 genetic requirements for polygenic autoimmune disease to develop?
- SENSITISATION to antigens: certain HLA alleles increase disease risk, thus HLA associations are more common. Immune system ready to attack self antigen
- OVERCOMING PERIPHERAL TOLERANCE (mutations in mechanisms that inhibit peripheral immune system)
What are the genetic polymorphisms of polygenic auto-immune disease?
PTPN 22
- Protein tyrosine phosphatase non-receptor 22.
- Suppresses T cell activation.
- SLE, T1DM, RA.
CTLA4
- Cytotoxic T lymphocyte associated protein 4. Expressed by T cells + transmits inhibitory signal to control T cell activation.
- SLE, T1DM, RA, AI thyroid disease.
What is the association between polygenic auto-immune diseases and HLA presentations?
HLA presentation of antigen is required for development of T cell + T cell-dependent B cell responses.
What is the susceptibility allelle and relative risk (fold) increase of Goodpasture Disease?
HLA -DR15
10
What is the susceptibility allelle and relative risk (fold) increase of Grave’s Disease?
HLA-DR3
4
What is the susceptibility allelle and relative risk (fold) increase of SLE?
HLA-DR3
6
What is the susceptibility allelle and relative risk (fold) increase of T1DM?
HLA -DR3/DR4
25
What is the susceptibility allelle and relative risk (fold) increase of RhA?
HLA-DR4
4
What is the Gel and Coobs classification for hypersensitivities?
TI: Anaphylactic
Immediate hypersensitivity, allergy, IgE mediated. Mast cells + Eosinophils. (Rarely self antigen)
TII: Cytotoxic
Antibody reacts with CELLULAR antigen.
TIII: Immune complex.
Antibody reacts with SOLUBLE antigen to form an immune complex.
TIV: Delayed type.
T-cell mediated response.
Describe the immunopathogenic mechanisms of receptor activation or blockade in Type II hypersensitivity reaction (aka Type V)
Antibody activates receptor on binding e.g. Graves
Antibodies to TSHr - stimulates action of thyroid stimulating hormone- production of T3 + T4
(reaction with Cellular antigen, but not cytotoxic)
Which immunopathogenic mechanisms of antibody dependent destruction occur in Type II hypersensitivity reactions?
Fc Complement activation + cell lysis
Bind Fc receptors on NK cells- release of cytotoxic granules + membrane attack
Bind Fc receptors on macrophages- phagocytosis
What generally results from immune complex formation in type III hypersensitivity reactions?
Complexes deposit in vessels
Activate complement + innate cells
Cytokine release, increased vascular permeability
Can cause small amount of bleeding + purpuric rash
Cutaneous vasculitis: complexes in vessels irritating skin
Glomerulonephritis: complexes in kidney
Arthritis: complexes in joints
What are 4 Type II antibody driven auto-immune diseases?
Goodpasture Disease
Pemphigus vulgaris
Graves Disease
Myaesthenia Gravis
Which auto-antigen and clinical manifestation is associated with Goodpasture Disease?
Noncollagenous domain of BM collagen type IV (in lungs + kidneys)
Glomerulonephritis
Pulmonary hemorrhage.
Which auto-antigen and clinical manifestation is associated with Grave’s Disease?
Thyroid stimulating hormone (TSH) receptor
Hyperthyroidism
Which auto-antigen and clinical manifestation is associated with pemphigus vulgaris?
Epidermal cadherin (skin)
Blistering of skin
Which auto-antigen and symptoms are associated with myaesthenia gravis?
Acetylcholine receptor
Muscle weakness
What is a Type III immune complex driven autoimmune disease?
SLE
Which auto-antigen and clinical manifestations are associated with SLE?
DNA, Histones, RNP
Rash, glomerulonephritis, arthritis
What are the 2 T cell mediated mechanisms in Type IV hypersensitivity reactions?
HLA I present antigen to CD8 T cells
Cytolytic granule release (Perforin/ Fas pathways)
HLA II present antigen to CD4 T cells
Produce IFN gamma- macrophages release TNF + inflammatory cytokines, upregulate HLA
What is a Type IV T-cell mediated disease?
T1DM
Which auto-antigen and symptoms are associated with T1DM?
Pancreatic b-cell antigen
b-cell destruction: CD8+ T-cells
What are 6 organ specific diseases mediated by organ specific antibodies?
Graves
Hashimotos thyroiditis
T1DM
Pernicious anaemia
Myaesthenia gravis
Goodpasture disease
Which antibodies are specific for Rheumatoid Arthritis?
Rheumatoid factor
Anti-CCP antibody
What are 4 multisystem diseases mediated by anti-nuclear antibodies?
SLE
Sjogren’s syndrome
Systemic sclerosis
Dermato/Polymyostis
What antibodies are specific for ANCA-associated vasculitis?
Anti-neutrophil cytoplasmic antibody
(ANCA)
What is the pathophysiology of Graves Disease?
Excessive production of thyroid hormones.
- Stimulating IgG autoantibodies stimulate TSH-receptor
- Induce uncontrolled overproduction of thyroid hormones.
- -ve feedback (Thyroxine) CAN’T override antibody stimulation.
What is the evidence that Graves Disease is mediated by IgG antibodies?
- Antibodies stimulate thyrocytes in vitro.
- Passive transfer of IgG from patients to rats often produces similar Sx.
- Babies born to mothers with Graves’ may show transient hyperthyroidism.
What is the commonest cause of hypothyroidism in iodine-replete areas?
Hashimoto’s Thyroiditis
What is the pathophysiology of Hashimoto’s Disease?
T + B cell infiltration of Thyroid leads to Goitre.
A/w anti-thyroid peroxidase antibodies + anti-thyroglobulin antibodies:
- Presence correlates with thyroid damage + lymphocyte inflammation.
- Some shown to induce damage to thyrocytes.
How is Hashimoto’s Thyroiditis considered to exhibit the bystander phenomenon?
TIV reaction damages Thyrocytes + expose cellular components (not usually exposed to immune system e.g. Thyroid peroxidase)
This can stimulate secondary antibody formation e.g. anti-thyroid peroxidase
Describe the T cell involvement in pancreatic islet cell destruction in T1DM
CD8 T cells recognise auto-antigens presented by HLA I molecules on beta cells (GAD + IA2)
Kill beta cells
How are antibodies related to the development of T1DM?
Antibodies pre-date development of disease.
Detection of antibodies not diagnostic as not all have them
What is the pathophysiology of T1DM?
Cellular antigen-antibody (TII) + T cell element - both contribute
- Anti-islet cell antibodies
- Anti-insulin antibodies
- Anti-GAD antibodies
- Anti-IA-2 antibodies
3-4 of above: highly likely to develop T1DM
Which diseases are the following autoantibodies associated with?
a) Anti-TSH R antibody (Anti-thyroid stimulating hormone receptor antibody)
b) Anti-thyroglobulin antibodies
c) Anti-thyroid peroxidase antibodies
a) Graves disease (hyperthyroidism)
b) Hashimoto disease
c) Hashimoto disease
What is the pathophysiology of pernicious anaemia?
Failure of Vit B12 absorption: B12 deficiency.
Causes Macrocytic anaemia.
Antibodies to gastric parietal cells or intrinsic factor- useful in dx.
What is a severe complication of pernicious anaemia?
Subacute combined degeneration of cord (posterior + lateral columns):
Peripheral neuropathy
Optic neuropathy.
Why is it important to check for antibodies in vitamin B12 deficiency?
If immune mediated (anti-IF or anti-parietal cell) won’t absorb B12 oral supplements
Needs IM B12
Which antibody is more sensitive for PA? Which is more specific?
Sensitive: Anti-gastric parietal cell
Specific: Anti-IF
Which gastroenterological diseases are the following autoantibodies associated with?
a) Anti-intrinsic factor antibody
b) Anti-gastric parietal cell antibody
c) Anti-TTG (anti-tissue transglutaminase antibody)
d) Anti-endomyosial antibody
e) P-ANCA (anti-neutrophil cytoplasmic antibody, perinuclear staining)
Anti-IF: Pernicious anaemia
Anti-gastric parietal cell: Pernicious anaemia
Anti-TTG: Coeliac
Anti-endomyosial: Coeliac
P-ANCA: UC > Crohns
Which liver diseases are the following auto-antibodies associated with?
a) ANA (anti-nuclear antibodies)
b) SMA (smooth muscle antibodies)
c) Anti-LKM (antibodies vs liver kidney microsomal proteins)
d) AMA (anti-mitochondrial antibody
e) P-ANCA (anti-neutrophil cytoplasmic antibody, perinuclear staining)
ANA: AI hepatitis, Primary biliary cholangitis
SMA: AI hepatitis
Anti-LKM: AI hepatitis
AMA: Primary biliary cholangitis
P-ANCA: AI hepatitis, Primary biliary cholangitis
Describe what happens following arrival of an action potential in myasthenia gravis?
Antibodies bind to ACh receptors
ACh released, but can’t bind
Failure of depolarisation + absence of muscle action potential
Causes muscle weakness
Characterise the weakness in Myasthenia Gravis
Weakness esp on repetitive activity
Sx worse at end of day
Becomes harder + harder to activate post synaptic neurone with each use- less available receptors due to antibody binding.
What is the pathophysiology of myaesthenia gravis?
Anti-acetylcholine receptor antibodies present in ~75%: useful in dx.
Offspring of affected mothers may experience transient neonatal myaesthenia.
What are the antibodies seen in Lambert Eaton syndrome? How does this weakness present?
VGCC
The more you use the muscle, the less fatigued it gets
Small print
Which diseases are the following auto-antibodies associated with?
a) Anti-acetylcholine receptor antibody
b) Anti-striational antibody
c) Anti-AQP4 (aquaporin)
d) Anti-MOG (myelin oligodendrocyte glycoprotein)
e) Anti-NMDA receptor (Anti-N-methyl D-aspartate (NMDA) receptor)
f) Anti-GABA receptor (gamma aminobutyric acid receptor)
a) Myaesthenia Gravis
b) Myaesthenia Gravis with myositis
c) Neuromyelitis optica spectrum disorder (NMOS)
d) Optic neuritis, encephalomyelitis
e) Encephalitis (may be malignancy associated)
f) Seizures (may be malignancy associated)
What antibodies underpin the pathology of Goodpasture’s disease? What is seen on renal biopsy?
Anti-(glomerular) basement membrane antibodies (Anti-GBM)
GBM expressed in lung + kidney
Biopsy: Crescentic nephritis
Give 3 features of Goodpasture’s disease
Glomerulonephritis
Pulmonary haemorrhage
Haemoptysis
What diseases are the following auto-antibodies associated with?
a) Anti-glomerular basement membrane (GBM) antibody
b) P-ANCA (anti neutrophil cytoplasmic antibody, perinuclear staining, anti-myeloperoxidase)
c) C-ANCA (anti-neutrophil cytoplasmic antibody, cytoplasmic staining, anti-proteinase 3)
a) Goodpasture disease.
b) ANCA associated vasculitis: Microscopic polyangiitis / Eosinophilic granulomatosis with polyangiitis.
c) ANCA associated vasculitis: Granulomatosis with polyangiitis
What are the genetic components are associated with RA?
HLA DR4 (DRB1 0401, 0404, 0405) alleles
HLA DR1 (DRB1 0101) alleles
Peptidyl arginine deiminase (PAD)2 + PAD4 polymorphisms
PTPN22 polymorphism.
What is the pathophysiology of rheumatoid arthritis?
PAD 2 + 4: Enzymes that deaminate arginine to citrulline.
Polymorphisms a/w increased citrullination.
HLA alleles bind arthitogenic citrullinated peptides, present to T cells
High load of citrullinated proteins increases risk of RA
What environmental factors increase citrullination in rheumatoid arthritis?
Smoking a/w development of erosive disease + increased citrullination.
Porphyromonas gingivalis gum infection a/w RA. P. gingivalis is only bacterium known to express PAD enzyme + thus promote citrullination.
Which antibodies are in RA?
Antibodies to cyclic citrullinated peptide (Anti-CCP):
- Bind to peptides in which arginine has been converted to citrulline by PAD.
- ~95% specificity
- ~60-70% sensitivity
- Best blood test for dx of RA
What is rheumatoid factor?
IgM antibody directed against the common (Fc) region of human IgG.
IgM anti-IgG antibody is most commonly tested although IgA + IgG RFs can present in some individuals.
~60-70% specificity + sensitivity
Is diagnosis of RA based on presence of anti-CCP or RF alone?
No
Significant no. patients are seronegative (have neither)
Which of the following is an example of Gel and Coombs type III hypersensitivity?
- Goodpasture disease
- Eczema
- SLE
- Multiple sclerosis
- Graves disease
SLE
Which of the following antibodies are characteristically found in Myaesthenia Gravis?
- Anti-GAD antibody
- Anti-thyroglobulin antibody
- Anti-basement membrane antibody
- Anti-intrinsic factor antibody
- Anti-acetylcholine receptor antibody
- Anti-cyclic citrullinated peptide antibody
- Anti-TSH receptor antibody
Anti-acetylcholine receptor antibody
Which of the following antibodies are characteristically found in Pernicious Anaemia?
- Anti-GAD antibody
- Anti-thyroglobulin antibody
- Anti-basement membrane antibody
- Anti-intrinsic factor antibody
- Anti-acetylcholine receptor antibody
- Anti-cyclic citrullinated peptide antibody
- Anti-TSH receptor antibody
Anti-intrinsic factor antibody
