Immunology: Autoimmune and Autoinflammatory diseases 1 + 2 Flashcards
Definition of autoinflammatory disease
Immunopathology in the absence of a pathogen, caused by the innate immune system.
Definition of autoimmune disease
Immunopathology in the absence of a pathogen, caused by the adaptive immune response
Definition of monogenic and polygenic immune diseases
single gene mutation vs multiple gene mutations causing the disease
What is the difference between an autoinflammatory disease Vs an autoimmune disease?
Autoinflammatory disease is immunopathology in the absence of a pathogen caused by the innate immune response, whereas autoimmune diseases are caused by the adaptive immune response.
A 19 year old Italian man presents to his GP with fevers lasting for 2-4 days, with abdominal pain, chest pain, arthritis and a rash. His white cells, CRP, ESR and amyloid A are raised. What is the most likely diagnosis?
Familial Mediterranean fever
monogenic auto-inflammatory disease
A 19 year old Italian man presents to his GP with fevers lasting for 2-4 days, with abdominal pain, chest pain, arthritis and a rash. His white cells, CRP, ESR and amyloid A are raised. How should this patient be treated?
- Colchicine: Binds to tubulin in neutrophils and disrupts neutrophil functions, including migration and chemokine secretion.
- Anakinra: Interleukin 1 receptor antagonist
- Etanercept: TNF alpha inhibitor
A 19 year old Italian man presents to his GP with fevers lasting for 2-4 days, with abdominal pain, chest pain, arthritis and a rash. His white cells, CRP, ESR and amyloid A are raised. What complications may arise in this patient?
Amyloidosis, leading to nephrotic syndrome and renal failure (Familial Mediterranean fever)
What is Colchicine?
An anti-gout medication that binds to tubulin in neutrophils and disrupts neutrophil functions, including migration and chemokine secretion. It is also used to treat familial Mediterranean fever.
An example of a monogenic auto-inflammatory disease
Familial Mediterranean Fever
-TRAPS
Outline the pathophysiology of autoinflammatory diseases
-Local factors at sites predisposed to disease lead to activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage
What monogenic mutations cause auto-inflammatory disease?
- NLRP3: Gain of function mutation. Increased NALP3/Cryopyrin causes increased activity of the inflammasome complex
- MEFV mutation: Decreased pyrin-Marenostrin causes increased activity of the inflammasome complex (ie neutrophil activation). Pyrin-Marenostrin is a protein expressed mainly in neutrophils
What is the inflammasome complex?
Causes increased interleukin 1, NFKappaB and apoptosis
Outline the pathophysiology of autoimmune disease
- Aberrant T cell and B cell responses in primary and secondary lymphoid organs lead to breaking of tolerance (Of self) with development of immune reactivity towards self-antigens (autoreactive T cells) and formation of organ-specific auto-antibodies.
- HLA associations are common in polygenic subtype
- Auto-antibodies are present.
What is ALPS-1/APECED?
- Auto-immune polyendocrine syndrome type 1
- Auto-immune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome
What is the pathophysiology of ALPS-1/APECED?
- Defect in AIRE (Auto-immune regulator)
- Defect in AIRE leads to failure of central tolerance (Autoreactive T cells and B cells)
- AIRE is a transcription factor involved in development of T cell tolerance in the thymus. It upregulates expression of self-antigens by thymic cells. Promotes T cell apoptosis.
A 6 year old boy presents to his GP with fatigue dizziness, fever, muscle aches and spasms in the muscles around the mouth. His blood pressure is 64/40 Lab investigations reveal a potassium of 6mmol/l, a serum calcium of 1.5mmol/l and a low PTH. What is the most likely diagnosis?
-Addisons and Hypoparathyroidism secondary to APS1/APECED (Auto-immune polyendocrine syndrome)
-An 11 year old boy presents to A&E with fatigue, dizziness and fever. Further investigation reveals blood pressure of 50/45 and hyperkalaemia. A blood test shows presence of antibodies for IL17 and IL22. What is the most likely diagnosis?
-Addison’s secondary to APECED
An example of monogenic auto-immune disease
- APS-1/APECED (Auto-immune polyendocrine syndrome type 1/ Auto-immune polyendocrinopathy Candidiasis ectodermal dystrophy syndrome)
- ALPS (Auto-immune lymphoproliferative syndrome)
What monogenic mutations cause auto-immune disease?
- Mutations in Foxp3
- Foxp3 is required for development of t regulatory cells - Failure to negatively regulate T cell responses cause autoreactive B cells
Outline the pathophysiology of Auto-immune lymphoproliferative syndrome
-Mutations in FAS pathway causes a defect in the apoptosis of lymphocytes, leading to failure of tolerance and failure of lymphocyte count regulation.
An 11 year old girl, presents to her GP with pallor and fatigue. On examination she has splenomegaly and lymphadenopathy. She has a blood sample taken for flow cytometry which revealse double negative CD 4- CD8- cells and molecular genetics reveal a Foxp3 mutation. What is the most likely diagnosis?
Auto-immune lymphoproliferative syndrome
What flow cytolometry results for T cells indicate the presence of an autoimmune condition?
Double negative T cells (CD4- and CD8-)
What conditions does a mutation in the Foxp3 gene lead to?
- Diabetes Mellitus
- Hypothyroidism
- Enteropathy
- Dermatitis
Polygenic auto-inflammatory diseases examples
- Crohns disease
- Ulcerative colits
- Osteoarthritis
- Giant cell artheritis
- Takayasu’s arteritis
What mutations are associated with Crohns disease?
- NOD2/IBD1/CARD-15: mutation present in 30% of patients
- intracellular receptor for bacterial products, stimulates NFKb and induces autophagy in dendritic cells. Leads to auto-inflammatory disease.
Pathophysiology of Crohns disease
- genetic mutations affecting the innate immune response, changes in the intestinal microbiota and environmental factors (ef smoking)
- …causing the expression of pro-inflammatory cytokines, leukocyte recruitment and release of proteases and free radicals,
- …leading to focal inflammation in and around the crypts, formation of granulomata and tissue damage with ulceration of the mucosa.
A 21 year old man presents to his GP with abdominal pain and tenderness, diarrhoea, with blood in stools, fevers and malaise. Most likely diagnosis?
-Crohn’s disease
A 21 year old man presents to his GP with abdominal pain and tenderness, diarrhoea, with blood in stools, fevers and malaise. How should this patient be treated?
- (Crohn’s disease)
- Corticosteroid (eg budesonide)
- Anti-TNF alpha antibody
Mixed pattern autoimmune diseases:
- Ankylosing spondylitis
- Psoriatic arthritis
- Behcet’s syndrome
Ankylosing spondylitis genetic polymorphisms
- HLA B27: Presents antigen to CD8 T cells. Ligand for killer immunoglobulin receptor.
- IL23R
- ILR2
Pathophysiology of ankylosing spondylitis
-Enhanced inflammation occurs at specific sites where there are high tensile forces in the skeletal system (enthuses, sites of insertion for ligaments or tendons)
A 77 year old woman complains to her GP about low back pain and stiffness and pain in her large joints. Her spine appears to be kyphotic around the thoracic level. What is the most likely diagnosis?
Ankylosing spondylitits.
A 77 year old woman complains to her GP about low back pain and stiffness and pain in her large joints. Her spine appears to be kyphotic around the thoracic level. What is the most appropriate treatment option?
- (Ankylosing spondylitits)
- Non-steroidal anti-inflammatory drugs (eg Aspirin)
- Immunosuppression
- Anti-TNF alpha
- Anti-IL17
Polygenic auto-immune disease examples (Big dogs)
- Rheumatoid arthritis
- Myaesthenia gravis
- Pernicious anaemia
- Addisons disease
- Systemic lupus erythematosus
HLA polymorphisms associated with autoimmune disease (2 examples)
- HLA-DR3/DR4: 25 fold increased risk of type I diabetes
- HLA -DR15: 10 fold increased risk of Goodpasture’s disease
Polymorphisms that lead to excess T-cell activation, causing autoimmune disease
- PTPN 22 (Protein tyrosine phosphatase non-receptor 22): Lymphocyte specific tyrosine phosphatase which suppresses T cell activation. Variants found in SLE, Type I diabetes and rheumatoid artheritis.
- CTLA4 (cytotoxic T lymphocyte associated protein 4): Expressed by T cells, obviously, and transmits inhibitory signal to control T cell activation. Variants found in SLE, Type I diabetes, auto-immune thyroid disease and rheumatoid arthritis.
Gel and Coombs effector mechanisms of immunopathology
- Type I: Immediate hypersensitivity which is IgE mediated
- Type II: Antibody reacts with cellular antigen
- Type III Antibody reacts with soluble antigen to form an immune complex
- Type IV: Delayed type hypersensitivity, T-cell mediated response
Polygenic auto-immune disease, classified by Gel and Coomb’s classification:
- Type I: Immediate hypersensitivity which is IgE mediated
- Rarely autoimmune pathology here.
- Type II: Antibody reacts with cellular antigen
- Goodpasture’s disease: Antibodies against basement membrane collagen type IV.
- Pemphigus vulgaris: Antibodies against Epidermal cadherin.
- Graves disease: Antibodies against TSH receptors.
- Myaesthenia Gravis: Antibodies against acetylcholine receptors.
- Type III Antibody reacts with soluble antigen to form an immune complex
- SLE: Autoantigen: DNA, Histones, RNP
- Rheumatoid arthritis: Autoantigen: Fc region of IgG.
- Type IV: Delayed type hypersensitivity, T-cell mediated response
- Insulin dependent diabetes mellitus. Autoantigen, pancreatic B-cell antigen.
- Rhuematoid arthritis
- MS. Autoantigen: Myelin basic protein proteolipid protein
A 46 year old woman presents to her GP with nervousness, palpitations, intolerance to heat and diarrhoea. On examination, she has a goitre and exophthalmos. What is the most likely diagnosis?
Graves Disease: IgG antibodies against TSH receptors.
A 64 year old woman presents to her doctors with lethargy, dry skin and hair, constipation and intolerance to the cold. On examination she has a goitre and What is the most likely diagnosis?
Hashimoto’s thyroiditis: Anti-thyroid peroxidase antibodies formed or anti-thyroglobulin antibodies. Antibodies are not clinically relevant, just TSH and T4/T3.
An 8 year old boy is brought to the doctors by his mother. She says he is feeling thirsty, urinates a lot and is tired all the time. A urine dipstick confirms glycosuria. Most likely diagnosis?
Type 1 diabetes (Insulin dependent). CD8+ T-cell infiltration of pancreas islet cells. Antibodies are also produced (Not clinically useful) eg Anti-islet cell antibodies.
A 46 year old woman presents to her GP complaining of tiredness and numbness in her feet. On examination, she appears pale. Her blood count show Hb 84 g/L, MCV 108 fL, low B12 and normal folate. What is the most likely diagnosis?
Pernicious Anaemia
- Antibodies to gastric parietal cells or intrinsic factor, are useful in diagnosis.
- Rule out reduced intake.
A 21 year old woman goes to their GP with drooping eyelids, weakness, particularly on repetitive activity, with worse symptoms at the end of the day. What is the most likely diagnosis?
-Myaesthenia Gravis: Antibodies for Acetylcholine receptors on post-synaptic membrane. Anti-acetylcholine receptor antibodies are present in most patients. Offspring may experience transient neonatal myaesthenia.
A 46 year old man presents to his GP with haemoptysis, infrequent urination and swelling of the legs. On examination, he has bilateral widespread crackles. Further investigation shows serum creatinine of 472 mcmol/L. Urine microscopy shows haematuria and proteinuria. Chest X ray shows widespread shadowing. Elevated TLCO (Transfer factor for Carbon Monoxide). Yet more investigation reveals presence of anti-basement membrane antibodies and crescentic nephritis on biopsy of the kidney. What is the most likely diagnosis?
- Goodpasture’s disease!
- Antibodies specific for glomerular basement membrane disease underpin the pathology and are useful in diagnosis of anti-glomerular basement membrane disease (Goodpasture’s disease)
- Type II hypersensitivity.
A 54 year old woman visits her GP complaining of pain, stiffness and swelling of the small joints in her hands. On investigation, she has a normochromic anaemia, with a high ESR and CRP. Most likely diagnosis?
- Rheumatoid arthritis: Antibodies to cyclic citrullinated peptide
- Binds to arginine residues that have been converted to citrulline by peptidylarginine deaminae (PAD).
- Rhuematoid factor: antibody against the Fc region of human IgG
- HLADR4 and HLA DR1 predispose
- PTPN22, PAD2 and PAD4 polymorphisms all predispose
- Smoking predisposes
A 21 year old female presents with 4 months history of fatigue, generalised arthralgia, particularly of the small joints and hands, mouth ulcers, hair loss and a butterfly rash. What is the most likely diagnosis?
- Systemic lupus erythematosus (Not Crohn’s)
- Antibodies bind to antigens of intracellular proteins (eg nuclear antigens), forming immune complexes.
- Immune complexes deposit in tissues (Skin, joints, kidney)
- Immune complexes activate complement (Classical pathway)
- Immune complexes stimulate cells expressing Fc and complement receptors.
- Gene mutations encoding compliment, MBL, CRP.
- Gene mutations affecting cellular activation
- Antinuclear antibody formed
A 77 year old woman presents to her GP with, pale spots in her skin, difficulty swallowing and “tightening of the hands”. On examination, she has raynauds and telangiectasia. Investiagtions reveal she has pulmonary hypertension. What is the most likely diagnosis?
- Systemic Sclerosis (CREST features)
- Calcinosis, Raynauds, oEsophageal dismotility, Sclerodactyly, Telangectasia.
- ANA staining is an important prognostic factor in systemic sclerosis
- Differentiates between diffuse cutaneous and limited cutaneous SC.
