Lecture 7 - Autoimmune Diseases Flashcards
What are the criteria for autoimmune disease?
- Auto-antibodies or auto-reactive T cells found in disease
- Auto-antibodies/T cells found at site of damage (organ)
- Level of auto-antibody or T cell response reflect disease activity
- Reduction of antibody or T cell response leads to reduction of disease
- Transfer of autoantibody or T cell to another host leads to disease in recipient
- Immunization with autoantigen causes disease
List the possible triggers for autoimmunity
- Cross reactivity with microbial antigen
- Sequestered antigen
- Polyclonal activation
- Non-infectious triggers
What are the mechanisms of central self tolerance?
Central:
– Receptor editing
– Deletion
What are the mechanisms of peripheral self tolerance?
Peripheral: – Anergy – Clonal Ignorance – T regulator cell – Fas – Fas L mediated apoptosis
What ENA are associated with SLE?
- dsDNA (90% of SLE)
- Smith Ag (5 - 40% of SLE)
- Nucleosomes - histone & dsDNA (40 - 70% of SLE)
- Proliferating cell nuclear antigen (3% of SLE)
- Ribosomal P protein (10% of SLE)
What two mechanisms that explain the possible cause of SLE?
- SLE people may have defective mechanism of clearing DNA after apoptosis, so exposing the DNA as antigen
- SLE may in part be due to Langerhans cell dysfunction
- Drugs may trigger SLE
What is the antigen that the auto-antibodies are directed against in Goodpasture’s syndrome?
α3 chain of collagen type IV
What are blocking and binding antibodies in relation to Pernicious anaemia?
- Blocking: binds the intrinsic factor to B12
- Binding: binds the intrinsic factor to the ileal receptor
How do anti-parietal cell antibodies (APC) come about and what part do they play in the immunopathology of Pernicious anaemia?
- Anti-parietal cell antibody found in 90% of cases of pernicious anaemia
- Antigen is gastric proton pump ATPase
- Not involved in Pathology of disease since antigen is not exposed in vivo? – Damaged parietal cells leads to reduction of intrinsic factor production and so reduction of B12 absorption.
- Damage to parietal cells may expose antigen to immune system and so production of APC?
- Used as screening test
Diabetes mellitus type 1
- Young <40
- Normal/low weight
- Caucasian
- Abrupt onset
- Lack of insulin
- Autoimmune
- Weak genetic component
- 10% of Diabetes patients
Describe the immunopathology of Diabetes mellitus type 1.
- Destruction of the β-cells of islets of langerhans in pancreas
- Cytotoxic T cells and cytokines
- Followed by auto-antibodies – Anti-Islet cell antibodies (ICA)
- β-cells responsible for insulin production
• Auto-antigens:
– Glutamic acid decarboxylase (GAD)
– Tyrosine phosphatase (IA-2) – Insulin
What are the acute and long term complications of Diabetes mellitus type 1?
• Ketoacidosis
– Due to lack of insulin there is unrestrained lipolysis and in adipose tissue
– Elevated levels of circulating fatty acids resulting in elevated ketone body production by the liver (metabolic carboxylic acids)
– Excess accumulation of metabolic acids
– Metabolic acidosis
Celiac disease is a response to gluten. What is the main protein component of gluten that is the antigen in this disease and what is the enzyme that process it.
• Main protein involved in the development of Celiac disease in gluten is α-gliadin
• The enzyme tissue transglutaminase (tTG) modifies (deamination) α-gliadin
– Converts glutamine to negatively charged glutamic acid
– This modified protein leads to disease
Why are people that are HLA-DQ2 more prone to getting Celiac disease.
- The modified α-gliadin binds to the unique peptide-binding grove of HLA-DQ2 (on APC)
- This then activates CD4 T cells (to induce a specific antiα-gliadin response)
– Activated CD4 T cells produce INF-ɣ and TNF leading to inflammation
– Activated CD4 T cells kill epithelial cells by binding Fas (apoptosis)
– Activation of Cytotoxic T cells (CD8) and NK cells
• Presence of α-gliadin in epithelial cells causes stress
Describe the immunopathology of celiac disease
• Celiac disease is not strictly an autoimmune disease
– Entirely dependant on a foreign antigen (gluten)
– No specific immune response to self antigen causing illness
– But has features of an autoimmune disease
• Antibodies are made against tissue transglutaminase (tTG)
– Gluten can complex with tTG and be taken up by B cells
– Activated T cells can provide help
– Production of anti-tTG antibodies
– No evidence that these antibodies contribute to disease
– Serum anti-tTG IgA antibody test specific for Celiac disease
Antibodies involved in Hashimoto’s thyroiditis
– Anti-thyroglobulin antibodies
• Precursor of thyroglobulin
• Over 90% of patients with Hashimoto’s
– Anti-thyroid peroxidase (anti-TPO) antibodies
• > 80% of patients with Hashimoto’s
Clinical presentation of Hashimoto’s thyroiditis
- Early in disease there may be extra release of T3/T4 due to damage and compensation (Appears like Hyperthyroidism)
- Onset 30 -60 years, females (7 X more than Males)
- HLA-DR3, 4, 5 associated, while DQ1 protective
- Goiter - enlarged thyroid (compensatory)
- Fatigue, dry coarse cold skin, weight gain, mild depression, slow speech and movement
- Myxoedema (puffy face, pasty skin, large tongue)
Hashimoto’s thyroiditis (diagnosis and treatment)
- Low T4 and elevated TSH – (T3 sometimes low)
- ELISA (or other) for anti-thyroglobulin and/or anti-TPO
- Treated with Thyroglobulin (T3 and T4) replacement therapy
Diabetes mellitus type 2
- Middle age / older >40
- Overweight
- All races (indigenous Australian at higher risk)
- Slow onset
- Insulin resistance
- Probably a variety of mechanisms
- Strong genetic component
- 90% of Diabetes patients
Ketoacidosis
• Symptoms
– Nausea (vomiting), confusion, thirst, headache, abdominal pain, drowsiness, acetone breath, dehydration
– Ketone bodies in urine, lowered blood pH, hyperventilation
• Treatment
– IV insulin
– IV fluids (saline)
Ketoacidosis
• Symptoms
– Nausea (vomiting), confusion, thirst, headache, abdominal pain, drowsiness, acetone breath, dehydration
– Ketone bodies in urine, lowered blood pH, hyperventilation
• Treatment
– IV insulin
– IV fluids (saline)
MHC
- Strongest association with autoimmune diseases
- HLA contributes approx 50% of genetic susceptibility in most autoimmune diseases
- The strongest association is between HLA-B27 and ankylosing spondylitis
Non-HLA genes
- PTPN22
- IL10
- BLK
- IL2RA
- NOD2
PTPN22
Function: Protein tyrosine phosphatase (T & B cell signalling)
Disease: RA, Type 1 diabetes, Inflammatory bowel disease
IL10
Function: Immune suppression - down regulate costimulatory molecules, inhibits TH1
Disease: Inflammatory bowel disease, SLE, Type 1 diabetes
BLK
Function: B cell tyrosine kinase (B cell activation)
Disease: SLE, RA
IL2RA
Function: IL-2 receptor chain (T cell activation)
Disease: Multiple sclerosis, type 1 diabetes
NOD2
Function: Cytoplasmic sensor of bacteria
Disease: Inflammatory bowel disease
NOD2
Function: Cytoplasmic sensor of bacteria
Disease: Inflammatory bowel disease
Tolerance
• Tolerance – unresponsiveness to an antigen that is induced by previous exposure to that antigen
• Central Tolerance – during lymphocyte maturation
– Bone marrow for B cells, Thymus for T cells
• Peripheral Tolerance – mature lymphocytes
– Tissue specific self tolerance
