W4L7 - Autoimmune Disease Examples Flashcards
Goodpasture’s Syndrome
Antibodies to basement membrane of Glomeruli in Kidneys and lungs
Anti-glomerular basement membrane antibodies detected (anti-GBM, IgG) in serum
- biopsy of kidney will show IgG deposition along basement membrane
20% of rapid progressive glomerulonephritis
Respiratory disease precedes renal disease (intra alveolar haemorrhage and necrotizing alveolitis followed by nephritis)
Target antigen is α3 chain of collagen type IV.
Goodpasture’s Syndrome - Pathology & Treatment
May be due to cross reaction (molecular mimicry) with respiratory pathogens Exposure to certain hydrocarbons - may damage alveolar basement membranes - exposing sequestered antigens - strong association with cigarette smoking Treated with aggressive immunosuppressive therapy - high dose steroids - cyclophosphamide - plasmaphoresis Main risk is massive lung haemorrage Renal failure if > 85% glomeruli damaged Fatal without treatment
Pernicious Anaemia
Malabsorption of vitamin B12 due to:
1. Deficiency in intrinsic factor
2. Anti-intrinsic factor antibodies
- blocking antibody which blocks the receptor site on intrinsic factor for B12 (B12 needs intrinsic factor for absorption)
- binding antibody which binds intrinsic factor at site for binding to ileum preventing absorption of intrinsic factor-B12 complex
- possible molecular mimicry with Helicobacter pylori
B12 required for RBC development
If don’t have B12 => megaloblastic anaemia
Most patients >60 years old, female
Anti-Parietal Cell (APC) Antibodies
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
Pernicious Anaemia - Treatment
B12 given orally is of no benefit since absorption is the problem
Intravenous B12 injected – by pass gut
High dose B12 sublingually
Diabetes Mellitus
Affects up to 8% of European and Asian people
Estimated that only 50% diagnosed
Symptoms
- polyuria (frequent urination)
- polydipsia (increased thirst)
- polyphagia (increased hunger)
- weight loss
- others: blurred vision, fatigue, itchiness, peripheral neuropathy, infections, dizziness
Many people have no symptoms in first few years
Insulin Dependent Diabetes Mellitus (IDDM)
Type 1 - insulin dependent - 1a : immunological destruction of β-cells of islets of langerhans in pancreas - 1b: destruction of β-cells without immunological cause - acute onset - young (<30 years of age) - 10-20% of cases of diabetes mellitus Type 2 - non-insulin dependent - 80–90% of cases - insulin resistance - insidious onset - older (>40)
Risk Factors for Type 2 Diabetes
Obesity Family history (genetic) Increased blood pressure Increased LDL cholesterol Sedentary lifestyle
Diagnosis of Diabetes Mellitus
Glucosuria
Fasting glucose
- fast overnight, take blood, measure glucose
2 hour post (glucose tolerance test GTT)
- take blood, measure glucose
- give dose of glucose (75g oral, adjusted for children by weight)
- after 2 hours take blood, measure glucose
Glycated haemoglobin (HbA1c)
- as plasma glucose increases haemoglobin becomes glycated
Pathology of Type 1 Diabetes
Destruction of the β-cells of islets of langerhans in pancreas Due cytotoxic T cells and cytokines This is 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
Genetics of IDDM
Linked to many genes - insulin gene (chromosome 11) - HLA genes - approximately 11 other non-HLA genes HLA - HLA-DR3 and DR4 - 40% of Caucasian diabetics heterozygous DR3/DR4 - HLA-DQ - alleles with aspartate at position 57 of the β chain are protective - without confer risk
Type 1 Diabetes Tests
Type 1 Diabetes Mellitus (IDDM) is not diagnosed by immunological tests
- glucosuria, Fasting glucose, GTT, HbA1c
ICA is a good predictor that patient will develop IDDM
- immunofluorescence for ICA
- ELISA for anti-GAD, anti-IA-2, anti-insulin
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
Ketoacidosis Symptoms
Nausea (vomiting) Confusion Thirst Acetone breath Ketone bodies in urine Lowered blood pH Hyperventilation
Treatment for Ketoacidosis
IV insulin IV fluids (saline)
Long Term Complications of Diabetes
Retinopathy - loss of vision due to haemorrhage - blindness (people over 60 yrs) - 7 to 10 yrs after onset Nephropathy - renal failure - 8 to 12 yrs after onset Atherosclerosis - elevated risk - possible stroke, coronary artery disease Neuropathy - decreased peripheral sensation - can’t feel injuries, numbness, tinging in toes
Celiac Disease
Celiac disease is a chronic inflammatory condition in the upper small intestine, due to an immune response to gluten
Gluten is a complex protein present in wheat, oats and barley
Removal of gluten from the diet restores normal gut function
Leads to malabsorption
- loss of intestinal villi (villous atrophy)
- increase size of sites of epithelial renewal (crypt hyperplasia)
T cells, macrophages and plasma cells in lamina propria and epithelial layer
Gluten stimulates both innate and adaptive immune response
Immunopathology of Celiac Disease
Only a limited number of proteins can induce Celiac disease
Main protein involved in the development of Celiac disease in gluten is α-gliadin
Gluten is absorbed in epithelial cells of intestine
The enzyme tissue transglutaminase (tTG) modifies (deamination) α-gliadin
- converts glutamine to negatively charged glutamic acid
- this modified protein leads to disease
The modified α-gliadin binds to the unique peptide-binding grove of HLA-DQ2 (on APC)
- activate APC (presentation of antigen)
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
- contributing to cytokine production (IL-15)
- expressing stress markers
Why don’t we all have Celiac Disease?
Oral tolerance mechanisms prevent T cell response to food protein
Why are these not working in Celiac disease?
Celiac disease require HLA-DQ2 or DQ8, so this partly explains why many people don’t get disease
- however most people with HLA-DQ2 or DQ8 also don’t get Celiac disease
