W4L7 - Autoimmune Disease Examples

Question 1

Goodpasture’s Syndrome

Answer 1

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.

Question 2

Goodpasture’s Syndrome - Pathology & Treatment

Answer 2

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

Question 3

Pernicious Anaemia

Answer 3

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

Question 4

Anti-Parietal Cell (APC) Antibodies

Answer 4

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

Question 5

Pernicious Anaemia - Treatment

Answer 5

B12 given orally is of no benefit since absorption is the problem
Intravenous B12 injected – by pass gut
High dose B12 sublingually

Question 6

Diabetes Mellitus

Answer 6

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

Question 7

Insulin Dependent Diabetes Mellitus (IDDM)

Answer 7

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)

Question 8

Risk Factors for Type 2 Diabetes

Answer 8

Obesity
Family history (genetic)
Increased blood pressure
Increased LDL cholesterol
Sedentary lifestyle

Question 9

Diagnosis of Diabetes Mellitus

Answer 9

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

Question 10

Pathology of Type 1 Diabetes

Answer 10

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

Question 11

Genetics of IDDM

Answer 11

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

Question 12

Type 1 Diabetes Tests

Answer 12

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

Question 13

Ketoacidosis

Answer 13

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

Question 14

Ketoacidosis Symptoms

Answer 14

Nausea (vomiting)
Confusion
Thirst
Acetone breath
Ketone bodies in urine
Lowered blood pH
Hyperventilation

Question 15

Treatment for Ketoacidosis

Answer 15

IV insulin
IV fluids (saline)

Question 16

Long Term Complications of Diabetes

Answer 16

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

Question 17

Celiac Disease

Answer 17

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

Question 18

Immunopathology of Celiac Disease

Answer 18

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

Question 19

Why don’t we all have Celiac Disease?

Answer 19

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