T1 L12 & 13 Autoimmune diseases Flashcards
What is autoimmunity?
Immune responses to self antigens
Also known as auto-reactivity
What is an autoimmune disease?
Adaptive immune responses to self-antigens contribute to tissue damage
What is tolerance?
State of immunological non-reactivity to an antigen
Why isn’t inflammatory bowel disease an autoimmune disease?
While it involves the immune system it doesn’t involve adaptive immune responses to self antigens
What is the mechanism for immunological hierarchy tolerance?
CD4 T-cells aren’t activated unless antigen is presented with an ‘inflammatory’ context with TLR ligation
What is the mechanism for antigen segregation?
Physical barriers to sequestered antigen
What is the mechanism for peripheral anergy?
Weak signalling between APC / CD4 T-cell without co-stimulation causes T-cells to become non-responsive
What is the mechanism for regulatory T-cells?
CD25+ Foxp3 positive T-cells and other regulatory T-cells actively suppress immune responses by cytokine and juxtacrine signalling
What is the mechanism for cytokine deviation?
Changes in T-cell phenotype e.g. Th1 to Th2 may reduce inflammation
What is the mechanism for clonal exhaustion?
Apoptosis post-activation by activation-induced cell death
Give examples of organ-specific autoimmune diseases?
Type 1 diabetes mellitus Pemphigus, pemphigoid Graves disease Hashimoto's thyroiditis Autoimmune cytopenias - anaemia, thrombocytopenia
Give examples of non-organ specific autoimmune diseases
Systemic lupus erythematosus
Rheumatoid arthritis
What does type II hypersensitivity refer to?
Diseases where antibody is clearly pathogenic i.e. causes disease / tissue damage directly
What is the criteria for autoimmune antibody-mediated disease?
Diseases can be transferred between experimental animals by infusion of serum or during gestation to cause problems in foetus / neonates
Removal of antibody by plasmapheresis is beneficial
Pathogenic antibody can be identified and classified
What are the signs and symptoms of autoimmune hyperthyroidism?
Tachycardia Palpitations Tremor Anxiety Heat intolerance Goitre Grave's ophthalmopathy
Describe the physiology of the thyroid in Grave’s disease
Autoimmune B cell makes antibodies against TSH receptor that also stimulates thyroid hormone production
Thyroid hormones shut down TSH production but have no effect on autoantibody production which continues to cause excess thyroid hormone production
What is affected in myasthenia gravis?
Muscle weakness and fatigability
Eyelids, facial muscles, chewing, talking and swallowing are most often affected
How does spontaneous urticaria occur?
IgG FceR1 antibody cross-links mast cell receptor leading to degranulation.
This causes hives and swelling
What is type IV hypersensitivity?
Tissue damage directly mediated by T-cell dependent mechanisms
Give examples of T-cell mediated autoimmunity
Autoimmune hypothyroidism
Coeliac
Type 1 diabetes mellitus
What is the evidence for genetics in autoimmunity?
Rare monogenic disorders of immune system that are associated with autoimmune diseases
Mouse models rely on genetically susceptible strains
Enrichment in families, most attributable to HLA assocations
What is the evidence that environment has a role in autoimmunity?
Littermates in group of non-obese diabetic mice have identical genetic background and similar environment but there is variability in the development of type 1 DM
What is APACED?
Autoimmune polyglandular syndrome candidiasis and ectodermal dystrophy
What gene is involved in APACED?
AIRE gene mutation leading to failure of negative selection
What does the AIRE gene normally do?
Regulates ectopic expression of tissue-specific antigens in thymus
Why is candidiasis a feature of APACED?
Antibodies to IL-17 which is an important cytokine in host defence against fungi at mucosal surfaces
What is DiGeorge syndrome?
Migration failure of 3rd/4th branchial arches
What are the signs of DiGeorge syndrome in a full phenotype?
Absent parathyroids leading to low calcium and tetany
Cleft palate
Congenital heart defects
Thymic aplasia leading to low numbers of T-cells and immunodeficiency
What is IPEX?
Immune dysregulation polyendocrinopathy enteropathy X-linked
Rare X-linked mutation affecting Foxp3 gene
Abrogates production of CD4+, CD25+, FoxP3, regulatory T-cells
What are the key features of IPEX?
Inflammatory bowel disease
Dermatitis
Organ-specific autoimmunity
What does HLA B27 mean?
Expresses serotype 27 at B locus of HLA class I
What are the 2 classes of the HLA system?
Class I: A, B, C
Class II: DR, DP, DQ
What does HLA DR2 mean?
Expresses serotype 2 at locus 2 of HLA class II
What is coeliac disease?
Common inflammatory disease of small bowel with GI & extra-GI features
Characteristics of autoimmune disease but triggered by exogenous antigen (gluten) in pre-disposed antigens
What are the main manifestations in coeliac disease?
Malabsorption
- Loose stool
- Weight loss
- Vitamin deficiency
- Anaemia
- Poor growth in children
Describe the histological features in advanced coeliac disease
Total villous atrophy
Crypt hyperplasia
Lymphocyte infiltration
What HLA do those with coeliac express?
HLA-DQ2, HLA-DQ8 or both
What happens to HLA molecules in coeliac disease when gluten is consumed?
Dietary gliadin (wheat, rye, barley) is degraded by gut tissue transglutaminase 2 enzyme during digestion to produce gliadin peptides HLA DQ2/8 molecules can present these gliadin peptides to T-cells if the appropriate T-cell receptors are present
Describe molecular mimicry
Epitopes relevant to pathogen are shared with host antigens
1) Viral infection
2) Presentation of viral peptides to CD4 T-cell via MHC II leads to T-cell activation
3) Viral peptides are similar to host-derived peptide
4) Activated T-cell now reacts strongly to self peptide and initiates inflammation
What does molecular mimicry depend on?
MHC molecules to present this critical epitope that is common to both virus and host
T-cell to recognise it
What are some examples of molecular mimicry?
Autoimmune haemolysis after mycoplasma pneumonia
Rheumatic fever
How is autoimmune haemolytic after mycoplasma pneumonia an example of molecular mimicry?
Mycoplasma antigen has homology to ‘I’ antigen on RBC
IgM antibody to mycoplasma may cause transient haemolysis
How is rheumatic fever an example of a molecular mimicry?
Inflammatory disease occurring after streptococcal infection
Anti-streptococcal antibodies believed to cross-react with connective tissue
Describe the pathophysiology of type I diabetes
Lack of insulin –> impaired cellular uptake glucose –> polyuria, polydipsia, polyphasic, weight loss
Why is it important to differentiate type 1 diabetes from monogenic diabetes?
Can present with similar phenotype but require different management
Why is it important to differentiate type 1 diabetes from type II diabetes?
Type II DM has older onset, some insulin secretion, ketoacidosis is less likely
Insulin isn’t necessarily required
What is the evidence that type 1 DM is an autoimmune disease?
Islet cell autoantibodies are detectable for months to years before onset of clinical disease
HLA associations
Mouse model
Early pancreatic biopsy shows infiltration with CD4/8 T cells
Describe the genetics of autoimmune type 1 DM
Concordance in monozygotic twins is almost 100%
HLA class II alleles are major defined genetic risk factor
- DR3 or DR4 has relative risk of 6
- DR3 and Dr4 has relative risk of 15
Describe the evidence for Coxsackie virus being a trigger for type 1 DM
Stronger immune response to virus in cases compared to controls
Viral infection can cause pancreatitis in mice and humans
Protein 2C Coxsackie virus has homology with islet cell antigen glutamic acid decarboxylase
What are the 3 detection methods for immunology?
Indirect immunofluorescence
Solid-phase immunoassay
Direct-immunofluorescence
What are the 3 stages of indirect immunofluorescence?
1) Incubate
- glass slide with tissue of interest, harvested from animal source
- patient serum that does (or doesn’t) contain antibodies
2) Detect
- add detection antibody labelled with fluorescent marker
3) Read
- look for fluorescence under microscope
Why is it important to identify type 1 diabetes?
Risk of ketoacidosis
Requires insulin
Monogenic diabetes and type 2 diabetes require different approach
What are the 6 stages of solid-phase immunoassay?
1) Coat each well of plastic 96-well plate with tTG antibody
2) Block well using milk-powder solution
3) Add patient samples to wells
4) Add secondary antibody
5) Add substrate
6) Compare colour change to calibration curve
Why is the well in solid-phase immunoassay blocked using milk-powder solution?
Gets rid of spare spaces on plastic that biological molecules can bind to.
Why are the samples incubated in solid-phase immunoassay?
To allow time for tTG antibody in sample to react with tTG antibody
What is the secondary-antibody in solid-phase immunoassay?
Anti-IgA antibody which binds to IgA Fc regions
Covalently linked to enzyme such as horse radish peroxidase
What is the colour change in solid-phase immunoassay measured with?
Photocell
How is calibration curve set uo?
Set up wells with known concentrations of tTG antibody
Done by serial dilution
Photocell readings from each well used to create standard curve
What are the steps of direct immunofluorescence?
1) Prepare tissue biopsy / slide - take biopsy of affected tissue, if damage is mediated by antibody the antibody will already be stuck to its antigen in the tissue.
2) Detect - add detection antibody labelled with fluorescent marker
3) Read - look for fluorescence under microscope
Describe the bullous skin disease pemphigoid
Thick-walled bullae, rarely on mucous membranes
Fulfils criteria for antibody-mediated disease
Linear deposition of antibody which activates complement to produce skin dehiscence and tense blister
What is the target in pemphigoid?
Antigen at demo-epidermal junction
Describe the bullous skin disease pemphigus
Thin-walled bullae on skin and mucus membranes. Rupture easily
Fulfils criteria for antibody-mediated disease
What is the target in pemphigus?
Intercellular cement protein desmoglein 3 in superficial skin layers
How is coeliac disease diagnosed?
Target antigen is tissue transglutaminase (tTG)
HLA typing increasingly used
- absence of HLA DQ2/8 makes coeliac disease very unlikely
- presence of HLA DQ2/8 isn’t indicative of coeliac disease
What is pernicious anaemia?
Autoimmune destruction of gastric parietal cells
Vitamin B12 absorbed in terminal ileum - requires intrinsic factor
Once liver store is depleted it causes anaemia, neurological and sub fertility issues
Why is the aim of AID treatment often just to manage consequences and not treat immunology?
Immunosuppressive drugs are toxic
By time disease is over, damage may have already been done and immunosuppression would be unhelpful
Give examples of treatments for AID
Thyroxine for underachieve thyroid
Carbimazole, surgery or drugs for thyrotoxicosis
Insulin for diabetes
B12 for pernicious anaemia
Give examples of immunomodulation drugs
Systemic corticosteroids Small molecule immunosuppressive drugs - methotrexate - azathiprine - ciclosporin High dose IV immunoglobulin
What does plasmapheresis do?
Removes antibodies from bloodstream
May be useful in antibody-mediated diseases
