12. Autoimmune diseases 1

Question 1

Define autoimmune diseases

Answer 1

Where adaptive immune responses to self-antigens contribute to tissue damage

Question 2

Tolerance

Answer 2

a state of immunological non-reactivity to an antigen

Autoimmunity is a failure of tolerance

Question 3

Negative selection

Answer 3

Reduces autoreactive T cells

Can be rigorous- increasing susceptibility to infections or permissive (increasing risk of autoimmunity)

Question 4

Mechanisms of peripheral tolerance [6]

Answer 4

Immunological hierarchy- CD4 T cell will not be activated unless antigen is presented in an ‘inflammatory’ context with TLR ligation

Antigen segregation- immune priviledge sites

Peripheral anergy- no costimulation of CD40L inhibition

Regulatory T cells

Cytokine deviation- Change in T cell phenotype eg Th1 to Th2 may reduce inflammation

Clonal exhaustion- Apoptosis post-activation by activation-induced cell death

Question 5

Pathogenic mechanism of Type 2 hypersensitivity diseases [5]

Answer 5

diseases where an antibody is clearly pathogenic (autoantibodies)

Question 6

Examples of antibody-mediated diseases

Answer 6

Autoimmune haemolytic anaemia

Autoimmune thrombocytopaenia

Question 7

Autoimmune haemolytic anaemia

-clinical presentation

Answer 7

Type 2 hypersensitivty

• Anti-RBCs autoantibodies are generated and bind to RBCs
• RBCs are seen as pathogenic and are destroyed by phagocytosis and activate complement

Clinical presentation- anaemia
jaundice

Question 8

Autoimmune thrombocytopaenia

-clinical presentation

Answer 8

pupura, rash

Question 9

Give an example of antibody mediated disease affecting thyroid function

Answer 9

Graves disease

Symptoms of hyperthyroidism (tachycardia, palpitations, tremor, anxiety, heat intolerance etc)

Goitre
Grave’s ophthalmopathy

Question 10

Graves disease immunology

Answer 10

Pituitary gland secretes TSH to induce release of TH

TH acts on pituitary to shut down production of TSH (neg feedback)

Autoimmune B cell makes ab against TSH receptor to also stimulate TH

TH shuts down TSH production but have no effect on autoantibody production, so XS TH

Question 11

Myasthenia gravis

Answer 11

Type 2 hypersensitivity
Antibody-mediated autoimmune disease

ACh receptors internalised and degraded, no Na+ influx, no muscle contraction

Symptoms: Muscle weakness and fatigability

Signs: Eyelids, facial muscles, chewing, talking and swallowing most often affected

Ptosis at rest, becoming markedly worse after patient asked to close and open eyes repeatedly

Question 12

Spontaneous urticaria

Answer 12

IgG FcεR1 antibody cross-links mast cell receptor causing degranulation.

Presents

• Hives
• Swelling

Question 13

Type IV hypersensitivity

Answer 13

Tissue damage is directly mediated by T cell-dependent mechanisms

Question 14

Autoimmune Hypothyroidism

Answer 14

T cell mediated
Type 4 hypersensitivity reaction

Autoimmune destruction of thyroid: organ infiltrated by CD4 and CD8 T cells

Question 15

APACED

Answer 15

Monogenic disorder

• AIRE gene regulates ectopic expression of tissue-specific antigens in thymus
• AIRE mutations result in failure of negative selection
• Associated with organ specific autoimmune diseases

Candidiasis also a key feature of the disease

Question 16

DiGeorge syndrome

Answer 16

22q11.2 deletion syndrome
Absent parathyroids and thymus
Deficiency of T cells

Question 17

Coeliacs disease

Answer 17

Exogenouse gluten is considered antigenic and broke down into gliadin peptides using transglutaminase 2

Question 18

IL-17

Answer 18

Cytokine important in host defence against fungi at mucosal surfaces

Antibodies to IL-17 can result in APACED

Question 19

IPEX

Answer 19

immune dysregulation, polyendocrinopathy, enteropathy, X-Linked

Exceedingly rare X Linked mutation affecting Forkhead p3 (FoxP3) gene
Abrogates production of CD4+CD25+FoxP3+ regulatory T cells

Key features:
Inflammatory bowel disease
Dermatitis
Organ-specific autoimmunity

Question 20

Outline the HLA naming system

Answer 20

APCs present processed peptide to T cells in combination with highly polymorphic MHC (HLA) molecules

Encoded by the HLA system on chr6

Class 1: A,B,C
Class 2: DR, DP, DQ

Question 21

Patients with Coeliacs disease express which tissue type

Answer 21

HLA-DQ2
HLA-DQ8
………or both

Question 22

Pathogenesis of Coeliacs disease

Answer 22

The damage is mediated by
T cells; note that antibodies
are produced, but do not
contribute to tissue damage