L12- autoiimune diseases

Question 1

define Autoimmunity

Autoimmune diseases

Tolerance

Failure of tolerance

Answer 1

1- Immune response to self antigens

2- in which adaptive responses to self-antigens contribute to tissue damage

3- a state of immunological non-reactivity t an antigen

4- Represented by autoimmunity

Question 2

how is the adaptive immune system prone to auto immunity:

Answer 2

although some antibodies are negatively selected for (promoting peripheral tolerance mechanisms, although some potentially auto-reactive T cells are produced ), others are either permissively allowed or rigorously selected for.

Those that are rigorously selected for exhbit:1-lower risk of autoimmunity, 2-poor repertoire, 3- increased susceptibility to infection

Permissively-1-broad repertoire, 2- lower risk of infection, 3- higher risk of autoimmunity

Question 3

list and explain some peripheral tolerance mechanisms

Answer 3

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

Antigen segregation- Physical barriers to sequestered antigen (‘immunological privilege’)

Peripheral anergy
- Weak signalling between APC/ CD4 T cell without co-stimulation causes T cells to become non-responsive

Regulatory T cells
-CD25+FoxP3 positive T cells and other types of regulatory T cells actively suppress immune responses by cytokine and juxtacrine signalling

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 4

give 2 classifications of autoimmune antibodies and their examples

Answer 4

1-organ specific and 2-non-organ specific

1- T1 diabetes mellitus, graves disease, hashimotos

2- systemic lupus erythematosus, Rheumatoid arthritis

Question 5

what is type 2 hypersensitivity and its criteria :

Answer 5

Refers to diseases where an antibody is clearly pathogenic ie causes disease/ tissue damage directly

Disease can be transferred between experimental animals by infusion of serum, or during gestation to cause problems in fetus/ neonate

Removal of antibody by plasmapharesis is beneficial

A pathogenic antibody can be identified and characterised

Question 6

describe Antibody-mediated disease: autoimmune cytopenias

Answer 6

1: Autoimmune haemolytic anaemia- red blood cells plus anti-RBC autoantibodies

can cause complement activation and intravascular haemolysis- leads to rbc destruction and lysis

or FCR+ cells in fixed mononuclear phagocytic system-phagocytosis and RBS destruction

2: also autoimmune thrombocytopenia

Question 7

Describe graves disease

Answer 7

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

• Goitre
• Grave’s ophthalmopathy due to poorly-understood retro-orbital inflammation

Has all the characteristics of an antibody-mediated disease:

• Neonatal hyperthyroidism if mother is affected
• Serum transfers disease between experimental animals
• Antibody detected and characterised

Question 8

how is graves thyroiditis caused

Answer 8

• TSH acts on thyroid inducing release of thyroid hormones
• Autoimmune B cells makes antibodies against TSH receptor that also stimulate thyroid hormone production
• thyroid hormones act on pituitary to shut down production of TSH, suppressing further thyroid hormone synthesis
• throid hormones shut down TSH production but have no effect on autoantibody production, which continues to cause excessive thyroid hormone production

Question 9

what are the symptoms of myasthenia gravis

Answer 9

• Muscle weakness and fatigability
• 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 10

what causes myasthenia gravis

Answer 10

Its an antibody-mediated autoimmune disease where :

• antibodies attack the ACH receptors which result in them being internalised and degraded
• this means there is no influx of na and therefore no muscle contraction

Question 11

describe spontaneous Urticaria

Answer 11

IgG FcεR1 antibody cross-links mast cell receptor causing degranulation. Manifests with hives and swelling

Question 12

A note about antibodies and autoimmune disease

Answer 12

In these examples, the auto-antibody is said to be ‘pathogenic’ as it is directly leading to disease
Auto-antibodies are also found in myriad other autoimmune diseases
These antibodies seem to be produced as a by-product of the inflammatory process. They don’t fulfil the criteria to be pathogenic
They are useful for diagnosis – see next lecture, eg
Tissue transglutaminase antibody (coeliac), islet cell antibody (diabetes), gastric parietal cell antibody (pernicious anaemia) etc etc

Question 13

what is type 4 hypersensitivity according to Gell and coombes

Answer 13

Tissue damage is directly mediated by T cell-dependent mechanisms:

• T cells activate macrophages and other elements of innate immunity
• CD8 T cells damage tissue directly

Much more difficult to demonstrate autoreactive T cells in vitro than it is to demonstrate antibody

Experimental models rely on genetically susceptible animals that are sensitised, often by exposure to a self-antigen with an adjuvant

Question 14

describe T cell-mediated autoimmunity: autoimmune hypothyroidism (Hashimotos thyroiditis)

Answer 14

Commonest cause of hypothyroidism in industrialised countries

Particularly women over 30

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

Question 15

name some other T cell mediated autoimmune diseases

Answer 15

Coeliac: see later slides

Type 1 diabetes mellitus: see later slides

Question 16

what are the evidence that genetics is importance in regards to autoimmunity

Answer 16

Evidence for importance:

Rare monogenic disorders of the immune system that are associated with autoimmune diseases

Mouse models rely on genetically susceptible strains eg NOD mouse

Enrichment in families, mostly attributable to HLA associations

Environment clearly also important

Question 17

evidence of genetics importance in autoimmunity for mice studies

Answer 17

Littermates in this group of non-obese diabetic mice have an identical genetic background and a very similar environment, but even so there is variability in the development of type 1 diabetes mellitus. Note also that female mice are more susceptible.

Question 18

describe Monogenic disorders and autoimmunity: APACED(autoimmune polyglandular syndrome, candidiasis and ectodermal dystrophy

Answer 18

AIRE gene regulates ectopic expression of tissue-specific antigens in thymus

AIRE mutations result in failure of negative selection

Strongly associated with organ-specific auutoimmune diseases (type 1 diabetes, vitiligo, alopecia, autoimmune adrenal disease etc)

Results from antibodies to IL-17 – this cytokine seems to be important in host defence against fungi at mucosal surfaces

Question 19

describe DiGeorge syndromes

Answer 19

Failure migration 3th/ 4th branchial arches

Full phenotype:

• Absent parathyroids (low calcium, tetany)
• Cleft palate
• Congenital heart defects
• Thymic aplasia (low T cell numbers, immunodeficiency)

Microdeletions chromosome 22

Variable presentation

• May affect any of above in isolation
• Huge spectrum of immunodeficiency from mild-SCID-like
• Autoimmunity is also common

Question 20

describe Monogenic disorders and autoimmunity: IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-Linked)

Answer 20

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 21

describe Monogenic disorders and autoimmunity: classical complement deficiency

Answer 21

Immune complexes are cleared by phagocytes; process enhanced by phagocyte Fc receptors and C3b receptors

Deficiency of C1q/ C2/ C4 predispose to lupus, presumably because immune complexes cannot be cleared effectively (see Professor Davies lecture)

In addition to lupus, some patients may suffer from recurrent bacterial infections

Question 22

what IS THE The HLA system

Answer 22

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

Encoded by the HLA system on chromosome 6
Class I: A, B, C
Class II: DR, DP and DQ

Complex nomenclature used to describe ‘tissue type’ in an individual
Eg HLA B27=expresses serotype 27 at B locus of HLA class I
EG HLA DR2=expresses serotype 2 at locus 2 of HLA class II

Strong association between the expression of HLA molecules and some autoimmune diseases

Question 23

describe coeliac disease

Answer 23

A very common inflammatory disease of the small bowel with gastrointestinal and extra-gastrointestinal features:

• Up to 1% UK population affected
• More common in women
• Majority undiagnosed

Characteristics of an autoimmune disease, but unusually triggered by an exogenous antigen (gluten) in pre-disposed individuals

Main manifestations are malabsorption (loose stool, weight loss, vitamin deficiency, anaemia, poor growth in children) but myriad others now recognised

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

Inflammation resolves with
strict gluten avoidance

30-50% of Europeans express
HLA-DQ2 and/ or HLA-DQ8 –
not clear which additional genetic/ environmental factors are important in
coeliac

Question 24

what occurs to the Villi in coeliac disease

Answer 24

Total villous atrophy, crypt hyperplasia and lymphocyte infiltration in advanced disease

Question 25

How is HLA and ceoliac disease related

Answer 25

Dietary gliadin (wheat, rye and barley) is degraded by gut tissue transglutamine 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