Autoimmune Diseases 1

Question 1

Selection of adaptive immune lymphocytes

• Receptors of these cells produced by random somatic recombination events between VDJ gene segments - produce functional T and B cell receptors
• … … ensures receptors are useful (e.g. T cells - ensure they can recognise self-antigen in context of MHCII)
• … … reduces autoreactivity (Deletes T cells expressing receptors expressing very high affinity for self-antigen)
• Naive B and T cell receptors - repertoire
• Upon infection - expansion of best populations
• … of infection - Most die, some become memory cells

Answer 1

• Receptors of these cells produced by random somatic recombination events between VDJ gene segments - produce functional T and B cell receptors
• Positive selection ensures receptors are useful (e.g. T cells - ensure they can recognise self-antigen in context of MHCII)
• Negative selection reduces autoreactivity (Deletes T cells expressing receptors expressing very high affinity for self-antigen)
• Naive B and T cell receptors - repertoire
• Upon infection - expansion of best populations
• Resolution of infection - Most die, some become memory cells

Question 2

Cytokine deviation (Tolerance) - Mechanism

• Change in T cell … eg Th1 to Th2 may reduce inflammation

Answer 2

• Change in T cell phenotype eg Th1 to Th2 may reduce inflammation

Question 3

Classification of AID (autoimmune disease) with a few examples

• …-specific
  
  • E.g. T1 Diabetes, Pemphigus/pemphigoid, Graves disease, Hashimotos thryoiditis, Autoimmune cytopenias;anaemia, thrombocytopenia
• …-system
  
  • E.g. Systemic lupus erythematosis, Rheumatoid arthritis, Sjogren’s syndrome

Answer 3

• Organ-specific
  
  • E.g. T1 Diabetes, Pemphigus/pemphigoid, Graves disease, Hashimotos thryoiditis, Autoimmune cytopenias;anaemia, thrombocytopenia
• Multi-system
  
  • E.g. Systemic lupus erythematosis, Rheumatoid arthritis, Sjogren’s syndrome

Question 4

Pathogenic mechanisms in AID: autoantibodies

• Type … hypersensitivity according to Gell and Coombes classification
• Refers to diseases where an antibody is clearly pathogenic ie causes disease/ tissue damage directly
• Criteria:
  
  • 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

Answer 4

• Type II hypersensitivity according to Gell and Coombes classification
• Refers to diseases where an antibody is clearly pathogenic ie causes disease/ tissue damage directly
• Criteria:
  
  • 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 5

Autoimmune diseases - in which adaptive immune responses to …-antigens contribute to … damage

Answer 5

Autoimmune diseases - in which adaptive immune responses to self-antigens contribute to tissue damage

Question 6

Candidiasis is a key feature of what disease?

Answer 6

APACED (autoimmune polyglandular syndrome, candidiasis and ectodermal dystrophy) - Results from antibodies to IL-17 – this cytokine seems to be important in host defence against fungi at mucosal surfaces

Question 7

Coeliac disease

• A very common inflammatory disease of the small bowel with gastrointestinal and extra-gastrointestinal features
  
  • Up to ….% UK population affected
  • More common in …
  • Majority undiagnosed
• Characteristics of an autoimmune disease, but unusually triggered by an exogenous … (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

Answer 7

• 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

Question 8

Antibody-mediated autoimmune disease: autoimmune hyperthyroidism (Graves Disease)

• Symptoms of … (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 … if mother is affected
  • Serum transfers disease between experimental animals
  • Antibody detected and characterised

Answer 8

• 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 9

List THREE examples of autoimmune diseases where the pathogenesis is definitely directly mediated by a pathogenic antibody.

Answer 9

• Grave’s disease
• Autoimmune cytopenias
• Myasthenia gravis

Question 10

Pathogenic mechanisms in AID: autoantibodies

• Type II hypersensitivity according to Gell and Coombes classification
• Refers to diseases where an antibody is clearly … ie causes disease/ tissue damage directly
• Criteria:
  
  • 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

Answer 10

• Type II hypersensitivity according to Gell and Coombes classification
• Refers to diseases where an antibody is clearly pathogenic ie causes disease/ tissue damage directly
• Criteria:
  
  • 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 11

Antibody-mediated autoimmune disease: Grave’s thyroiditis

• Pituitary gland secretes TSH, acts on thryoid to induce release of thyroid hormones
• Thyroid hormones act on the pituitary to shut down production of TSH, suppressing further thyroid hormone synthesis (feedback suppression)
• Autoimmune B cell makes antibodies against … receptor that also stimulate thyroid hormone production
• Thyroid hormones shut down TSH production but have no effect on autoantibody production, which continues to cause … thryoid hormone production

Answer 11

• Pituitary gland secretes TSH, acts on thryoid to induce release of thyroid hormones
• Thyroid hormones act on the pituitary to shut down production of TSH, suppressing further thyroid hormone synthesis (feedback suppression)
• Autoimmune B cell makes antibodies against TSH receptor that also stimulate thyroid hormone production
• Thyroid hormones shut down TSH production but have no effect on autoantibody production, which continues to cause excessive thryoid hormone production

Question 12

Pathogenic mechanisms in AID: T cells

• Type … hypersensitivity according to Gell and Coombes
• 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 …, often by exposure to a self-antigen with an …

Answer 12

• Type IV hypersensitivity according to Gell and Coombes
• 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 13

Antibody-mediated disease: autoimmune cytopenias

• Causing anaemia and mild form of …
• Can affect any part of blood compartment - affecting platelets = autoimmune …

Answer 13

• Causing anaemia and mild form of jaundice
• Can affect any part of blood compartment - affecting platelets = autoimmune thrombocytopaenia

Question 14

Pathogenic mechanisms in AID: T cells

• Type IV hypersensitivity according to Gell and Coombes
• Tissue damage is directly mediated by T cell-… mechanisms
  
  • T cells activate … and other elements of innate immunity
  • CD8 T cells damage tissue directly
• Much more difficult to demonstrate … 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

Answer 14

• Type IV hypersensitivity according to Gell and Coombes
• 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 15

Genetics and autoimmunity

• Evidence for importance:
  
  • … monogenic disorders of the immune system that are associated with autoimmune diseases
  • … models rely on genetically susceptible strains eg NOD mouse
  • Enrichment in families, mostly attributable to HLA associations
• Environment clearly also important

Answer 15

• 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 16

… represents a failure of tolerance

Answer 16

Autoimmunity represents a failure of tolerance

Question 17

What syndrome develops as a result of failure migration 3th/ 4th branchial arches?

Answer 17

DiGeorge syndrome

Question 18

Systemic lupus erythematosis, Rheumatoid arthritis, Sjogren’s syndrome are all examples of …-… autoimmune diseases

Answer 18

Systemic lupus erythematosis, Rheumatoid arthritis, Sjogren’s syndrome are all examples of multi-system autoimmune diseases

Question 19

Antibody-mediated autoimmune disease: myasthenia gravis

• Muscle … and …
• Eyelids, facial muscles, chewing, talking and swallowing most often affected

Answer 19

• Muscle weakness and fatigability
• Eyelids, facial muscles, chewing, talking and swallowing most often affected

Question 20

Selection of adaptive immune lymphocytes

• Receptors of these cells produced by random somatic recombination events between … gene segments - produce functional T and B cell receptors
• Positive selection ensures receptors are useful (e.g. T cells - ensure they can recognise self-antigen in context of MHCII)
• Negative selection reduces … (Deletes T cells expressing receptors expressing very high affinity for self-antigen)
• Naive B and T cell receptors - repertoire
• Upon infection - expansion of best populations
• Resolution of infection - Most …, some become … …

Answer 20

• Receptors of these cells produced by random somatic recombination events between VDJ gene segments - produce functional T and B cell receptors
• Positive selection ensures receptors are useful (e.g. T cells - ensure they can recognise self-antigen in context of MHCII)
• Negative selection reduces autoreactivity (Deletes T cells expressing receptors expressing very high affinity for self-antigen)
• Naive B and T cell receptors - repertoire
• Upon infection - expansion of best populations
• Resolution of infection - Most die, some become memory cells

Question 21

T1 Diabetes, Pemphigus/pemphigoid, Graves disease, … thryoiditis, Autoimmune cytopenias;anaemia, thrombocytopenia are all examples of …-… autoimmune diseases

Answer 21

T1 Diabetes, Pemphigus/pemphigoid, Graves disease, … thryoiditis, Autoimmune cytopenias;anaemia, thrombocytopenia are all examples of organ-specific autoimmune diseases

Question 22

DiGeorge syndrome

• Failure migration 3th/ 4th branchial arches
• Full phenotype:
  
  • Absent … (low calcium, tetany)
  • … palate
  • … heart defects
  • Thymic … (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

Answer 22

• 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 23

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

• Commonest cause of hypothyroidism in industrialised countries
• Particularly women over …
• Autoimmune … of thyroid: organ infiltrated by CD4 and CD8 T cells

Answer 23

• Commonest cause of hypothyroidism in industrialised countries
• Particularly women over 30
• Autoimmune destruction of thyroid: organ infiltrated by CD4 and CD8 T cells

Question 24

DiGeorge syndrome

• Failure … 3th/ 4th branchial arches
• Full phenotype:
  
  • Absent parathyroids (low …, tetany)
  • Cleft palate
  • Congenital heart defects
  • … aplasia (low T cell numbers, immunodeficiency)
• Microdeletions chromosome …
• Variable presentation
  
  • May affect any of above in isolation
  • Huge spectrum of immunodeficiency from mild-SCID-like
  • … is also common

Answer 24

• 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 25

NOTE: there are myriad inflammatory diseases (sarcoidosis, inflammatory bowel disease etc) that clearly involve the immune system but are not classified as autoimmune diseases, because they have not been demonstrated to involve ... immune responses to ... antigens

Answer 25

NOTE: there are myriad inflammatory diseases (sarcoidosis, inflammatory bowel disease etc) that clearly involve the immune system but are not classified as autoimmune diseases, because they have not been demonstrated to involve **adaptive** immune responses to **self** antigens

Question 26

* The adaptive immune system is prone to autoimmunity * Rigorous negative selection would mean a ... risk of autoimmunity, but a ... repertoire and therefore ... susceptibility to infection * Permissive negative selection would mean a ... repertoire and therefore a ... risk of infection but a ... risk of autoimmunity * Always be some potentially auto reactive T-cells produced - Peripheral ... mechanisms used to keep this process in check - if this fails, autoimmunity = ... ...

Answer 26

* The adaptive immune system is prone to autoimmunity * Rigorous negative selection would mean a **low** risk of autoimmunity, but a **poor** repertoire and therefore **increased** susceptibility to infection * Permissive negative selection would mean a **broad** repertoire and therefore a **lower** risk of infection but a **higher** risk of autoimmunity * Always be some potentially auto reactive T-cells produced - Peripheral **tolerance** mechanisms used to keep this process in check - if this fails, autoimmunity = **autoimmune diseases**

Question 27

_Monogenic disorders and autoimmunity: APACED (autoimmune polyglandular syndrome, candidiasis and ectodermal dystrophy)_ * AIRE gene regulates ectopic expression of tissue-specific antigens in thymus * AIRE mutations result in ... of negative selection * Strongly associated with organ-specific auutoimmune diseases (type 1 diabetes, vitiligo, alopecia, autoimmune adrenal disease etc) * Candidiasis also a key feature of the disease * Results from antibodies to IL-... – this cytokine seems to be important in host defence against fungi at mucosal surfaces

Answer 27

* 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) * Candidiasis also a key feature of the disease * Results from antibodies to IL-**17** – this cytokine seems to be important in host defence against fungi at mucosal surfaces

Question 28

_HLA and coeliac_ * Virtually all affected individuals express: * HLA-DQ... * HLA-DQ8 * .........or both

Answer 28

* Virtually all affected individuals express: * HLA-**DQ2** * HLA-DQ8 * .........or both

Question 29

Spontaneous urticaria manifests with ... and ...

Answer 29

Spontaneous urticaria manifests with **hives** and **swelling**

Question 30

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

Answer 30

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

Question 31

_Antibody-mediated autoimmune disease: autoimmune hyperthyroidism (Graves Disease)_ * Symptoms of hyperthyroidism (tachycardia, palpitations, tremor, anxiety, heat intolerance etc) * A G... * 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 * ... transfers disease between experimental animals * Antibody ... and ...

Answer 31

* 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 32

What is IPEX?

Answer 32

* Monogenic disorders and autoimmunity: IPEX (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

Question 33

What disease is present in bottom photo?

Answer 33

Question 34

_HLA and coeliac_ * Dietary ... (wheat, rye and barley) is degraded by gut tissue transglutamine 2 enzyme during digestion to produce ... peptides * HLA DQ2/ 8 molecules can present these ... peptides to T cells if the appropriate T cell receptors are present

Answer 34

* 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

Question 35

_HLA and coeliac_ * Dietary gliadin (wheat, rye and barley) is degraded by gut tissue ... 2 enzyme during digestion to produce gliadin peptides * HLA DQ2/ 8 molecules can present these gliadin peptides to T cells if the ... T cell receptors are present

Answer 35

* 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

Question 36

_Immunological hierarchy (Tolerance) - Mechanism_ * CD4 T cell will not be activated unless antigen is presented in an ‘inflammatory’ context with ... ligation

Answer 36

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

Question 37

The adaptive immune system is prone to ...

Answer 37

The adaptive immune system is prone to **autoimmunity** * **Rigorous** negative selection would mean a **low risk of autoimmunity, but a poor repertoire and therefore increased susceptibility to infection** * **Permissive** negative selection would mean a **broad repertoire and therefore a lower risk of infection but a higher risk of autoimmunity** * Always be some potentially auto reactive T-cells produced - Peripheral tolerance mechanisms used to keep this process in check - if this fails, autoimmunity = autoimmune diseases

Question 38

_Clonal exhaustion (Tolerance) - Mechanism_ * ... post-activation by activation-induced cell death

Answer 38

* **Apoptosis** post-activation by activation-induced cell death

Question 39

_Regulatory T cells (Tolerance) - Mechanism_ * CD25+FoxP3 positive T cells and other types of regulatory T cells actively suppress immune responses by cytokine and ... signalling

Answer 39

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

Question 40

_Peripheral anergy (Tolerance) - Mechanism_ * Weak signalling between APC/ CD4 T cell without co-stimulation causes T cells to become ...-...

Answer 40

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

Question 41

_Classification of AID (autoimmune disease) with a few examples_ * Organ-specific * E.g. T1 Diabetes, Pemphigus/pemphigoid, Graves disease, ... thryoiditis, Autoimmune cytopenias;anaemia, thrombocytopenia * Multi-system * E.g. Systemic lupus ..., ... arthritis, Sjogren's syndrome

Answer 41

* Organ-specific * E.g. T1 Diabetes, Pemphigus/pemphigoid, Graves disease, **Hashimotos** thryoiditis, Autoimmune cytopenias;anaemia, thrombocytopenia * Multi-system * E.g. Systemic lupus **erythematosis**, **Rheumatoid** arthritis, Sjogren's syndrome

Question 42

_Peripheral tolerance mechanisms_ * Failure of peripheral tolerance mechanisms may allow ... of potentially auto-reactive T cells, leading to the development of ... ...

Answer 42

* Failure of peripheral tolerance mechanisms may allow **activation** of potentially auto-reactive T cells, leading to the development of **autoimmune disease**

Question 43

_Multiple pathogenic immune mechanisms underlie autoimmune diseases_ * ‘It is a vast oversimplification to consider most autoimmune diseases to be mediated solely by one part of the immune system. It is more useful instead to consider that autoimmune responses, like responses to pathogens, engage the integrated immune system and therefore typically require T cells, B cell and APC’ * Charles Janeway * This is particularly true of the chronic, multi-system autoimmune disorders such as ... arthritis (see symposium) and S.. , where multiple immune mechanisms become involved

Answer 43

* ‘It is a vast oversimplification to consider most autoimmune diseases to be mediated solely by one part of the immune system. It is more useful instead to consider that autoimmune responses, like responses to pathogens, engage the integrated immune system and therefore typically require T cells, B cell and APC’ * Charles Janeway * This is particularly true of the chronic, multi-system autoimmune disorders such as **rheumatoid** arthritis (see symposium) and **SLE**, where multiple immune mechanisms become involved

Question 44

What are the main manifestations of coeliac disease?

Answer 44

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

Question 45

_Monogenic disorders and autoimmunity: IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-Linked)_ * What are the key features? (3)

Answer 45

* Key features: * Inflammatory bowel disease * Dermatitis * Organ-specific autoimmunity

Question 46

_Monogenic disorders and autoimmunity: APACED (autoimmune polyglandular syndrome, candidiasis and ectodermal dystrophy)_ * AIRE gene regulates ectopic expression of tissue-specific antigens in thymus * AIRE mutations result in failure of ... selection * Strongly associated with organ-specific auutoimmune diseases (type 1 diabetes, vitiligo, alopecia, autoimmune adrenal disease etc) * ... also a key feature of the disease * Results from antibodies to IL-17 – this cytokine seems to be important in host defence against fungi at mucosal surfaces

Answer 46

* 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) * **Candidiasis** also a key feature of the disease * Results from antibodies to IL-17 – this cytokine seems to be important in host defence against fungi at mucosal surfaces

Question 47

Autoimmunity represents a failure of ...

Answer 47

Autoimmunity represents a failure of **tolerance**

Question 48

_Pathogenic mechanisms in AID: T cells_ * Type ... hypersensitivity according to Gell and Coombes * Tissue damage is directly mediated by T cell-dependent mechanisms * T cells activate macrophages and other elements of innate immunity * CD.. 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

Answer 48

* Type **IV** hypersensitivity according to Gell and Coombes * 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 49

_Coeliac pathogenesis_ * The damage is mediated by ... cells; note that antibodies are produced, but do not contribute to tissue damage * Inflammation resolves with strict gluten ... * 30-50% of Europeans express HLA-DQ2 and/ or HLA-DQ8 – not clear which additional genetic/ environmental factors are important in coeliac

Answer 49

* 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 50

_The HLA system_ * APCs present processed peptide to T cells in combination with highly polymorphic ... (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 ... diseases

Answer 50

* 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 51

_Antibody-mediated autoimmune disease: myasthenia gravis_ * Production of ... antibody against the acetylcholine receptor * Reduces normal transmission at neuromuscular junction - fatigability and ...

Answer 51

* Production of **pathogenic** antibody against the acetylcholine receptor * reduces normal transmission at neuromuscular junction - fatigability and **weakness**

Question 52

_Monogenic disorders and autoimmunity: IPEX (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: * –... ... disease * –Dermatitis * –Organ-specific ...

Answer 52

* 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 53

_A note about antibodies and autoimmune disease_ * In these examples, the auto-antibody is said to be ‘...’ 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 ... * They are useful for diagnosis – see next lecture, eg * Tissue transglutaminase antibody (...), islet cell antibody (...), gastric parietal cell antibody (pernicious anaemia) etc etc

Answer 53

* 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 54

Autoimmunity (or auto-reactivity) = immune responses to ...-...

Answer 54

Autoimmunity (or auto-reactivity) = immune responses to **self-antigens**

Question 55

_Spontaneous urticaria_ * IgG FcεR1 antibody cross-links mast cell receptor causing ... * Manifests with ... and swelling

Answer 55

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

Question 56

_The HLA system_ * APCs present processed peptide to T cells in combination with highly polymorphic MHC (HLA) molecules * Encoded by the HLA system on chromosome ... * Class ...: A, B, C * Class ...: 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 ... diseases

Answer 56

* 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 57

_T cell-mediated autoimmunity: autoimmune hypothyroidism (Hashimotos thyroiditis)_ * Commonest cause of hypothyroidism in industrialised countries * Particularly ... over 30 * Autoimmune destruction of thyroid: organ infiltrated by ... and ... T cells

Answer 57

* Commonest cause of hypothyroidism in industrialised countries * Particularly **women** over 30 * Autoimmune destruction of thyroid: organ infiltrated by **CD4** and **CD8** T cells

Question 58

What is the commonest cause of hypothyroidism in industrialised countries?

Answer 58

Hashimotos thyroiditis

Question 59

_Coeliac disease - Appearance_ * Normal vs Coeliac disease

Answer 59

Question 60

...=a state of immunological non-reactivity to an antigen

Answer 60

**Tolerance**=a state of immunological non-reactivity to an antigen

Question 61

_Antigen segregation (Tolerance) - Mechanism_ * ... barriers to sequestered antigen (‘immunological privilege’)

Answer 61

* **Physical** barriers to sequestered antigen (‘immunological privilege’)

Question 62

_Coeliac pathogenesis_ * The damage is mediated by T cells; note that antibodies are produced, but do not contribute to tissue damage * ... resolves with strict gluten avoidance * ..-..% of Europeans express HLA-DQ2 and/ or HLA-DQ8 – not clear which additional genetic/ environmental factors are important in coeliac

Answer 62

* 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 63

Coeliac disease has characteristics of an ... disease, but unusually triggered by an exogenous antigen (...) in pre-disposed individuals

Answer 63

Coeliac disease has characteristics of an **autoimmune** disease, but unusually triggered by an exogenous antigen (**gluten**) in pre-disposed individuals