Autoimmunity

Question 1

Define what autoimmunity is

Answer 1

• This is the presence of immune responses (autoreactive T & B-cells) of an organism against self-tissue/cells
• Resulting in significant tissue/organ damage &/or chronic inflammation

Question 2

Describe the pathogenesis of autoimmune diseases

Answer 2

Autoimmunity diseases develop when self-reactive lymphocytes escape from these tolerance mechanisms and become activated

Question 3

Autoreactive T cells and B cells are generated normally in primary lymphoid tissues during lymphopoiesis but are normally killed or inactivated by protective (tolerance) mechanisms, what are these mechanisms ?

Answer 3

1. Deletion of self-reactive lymphocytes in primary lymphoid tissues (central tolerance) where they are made
2. Inactivation of self-reactive lymphocytes in peripheral tissues that escape central tolerance (peripheral tolerance) e.g. Regulatory T cells (TREG cells)

Question 4

Define what is meant by self-tolerance

Answer 4

Self-Tolerance = non-responsiveness of lymphocytes to specific self-antigens

Question 5

What is the funtion of regulatory T-cells ?

Answer 5

• Regulatory T Cells make up 5-10% of the normal CD4+ T cell population
• They function to suppress hyper-reactive or auto-reactive T cells (inactivation of lymphocytes –Via production of anti-inflammatory cytokines

Question 6

Describe the genetic influences in autoimmune disease development

Answer 6

Autoimmune disorders may result from:

1. Single gene defects causing autoimmune diseases are rare such as IPEX syndrome
2. Most autoimmune diseases result from complex genetic interplay involving HLA genes, Genes determining sex & Other immune response genes

Question 7

Describe what IPEX syndrome is and its inheritance

Answer 7

• It is a rare X-linked autoimmune disorder which results from mutation in the FOXP3 gene, which is essential for the normal development of regulatory T-cells.
• Hence, IPEX is a failure of peripheral tolerance mechanisms due to defective/absent regulatory T cells (Tregs)

Question 8

Who is only affected by IPEX syndrome and why?

Answer 8

Males - due to being X-linked

Question 9

What are the clinical features of IPEX syndrome ?

Answer 9

Presents early in childhood with:

• Severe infections
• Intractable diarrhoea
• Eczema
• Very early onset insulin dependent diabetes mellitus
• Autoimmune manifestations

Question 10

What is the treatment of IPEX syndrome ?

Answer 10

• Cure: hematopoietic stem cell transplantation (HSCT)
• Supportive care: immunosuppressive drugs + total parental nutrition

Question 11

What are Major Histocompatibility (MHC) molecules/ HLA (Human Leucocyte Antigen) molecules and what are they needed for ?

Answer 11

• MHC molecules in humans are also referred to as HLA (Human Leucocyte Antigen) molecules
• T-cells require protein antigens to be processed and presented to their T-cell antigen receptor (TCR) in complex with Major Histocompatibility Complex (MHC) molecules

Question 12

What are the different types of HLA/MHC molecules and which cells express them?

Answer 12

There are class I & class II molecules:

1. All nucleated cells express several types of Class I molecules on their cell surface - HLA-A, HLA-B and HLA-C
2. Specialised antigen-presenting cells also express additional Class II molecules - HLA-DR, HLA-DQ and HLA-DP

Question 13

HLA/MHC class I and II molecules are encoded by what?

Answer 13

HLA (MHC) class I and II genes, each of which is highly polymorphic

Question 14

Why are HLA/MHC genes & in turn molecules highly pleomorphic ?

Answer 14

To maximise the net ability to bind all antigenic peptides through having:

• Multiple different subtypes of HLA molecules
• Individual HLA molecules exhibit significant allelic diversity

Question 15

List some of the risk factors for the development of autoimmune disorders

Answer 15

• Women of childbearing age
• People with a family history
• People who are around certain things in the environment - infection, smoking, hormone levels
• People of certain races or ethnic backgroundse.g. T1DM is more common in white people. Lupus is most severe for African-American and Hispanic people.
• Antigen sequestration - tissues which do not communicate with blood or lymph (testis, eye, brain). Self-antigens normally sequestered from the immune system can become exposed and cause an autoimmune reaction during infections/trauma

Question 16

How are autoimmune diseases classified ?

Answer 16

1. Organ-specific diseases
2. Non-organ specific or multisystem autoimmune diseases

Question 17

What are the 2 autoimmune disorders mediated by type II hypersensitivity reactions ?

Answer 17

1. Goodpasture’s syndrome (antibodies bind to basement membrane)
2. Graves’ disease (antibodies bind to TSH receptor)

Question 18

What is the autoimmune disorder mediated by type III hypersensitivity ?

Answer 18

SLE

Question 19

What is the autoimmune disorder mediated by type IV hypersensitivity ?

Answer 19

RA