Diseases of the Immune System 1

Question 1

What is central tolerance?

What is peripheral tolerance?

Answer 1

CT - During differentiation of lymphocytes we have mechanisms to prevent the generation of mature lymphocytes which may recognise self antigens (e.g. education & selection of T cells in the thymus)

PT - We have additional mechanisms to reduce the chance of mature cells being activated

Question 2

How do we have soo many TLRs (lymphocyte receptors)?

Answer 2

• The TCR and BCR genes are chopped up into segments and stuck back together to make different receptors
• Receptors are made from the recombination of gene clusters.

Question 3

Explain B cell receptor development

Answer 3

Question 4

How are B cells tested for auto reactivity before leaving the bone marrow?

Answer 4

Question 5

Explain T cell development

Answer 5

Question 6

How do we teach T cells about ALL the antigens in the body?

Answer 6

• Autoimmune regulator (AIRE) - gene
• AIRE is expressed in the nucleus of thymic medullary stromal cells
• It is a transcriptional regulator which induces the expression of self proteins in the thymus. (problems = autoimmune diseases)

Question 7

Why is there slow destruction of tissue when there is loss of AIRE gene?

Answer 7

Question 8

Draw a Natural T regulatory cell & how it works

Answer 8

Question 9

Explain inducible Tregs

Answer 9

Question 10

Explain dysregulation of Th17 cells and Tregs in the inflammatory process

Answer 10

• In humans Th17 cells are associated with several diseases including RA, SLE, MS, Psoriasis and IBD
• Chronic inflammation and tissue damage will continue to promote the expansion of Th17 cells (IL-6 &IL-1)
• IL-17 promotes the release of more pro-inflammatory mediators and MMPs. Disruption of this is a target for treatment of inflammatory diseases.
• Tocilizumab (TCZ) is a humanized anti-IL-6 receptor antibody which disrupts Th17 cells production
• LOSS of Treg function (when mutation in Foxp3 gene) –> IPEX syndrome (Immunodeficiency disorder)

Question 11

Types of immunodefiency & define

Answer 11

Immunodeficiency - failure of the immune system to protect the body adequately from infection, due to the absence or insufficiency of some component process or substance

1. Primary - Inherited mutations
2. Secondary - Acquired from diseases or environmental factors (e.g. starvation, HIV)

Question 12

What are some problems with lymphocyte generation?

Answer 12

• Severe Combined Immunodeficiency (SCID)
  
  • A defect In T Cell development which mean patients cannot make T-Cell dependent antibody responses.
  • Most common is X-linked

Question 13

3 approaches to treatment of X-linked SCID

Answer 13

• Prophylactic treatment – Sterile environment, antibiotics, immunoglobulins.
• Bone Marrow Transplant – Relies on close HLA match and succesful reconstitution.
• Gene therapy – First trial in 1990s with adenosine deaminase (ADA) SCID replaced the gene in peripheral T cells which survived for a decade.

Question 14

Explain AIDS

Answer 14

Acquired Immune deficiency syndrome (AIDS)

• Caused by the human immunodeficiency virus (HIV)
  
  • HIV targets cells which express CD4 and uses CCR5 or CXCR4 as a co-receptor
  • Infect mucosal CD4+ cells and spreads in Lymph nodes as T cells enriched with CCR5

1. Acute Phase
   
   • Influenza like symptoms in 80% cases ↓ in circulating CD4, activation of CD8. Virus killing and antibody production.
2. Clinical Latency
   
   • Get persistent replication of virus and CD4 cell count falls. Virus mutates rapidly to avoid CD8 cells.
3. AIDS
   
   • 6-20years after latency

LOW numbers of CD4+ cells

Question 15

New therapy for AIDS patients

Answer 15

New Therapies – Chimeric antigen receptor T Cells