Zee’s autoimmunity, basic concept and examples

Lecture objectives:1. Introduce areas of autoimmunity2. Key features of immune system and autoimmunity3. Examples of autoimmune diseases4. Current treatment strategies

Summary points: Immune tolerance mechanisms have evolved to reduce extent of autoimmunity Genetic association with many autoimmune diseases, HLA being the most prominent

association Signs of autoimmune disease comes long after it has already occurred No known cures for autoimmune diseases Treatments mediate immune response, target inflammatory mediator, block/alters immune

cell function HSCT is actively trailed for RA, MS, SLE

1. Introduce areas of autoimmunity

Adaptive immunity is simply the appropriate immune response should the immune system be targeting a FOREIGN PATHOGEN.

When this adaptive immune system targets SELF, this is known as AUTO-IMMUNITY.

Reasons why autoimmunity occur: Body routinely selects/destroys T-cells and B-cells

o High affinity for self T/B cells are DESTROYEDo Low affinity for self T/B cells are SELECTED – Positive selection

Somatic recombinationo May variations due to V-D-J joining creates many kinds of T and B-cells

Resulto System is not imperfect – Some high affinity cells are not destroyed and are

released into the bodyo These high affinity cells bind to self, and cause autoimmune diseases

People get autoimmune diseases because of:o Genetic predispositiono Environmental factors

2. Key features of immune system and autoimmunity

Feature ExplanationTakes time before clinically relevant Autoantibodies affect some cells and progressively gets

worse – Minor effects at the start, can get worse after exposure to environmental triggers(T1DM)

Specific immune cell causes the autoimmune disease

For specific diseases, either the antibody (e.g. IgE) or T-cells (CD4, CD8) are the ones that cause the disease – not the entire immune system at fault (i.e. people do not get all autoimmune disease, just some types!)

3. Examples of autoimmune disease4. Current treatment strategies

Type I diabetes Rheumatoid Arthritis Multiple SclerosisPathophysiology Targets insulin-secreting beta

cells of the islets of LangerhansChronic inflammatory environment within joint; immune cells cause cartilage destruction

Event within CNS leading to antigen presentation

Auto-antigens InsulinProtein tyrosine phosphateIGRP

(Not known but) Collagen, proteoglycans, heat-shock protein

Localised to myelin sheaths which are produced by oligodendrocytes

Specific immune cell cause CD4, CD8, B cellsIslet: CD8 T cells

MHC presence suggests T-cell involvementAnti-IgG rheumatoid factorImmune complexes (cytokines)

CD8 cells

Treatment - Insulin replacement, but increases risk of chronic hypercycaemia and co-morbidities- Islet transplant (tissue rejection)- Autologous HSCT

No cure- Anti-TNF-a: Targets inflammatory cytokines combined with low dose methotrexate- Autologous bone marrow transplantation

No cure- Anti-VLA4 humanised antibody treatment- Interferon beta treatment- Glatriamer acetate that mimics myelin and binds to MHC - Autologous bone marrow transplantation

Other stuff Increase in number of autoantibodies is evidence of immune response spreading to other targets