Genetic Susceptibility to Autoimmune Diseases & Mechanisms

• In AD, there’s a genetic susceptibility, in the vast majority of cases.

◦ This is due to many different genes acting together resulting in a failure of self tolerance and the
development of self reactive lymphocytes.

• Coupled with these multiple genetic factors, are environmental stimuli such as tissue injury, inflammation,
infection and so on.

• The above mechanisms can lead to the activation of tissue antigen presenting cells and these antigen presenting
cells can activate self reactive lymphocytes, which then become self reactive effector lymphocytes that are
actually going to carry out the damage that is occurring.

• There’ll be tissue injury, and the result will be autoimmune disease.

Examples of Autoimmune Disease Susceptibility Genes -

• Animal studies have shown that in a given autoimmune disease, as many as 20 or 30 different genes can
contribute.

• The genes that have been identified both in animal studies and in human patients include the following:

• The MHC is nearly always implicated.

◦ The MHC is involved in antigen presentation to T-cells.
◦ Virtually all polygenic autoimmune diseases, which is 99% of autoimmune diseases, have a MHC
influence on their development.

• CTLA4
◦ This is molecule that’s found on the surface of T-cells, and acts as a kind of negative regulator of T-cells,
and stops excessive T-cell responses.
◦ This gene or polymorphisms of this gene have been implicated in thyroid autoimmune diseases, in type I
diabetes and in rheumatoid arthritis.

• PTPN22
◦ This is a molecule that’s involved in antigen receptor signaling.
◦ It is implicated in thyroid autoimmune disease, type I diabetes and rheumatoid arthritis.

• Polymorphisms of complement components, particularly C1q, C2 and C4

◦ Involved in the development of systemic lupus erythematosus.

• Polymorphisms in the interleukin-2 gene

◦ The IL-2 gene is involved in stimulating lymphocytes.
◦ This gene is implicated in rheumatoid arthritis, type I diabetes and multiple sclerosis.

• The immunosuppressive cytokine IL-10

◦ Inhibitory effects
◦ Polymorphisms of the IL-10 gene have been implicated in SLE and type I diabetes.

• BLK
◦ This molecule is involved in B-cell signaling
◦ It has been implicated in SLE as well as in rheumatoid arthritis.

MHC Associations in Autoimmune Disease

• MHC Class I
◦ Myasthenia Gravis
‣ Individuals that are HLA-B8 have a relative risk of three (3) for the development of myasthenia
gravis.
‣ I.e., if an individual happens to be HLA-B8 rather than other HLA-B variants, they are three (3) times
more likely to develop myasthenia gravis.

◦ Ankylosing spondylitis
‣ The relative risk is 87 for individuals with HLA-B27.
• Note: Only around about 10% of individuals that are HLA-B27 develop ankylosing spondylitis.
So although the relative risk is really pretty high, other genes and environmental factors are
required in order to develop ankylosing spondylitis.
• MHC Class II
◦ Hashimoto’s disease ( autoimmune disease of the thyroid gland)
‣ HLA-DR5 is more commonly seen in these individuals, giving a relative risk of three (3).

◦ Type I diabetes
‣ HLA-DQ8 confers a relative risk of 14.
‣ If an individual has both HLA-DQ8 and HLA-DQ2, the relative risk goes up to 20.
‣ Some MHC genes are actually protective against autoimmune disease (e.g., DQ6 gives a relative risk
of 0.2. I.e., an individual that has HLA-DQ6 is protected against the development of type I diabetes.)

Role of Infection in the Development of Autoimmune Disease -

• Usually, encounter with self antigens will lead to tolerance, because there is an absence of co-stimulatory
molecules. I.e., the resting dendritic cell that isn’t expressing CD80 and CD86 at any great level will not provide
co-stimulation to the T-cell.
◦ This will result in self tolerance usually by anergy.

• Microorganisms contain Pathogen Associated Molecular Patterns (PAMPS) that will be recognized by the
Pattern Recognition Receptors (PRRs) on dendritic cells.
◦ This recognition causes the up-regulation of co-stimulatory molecules on the dendritic cell (e.g., the B7
molecules, B7.1 CD80, B7.2 CD86)
◦ These will interact with the molecule CD28 on the surface of the T-cell causing this self reactive T-cell to
become activated leading to autoimmunity, which in some cases may be pathogenic autoimmunity, leading
to autoimmune disease.

There are a number of ways in which infection may lead to the development of autoimmune disease:

• Molecular mimicry:
◦ This is caused by a sharing of either structures or sequence between self antigens and microbial antigens.
◦ Example:
‣ Consider a self reactive T-cell that is also capable of recognizing a microbial peptide, because there’s
a sequence in the microbial peptide that is similar to a sequence in a self antigen.
‣ Therefore there will be activation of T-cells due to this sharing of sequence between the microbial
protein and the self protein.
‣ So the peptide sequence sitting in the MHC will be the same between the microbe and self.
‣ So a normal immune response, is developed against an infection.
‣ But unfortunately, some self peptides have the same sequence and therefore the T-cells will recognize
not only the foreign microbial proteins but also self proteins again leading to the development of
autoimmunity which in some cases may be pathogenic and lead to autoimmune disease.