Autoimmune Diseases

Continuing on from my posts on hypersensitivity, where your immune system reacts inappropriately to an innocuous antigen, I'm now going to talk about autoimmune diseases, where your immune system reacts inappropriately to your own body! Such autoimmune diseases are rare, but the risk of developing one may be linked to your own personal brand of MHC molecules.

Development of Tolerance

Just as a reminder, both B-cells and T-cells undergo negative selection to reduce the possibility of self-reaction. This process is called central tolerance when it happens in the primary lymphoid organs (bone marrow and thymus), or peripheral tolerance when it happens somewhere else. A B-cell that is self-reactive will be stimulated to undergo apoptosis or receptor editing, as outlined here. T-cells that are self-reactive are stimulated to undergo apoptosis, as outlined here. If central tolerance fails to weed out all of the self-reactive cells, regulatory T-cells (which I've spoken about here) swoop in and play a role in peripheral tolerance.

Tolerance is defined as immunological unresponsiveness to self-antigens. Regulatory T-cells can bind to MHC-II displaying "self" peptides on B-cells, causing either anergy (i.e. making the cell unreactive), apoptosis and/or release of cytokines that inhibit surrounding autoreactive T-cells. (At least, that's my understanding of how it works.)

Breaking of Tolerance

There are several ways in which tolerance can be broken.

Infection with certain viruses

Certain viruses can cause activation of immune cells. For example, the Epstein-Barr virus (EBV), which is responsible for infectious mononucleosis (a.k.a. "the Kissing Disease") causes random activation of B-cells. Some of these B-cells might include anergic self-reactive B-cells. When activated, they are obviously no longer anergic- they're ready to kill and wreak havoc. Since many B-cells are activated at once, many non-specific antibodies are produced.

This method was discovered via experiments with mice. Transgenic mice were made that express a nucleoprotein from the LCMV virus in their pancreatic β cells. These mice built up tolerance to the nucleoprotein, but still had some anergic B-cells that were reactive against it. When these mice were infected with LCMV, these anergic B-cells became active and killed the pancreatic β cells that were also expressing the nucleoprotein. As a result, these rats became diabetic.

Release of sequestered antigen

There are several antigens around the body that usually "hide" from the immune system- for example, in the brain, eyes and testes. (I've mentioned how this affects the brain here.) When these organs are damaged, these normally "hidden" antigens may be released, causing activation of T-cells. The T-cells then go around and start attacking the source of the antigen.

Molecular mimicry

Some pathogens have antigens that are very similar to our own. For example, some of the antigens on the cell wall of streptococci are similar to those in our heart. Hence, antibodies against streptococcus can cause rheumatic fever and rheumatic heart disease. I've gone more into depth on rheumatic fever in an earlier post for PHGY350.

Other Autoimmune Diseases

The remaining autoimmune diseases that I'm going to cover will draw on many principles of types II, III and IV hypersensitivity, which I've covered in a previous post.

Graves' Disease

I've covered Graves' Disease before, but just a recap: autoreactive B-cells make antibodies against the TSH receptor, causing the thyroid to produce more thyroid hormones. This is one cause of primary hyperthyroidism. Graves' Disease can be considered to be similar to type II hypersensitivity in that IgG is reacting against cell-surface antigens.

Myasthenia Gravis

Myasthenia gravis is also similar to type II hypersensitivity, in which IgG is reacting against cell-surface antigens. In this case, IgG is reacting against acetylcholine receptors on muscle cells, causing them to be endocytosed and degraded. As these receptors are required for muscle contraction, myasthenia gravis manifests in abnormal muscular weakness, fatigue and ptosis (droopy eyelids).

Rheumatoid Arthritis

In contrast to the past couple of diseases, rheumatoid arthritis is more similar to type III hypersensitivity, in which IgG reacts against a soluble antigen and immune complexes are formed. These immune complexes are formed in joints, causing redness, pain and swelling (so basically just inflammation) in the lining of joints. 80% of people with rheumatoid arthritis are positive for rheumatoid factor (RF), which is essentially IgG or IgM binding to self-antigens on other antibodies (usually IgG).

Systemic Lupus Erythematosus (SLE)

SLE is also similar to type III hypersensitivity. In SLE, antibodies are created against self-DNA, resulting in immune complexes and inflammation in many areas of the body. Blood vessels, the heart, lungs, joints, kidneys and skin can all be affected, with some patients developing a characteristic "butterfly rash" on the face. Steroids may be prescribed to reduce inflammation.

Diseases similar to type IV hypersensitivity

Some diseases have characteristics in common with type IV hypersensitivity, which is mediated by T-cells, macrophages etc. These include diabetes and multiple sclerosis. Rheumatoid arthritis also involves some antigens which are attacked in a process similar to type IV hypersensitivity.