It has been said that “all diseases are due to allergy”. It may not be far from the truth.
The concept of the causation of disease is changing.
Diseases of unknown origin were described as idiopathic, essential or cryptogenic in the past. Immune system and genetic abnormalities are now being discovered in most of these diseases.
Perhaps the most important of these is the discovery of regulatory T-cells or TREGS and their abnormalities in disease.
TREGS are types of white cells called lymphocytes which control the activity of the immune system. The TREG cells involved include lymphocytes known as CD4+ and CD25+ lymphocytes.
When TREGS are less active the immune system becomes more activated as happens with auto-immune disease e.g. diabetes.
When TREGS are more active the immune system becomes less activated as happens in infection and cancer.
How does the immune system work?
The immune system is exposed to a substance.
Substances tend to be bacteria, viruses, ingestants e.g. food/drink, inhalants e.g. pollen/atmospheric pollutants or contact substances e.g. deodorant/soaps. These substances are called exogenous substances.
Sometimes the substance is made by the body itself and is then called endogenous. If the substance is made in excessive quantities due to abnormal metabolism the immune system may regard the substance as “non-self”. Cancer cells are also regarded as “non-self”.
Substances are ingested by immune cells called macrophages and digested (n.b. macrophages in the brain are called microglia) . Pieces of the substance are exposed on the macrophage cell surface (MHC II complexes). The macrophages are now called antigen presenting cells or APCs. White cells called T helper lymphocytes attach to these complexes.
There then follows various types of response known as Th(helper)1, Th2, Th3 and Th17 responses. The Th1 response is associated with allergy and the Th2 response is associated with auto-immune disease.
Substances called cytokines and antibodies are released which cause tissue damage.
White cells called killer cells destroy “non-self” cells e.g. cancer cells and bacteria/viruses.
This is called the immunogenic response.
What do TREG cells do?
If substances presented to the immune system by the APCs are recognised by TREGS as “non-self” the TREG cells allow the immunogenic response to proceed.
If substances presented to the immune system by the macrophages are recognised by TREGS as “self” the TREG cells suppress the immunogenic response.
How is TREG activity abnormal in different diseases?
Infection – TREG activity is overactive and reduces the immune response towards bacteria/viruses.
Cancer – TREG activity is overactive and reduces the immune response towards cancer cells.
Auto-immune disease/allergy – TREG activity is underactive and increases the immune response towards the body`s own tissues.
What examples are there of TREG abnormalities in brain disease.
1. Acute infection (encephalitis)
Some studies have found that there is a relative deficiency of TREGS in patients with severe acute brain infection (encephalitis) when compared to those with mild disease.
This suggests that increasing brain TREGS in acute encephalitis may provide protection against a tissue damaging immunogenic response.
TREG numbers surrounding the area of brain affected by a stroke increase and reduce the immunogenic response and further tissue damage.
This suggests that increasing brain TREGS following a stroke may provide protection against a further damaging immunogenic response.
3. Brain cancer
Patients with more aggressive brain tumours which have worse outcomes have more TREGS within the tumour.
This suggests that reducing TREG activity within brain tumours may increase the immunogenic response to the tumour and a better outcome.
What is the importance of these findings for the future?
1. TREG lowering drugs
Aciclovir, a drug used to treat herpes, is known to lower TREGS and is being considered as part of the treatment for brain tumours.
2. Removing or depleting TREGS from the body
Depletion of TREGS led to an improved survival in patients with TREG-rich brain tumours.
3. Increasing TREGS
Increasing TREGS resulted in suppression of microglia and the immunogenic response in the parts of the brain (nigrostriatal area) affected by Parkinson`s disease.
Manipulation of TREGS will be a challenging but could be an eventually rewarding approach to the treatment of brain disease in the future. Unfortunately, it has been difficult to transfer laboratory findings into human application at the present time.
TREG depletion in tumor treatment
TREG enhancement in Parkinson`s disease