WHAT CAUSES AUTOIMMUNITY?
Research indicates that genetic factors together with exposure to environmental triggers may cause immune dysregulation and the development of Autoimmunity. Multiple factors add up to create the perfect storm.
​
The balance of immunity (diagram below). Genetics and environmental triggers promote the development of Autoimmune disease. Balance must be maintained between Regulatory T cells & pathogenic T effector cells.
Reference: (Vojdani, 2014)
GENETICS
HLA - CTLA4 - FOXP3 - PTPN22 - STAT3- TNF - IL6
Epidemiologic studies implicate both genetic predisposition and epigenetic modifications in loss of tolerance and Autoimmunity. Small changes in the DNA code, called polymorphisms, in specific genes increase a person’s risk of developing autoimmune disease. There isn't one specific gene (monogenic) for Autoimmunity, there are multiple interacting susceptibility genes (polygenic) that work together to produce an abnormal phenotype. A predisposition to Autoimmune disease will be the net effect of enhancing and protective genes. Genes may also define the target organs e.g. HNF1A genotype is associated with Diabetes. Once the genes switch on for Autoimmune disease they don't switch off.
​
Interestingly, the x chromosome is known to contain the largest number of immune-related genes of the whole human genome. Since females account for a larger % of the population with Autoimmune diseases, this area of research has sparked much interest. There are many genes and gene families that have been correlated with different Autoimmune diseases. In the 70's, the human leukocyte antigen (HLA) region of the genome, first became linked to Autoimmune disease. These genes are involved in presenting antigens to immune cells and are now known to account for high risk for many Autoimmune diseases. Interestingly, researchers in Japan are compiling a first-of-its-kind genetic database for Autoimmune and autoinflammatory diseases. This resource will allow experts to more deeply understand how immune disorders develop. Infections can initiate Autoimmune disease if you have a genetic predisposition. For example human parvovirus can turn on Celiac disease if you have the genotype for celiac which is HLA Q2 and 8.
​
An visual example of the complex biochemistry in an epigenetic cell mechanism in Lupus (diagram below)
Environmental factors, such as cigarette smoke, chemicals and viral infections cause oxidative stress, which activates the mTOR pathway which inhibits DNA methyltransferase 1 (DNMT1). Oxidative stress contributes to CD4+ T cells (an immune cell) becoming autoreactive and hence Autoimmunity.
Reference: Anaya JM, Ramirez-Santana C, Alzate MA, Molano-Gonzalez N and Rojas-Villarraga A (2016) doi.org/10.3389/fimmu.2016.00139
ENVIRONMENTAL TRIGGERS
PATHOGENS - INFECTIONSÂ - FOODS - HEAVY METALS - MEDICATIONS - HORMONES - LACK OF SLEEP - LACK OF EXCERCISE - STRESS - TRAUMA -Â MOLD - OVER EXCERCISING - POLLUTION - CHEMICALS
Studies of genetically similar populations living in different conditions suggest environmental influences play a role. The Autoimmune ecology describes interactions between individuals and various factors from their environment leading to a breakdown in immune tolerance and the development of Autoimmune disease.
​
Modern Living is fast paced and ever changing. We are exposed to hundreds and thousands of chemical compounds in our foods, air, water, soil, personal care products, medications, and household cleaners during manufacture, distribution, use, and disposal of products.
​
In addition, stressful life events, infections, pollution, lack of sleep, changing diets, lack of exercise, cigarette smoke or alcoholic drink compositions, drugs, dietary supplements, cosmetics, hair dyes, ultraviolet and other radiation, electric and magnetic fields can all have an impact on the body's delicate immune recognition system.
​
It would be a challenging task to estimate our full exposure and the long term impact of infectious and non infectious environmental agents. Clinical and epidemiologic investigations show that environmental factors may impact multiple immune system checkpoints in the complexity of an individual's unique genetics to trigger onset and drive the progression of Autoimmunity.
​
Its absolutely crucial to understand the root cause of what could be triggering an Autoimmune condition. Reducing exposure to that trigger will lower inflammation in the body and help towards keeping a control on the disease. Lab testing can help identify triggers by identifying antibodies towards the toxin, food or pathogen.
IMMUNE DYSREGULATION
Immunology research suggests there are multi factorial immune mechanisms that play a role in the development of Autoimmunity. These mechanisms will vary across individuals and also as Autoimmunity progresses within the individual, they may have a combination of these mechanisms causing imbalance. For example if two individuals present with Multiple Sclerosis, they may have different mechanisms that have led to the disease. This is why it is very important to have a personalised approach to Autoimmune conditions and to understand the biology of that individual to target these imbalances directly. Autoimmunity is complex, it involves multi-orchestrated immune responses, its never just one thing that is going wrong, that is what makes it difficult to cure.
​
Examples of causes of immune dysregulation in Autoimmunity, these may be discussed further across this website:
​
Abnormal T Cell differentiation into TH-1, TH-2, TH17, TH9, TH22, Tfh cells causing immune imbalance
Barrier permeability (Lungs, Gut, Blood Brain Barrier) leading to endotoxemia and high pathogen load
Active Infection (viral, bacterial, fungal) with a pathogen causing upregulation of the immune system
Overactive phagocytic cells (monocytes, neutrophils, eosinophils, macrophages, dendritic cells, basophils)
Dysfunction of immune cells (regulatory T cells (TReg), cytotoxic T cells (CD8), suppressive T cells (CD4), T Helper cells, B cells) causing immune dysregulation
Low white blood cells production due to immune exhaustion and chronicity of infection
Dysregulation in complement protein function causing upregulation of adaptive immune system
Chemicals binding to immune and endocrine receptors
Chemicals binding to tissue proteins forming neo-antigens this is called Haptenation
Abnormal microbiome causing dysbiosis and a dysregulated immune function
Psycho-neuro immune implications of immune dysregulation eg stress
Brain injury can lead to immune dysregulation
Dysfunction in autophagy ie breakdown and clearance of healthy cells causing immune system to dysfunction
The immune system can confuse the body's own proteins with a foreign antigen, this is molecular mimicry
Different chemicals and pathogens can infiltrate DNA and change cell structure
And there are many more...
The interplay between Autoimmunity, dysbiosis, intestinal permeability, immune dysregulation & inflammation. (These concepts are implicated in the causes of Autoimmunity, you can learn more about them in Education).
Reference: (Bradley Leech, Bradley McEwen, and Eric Owusu Sekyere, 2020).
doi.org/10.1089/act.2020.29287.ble
