Autoimmunity occurs when the immune system, which usually protects the body, mistakenly targets the body's own cells and tissues. There are about 100 different autoimmune conditions that affect 5-9% of the adult world population.
Lab testing shows that an increasing number of Americans have positive antibody results that may suggest autoimmunity. These autoantibodies can sometimes be detected in the blood years before the actual appearance of clinical symptoms. This is because autoimmune conditions may progress through stages such as initiation (activation), propagation (symptom presentation), tissue damage, degeneration, and deformation.
Detecting autoimmune conditions at the initiation stage, rather than at the stage of degeneration and deformation, may help in managing the condition more effectively. Blood tests that measure antibodies against ANA, ENA, dsDNA, RF, actin, mitochondria, and immune complexes can be used for screening. This screening at the subclinical stage provides a window of opportunity for healthcare providers to consider early intervention.
[signup]
Introduction
According to experts, autoimmunity is when the body fails to recognize its own tissue, leading to an immune response against its cells and tissue antigens. Any condition resulting from such an abnormal immune response is labeled an autoimmune condition.
Autoimmune conditions affect 5-9% of the world’s population and can be identified by the presence of certain autoantibodies and autoreactive cells. One way to understand this is to think of the immune cells as the body’s defensive army; if the regulatory T-cell (Treg) is not functioning properly, the autoantibodies and autoreactive cells may start attacking the body's own tissues.
In autoimmune conditions, it seems that certain autoantibodies or reactive T cells against defined self-antigens can appear in the blood years before the development of active symptoms. Studies show that autoantibodies can be present in the blood from 3 months to 19 years before the development of different autoimmune conditions.
A comprehensive review by Ma et al. published in the Journal of Autoimmunity in 2017 suggested that the causes of autoimmune conditions may include a combination of genetic predisposition and environmental factors that influence gene expression through mechanisms like epigenetics. It also showed that autoantibodies had been detected in most autoimmune conditions before the appearance of clinical symptoms.
For example, it was demonstrated that antinuclear antibody (ANA) and ribonuclear protein/extractable nuclear antigens (ENA) may appear in the blood of individuals with lupus and Sjögren’s syndrome 7-8 years before symptoms, while the presence of anti-mitochondrial M2 antibody in the blood may precede the clinical manifestation of primary biliary cirrhosis by 19 years. This is because autoimmune conditions may develop through stages such as initiation, activation, propagation and symptom presentation, tissue damage, degeneration, or deformation.
Individuals in the initiation phase, even with the presence of antibodies in the blood, may not be aware of early clinical symptoms either because their healthcare provider does not order any specialized blood tests or they consider standard tests as sufficient, and thus screening for possible autoimmunity may not be done correctly.
Diagnosing an autoimmune condition can be a time-consuming and challenging task. This is because many of these conditions share similar symptoms, making it difficult for healthcare practitioners to identify the specific autoimmune condition. Initial symptoms may include fatigue, aching tendons or muscles, inflammation, and low fever. Many individuals are not diagnosed until these symptoms become more pronounced.
Furthermore, autoimmune conditions are reportedly on the rise. About 52 million Americans are affected by autoimmune-related conditions.
In a study published in 2020 in the journal Arthritis & Rheumatology by the National Institute of Environmental Health, Dr. F. Miller and his group reported that while in the 1970s, only 4% (8 million) of the population were ANA positive, ANA positivity between 1988-1991 increased to 11% (22 million), and from 2011-2012 rose to 15.9% or 41 million.
These scientists suggested that because people have not changed genetically in the past 50 years, factors related to the environment and lifestyle could be involved in the increase of ANA in the population.
This role of environmental triggers was addressed in three different manuscripts, one published in 2015 in the Journal of Autoimmunity, and the additional two in the Journal of Pathophysiology in 2021 and 2022 by this author.
Overall, the data suggests that currently, at least 41 million Americans may be in the process of developing some kind of autoimmune condition without having any clinical symptoms. Thus, early detection of autoimmune conditions at a subclinical stage is important because it provides a window of opportunity for intervention.
Diagnosis of Autoimmune Conditions
The diagnosis of autoimmune conditions is based on clinical symptoms and serological assays such as ANA, ENA, rheumatoid factor (RF), and immune complexes.
The detection of other autoantibodies can be employed for more specific determination of autoimmune conditions, such as double-stranded DNA antibody elevation in lupus erythematosus and citrullinated peptide antibody in rheumatoid arthritis, and actin and mitochondrial antibody in autoimmune liver disease.
Furthermore, autoantibodies can help determine the progress of the condition and whether or not therapy implementation has been effective.
Biomarkers Used in Preclinical and Clinical Diagnosis of Autoimmune Conditions
ANA (Antinuclear Antibodies)
ANA are antibodies that may target normal proteins in the nucleus of the body cell. Abnormal levels of ANA are used as a screening for many autoimmune conditions.
High levels of ANA are detected in individuals with rheumatoid arthritis, scleroderma, lupus, vasculitis, Sjögren’s syndrome, and mixed connective tissue disease (MCTD).
ENA (Extractable Nuclear Antigen)
These antibodies may target normal proteins called ribonucleoproteins or proteins that do not contain DNA.
Because ANA is found in a wider variety of connective tissue conditions, it cannot detect specific conditions, but it is used as a sensitive screening assay. In comparison, elevated ENA can contribute significantly to the diagnosis and prognosis of individuals suspected of a variety of connective tissue conditions such as scleroderma, polymyositis, Sjögren’s syndrome, and systemic lupus erythematosus (SLE).
Overall positive ENA indicates a reaction with SSA, SS-B, Sm, RNP, SCL-70, and Jo-1 antigens which requires specific testing. Autoantibodies against ENA occur in a large number of individuals with systemic rheumatic conditions.
dsDNA (Double Stranded Deoxyribonucleic Acid)
Autoantibodies to single-stranded and double-stranded DNA are detected in different autoimmune conditions. While these antibodies are not disease-specific, single-stranded DNA antibodies are detected in the blood of individuals with a range of autoimmune conditions that include SLE, drug-induced lupus, MCTD, RA, scleroderma, and Sjögren’s syndrome. But anti-dsDNA is more specifically detected in the blood of individuals with SLE, where immune complex formation between antigen and antibody, along with the involvement of complement, together may play a role in the induction of inflammation and damage to the renal and vascular tissues.
RF (Rheumatoid Factor)
This IgM antibody is produced by the immune system and may work against our IgG when it aggregates.
Factors that aggregate IgG:
- IgG drug conjugate
- IgG bacterial antigen conjugate
- IgG lectin conjugate
RF is the most consistent serological marker found in about 70-80% of individuals with RA. Elevated RF is detected in the blood of individuals with parasitic conditions, liver conditions, sarcoidosis, and SLE. An increase in the level of RF may accompany a variety of acute immune responses, particularly infections with different viruses, including Epstein Barr Virus (EBV).
Anti-Actin or Smooth Muscle Antibody
Actin is a major component of smooth muscle. Antibodies are usually directed against the actin component of the cytoskeleton. Usually, low amounts of these antibodies are detected in 3-18% of sera obtained from the general population. However, anti-actin antibodies are found in 52-85% of individuals with autoimmune hepatitis (AIH) or chronic active hepatitis (CAH) and 22% of individuals with primary biliary cirrhosis (PBC).
Mitochondrial Antibodies
The mitochondrial (M2) antigen is part of the pyruvate dehydrogenase (PDH) complex of tightly organized polypeptides and cofactors that work together in concert. The enzyme converts pyruvate into acetyl-coenzyme A in the citric acid cycle, which is important in cellular respiration inside the mitochondria. Anti-mitochondrial antibodies (AMA) are detected in individuals with PBC.
Since the presence of AMA can precede the development of symptomatic conditions, the ability to identify the presence of markers for PBC can contribute to earlier diagnosis and management and may help to slow the progression of the condition.
Note: Chemical xenobiotics used in cosmetics and food additives were discovered to share homology with PDH and mitochondrial antigen. Thus mitochondrial antibodies may also be detected in the blood due to a reaction to these xenobiotics.
Circulating Immune Complexes (CIC)
Circulating immune complexes that bind C1q complement are present in human serum in small quantities that are removed by the Kupffer cells of the liver. However, in the presence of overwhelming amounts of antigens and antibodies, antigen-antibody interactions and abnormal liver function can result in the formation of immune complexes.
If these complexes are deposited in vascular structures, the result can be a complex immune condition accompanied by tissue damage.
High levels of C1q binding immune complexes are detected in individuals with an active humoral immune response to infectious agents and other environmental factors. Very significant elevations of immune complexes were reported in cancer patients, and their levels correlated with the stage of the condition.
Immune complexes can be deposited in the joints and kidneys, contributing to inflammation and autoimmune conditions such as rheumatoid arthritis, lupus, and nephropathy.
The Importance of Identifying Early Autoimmune Events
Understanding the immunologic response specific to inciting agents is important for identifying the early events necessary for the development of autoimmunity and other conditions. It is believed that understanding the exposome-induced antibody response will provide insights into the early events necessary for creating and expanding autoreactive T and B cells, a key feature of the autoimmune response.
Summary
Identifying early events in the course of condition development is a core principle of functional medicine and personalized lifestyle medicine.
In this article, we have mentioned that environmental factors may play a role in inducing autoimmunity, and we have only touched on infections, one of the commonest of these environmental triggers. Examples of infections that may play a role in autoimmunity include viruses such as EBV, CMV, HSV-1, HSV-2, HHV-6, VZV, measles, SARS-CoV-2, and Lyme disease and its co-infections.
More information about these infections, their involvement with the silent epidemic of autoimmunity, and the importance of the reliable and accurate measurement of their biomarkers will be discussed in additional articles.
%201.svg){kind=logo}
