Disease Development - Autoimmune Disease  |  Johns Hopkins Pathology (2022)

Disease Development - Autoimmune Disease | Johns Hopkins Pathology (1)

How do autoimmune diseases unfold?

Although we do not know what causes autoimmune diseases, we have learned a great deal about their "pathogenesis" (or "natural history")—how the disease progresses over time and damage ensues.

Three factors are at play in the pathogenesis of autoimmune diseases: genes, immune system, and the environment where the patient lives. The genes confer what is called "predisposition" or genetic susceptibility. The immune system becomes dysregulated and provides the tools for executing the pathological damage. The environment delivers the triggers that may make the autoimmune disease clinically apparent.

We have also learned that autoimmune diseases are chronic conditions: they require a long time (years) before they become clinically evident and diagnosis (so, they have long latent phase), and then last for decades (often a life time) once diagnosed.


An undeniable role for the genes

Autoimmune diseases tend to occur in the same family (the so-called "familial aggregation)". Similarly, the concordance rate of a given autoimmune disease in identical twins (typically between 25% and 50%) is about 10 times higher than that in fraternal twins (typically between 2% and 8%). These observations indicate that autoimmune diseases are strongly influenced by the patient's genes.

Is there an "autoimmune disease gene"?

Decades of effort have been devoted to study the genetics of many autoimmune diseases, with the main goal of identifying the autoimmune gene or genes. Results have shown that there isn’t a single autoimmune gene.

Autoimmune diseases, for the vast majority of cases, do not fit any simple pattern of inheritance. On the contrary, they are thus considered polygenic (multifactorial) diseases.

Disease Development - Autoimmune Disease | Johns Hopkins Pathology (2)

Different Genes, Different Odds

Numerous genes have been shown to increase the risk of developing autoimmune diseases. The individual impact of each of these genes, however, is very small. In other words, each gene confers only a small increase in susceptibility, measured in the order of percent change (an odds ratio, OR, comprised between values of 1 and 2), rather than in fold change (an OR ratio greater than 2).

Among the constellation of genes that have been associated with increased susceptibility to autoimmunity, the brightest star is unquestionably the MHC locus (in humans called HLA locus). For most autoimmune diseases where genetic studies have been performed, HLA has emerged as the locus with the strongest association: for example, the DQ8 allele in type 1 diabetes (OR around 7), DR3 in Sjögren syndrome (OR around 9) and Graves disease (OR around 3), DR2 in ulcerative colitis (OR around 4), etc.

As one moves away from the HLA locus, the strength of the association markedly decreases (odds ratios smaller than 2). The graph adapted from Concannon P et al (N Eng J Med, 2009) shows some of the 50 or so genes that have been associated with type 1 diabetes and their strength of association.

Autoimmune Genes are Scattered throughout the Genome

Autoimmune genes are found in many chromosomes. For example, in systemic lupus erythematosus, over 80 genes have been identified in each of our 22 plus XY chromosomes, as nicely illustrated in this drawing (from Chen L et al, Curr Opin Rheumatol, 2017).

Since autoimmune disease genes are many and individually have low impact, they have been particularly challenging to study.

(Video) Autoimmunity Day 2012 Part One

Rarely, autoimmune diseases are caused by a single gene defect

In a handful of cases, autoimmune diseases are monogenic, that is arise from defects in a single gene. Although rare, these monogenic autoimmune diseases have yielded fantastic insights into autoimmunity because disease manifestations are easier to understand when deriving from a single defect.

Five examples of autoimmune diseases caused by a single gene defect are shown in the table below.

APS-1ALPSIPEX syndromeImmunodeficiency 41 with autoimmunityCVID 8 with autoimmunity
Affected geneAIREFas (type 1a)
FasL (type 1b)
caspase 10 (type 2a)
caspase 8 (type 2b)
PRKCD (type 3)
NRAS (type 4)
CTLA-4 (type 5)
FOXP3IL2 receptor ALRBA
Mode of inheritanceAutosomal recessiveAutosomal recessiveX-linkedAutosomal recessiveAutosomal recessive
Median age of onset3 yearsvariable2 weeks1 month2 years
Defining clinical featuresAt least 2 of these major features: muco-cutaneous candidiasis, Addison disease, hypoparathyroidismLymphadenopathy, splenomegaly, autoimmune cytopenias, other types of autoimmune diseasesDermatitis colitis, hemolytic anemia, thyroiditis, type 1 diabetes, exaggerated response to viral infectionsRecurrent viral, fungal, and bacterial infections, lymphadenopathy, autoimmune enteropathy, dermatitisRecurrent respiratory infections, hemolytic anemia, idiopathic thrombocytopenic purpura, inflammatory bowel disease
Disease Development - Autoimmune Disease | Johns Hopkins Pathology (3)

APS-1: The Most Studied Autoimmune Disease Caused by a Single Gene Defect

APS-1 is characterized by at least two of three clinical features: muco-cutaneous candidiasis, Addison disease, and hypoparathyroidism. Patients also have many additional organ-specific autoimmune diseases (such as thyroiditis, type 1 diabetes, vitiligo, autoimmune gastritis, premature ovarian failure, testicular failure, etc). There is great variability in the types of autoimmune diseases patients with APS-1 develop, as well as in the time these diseases develop, even when the AIRE mutation is the same and patients belong to the same family.

In APS-1 the defective gene is called AIRE (for autoimmune regulator).

AIRE plays a key role in establishing tolerance to self-antigens. AIRE is expressed in the nucleus of medullary epithelial cells in the thymus (see photo of a mTEC cell with AIRE protein in red) where it orchestrates the expression of peripheral self-antigens, such as insulin of the pancreatic beta cells or the acetylcholine receptor of the neuro-muscular junctions. T lymphocytes that mature in the thymus interact with mTEC cells: if by chance T cells have an antigen receptor that binds well to these peripheral self-antigens expressed by mTEC cells they are destroyed, and therefore do not exit the thymus to become part of the T-cell repertoire we have in the blood and secondary lymphoid organs (spleen and lymph nodes). If AIRE is mutated, however, a number of peripheral self-antigens are not presented anymore on mTEC cells, and thus the T cells that recognize them are not deleted in the thymus but rather escape into the periphery where they are available to cause autoimmune diseases.

Immune System

Patients with autoimmune diseases have multiple defects in regulatory mechanisms that normally prevent autoreactive lymphocytes to develop or control them if they do appear in the periphery.

Cellular Immunity

Numerous defects in cellular immunity have been demonstrated in animal models of autoimmune diseases or other experimental settings. Examples include decreased number or function of regulatory T cells, resistance of effector T cells to immune regulation, defective function of antigen-presenting cells (such as dendritic cells and macrophages). In the clinical setting, however, these studies of cellular immunity are still not popular because of high costs, technical difficulties (such as limited access to the organ targeted by autoimmunity), and overall feasibility.


Autoantibodies on the other hand (and the B lymphocytes that produce them) remain the main clinical indicator of an immunological dysfunction in patients with autoimmune diseases. For a long period of time, autoantibodies were considered a mere biomarker of disease and received limited attention in regards to their pathogenic role.

Recent years, however, have seen a resurgence in the interest on autoantibodies, both in terms of their diagnostic and predictive value. The presence of autoantibodies has taught us that immunological abnormalities are present years before the clinical diagnosis of an autoimmune disease.

For example, antibodies to glutamic acid decarboxylase-65, protein tyrosine phosphatase receptor type N, and insulin predict by several years the development of type 1 diabetes in asymptomatic first-degree relatives. Similarly, antibodies to Ro and La are present at least 5 years before the clinical diagnosis of systemic lupus erythematosus. And antibodies to thyroperoxidase precede by at least 7 years the clinical diagnosis of Hashimoto thyroiditis.

(Video) Autoimmunity Day at Johns Hopkins 2011 Part 3

These critical observations were made using the Department of Defense Serum Repository. Since 1985, this repository stores sera of active-duty military personnel as they are collected (every two years of service, and before and after each deployment). When soldiers are then diagnosed with an autoimmune disease, it is thus possible to check what was their autoantibodies status in earlier years, when they were asymptomatic and healthy.


A role for the environment

The incidence of autoimmune diseases has increased remarkably since they were first recognized as distinct medical entities in the 1950s. Part of the increase is undoubtedly secondary to a greater awareness in the medical community about these conditions. But the increase is too large to be explainable only by better diagnostics. Considering that human genes do not change in 50 years, that the concordance rate of a given autoimmune disease among monozygotic twins is not 100%, and that there is variation in prevalence of the same disease according to geographical locations, investigators have long looked at the environment to identify causes for autoimmunity.

A difficult topic to study

Of the three factors that contribute to the pathogenesis of autoimmune diseases (genes, immune system, and environment), environment is the one where firm, scientifically sound conclusions have been the most limited. Part of the difficulty arises from the fact that each individual autoimmune disease is not very common in the general population. This makes it very challenging to identify environmental factors associated with that disease, also because these factors are expected to confer only a small increase in risk. In addition, autoimmune diseases themselves can be difficult to categorize and define, have variable age at onset, and poorly predictable age at onset. These difficulties have meant that pretty much every possible environmental factor, from poor air quality and pollution to the ever-elusive local viral infection, has been associated with one autoimmune disease or another.

Some environmental factors that have been implicated with autoimmunity are:

  • infections (usually viral)
  • dietary components (feeding infants with cow’s milk instead of mother’s milk, gluten, lack of vitamin D, increased ingestion of iodine)
  • pollutants (chemicals like polychlorinated biphenyls)
  • drugs (such as streptozotocin, a form of chemotherapy)
  • stress

Affinity maturation: the process through which B cells mature and produce antibodies that have a greater affinity for their antigenic target. This process is more prominent when the immune response is well under way.

A receptor expressed on the surface of muscle cells at the junction between muscles and nerves. The receptor binds acetylcholine, a molecule released by the nerves that induces muscle contraction.

Enzymes that transfer phosphate groups from a donor (such as ATP) to proteins. Tyrosine kinase can become the target of an autoimmune response.

An autoimmune disease observed in infants caused by the passage of autoantibodies against Ro and/or La antigens from the mother to the baby. The disease can be very severe because these antibodies are capable of causing heart block.

An autoimmune disease caused by the presence of autoantibodies directed against desmoglein 1, a protein part of of the desmosome. Desmosomes are structures that keep cells of the skin tightly together. Antibodies disrupt this connection, resulting in the formation of blisters.

An autoimmune disease caused by the presence of autoantibodies directed against desmoglein 3, a protein part of the desmosome. Desmosomes are structures that keep cells of the skin tightly together. Antibodies disrupt this connection, resulting in the formation of blisters.

An autoimmune disease caused by the presence of autoantibodies directed against the blood platelets, which are necessary for normal blood clotting. Patients have characteristic bleeding manifestations.

An autoimmune disease caused by the presence of autoantibodies directed against the acetylcholine receptor, which is located on skeletal muscle. Patients have characteristic muscle weakness.

Aggregates of immune cells, mainly B cells and T cells, that develop in organs affected by autoimmunity, organs that normally do not contain lymphocytes.

(Video) Autoimmunity Day at Johns Hopkins 2011 Part 7

The human leukocytes antigen (HLA) system is the MHC in the human species.

The major histocompatibility complex (MHC) is a cluster of genes that make proteins expressed on the cell-surface that are involved in antigen processing and other immune functions. The MHC genes are the most polymorphic genes we have, meaning that the same gene has slightly different sequences in different people.

The position of a gene on a chromosome. When the same gene has different versions in different people, these versions (called "alleles") still occupy the same locus.

A technique used to quantify proteins (such as antibodies and antigens) based on how they scatter light when put in a solution.

Any virus, bacterium, parasite, or fungus that can enter into the human body and cause disease.

A technique used to determine the presence of antibodies in the patient's serum, revealed by their binding to a purified antigen of interest attached to a plastic plate. After binding to the antigen, the patient antibodies are detected by the addition of a commercially-available antibody directed against human antibodies that has been coupled to an enzyme.

A technique used to determine the presence of antibodies in the patient's serum, revealed by their binding to a purified antigen of interest attached to magnetic beads. After binding to the antigen, the patient antibodies are detected by the addition of a commercial antibody directed against human antibodies that has been coupled to a light-emitting molecule.

A technique used to determine the presence of antibodies in the patient's serum, revealed by their binding to a particular tissue substrate of interest. After binding to the tissue, the patient antibodies are detected by the addition of a commercial antibody directed against human antibodies that has been coupled to a fluorescent dye.

Immune checkpoints are molecules that normally regulate the immune response by putting a brake on T cells. When checkpoints are inhibited, T cells become unleashed and can be used to destroy cancer cells. At the same time, this inhibition of the checkpoints makes T cells more capable of causing autoimmune diseases.

T cells that recognize antigens belonging to the patient (such as thyroglobulin in he thyroid or myosin in the heart), rather than antigens in bacteria and viruses.

Consisting of or derived from many clones.

Several forms of alteration of the immune system where the normal balance between the various immune components is altered.

A disease initiated by infection with some Streptococcus species where the patient makes antibodies against these bacteria that however also recognize with heart antigens, such as cardiac myosin.

(Video) Autoimmunity Day 2012 Part Three

The part of the antigen that is recognized by an antibody or a T-cell receptor.

Also known as B cells, these lymphocytes have a surface receptor specific for one of many antigens. B cells also secrete antibodies that when directed against self components are called autoantibodies (as found in patients with autoimmune diseases).

Also known as T cells, these lymphocytes are one of the two lymphocyte types that have antigen-specific receptors on their surface and mediate adaptive immunity (the other type is the B lymphocyte).

Any molecule that can be recognized specifically by antibodies or T lymphocytes. Typically the recognition is focused on some parts of the antigen (rather than the entire antigen), which are called epitopes.

The type of antibodies that recognize antigens of the patient, always present in autoimmune diseases and sometimes causing them.

A normal component of the patient, such as a protein or a protein-nucleic acid complex, that becomes recognized by the patient's own antibodies and/or T lymphocytes during an autoimmune disease.

Proteins produced by B lymphocytes and plasma cells that recognize specific molecules called antigens.

The collection of characteristics of a person (morphological, physiological, biochemical, etc), as determined by his/her genotype and environment.

The hardening of a tissue caused by an abnormal deposition of collagen fibers. For example, sclerosis of the skin in scleroderma; and sclerosis of the kidney in diabetic patients who develop glomerular disease.

An autoimmune disease targeting the skin melanocytes and producing characteristic patches of discoloration that are disfiguring and dampen patient's self-esteem and quality of life.

A systemic autoimmune disease affecting the skin (dermatomyositis), the striated muscles (polymyositis), and often other targets (from the joints to the lungs).

An autoimmune disease predominantly targeting the thyroid gland, and mediated by autoantibodies that bind to and stimulate a receptor expressed on thyroid cells called TSH receptor.

A systemic autoimmune disease affecting the joints (with a pattern similar to rheumatoid arthritis) and a variety of other organs (ranging from kidney, heart, muscles, to the nervous system), the skin, and often other organs (such as lungs, and gastro-intestinal system).

(Video) Autoimmunity Day at Johns Hopkins 2011 Part 6

A systemic autoimmune disease affecting the joints (with a pattern similar to rheumatoid arthritis) and a variety of other organs (ranging from kidney, heart, muscles, to the nervous system).

A systemic autoimmune disease primarily targeting the membrane (called synovium) that line peripheral joints (such as those of the hand, elbow, shoulder, knee and hip).


How does autoimmune disease develop? ›

Autoimmune disease happens when the body's natural defense system can't tell the difference between your own cells and foreign cells, causing the body to mistakenly attack normal cells. There are more than 80 types of autoimmune diseases that affect a wide range of body parts.

What are the 7 autoimmune diseases? ›

What Are Autoimmune Disorders?
  • Rheumatoid arthritis. ...
  • Systemic lupus erythematosus (lupus). ...
  • Inflammatory bowel disease (IBD). ...
  • Multiple sclerosis (MS). ...
  • Type 1 diabetes mellitus. ...
  • Guillain-Barre syndrome. ...
  • Chronic inflammatory demyelinating polyneuropathy. ...
  • Psoriasis.
5 May 2022

What is the pathology of autoimmune disease? ›

The pathogenesis of autoimmune diseases involves a breach of immune tolerance, although many mechanisms may contribute to the generation of such a phenomenon. As is the case with many diseases, it is widely accepted that some combinations of genetic and environmental factors influence the development of autoimmunity.

What are the 3 most common autoimmune diseases? ›

Common ones include lupus, rheumatoid arthritis, Crohn's disease and ulcerative colitis. Autoimmune diseases can affect many types of tissues and nearly any organ in your body.

Who is most likely to develop an autoimmune disease? ›

According to a 2014 study, women get autoimmune diseases at a rate of about 2 to 1 compared to men — 6.4% of women versus 2.7% of men. The disease often starts during childbearing age (ages 15 to 44). Some autoimmune diseases are more common in certain ethnic groups.

Can you randomly develop an autoimmune disease? ›

Inheriting certain genes can make it more likely to get an autoimmune disease. But a combination of genes and other factors may trigger the disease to start. People who are around certain things in the environment — Certain events or environmental exposures may cause some autoimmune diseases, or make them worse.

What is the most common autoimmune disease in the world? ›

According to The Autoimmune Registry, the top 10 most common autoimmune diseases include:
  • Celiac disease.
  • Graves' disease.
  • Diabetes mellitus, type 1.
  • Vitiligo.
  • Rheumatic fever.
  • Pernicious anemia/atrophic gastritis.
  • Alopecia areata.
  • Immune thrombocytopenic purpura.

What are the top 10 autoimmune diseases? ›

Common autoimmune disorders include:
  • Addison disease.
  • Celiac disease - sprue (gluten-sensitive enteropathy)
  • Dermatomyositis.
  • Graves disease.
  • Hashimoto thyroiditis.
  • Multiple sclerosis.
  • Myasthenia gravis.
  • Pernicious anemia.
24 Apr 2021

Can a person have 2 autoimmune diseases? ›

For people who have more than one diagnosed autoimmune disease, it's called polyautoimmunity. The combination of three or more diagnosed autoimmune disorders in one person is called Multiple Autoimmune Syndrome (MAS).

Can you have 2 autoimmune diseases at the same time? ›

Multiple autoimmune syndrome is a condition in which patients have at least three distinct autoimmune conditions. Multiple autoimmune disorders occur with increased frequency in patients with a previous history of another autoimmune disease.

What are markers for autoimmune disease? ›

The antinuclear antibody test, anticardiolipin test, anticentromere test, etc. are often used to detect the presence of autoantibodies, which are basically the markers for various autoimmune diseases.

Can stress and anxiety cause autoimmune disease? ›

Physical and psychological stress has been implicated in the development of autoimmune disease, since numerous animal and human studies demonstrated the effect of sundry stressors on immune function.

Are you born with autoimmune disease or develop it? ›

It is difficult to suggest which risk factors place you at the greatest risk of an autoimmune disease. In some cases, you are simply predisposed at birth. At other times, the disease may be caused by conditions you cannot control, like EBV infections which occur in more than 90% of the population9.

What environmental triggers cause autoimmune diseases? ›

Currently, studies have shown that genetic predisposition accounts for approximately thirty percent of all autoimmune diseases. The rest, 70 percent, are due to environmental factors, including toxic chemicals, dietary components, gut dysbiosis, and infections (Figure 1).

Can you develop an autoimmune disease later in life? ›

Autoimmune diseases such as Sjögren's syndrome, lupus and rheumatoid arthritis are typically adult-onset. Or so it appears. Research over the past 20 years has shown that the auto-antibodies underlying autoimmune disease can be present for years, even decades before the disease manifests.

Can vitamin D reverse autoimmune disease? ›

Rheumatoid arthritis, polymyalgia rheumatica, and psoriasis were the most common conditions. No single autoimmune disease was reliably prevented by vitamin D supplementation. Only when the numbers of all the autoimmune diseases were combined did researchers see a benefit.

How long does it take for autoimmune disease to develop? ›

We have also learned that autoimmune diseases are chronic conditions: they require a long time (years) before they become clinically evident and diagnosis (so, they have long latent phase), and then last for decades (often a life time) once diagnosed.

What is the most fatal autoimmune disease? ›

Giant cell myocarditis: most fatal of autoimmune diseases.

What country has the most autoimmune diseases? ›

US and UK stand out with higher disease prevalence of two autoimmune diseases. Autoimmune diseases occur when a body's immune system attacks its own healthy cells.

Can you reverse autoimmune disease? ›

Autoimmune disease is a sign that there is something deeper going on in your body, and by getting to the root cause you can reverse your condition and live a symptom-free life.

What autoimmune disease is more common in females? ›

Women are more prone than men to Graves' disease and Hashimoto's thyroiditis. Graves' disease causes the thyroid to produce an excess of thyroid hormone (hyperthyroidism). It usually occurs between ages 30 and 50 (but can appear at any age) and appears seven to eight times more frequently in women then in men.

Why autoimmune diseases are more common now? ›

More and more people around the world are suffering because their immune systems can no longer tell the difference between healthy cells and invading micro-organisms. Disease defences that once protected them are instead attacking their tissue and organs.

Are there any fatal autoimmune diseases? ›

A Word From Verywell. In the large majority of cases, autoimmune diseases are not fatal, and those living with an autoimmune disease can expect to live a regular lifespan. There are some autoimmune diseases that can be fatal or lead to life-threatening complications, but these diseases are rare.

What autoimmune disease affects the brain? ›

Autoimmune encephalitis (AE) is a type of brain inflammation where the body's immune system attacks healthy cells and tissues in the brain or spinal cord. It is a rare, complex disease that can cause rapid changes in both physical and mental health.

Can autoimmune cause memory loss? ›

Encephalopathies — typically characterized by confusion, seizures, memory loss and behavioral changes — have been well-recognized as having an autoimmune cause.

What blood tests are done to check for autoimmune disorders? ›

One blood test for autoimmune disease is C-reactive protein (CRP). Another test is ESR (erythrocyte sedimentation rate) - this is done to assess an inflammation that is not from an infection or due to other reasons. One of the most common blood tests for detecting autoimmune disorders is ANA (antinuclear antibodies).

What autoimmune causes joint pain? ›

Several autoimmune diseases can cause joint pain and other symptoms that mimic rheumatoid arthritis (RA). These diseases most commonly include lupus, systemic scleroderma, and polymyalgia rheumatic.

What autoimmune diseases usually go together? ›

These include rheumatoid arthritis, multiple sclerosis, autoimmune thyroiditis, Sjogren's syndrome and others. Some diseases occur together more frequently, such as type 1 diabetes and celiac, because of a shared gene that predisposes for these diseases.

What are the chances of having 2 autoimmune diseases? ›

Disorders of an autoimmune nature are known to occur with increased frequency in patients with another autoimmune disease. About 25 percent of patients with autoimmune diseases have a tendency to develop additional autoimmune disorders (3).


1. Autoimmunity Day at Johns Hopkins 2011 Part 9
(Johns Hopkins Pathology)
2. Autoimmunity Day at Johns Hopkins 2011 Part 4
(Johns Hopkins Pathology)
3. Autoimmunity Day at Johns Hopkins 2011 Part 2
(Johns Hopkins Pathology)
4. Autoimmunity Day at Johns Hopkins 2011 Part 5
(Johns Hopkins Pathology)
5. Autoimmunity Day 2012 Part Two
(Johns Hopkins Pathology)
6. Haywire: Autoimmune Disorders in Women
(Johns Hopkins Medicine)

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