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Image 2: “A hand demonstrating extra pallor.” by James Heilman, MD. License: CC BY-SA 3.0

Introduction to Autoimmune Diseases

Etiology of Autoimmune Diseases

etiology-autoimmune-diseasesA lot of factors are implicated in the development of autoimmune diseases. For example, environmental factors such as diet and lifestyle have been found to be associated with their development. Physiologic and emotional stress have also been known to influence the gravity of diseases.

Overall it is more frequent in females (e.g. ♀ : ♂ Systemic lupus erythematosus 10 : 1). Although it can be more commin in males (e.g. ♀ : ♂ Ankylosing spondylitis 0.5 : 1).


The development of autoimmune diseases

Immune Tolerance and Autoimmune Regulator

In a healthy human being, the immune system is known to possess a characteristic that keeps autoimmune diseases at bay: its non-reactivity to self-antigens. This physiologic indifference is called tolerance. This property is achieved through various mechanisms.

Central immunological tolerance to self-antigens

During lymphoid development, several numbers of lymphocytes are produced. However, this production is far from perfect and some potentially self-reacting immature lymphocytes can be produced along with viable ones. Fortunately, lymphoid organs such as the thymus (for T cells) and the bone marrow (for B cells) are made up of self-antigens. A significant amount is also brought in by the blood. These antigens are helpful in determining which among the immature lymphocytes are unreactive to healthy cells within the body and are good to go.

During the maturation process, developing lymphocytes are put to test by reacting with these self-antigens. Those which do react with the self-antigen are deleted by apoptosis. This process is called negative selection.

The whole mechanism is only effective if self-antigens present in all of the parts of the body are present in the tissues involved in central tolerance. If the immature lymphocytes are only exposed to an insufficient amount of self-antigens, they would still attack their own body once deployed in the circulation.

Peripheral immunological tolerance to self-antigens

Although efforts are already employed in the generative lymphoid tissues in order to prevent the proliferation of self-reacting lymphocytes, some potentially autoimmune-disease causing cells do escape the system and enter the circulation.

The good thing is that the selection of functional lymphocytes fit for reacting only with harmful foreign pathogens does not end in the thymus and bone marrow. In peripheral tolerance, lymphocytes are continually screened for self-reactivity. This is made possible with the help of the peripheral tissues such as the lymph nodes, through anergy, T cell suppression or through deletion.

Anergy or functional unresponsiveness still involves the reaction of a self-reacting cell to a self-antigen but without the boost coming from the innate immunity. The self-reacting cell does not necessarily die but it becomes permanently unresponsive to the self-antigens from the rest of the body.

It is also established that helper T cells have the ability to block the self-reactivity of some mature T cells. This is possible because T cells contain inhibitory receptors in their surfaces that are responsible for binding to molecules unique to self-reacting T cells. The 2 receptors that are known to do this are CTLA-4 and PD-1. The latter is connected with cellular death or apoptosis.

The autoimmune regulator in the thymus

As mentioned, the thymus contains antigens that are important in the development of a functional repertoire of self-antigen-indifferent T cells. These molecules are similar to the ones found in peripheral tissues and could sometimes actually come from the organ of origin delivered via the blood. In addition to this, the thymus could also produce antigens that mimic the ones found in the periphery. This is made possible by the autoimmune regulator (AIRE) gene. Production is mainly in the medullary epithelial cells of the thymus.

Differentiation of T Cells Within the Thymus

Image: “Thymocytes enter the thymus and go through a series of developmental stages that ensures both function and tolerance before they leave and become functional components of the adaptive immune response.” by Heather Ketchum, Eric Bright on (Download for free at, License: CC BY 4.0

Genetic Susceptibility to Autoimmune Diseases and Mechanisms

Many studies have already proved that genetic polymorphisms are commonly involved in the development of autoimmune diseases. Afflicted individuals are found to have inherited multiple alleles necessary for them to confer susceptibility to certain autoimmunity. This genetic component works with environmental factors in order to bring about manifestations of autoimmunity.

Examples of autoimmune disease susceptibility genes

Gene Function Disease



Antigen presentation to T-cells

Immune regulation

Antigen receptor signaling

Nearly all polygenic autoimmune diseases

Thyroid autoimmune diseases, type I diabetes, theumatoid arthritis

Thyorid autoimmune diseases, type I diabetes, rheumatoid arthritis

C1q, 2, 4 Complement Systemic lupus erythematosus


Lymphocyte stimualation


Rheumatoid arthritis, type I diabetes, multiple sclerosis

Systemic lupus erythematosus, rheumatoid arthritis

BLK B-cell signaling Systemic lupus erythematosus, rheumatoid arthritis

MHC alleles

Major histocompatibility complexes or MHCs are surface proteins found on lymphocytes that are important in determining whether a substance is foreign or not. It is encoded by the human leukocyte antigen or HLA gene.

These two have been the most established genetic risk factor when it comes to autoimmune diseases. It has been found out that susceptible individuals actually have an increased amount of polymorphisms in the HLA allele. This fact hastens the screening and diagnosis of some autoimmune disease with the help of serologic testing techniques.

Although many studies have already established the link between HLA gene polymorphisms and autoimmune diseases, it is noteworthy that even healthy individuals may have these. This goes to prove that HLA polymorphisms have to go along with environmental factors to manifest autoimmunity.

MHC associations in autoimmune disease

Disease MHC association Relative risk
MHC class I

Myasthenia gravis

Ankylosing spondylitis







MHC class II

Hashimoto´s disease

Type I disease







HLA-DQ6 (protective)








Polymorphisms in non-HLA genes

In the same way, not all people afflicted with an autoimmune disease have higher counts of HLA polymorphisms when compared to healthy individuals. This is where variants in the genes coding for phenotypes that might work along with other risk factors come in. These alleles are usually involved in the regulation of lymphocyte production, differentiation, and maturation.

Inherited single-gene (Mendelian) abnormalities

Although somewhat rare compared to polymorphisms, single-gene abnormalities can be very pervasive and can readily manifest in individuals carrying the mutations. Most of the time, these mutations affect the mechanisms involved in tolerance and lymphocyte regulation. In specific, these Mendelian abnormalities can cause alterations in central tolerance, production of regulatory T helper lymphocytes, anergy and in peripheral deletion of autoimmune B and T lymphocytes.

Types of Autoimmune Diseases

Autoimmunity can take on various forms in various locations in the body. It has been known to manifest itself on the blood components (red blood cells and platelets); the kidney and lungsendocrine glandsmusclesconnective tissues, nervous system, and the gastrointestinal tract, among others.

There had been numerous cases of various autoimmune diseases that are already documented in the world today. They may come as a single complication or as a syndrome. Examples of which are listed below:

Disease Major consequence
Graves´disease Autoantibodies: Stimulatory

anti-TSH receptor

Results in Hyperthyroidism

 Thyroid epithelial cell

Thyroid epithelial cell

Rheumatoid arthritis Inflamed joints rheumatoid-arthritis
Hashimoto´s disease Autoantibodies: Thyroid perocidase, thyroglobulin

Lymphocytic infiltration of the thyroid

Destruction of thyroid tissue ⇒ Hypothyroidism


Thyroid epithelial cell

Sjögren´s syndrome Reduced secretory gland function
Pernicious anemia Vitamin B12-deficient anemia
Multiple sclerosis Demyelination
Ankylosing spondylitis Inflammation of spine and sacroiliac joints
Type I diabetes Autoantibodies: insulin, glutamic acid decarboxylase, insulinoma antigen-2 (IA-2) , zinc transporter 8

Lymphocytic infiltration of the pancreas

Destruction of β-cells in islets of Langerhans ⇒ Hyperglycemia



Systemic lupus erythematosus Skin, heart, joints, lungs, kidney, brain

Goodpasture’s Syndrome

A rare autoimmune disease, Goodpasture’s syndrome, involves both the lungs and the kidneys. This disease is essentially characterized by the destruction of the type IV collagen found in the basement membrane of the renal glomeruli and pulmonary alveoli which rapidly causes inflammation to these structures. It manifests as rapidly progressive glomerulonephritis and necrotizing hemorrhagic interstitial pneumonitis. Unlike most autoimmune diseases, it occurs among the younger population (teens or 20s) and is more common in men. It is known as AntiGBM disease.

Pathogenesis of Goodpasture’s syndrome


In Goodpasture’s syndrome, autoantibodies that target the basement membrane of glomeruli cause damages in the glomeruli. These antibodies specifically have a high preponderance to the noncollagenous domain of the α3 chain of the type IV collagen. It is known as  Goodpasture’s antigen. This particular collagen is required for the maintenance of the structure of the glomeruli.

The antibodies that have destroyed the glomeruli can cross-react with the basement membranes of other organs in the body. This is where pneumonitis in Goodpasture’s come into the picture. Since the structure of the alveoli is destroyed by the same antibodies, inflammatory processes ensue in this area.

The genetic component of this disease is associated with some polymorphisms, in particular, HLA subtypes. It is also speculated that this disease has to be manifested after exposure to physiologic stress such as viral infections, hydrocarbon solvent inhalation, and smoking. This is to make the antigens that trigger the basement membrane-damaging antibodies more available to the antibodies.

Clinical manifestations of Goodpasture’s syndrome

Goodpasture’s syndrome can be exhibited through pulmonary and renal signs and symptoms. During the disease’s process, patients suffering from the disease could show the following manifestations:

  • Hemoptysis
  • Focal pulmonary consolidations in the chest x-ray
  • Hematuria
  • Foam formation in the urine
  • Edema
  • Uremia

Therapy of Autoimmune Diseases

The approach to the treatment of autoimmune diseases is very diverse. Since problems in the immunity take on a lot of forms and can affect various parts of the body, drugs and other treatment modalities have been developed in order to come up with a selection of highly specific treatment choices that can be customized per patient.

These treatment modalities have also greatly improved the prognosis of the once fatal diseases. An example of which is plasmapheresis in Goodpasture’s syndrome. This technology involves the removal of circulating antibodies and other mediators in the plasma, thereby keeping the exaggerated immune component of the blood from destroying both the lungs and the kidneys. Immunosuppressive medications that are given in conjunction with plasmapheresis could also greatly halt the development of complications caused by Goodpasture’s syndrome. This combination can also be used in other autoimmune disorders.

Deciding which treatment modality among the hundreds of ways to tackle autoimmunity to include in the treatment regimen would mean that a deeper understanding of the disease progression of the autoimmune disorder should be observed. This is to ensure a safe and efficient curative and rehabilitative period.

Other forms of therapeutic approach to autoimmune diseases are listed below:

  • Replacement of missing component such as thyroxine (Hashimoto’s disease), insulin (type 1 diabetes mellitus), and vitamin B12 (pernicious anemia)
  • Inhibition of hormone production through surgery or chemical suppression
  • Thymectomy
  • Pharmacologic agents such as anticholinesterase drugs, cytokine agonists and inhibitors, adhesion molecule inhibition, disease-modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs, steroids, anti-B cells, anti-mitotic drugs
  • Pooled normal immunoglobulin (such as in Guillain-Barre syndrome and myasthenia gravis).

Review Questions

The correct answers can be found below the references.

1. Which of the following statements correctly describes negative selection in central tolerance?

  1. Mature lymphocytes that react with self-antigens are sent back to the thymus and blood marrow for destruction and disposal from the circulation.
  2. After exposure to self-antigens in the thymus, reactive T lymphocytes are inactivated or set off for apoptosis.
  3. Autoantibodies in the organs involved in central tolerance (thymus and bone marrow are specific to antigens coming from the same organs).
  4. None of the above

2. Which of the following is correct about the genetic component of the pathogenesis of autoimmune disorders?

  1. Mendelian single-gene mutations are very common among patients suffering from autoimmune disorders.
  2. The presence of multiple allele polymorphisms in the HLA gene is a cause of immediate concern due to possible overt autoimmune manifestations.
  3. The development of autoimmunity is a cross between genetic abnormalities and environmental factors.
  4. Non-HLA polymorphisms are responsible for abnormalities in the encoding of MHCs needed for antigen identification of lymphocytes.

3. Goodpasture’s syndrome is characterized by a simultaneous immunologic attack on the renal glomeruli and pulmonary alveoli. Which of the following describes the pathogenesis of this disorder?

  1. Autoantibodies destroy the type IV collagen that maintains the structure of glomeruli and alveoli.
  2. Immune complexes deposit in the glomeruli and alveoli, resulting in localized inflammatory reactions.
  3. Helper T cells identify the cells lining the glomeruli and alveoli as non-self and trigger a cascade of inflammatory reactions.
  4. None of the above
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