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Autoimmunity – Definition, Types, Tolerance, Pathogenesis, Mechanisms

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Sourav Bio

  • The immune system is a finely-tuned system that operates around-the-clock throughout life to protect the body against pathogens and aberrant cells. Even though the immune system is constantly exposed to self-antigens, it does not mount a defence against them.
  • Occasionally, these processes malfunction, resulting in damage to diverse tissues.
  • Autoimmunity is the production of autoantibodies and immunologically competent T cells against the body’s own tissues.
  • Autoimmune disorders are conditions in which the mechanisms of self-tolerance fail, and autoimmunity is the resulting condition.
  • Autoimmunity literally translates as “protection against self,” yet in practise it results in “self-injury.”
  • At the clinical level, autoimmunity appears to play a role in a number of seemingly unrelated disorders, including systemic lupus erythematosus (SLE), insulin-dependent diabetic mellitus, myasthenia gravis, rheumatoid arthritis, multiple sclerosis, and hemolytic anemias.
  • Ehrlich first hypothesised the possibility of tolerance to self-antigens in 1901, as well as the circumstances in which this mechanism would fail, resulting in “horror autotoxicus.”
  • Understanding the many immunological systems and illnesses has led to the same conclusions in recent years.

What is Autoimmunity?

  • The immunological responses of an organism against its own healthy cells, tissues, and other normal body components constitute autoimmunity.
  • Any disease caused by this type of immune reaction is referred described as a “autoimmune disease.”
  • Notable examples include celiac disease, post-infectious IBS, type 1 diabetes mellitus, Henloch Scholein Pupura (HSP) sarcoidosis, systemic lupus erythematosus (SLE), Sjogren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto’s thyroiditis, Graves’ disease, idiopathic thrombocytopen (MS). Steroids are commonly used to treat autoimmune conditions.
  • Autoimmunity refers to the presence of antibodies or T cells that respond with self-protein and is present in all individuals, including those in a state of optimal health. If self-reactivity can result in tissue damage, autoimmunity is the result.

General Features Of Immunologic Tolerance

  • Normal people are tolerant of their own (self) antigens because the lymphocytes that identify self antigens are eliminated, inactivated, or their specificity is altered.
  • The identification of antigens by particular lymphocytes results in tolerance.
  • Central tolerance can be generated in immature self-reactive lymphocytes in the generative lymphoid organs or in adult self-reactive lymphocytes at peripheral sites (peripheral tolerance).
  • Central tolerance occurs during the maturation of lymphocytes in the central (generative) lymphoid organs, when all growing lymphocytes undergo a stage in which antigen interaction may result in cell death or replacement of a self-reactive antigen receptor with a new one.
  • As a result of identifying self antigens, peripheral tolerance arises when mature lymphocytes become incapable of reacting to that antigen, are forced to undergo apoptosis, or are actively repressed by regulatory T cells.
  • Whether lymphocytes that recognise antigens become activated or tolerant depends on the features of the antigens, the stage of maturation of the antigen-specific lymphocytes, and the sorts of stimuli they experience when they meet self antigens.
  • The immune system may disregard certain self antigens.
  • In the absence of costimulatory signals, foreign antigens may limit immune responses by establishing tolerance in particular cells.
  • As a therapeutic strategy for minimising damaging immunological responses, the induction of immunologic tolerance may be utilised.
Central and peripheral tolerance to self antigens
Central and peripheral tolerance to self antigens


  • Tolerance is a state of specific immunological insensitivity to a particular antigen or epitope despite otherwise normal immune function.
  • Antigens present throughout embryonic development are typically regarded as self and do not provoke an immune response; hence, the host maintains tolerance to these antigens.
  • Due to the elimination of self-reactive T-cell precursors in the thymus, the foetus does not mount an immunological response.
  • On the other hand, antigens that are absent during the maturation process are deemed nonself and typically induce an immune reaction against them.

Mechanisms of Tolerance

T cells and B cells engage in tolerance, although T-cell tolerance plays the most significant function.

1. T-cell tolerance

The ideas of (a) clonal deletion, (b) clonal anergy, and (c) clonal ignorance explain T-cell tolerance.

a. Clonal deletion

  • The earliest theory of tolerance was the theory of clonal deletion described by Burnet, Fenner, and Medawar based on their studies with mice.
  • Recent studies reveal that early in life, T cells acquire the ability to differentiate between self and nonself by clonal deletion.
  • This process involves the elimination of T lymphocytes (negative selection) that attack antigens, primarily self-MHC (major histocompatibility complex) molecules present in the foetus at the time.
  • The self-reactive cells perish via apoptosis, a programmed cell death mechanism.

b. Clonal anergy

  • Clonal anergy is the process that renders self-reactive T lymphocytes ineffective.
  • The inability of these cells to develop an immune response due to insufficient costimulation is known as anergic.

c. Clonal ignorance

  • This term refers to selfreactive T lymphocytes that disregard self-antigens.
  • These self-reactive T cells disregard self-antigens due to their extremely low concentration.
  • Also, these self-reactive cells are kept ignorant by physical separation from the target antigens, such as blood–brain barrier.

2. B-cell tolerance

B lymphocyte tolerance is required to preserve nonreactivity to thymus-independent self antigens, such as polysaccharides and lipids. Additionally, B cell tolerance prevents antibody responses to protein antigens. Multiple ways have been identified via which self antigens might inhibit the development and activation of B cells.


A. Central Tolerance in B Cells

Immature B cells that identify self antigens in the bone marrow with a high degree of affinity either alter their specificity or are eliminated. In experimental models, the mechanisms of central B cell tolerance have been best described.

a. Receptor editing

  • If immature B cells recognise self antigens that are present in high concentration in the bone marrow, and especially if the antigen is displayed in multivalent form (e.g., on cell surfaces), a large number of antigen receptors on each B cell are cross-linked, thereby sending powerful signals to the cells.
  • B cells reactivate their RAG1 and RAG2 genes and commence a new cycle of VJ recombination at the immunoglobulin (Ig) light chain gene locus in response to such signalling. A V segment upstream of the previously rearranged VJ unit is linked to a J segment downstream.
  • As a result, the previously altered VκJκ exon in the self-reactive immature B cell is deleted and a new Ig light chain is produced, thus producing a B cell receptor with a new specificity.
  • This process, known as receptor editing, is a crucial mechanism for removing self-reactivity from the mature B cell repertoire.
  • If the edited light chain rearrangement is unsuccessful, the locus on the other chromosome may undergo rearrangement, and if that is unsuccessful, the light chain loci may undergo rearrangement.
  • A B cell that expresses a light chain has commonly undergone receptor modification.
Central tolerance in B cells
Central tolerance in B cells – Immature B cells that recognize self antigens in the bone marrow with high avidity (e.g., multivalent arrays of antigens on cells) die by apoptosis or change the specificity of their antigen receptors (receptor editing). Weak recognition of self antigens in the bone marrow may lead to anergy (functional inactivation) of the B cells.

b. Deletion

  • If editing fails, the immature B cells may be eliminated (i.e., they die by apoptosis) (i.e., they die by apoptosis). The mechanisms of deletion are not fully defined.

c. Anergy

  • If developing B cells recognise self antigens poorly (for instance, if the antigen is soluble and does not cross-link many antigen receptors or if the B cell receptors recognise the antigen with low affinity), the cells become functionally unresponsive (anergic) and leave the bone marrow in this state.
  • Anergy is caused by a decrease in antigen receptor expression and a block in antigen receptor signalling.

B. Peripheral B Cell Tolerance

Mature B lymphocytes that identify self antigens in peripheral tissues in the absence of appropriate T helper cells may become inactive or undergo apoptosis. If these T cells are destroyed or anergic, or if the self antigens are nonprotein antigens, helper T cell signals may be lacking. Since self antigens do not induce innate immune responses, B cells will not encounter any of the cytokines or other signals produced during such reactions. Thus, antigen identification without additional stimulation results in tolerance, just as it does in T cells. Peripheral tolerance mechanisms also remove autoreactive B cell clones that may be unintentionally created as a result of somatic mutation in germinal centres.

a. Anergy and deletion

  • Some self-reactive B lymphocytes that have been repeatedly stimulated by self antigens lose their ability to respond to additional stimulation. These cells require high levels of the growth factor BAFF/BLys for survival and cannot effectively compete for survival in lymphoid follicles with typical naive B cells that are less dependent on BAFF.
  • B cells that have encountered self antigens have a shorter lifespan and are destroyed more quickly than B cells that have not encountered self antigens.
  • B cells that attach to self antigens in the peripheral with high avidity may also experience apoptosis via the mitochondrial route regardless of growth factor requirement.
  • In germinal centres, the high rate of somatic mutation of Ig genes has the potential to generate self-reactive B cells.
  • Through the interaction of FasL on helper T cells and Fas on activated B cells, these B cells may be actively destroyed.
  • This interaction has previously been identified as the mechanism underlying the demise of self-reactive T cells.
  • Failure of this peripheral B cell tolerance pathway may contribute to the autoimmunity caused by mutations in the Fas and FasL genes in mice, as well as in individuals with the previously mentioned autoimmune lymphoproliferative disease.

b. Signaling by inhibitory receptors

  • Engaging multiple inhibitory receptors can decrease the response of B lymphocytes that identify self antigens with low affinity.
  • The role of these inhibitory receptors is to establish a threshold for B cell activation, which allows responses to foreign antigens with the assistance of T cells or innate immunity but not to self antigens.
  • Studies demonstrating that animals with abnormalities in the SHP-1 tyrosine phosphatase or the CD22 inhibitory receptor develop autoimmune uncovered this peripheral tolerance pathway.
  • Lyn phosphorylates ITIM motifs in the cytoplasmic tail of CD22, and this inhibitory receptor then recruits SHP-1, so inhibiting B cell receptor activation.
  • However, when inhibitory receptors like as CD22 are activated and what ligands they identify are unknown.
  • Animal models, such as genetically modified mice, have contributed significantly to our understanding of the processes of tolerance in T and B cells.
  • Active research focuses on applying this knowledge to comprehend the processes of tolerance to diverse self antigens in healthy persons and to determine why tolerance fails, giving rise to autoimmune disorders.
Peripheral tolerance in B cells
Peripheral tolerance in B cells – B cells that encounter self antigens in peripheral tissues become anergic or die by apoptosis. In some situations, recognition of self antigens may trigger inhibitory receptors that prevent B cell activation.

Tolerance Induced By Foreign Protein Antigens

  • It is possible to give foreign antigens in a manner that induces tolerance rather than immune responses.
  • The key to creating antigen-specific tolerance as a therapy option for immunologic illnesses is understanding how to induce tolerance through antigen delivery.
  • Protein antigens delivered subcutaneously or intradermally with adjuvants tend to promote immunity, whereas antigens supplied systemically at large dosages without adjuvants tend to generate tolerance.
  • In the absence of these second signals, T cells that detect the antigen may become anergic, die, or develop into regulatory cells.
  • There are numerous antigen characteristics and administration methods that can affect the equilibrium between immunity and tolerance.
  • When a protein antigen is administered orally, humoral and cell-mediated immune responses to immunisation with the same antigen are frequently suppressed. The term for this phenomena is oral tolerance.
  • Some systemic infections (such as those caused by viruses) may generate an immune response, but the response is reduced before the virus is eliminated, resulting in a condition of persistent infection.
  • In this case, there are virus-specific T cell clones, but they are unable to respond normally and remove the infection. This condition is referred to as clonal exhaustion, suggesting that antigen-specific lymphocyte clones provide an initial response before becoming anergic, or “exhausted.”
  • On virus-specific CD8+ T lymphocytes, there is some evidence that clonal depletion is caused by the overexpression of inhibitory receptors such as PD-1.
  • HIV-infected people and animal models of persistent viral infection have demonstrated this tendency. How certain bacteria upregulate T cell expression of inhibitory substances is unknown.
  • Some pathogens exploit clonal fatigue as a means of evading the immune system, as it can facilitate viral persistence.
  • Understanding this process could lead to the development of novel therapeutic approaches for some chronic viral illnesses, such as the use of PD-1– blocking antibodies.

Pathogenesis of Autoimmunity

The following pathogenic mechanisms have been hypothesised for autoimmunity:

  1. Release of sequestrated antigens
  2. Antigen alteration
  3. Epitope spreading
  4. Molecular mimicry

1. Release of sequestrated antigens

  • Sperm, the central nervous system, and the lens and uveal system of the eye are examples of sequestered or concealed tissues.
  • For different reasons, these locations are generally never exposed to the immune system. These locations are immunologically favoured.
  • When these hidden or sequestered antigens are exposed as a result of an injury, the immune system of the host—both cellular and humoral—does not recognise them as self, but rather as foreign, and therefore assaults them.
  • Lens protein, for instance, is contained within its capsule and has no interface with the circulatory system. Therefore, immune tolerance to lens protein does not develop during foetal development.
  • When this antigen is released into the bloodstream after an injury or cataract surgery, it induces an immunological reaction that damages the lens of the other eye.
  • Similarly, growing sperms reside within the lumen of the testicular tubules, which are walled off early in embryonic development, prior to the formation of the immune system.
  • Because these developing sperms are encased in a sheath of densely connected Sertoli cells, immune cells are unable to access them.
  • If these are exposed as a result of surgery, vasectomy, or injury, an immune response against the sperm results in aspermatogenesis, which can result in male sterility.
  • Intracellular antigens that are generally sequestered from the immune system include DNA, histones, and mitochondrial enzymes.
  • However, certain viral or bacterial infections, radiation exposure, and chemical exposure can destroy these cells and release sequestered intracellular antigens into the bloodstream. These antigens provoke a robust immunological response.
  • Against these antigens, autoantibodies are generated, which interact with subsequently released sequestered antigens.
  • This leads to the creation of immunological complexes, which are responsible for tissue damage. For instance, during a mumps infection, the virus damages the basement membrane of seminiferous tubules, provoking an immunological response and causing orchitis.

2. Antigen alteration

  • Certain physical, chemical, or biological stimuli can change tissue antigens, leading to the production of neoantigens on the cell surface.
  • These neoantigens are no longer identified as self; hence, they appear foreign to the immune system, provoking an immunological response.
  • SLE triggered by procainamide is one example of an autoimmune illness resulting from this mechanism.

3. Epitope spreading

  • Epitope spreading refers to the exposure of previously sequestered autoantigens as a result of viral infection-induced cell destruction.
  • It is hypothesised that this process contributes to the aetiology of autoimmunity.
  • These freshly exposed autoantigens or epitopes trigger autoreactive T cells, leading to the development of autoimmune disorders.
  • In experimental animal infections, for instance, an encephalomyelitis virus causes a condition resembling multiple sclerosis.
  • In this scenario, self-reactive T lymphocytes target cellular antigens, but not the virus responsible for the sclerosis-like sickness.
Pathogenesis of acute rheumatic fever
Pathogenesis of acute rheumatic fever

4. Molecular mimicry

  • Molecular mimicry is the association between infection with a specific microbial pathogen and the development of specific autoimmune disorders.

Pathological Process of Autoimmune

The pathogenic process of autoimmunity may be begun and maintained by (a) autoantibodies, (b) immune complexes containing autoantigens, and (c) autoreactive T cells. Each of these immunological systems plays a significant role in a variety of diseases or may be synergistically related, especially in multiorgan, systemic autoimmune diseases.

1. Autoantibodies

  • Diseases related with autoantibodies are defined by the presence of autoantibodies in the serum and the deposition of autoantibodies in tissues.
  • In some diseases, autoantibodies may be actively engaged in the pathogenesis, but in others, they may simply serve as disease indicators with no recognised harmful effect.
  • They may also have a role in initiating numerous pathogenic pathways that result in tissue damage and cell death.
  • In the aetiology of (a) myasthenia gravis, (b) pemphigus vulgaris, and (c) different autoimmune cytopenias, autoantibodies play a crucial role.

2. Immune complexes containing autoantigens

  • In autoimmune illnesses, the development of immunological complexes between self-antigens and autoantibodies, which results in organ destruction, is another pathogenic mechanism.
  • Only sufficiently sized immune complexes are able to activate the complement system and participate in the pathogenesis of autoimmune disorders.
  • Immune complexes play a significant part in the pathogenesis of systemic lupus erythematosus and polyarteritis nodosa, two exemplary autoimmune disorders.

3. Autoreactive T lymphocytes

  • Self-tolerance is not induced by antigens that are sequestered from circulation and, as a result, are not recognised by growing T cells in the thymus.
  • Later exposure of mature T cells to typically sequestered antigens could lead to their activation.
  • Examples include the induction of autoantibodies to sperms following vasectomy, sympathetic ophthalmitis, and the development of antibodies to myocardial cells following myocardial infarction.
  • In certain other circumstances, inappropriate expression of class II MHC molecules can also sensitise self-reactive T cells.
  • This is corroborated by clinical observations indicating an increase in the incidence of autoimmune illnesses in families, as well as by higher rates of clinical concordance among monozygotic twins.
  • Polyclonal B-cell activation can potentially initiate the onset of an autoimmune illness.

Types of Autoimmune Diseases

In autoimmune illnesses, different molecules, cells, and tissues are attacked. Table 20-1 = summarises damaged tissue, target antigens, and resulting autoimmune disorders. The autoimmune disorders can be classified generally as

  1. Organ-specific autoimmune disease.
  2. Systemic autoimmune diseases

1. Organ-Specific Autoimmune Diseases

These are disorders in which autoantibodies attack the tissue of a specific organ, hence harming only that organ. Addison’s disease, autoimmune hemolytic anaemia, Goodpasture’s syndrome, Graves’ disease, Hashimoto’s thyroiditis, idiopathic thrombocytopenic purpura, insulin-dependent diabetes mellitus, myasthenia gravis, pernicious anaemia, poststreptococcal glomerulonephritis, etc. are a few examples of such conditions. On the basis of tissue damage, these diseases can be further subcategorized as (a) diseases mediated by cell-mediated immunity and (b) autoantibody-mediated diseases.

A. Diseases mediated by the action of cell-mediated immunity

Some disorders where lymphocytes directly facilitate the primary mechanism of cell destruction are as follows:

a. Hashimoto’s thyroiditis

  • Hashimoto’s thyroiditis is predominately a subclinical disease in which no thyroid dysfunction is apparent and no treatment is required until the latter stages of disease.
  • It is suspected that a cell-mediated autoimmune response induced by unknown causes is responsible for the development of this disease.
  • The condition is particularly prevalent in middle-aged women who produce autoantibodies and TH1 cells that are specific for thyroid antigens.
  • It is the most prevalent kind of thyroiditis, and its progression is typically chronic. It happens most frequently between the third and fifth decades, with a 10:1 female to male ratio.
  • Functionally, the condition is characterised by a sluggish development to hypothyroidism and a gradual onset of symptoms.
  • The majority of hypothyroid individuals experience malaise, lethargy, cold intolerance, and constipation. Antithyroglobulin antibodies are typically utilised to confirm the diagnosis.

b. Addison’s disease (chronic primary hypoadrenalism)

  • This condition may be caused by exogenous factors (e.g., infection of the adrenal glands by Mycobacterium tuberculosis) or be idiopathic.
  • It is hypothesised that the idiopathic type has an immunological basis, as 50% of patients develop autoantibodies to the microsomes of adrenal cells (compared to 5% of the normal population).
  • It is hypothesised that autoantibodies directed against the adrenal glands perform the primary role in disease development.
  • Addison’s disease is characterised by weakness, fatigue, anorexia, nausea, vomiting, weight loss, and diarrhoea.
  • Increased skin pigmentation, vascular collapse, and hypotension are symptoms. The condition ultimately results in adrenal cortical atrophy and loss of function.
  • By demonstrating antiadrenal antibodies with an indirect immunofluorescence test, the diagnosis is validated.
  • Frequent associations exist between Addison’s disease and other autoimmune disorders, such as thyroiditis, pernicious anaemia, and diabetes mellitus.

c. Autoimmune Anemias

  • Pernicious anaemia, autoimmune hemolytic anaemia, and drug-induced hemolytic anaemia are examples of autoimmune anemias.
  • Autoantibodies to intrinsic factor, a membrane-bound intestinal protein on gastric parietal cells, cause pernicious anaemia. Intrinsic factor promotes vitamin B12 absorption from the small intestine.
  • The binding of autoantibodies to intrinsic factor inhibits vitamin B12 absorption mediated by intrinsic factor. In the absence of adequate vitamin B12, which is required for healthy hematopoiesis, the number of mature, functional red blood cells declines below normal levels.
  • Vitamin B12 injections are used to treat pernicious anaemia, thus avoiding the absorption deficiency.
  • A person with autoimmune hemolytic anaemia produces autoantibodies to RBC antigens, resulting in complement-mediated lysis or antibody-mediated opsonization and phagocytosis of red blood cells.
  • When certain medications, such as penicillin or the antihypertensive methyldopa, interact with red blood cells, the cells become antigenic.
  • The immunodiagnostic test for autoimmune hemolytic anemias is often a Coombs test in which red blood cells are treated with anti–human IgG antiserum.
  • If IgG autoantibodies are present on the red blood cells, the antiserum will agglutinate the cells.

d. Goodpasture’s Syndrome

  • Autoantibodies specific for certain basement membrane antigens bind to the basement membranes of the kidney glomeruli and the alveoli in Goodpasture’s syndrome.
  • Subsequent complement activation results in direct cellular injury and an inflammatory response mediated by the accumulation of complement split products.
  • Progressive kidney failure and lung bleeding result from damage to the glomerular and alveolar basement membranes.
  • Within a few months of the development of symptoms, death may occur. Along the basement membranes of Goodpasture’s syndrome patients’ biopsies stained with fluorescently labelled anti-IgG and antiC3b antibodies are linear deposits of IgG and C3b.


  • Insulin-dependent diabetic mellitus (IDDM), a disease affecting 0.2% of the population, is caused by an autoimmune attack on the pancreas.
  • The attack targets specialised insulin-producing cells (beta cells) that are dispersed throughout the pancreas in spherical clusters known as the islets of Langerhans.
  • The autoimmune onslaught kills beta cells, resulting in decreased insulin production and elevated blood glucose levels. Several causes contribute to the demise of beta cells.
  • First, activated CTLs travel inside an islet and initiate an assault on insulin-producing cells. During this response, the local synthesis of cytokines includes IFN-, TNF-, and IL-1. The development of autoantibodies can also be a factor in IDDM.
  • The initial CTL invasion and activation of macrophages, also known as insulitis, is followed by cytokine production and the presence of autoantibodies, which results in a cell-mediated DTH response.
  • It is believed that cytokines generated during the DTH response and lytic enzymes secreted by activated macrophages are responsible for the eventual death of beta cells.
  • Beta cell-specific autoantibodies may contribute to cell death by enhancing antibody-plus-complement lysis or antibody-dependent cell-mediated cytotoxicity (ADCC).
  • The irregularities in glucose metabolism produced by the death of islet beta cells lead to severe metabolic issues, including ketoacidosis and an increase in urine output.
  • The disease’s late stages are frequently characterised by atherosclerotic vascular lesions, which in turn induce gangrene of the extremities due to impaired vascular flow, renal failure, and blindness. Without treatment, death is possible.
  • The most common treatment for diabetes is daily insulin delivery. This is very beneficial in managing the disease, but because random doses are not the same as metabolically regulated continuous and controlled release of the hormone, regularly injected doses of insulin do not completely eliminate the disease’s complications.
  • A further complication of diabetes is that it can lie undiscovered for several years, allowing irreversible pancreatic tissue loss to develop prior to treatment.
Autoimmune disorders
Autoimmune disorders

B. Some Autoimmune Diseases Are Mediated by Stimulating or Blocking Auto-Antibodies

In certain autoimmune illnesses, antibodies function as agonists, attaching to hormone receptors in place of the normal ligand and promoting aberrant activity. This typically results in an increase in mediator production or cell proliferation. Autoantibodies may also behave as antagonists, binding hormone receptors but inhibiting receptor action. This typically results in decreased mediator secretion and progressive organ atrophy. Listed below are a few of this group’s most prominent representative disorders:

Myasthenia gravis

  • Myasthenia gravis is the prototypical autoimmune disease caused by antibodies that inhibit the immune system. It is a neuromuscular transmission disorder.
  • This condition is characterised by the production of autoantibodies that bind to acetylcholine receptors on the motor end-plates of muscles.
  • These antibodies inhibit the normal binding of acetylcholine and cause complement-mediated cell death.
  • Myasthenia gravis is typically characterised by an increase in fatigue and weakening in the muscles, which is exacerbated by physical activity.
  • Typically, extraocular muscles are the first to show signs of weakness, resulting in diplopia or ptosis. Additionally, the cheeks, tongue, and upper extremities are usually affected. Typically, proximal skeletal muscle involvement is observed.
  • Typically, the condition is characterised by spontaneous remission intervals. In myasthenia gravis, thymic anomalies are common. Approximately 10% of patients acquire malignant thymus tumours (thymomas).
  • Antibodies against the antiacetylcholine receptor corroborate the diagnosis.

Graves’ disease

  • Graves’ disease, also known as thyrotoxicosis, diffuse toxic goitre, and exophthalmic goitre, is caused by autoantibodies directed against the thyrotrophic hormone (thyroid-stimulating hormone [TSH]) receptor (TSH receptor antibodies).
  • In Graves’ disease, the TSH receptor antibodies (also known as long-acting thyroid stimulator, thyroid-stimulating immunoglobulin, and thyroid-stimulating antibodies) boost thyroid gland activity.
  • After attaching to the TSH receptor, these antibodies can increase the production of thyroid hormones by activating the adenylate cyclase system.
  • Approximately 80–90% of patients with Graves’ illness exhibit these antibodies, which are often of the IgG isotype.
  • Exophthalmos, often known as protruding eyeballs, is the typical manifestation of the illness.
  • In addition to an accelerated metabolic rate and weight loss, other hyperthyroidism symptoms include nervousness, weakness, sweating, heat sensitivity, and loose stools.
  • This condition is more prevalent in thirty-year-old women. Thyroid gland biopsies reveal widespread lymphoplasmacytic interstitial infiltration.
  • There are elevated levels of thyroid hormones (triiodothyronine, or T3, and thyroxine, or T4), higher absorption of T3, and antithyroid receptor antibodies, as determined by laboratory tests.

2. Systemic Autoimmune Diseases

In systemic autoimmune disorders, the immune response is directed against a broad spectrum of target antigens and affects multiple organs and tissues. These disorders are the outcome of a systemic deficiency in immune control that causes T cells and B cells to be overactive. Widespread tissue damage results from both cell-mediated immune responses and direct cellular damage induced by autoantibodies or immune complex buildup.

Systemic Lupus Erythematosus Attacks Many Tissues

  • The ratio of female to male patients is 10:1 for systemic lupus erythematosus (SLE), which is one of the greatest instances of a systemic autoimmune illness.
  • Fever, weakness, arthritis, skin rashes, pleurisy, and renal dysfunction are characteristics of SLE.
  • Lupus is more common among African-American and Hispanic women than in Caucasian women, but the reason for this is unknown.
  • Affected individuals may manufacture autoantibodies against a wide range of tissue antigens, including DNA, histones, RBCs, platelets, leukocytes, and clotting factors; the interaction of these auto-antibodies with their specific antigens results in a variety of symptoms.
  • For example, RBC- and platelet-specific autoantibodies can trigger complement-mediated lysis, resulting in hemolytic anaemia and thrombocytopenia, respectively.
  • When immunological complexes of autoantibodies with diverse nuclear antigens are deposited along the walls of tiny blood vessels, a hypersensitive reaction of type III ensues.
  • The complexes activate the complement system and form membrane-attack complexes and complement split products that cause vasculitis and glomerulonephritis by damaging the blood vessel wall.
  • In individuals with severe SLE, excessive complement activation results in blood levels of the complement split products C3a and C5a that are three to four times greater than usual.
  • C5a causes enhanced expression of complement receptor type 3 (CR3) on neutrophils, hence promoting neutrophil aggregation and adhesion to vascular endothelium.
  • As neutrophils adhere to small blood vessels, the quantity of neutrophils in circulation decreases (neutropenia), and various occlusions of small blood vessels arise (vasculitis). These obstructions can cause extensive tissue harm.
  • The typical antinuclear antibodies directed against double- or single-stranded DNA, nucleoprotein, histones, and nucleolar RNA are used to diagnose SLE in the laboratory. The indirect immunofluorescent labelling of nuclei with serum from SLE patients generates distinct nucleus staining patterns.

Multiple Sclerosis Attacks the Central Nervous System

  • Multiple sclerosis (MS) is the most prevalent disease-related cause of neurologic impairment in Western nations.
  • Mild symptoms include tingling in the limbs, whereas severe symptoms include paralysis or eyesight loss. The majority of MS diagnoses occur between the ages of 20 and 40.
  • This condition is characterised by the production of autoreactive T lymphocytes that contribute to the development of inflammatory lesions along the myelin sheath of nerve fibres.
  • Patients with active MS have activated T cells in their cerebrospinal fluid, which infiltrate brain tissue and generate distinctive inflammatory lesions that degrade myelin.
  • Myelin insulates the nerve fibres; hence, a breakdown in the myelin sheath results in a variety of neurologic dysfunctions. Epidemiological research reveal that MS is more prevalent in the Northern hemisphere and, surprisingly, the United States.
  • Those living north of the 37th parallel have a prevalence of 110–140 cases per 100,000 people, whereas those living south of the 37th parallel have a prevalence of 57–78 cases per 100,000 people.
  • And individuals from south of the 37th parallel who migrate north before the age of 15 take a new risk.
  • These startling statistics show that the risk of developing MS is influenced by environmental factors.
  • However, this is not the whole picture, as genetic impacts are equally significant. While the average person in the United States has a 1 in 1000 probability of acquiring MS, close relatives, such as children and siblings, have a 1 in 50 to 100 chance of developing the disease.
  • One in three identical twins of a person with MS will develop the condition. These findings are highly suggestive of the hereditary component of the disease. In addition, as mentioned in this chapter’s Clinical Focus, MS affects women two to three times more commonly than males.
  • As with most autoimmune disorders, the cause of MS is poorly understood. Nevertheless, there is some evidence that infection with some viruses may predispose a person to MS.
  • Certainly some viruses can cause demyelinating disorders, and it is tempting to hypothesise that virus infection plays a substantial role in MS, however there is currently no conclusive evidence implicating a specific virus.

Rheumatoid Arthritis Attacks Joints

  • Rheumatoid arthritis is a prevalent autoimmune illness that affects women between the ages of 40 and 60.
  • However, the hematologic, cardiovascular, and pulmonary systems are usually affected as well.
  • Numerous patients with rheumatoid arthritis develop rheumatoid factors, a collection of autoantibodies reacting with determinants in the Fc region of IgG.
  • This specific IgM antibody is the conventional rheumatoid factor. These autoantibodies combine with normal circulating IgG to generate IgM-IgG complexes that are deposited in the joints.
  • These immune complexes can activate the complement cascade, resulting in a type III hypersensitivity reaction that causes chronic joint inflammation.

Treatment of Autoimmune Diseases

  • Ideally, treatment for autoimmune illnesses should target only the autoimmune response while leaving the remainder of the immune system intact. This aim has not yet been achieved.
  • Current treatments for autoimmune disorders are not curative, but rather palliative, with the goal of lowering symptoms to offer an acceptable quality of life for the patient.
  • In general, these treatments inhibit the immune system in a non-specific manner and, as a result, cannot discriminate between a pathological autoimmune response and a protective immunological response.
  • Immunosuppressive medicines (e.g., corticosteroids, azathioprine, and cyclophosphamide) are frequently administered to inhibit lymphocyte growth.
  • Such medications can lower the severity of autoimmune symptoms by suppressing the immune response in general.
  • The general decrease in immunological reactivity, however, increases the patient’s susceptibility to infection and malignancy. Using cyclosporin A or FK506 to treat autoimmunity is a considerably more targeted method.
  • These drugs inhibit only antigen-activated T cells while sparing nonactivated T cells by blocking signal transduction mediated by the T-cell receptor.
  • In some cases of myasthenia gravis, the excision of the thymus has proven to be an effective therapeutic method.
  • Because patients with this condition frequently have thymic abnormalities (such as thymic hyperplasia or thymomas), adult thymectomy frequently increases the probability of symptom remission.
  • Plasmapheresis may provide patients with Graves’ illness, myasthenia gravis, rheumatoid arthritis, or systemic lupus erythematosus a short-term benefit. Using continuous-flow centrifugation, plasma is separated from a patient’s blood in this procedure.
  • The red blood cells are subsequently reconstituted in an appropriate medium and returned to the patient. Plasmapheresis has been advantageous for patients with autoimmune illnesses involving antigen-antibody complexes, which are eliminated with the plasma.
  • Even though removal of the complexes is transitory, it can result in a transient reduction in symptoms.
  • Positively, animal models of experimental autoimmunity have demonstrated that it is possible to establish specific immunity against the development of autoimmunity.

T-Cell Vaccination Is a Possible Therapy

  • Experiments with the EAE animal model provided the foundation for T-cell vaccination as a therapy for several autoimmune disorders.
  • EAE symptoms were not observed in rats treated with low concentrations (10–4) of cloned T cells specific for MBP. In contrast, when they were later confronted with a lethal dose of activated MBP-specific T cells or MBP in adjuvant, they became resistant to the development of EAE.
  • By crosslinking the cell-membrane components with formaldehyde or glutaraldehyde, it was discovered that the efficiency of these autoimmune T-cell clones as a vaccine may be improved.
  • When mice with active EAE were injected with crosslinked T cells, lasting remission of symptoms was found.
  • Apparently, the crosslinked T cells induce regulatory T cells specific for TCR variable-region determinants of autoimmune clones.
  • Presumably, these regulatory T cells suppress the autoantibody-producing T cells that cause EAE.

Peptide Blockade of MHC Molecules Can Modulate Autoimmune Responses

  • The identification and sequencing of numerous autoantigens has led to the development of novel techniques for modulating the activity of autoimmune T-cells.
  • For instance, in EAE, the encephalitogenic peptides of MBP have been thoroughly described.
  • It has been demonstrated that synthetic peptides varying from their MBP equivalent by a single amino acid can attach to the corresponding MHC molecule.
  • In addition, the clinical development of EAE was prevented when significant doses of this peptide were delivered with the comparable encephalitogenic MBP peptide.
  • Presumably, the synthetic peptide acts as a competitor by occupying the antigen-binding cleft on MHC molecules, so preventing the MBP peptide from binding.
  • In other research, inhibiting peptides complexed to soluble class II MHC molecules prevented the clinical development of EAE in mice by generating clonal anergy in the autoimmune T cells.

Monoclonal Antibodies May Be Used to Treat Autoimmunity

  • Several animal models have been successfully treated with monoclonal antibodies for autoimmunity. High percentages of (NZB NZW) F1 mice who received weekly injections of high doses of monoclonal antibody specific for the CD4 membrane molecule were able to recover from their lupus-like autoimmune symptoms.
  • Anti-CD4 monoclonal antibody treatment resulted in the elimination of lymphocytic infiltration and diabetes symptoms in NOD mice.
  • Due to the fact that anti-CD4 monoclonal antibodies inhibit or deplete all TH cells, independent of their specificity, they pose a hazard to the recipient’s overall immunological response.
  • Attempting to block only antigen-activated TH cells, as these cells are engaged in the autoimmune state, is one solution for this drawback.
  • To do this, researchers employed a monoclonal antibody directed against the component of the highaffinity IL-2 receptor, which is only produced by antigen-activated TH cells.
  • Due to the increased expression of the IL-2R subunit on autoimmune T cells, monoclonal antibody against the subunit (anti-TAC) may preferentially inhibit autoreactive T cells.
  • This strategy was evaluated on adult rats injected with activated MBP-specific T lymphocytes with or without anti-TAC. All of the control rats died from EAE, but six of the nine rats treated with anti-TAC exhibited no symptoms and the remaining three exhibited minor symptoms.
  • Several animal models demonstrating a link between autoimmune illness and restricted TCR expression have encouraged researchers to investigate whether blocking the favoured receptors with monoclonal antibody could be therapeutic.
  • By injecting PL/J mice with a monoclonal antibody specific for the V 8.2 T-cell receptor, MBP-induced EAE was avoided.
  • Even more encouraging was the discovery that the V 8.2 monoclonal antibody could also correct the symptoms of autoimmunity in mice with induced EAE, and that these mice displayed long-lasting remission.
  • Clearly, the use of monoclonal antibodies as a therapy for autoimmune disorders in humans presents promising prospects. Similarly, the relationship between certain MHC alleles and autoimmunity, as well as the evidence for excessive or improper MHC expression in some autoimmune diseases, suggests that monoclonal antibodies against appropriate MHC molecules may inhibit the development of autoimmunity.
  • Furthermore, since antigen-presenting cells express a variety of class II MHC molecules, it should be able to selectively inhibit an MHC molecule linked with autoimmunity while sparing the others.
  • In one study, the development of EAE was prevented by injecting mice with monoclonal antibodies to class II MHC molecules before administering MBP.
  • If the antibody was administered after MBP injection, EAE development was delayed but not halted. Monoclonal antibodies against HLA-DR and HLA-DQ have been found to reverse EAE in nonhuman monkeys.

Oral Antigens Can Induce Tolerance

  • When antigens are delivered orally, they tend to elicit tolerance, a condition of immunologic indifference. As indicated earlier in this chapter, mice fed MBP do not develop EAE after receiving a subsequent MBP injection.
  • This finding led to a double-blind pilot study in which 30 patients with multiple sclerosis were given a placebo or 300 mg of bovine myelin daily for a year.
  • The results of this trial indicated that T lymphocytes specific for MBP were reduced in the myelin-fed group; there was also some evidence that MS symptoms were reduced in male receivers (albeit the reduction was not statistically significant) but not in female recipients.
  • While the results of oral tolerance induction in mice were promising, it does not appear that the same is true for humans.
  • However, human clinical trials are still in their infancy, and it is possible that the peptides utilised thus far were not the most effective, or that the dosages were incorrect.
  • In the coming years, it is probable that further clinical trials will be done due to the promise demonstrated by animal research.


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  • Kono, D. H., & Theofilopoulos, A. N. (2017). Autoimmunity. Kelley and Firestein’s Textbook of Rheumatology, 301–317.e5. doi:10.1016/b978-0-323-31696-5.00019-x 
  • Delves, P. J. (1998). Autoimmunity. Encyclopedia of Immunology, 292–296. doi:10.1006/rwei.1999.0075 
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  • Silverstein, A. M. (2014). Autoimmunity. The Autoimmune Diseases, 11–17. doi:10.1016/b978-0-12-384929-8.00002-2


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