Autoimmunity

Autoimmunity
Parts of body affected by autoimmune diseases
Specialty	Immunology

In

Autoimmunity means presence of antibodies or T cells that react with self-protein and is present in all individuals, even in normal health state. It causes autoimmune diseases if self-reactivity can lead to tissue damage.^[4]

History

In the later 19th century it was believed that the immune system was unable to react against the body's own tissues. Paul Ehrlich, at the turn of the 20th century, proposed the concept of horror autotoxicus. Ehrlich later adjusted his theory to recognize the possibility of autoimmune tissue attacks, but believed certain innate protection mechanisms would prevent the autoimmune response from becoming pathological.^{[citation needed]}

In 1904 this theory was challenged by the discovery of a substance in the serum of patients with paroxysmal cold hemoglobinuria that reacted with red blood cells. During the following decades, a number of conditions could be linked to autoimmune responses. However, the authoritative status of Ehrlich's postulate hampered the understanding of these findings. Immunology became a biochemical rather than a clinical discipline.^[5] By the 1950s the modern understanding of autoantibodies and autoimmune diseases started to spread.^{[citation needed]}

More recently it has become accepted that autoimmune responses are an integral part of vertebrate immune systems (sometimes termed "natural autoimmunity").^[6] Autoimmunity should not be confused with alloimmunity.

Low-level autoimmunity

While a high level of autoimmunity is unhealthy, a low level of autoimmunity may actually be beneficial. Taking the experience of a beneficial factor in autoimmunity further, one might hypothesize with intent to prove that autoimmunity is always a self-defense mechanism of the mammal system to survive. The system does not randomly lose the ability to distinguish between self and non-self; the attack on cells may be the consequence of cycling metabolic processes necessary to keep the blood chemistry in homeostasis.^{[citation needed]}

Second, autoimmunity may have a role in allowing a rapid immune response in the early stages of an infection when the availability of foreign

Immunological tolerance

Pioneering work by

]

Three hypotheses have gained widespread attention among immunologists:

• Clonal deletion theory, proposed by Burnet, according to which self-reactive lymphoid cells are destroyed during the development of the immune system in an individual. For their work Frank M. Burnet and Peter B. Medawar were awarded the 1960 Nobel Prize in Physiology or Medicine "for discovery of acquired immunological tolerance".
• Clonal anergy theory, proposed by Nossal, in which self-reactive T- or B-cells become inactivated in the normal individual and cannot amplify the immune response.^[8]
• Idiotype network theory, proposed by Jerne, wherein a network of antibodies capable of neutralizing self-reactive antibodies exists naturally within the body.^[9]

In addition, two other theories are under intense investigation:

• Clonal ignorance theory, according to which autoreactive T cells that are not represented in the thymus will mature and migrate to the periphery, where they will not encounter the appropriate antigen because it is inaccessible tissues. Consequently, auto-reactive B cells, that escape deletion, cannot find the antigen or the specific helper T cell.^[10]
• Suppressor population or Regulatory T cell theory, wherein regulatory T-lymphocytes (commonly CD4⁺FoxP3⁺ cells, among others) function to prevent, downregulate, or limit autoaggressive immune responses in the immune system.

Tolerance can also be differentiated into "central" and "peripheral" tolerance, on whether or not the above-stated checking mechanisms operate in the central lymphoid organs (thymus and bone marrow) or the peripheral lymphoid organs (lymph node, spleen, etc., where self-reactive B-cells may be destroyed). It must be emphasised that these theories are not mutually exclusive, and evidence has been mounting suggesting that all of these mechanisms may actively contribute to vertebrate immunological tolerance.

A puzzling feature of the documented loss of tolerance seen in spontaneous human autoimmunity is that it is almost entirely restricted to the autoantibody responses produced by B lymphocytes. Loss of tolerance by T cells has been extremely hard to demonstrate, and where there is evidence for an abnormal T cell response it is usually not to the antigen recognised by autoantibodies. Thus, in rheumatoid arthritis there are autoantibodies to IgG Fc but apparently no corresponding T cell response. In systemic lupus there are autoantibodies to DNA, which cannot evoke a T cell response, and limited evidence for T cell responses implicates nucleoprotein antigens. In Celiac disease there are autoantibodies to tissue transglutaminase but the T cell response is to the foreign protein gliadin. This disparity has led to the idea that human autoimmune disease is in most cases (with probable exceptions including type I diabetes) based on a loss of B cell tolerance which makes use of normal T cell responses to foreign antigens in a variety of aberrant ways.^[11]

Immunodeficiency and autoimmunity

There are a large number of immunodeficiency syndromes that present clinical and laboratory characteristics of autoimmunity. The decreased ability of the immune system to clear infections in these patients may be responsible for causing autoimmunity through perpetual immune system activation.^[12]

One example is common variable immunodeficiency (CVID) where multiple autoimmune diseases are seen, e.g.: inflammatory bowel disease, autoimmune thrombocytopenia and autoimmune thyroid disease.^{[citation needed]}

Familial hemophagocytic

are commonly seen in such individuals. Presence of multiple uncleared viral infections due to lack of perforin are thought to be responsible.

In addition to chronic and/or recurrent infections many autoimmune diseases including arthritis, autoimmune hemolytic anemia, scleroderma and

(XLA). Recurrent bacterial and fungal infections and chronic inflammation of the gut and lungs are seen in chronic granulomatous disease (CGD) as well. CGD is a caused by decreased production of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by neutrophils. Hypomorphic RAG mutations are seen in patients with midline granulomatous disease; an autoimmune disorder that is commonly seen in patients with also autoimmunity and infections coexist: organ-specific autoimmune manifestations (e.g., hypoparathyroidism and adrenocortical failure) and chronic mucocutaneous candidiasis. Finally, ]

Genetic factors

Certain individuals are genetically susceptible to developing autoimmune diseases. This susceptibility is associated with multiple genes plus other risk factors. Genetically predisposed individuals do not always develop autoimmune diseases. Three main sets of genes are suspected in many autoimmune diseases. These genes are related to:^[citation needed]

• Immunoglobulins
• T-cell receptors
• The major histocompatibility complexes (MHC).

The first two, which are involved in the recognition of antigens, are inherently variable and susceptible to recombination. These variations enable the immune system to respond to a very wide variety of invaders, but may also give rise to lymphocytes capable of self-reactivity.

• HLA DR2 is strongly positively correlated with
  systemic lupus erythematosus, narcolepsy^[13] and multiple sclerosis
  , and negatively correlated with DM Type 1.
• HLA DR3 is correlated strongly with Sjögren syndrome, myasthenia gravis, SLE, and DM Type 1.
• HLA DR4 is correlated with the genesis of
  Type 1 diabetes mellitus, and pemphigus vulgaris
  .

Fewer correlations exist with MHC class I molecules. The most notable and consistent is the association between HLA B27 and spondyloarthropathies like ankylosing spondylitis and reactive arthritis. Correlations may exist between polymorphisms within class II MHC promoters and autoimmune disease.

The contributions of genes outside the MHC complex remain the subject of research, in animal models of disease (Linda Wicker's extensive genetic studies of diabetes in the NOD mouse), and in patients (Brian Kotzin's linkage analysis of susceptibility to SLE).

Recently, PTPN22 has been associated with multiple autoimmune diseases including Type I diabetes, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, Graves' disease, Addison's disease, Myasthenia Gravis, vitiligo, systemic sclerosis juvenile idiopathic arthritis, and psoriatic arthritis.^{[14][clarification needed]}

Sex

Ratio of female/male incidence of autoimmune diseases
Hashimoto's thyroiditis	10:1[15]
Graves' disease	7:1[15]
Multiple sclerosis (MS)	2:1[15]
Myasthenia gravis	2:1[15]
Systemic lupus erythematosus (SLE)	9:1[15]
Rheumatoid arthritis	5:2[15]
Primary sclerosing cholangitis	1:2

Most autoimmune diseases are

.

The reasons for the sex role in autoimmunity vary. Women appear to generally mount larger inflammatory responses than men when their immune systems are triggered, increasing the risk of autoimmunity. Involvement of

sex steroids is indicated by that many autoimmune diseases tend to fluctuate in accordance with hormonal changes, for example: during pregnancy, in the menstrual cycle, or when using oral contraception. A history of pregnancy also appears to leave a persistent increased risk for autoimmune disease. It has been suggested that the slight, direct exchange of cells between mothers and their children during pregnancy may induce autoimmunity.^[17]

This would tip the gender balance in the direction of the female.

Another theory suggests the female high tendency to get autoimmunity is due to an imbalanced

autoimmune thyroiditis.^[19]

Other complex X-linked genetic susceptibility mechanisms are proposed and under investigation.

Environmental factors

Infectious diseases and parasites

An interesting inverse relationship exists between infectious diseases and autoimmune diseases. In areas where multiple infectious diseases are endemic, autoimmune diseases are quite rarely seen. The reverse, to some extent, seems to hold true. The hygiene hypothesis attributes these correlations to the immune-manipulating strategies of pathogens. While such an observation has been variously termed as spurious and ineffective, according to some studies, parasite infection is associated with reduced activity of autoimmune disease.^[20][21][22]

The putative mechanism is that the parasite attenuates the host immune response in order to protect itself. This may provide a serendipitous benefit to a host that also has autoimmune disease. The details of parasite immune modulation are not yet known, but may include secretion of anti-inflammatory agents or interference with the host immune signaling.

A paradoxical observation has been the strong association of certain microbial organisms with autoimmune diseases. For example,

B-lymphocytes

, and production of large amounts of antibodies of varying specificities, some of which may be self-reactive (see below).

Chemical agents and drugs

Certain chemical agents and drugs can also be associated with the genesis of autoimmune conditions, or conditions that simulate autoimmune diseases. The most striking of these is the drug-induced lupus erythematosus. Usually, withdrawal of the offending drug cures the symptoms in a patient.

Cigarette smoking is now established as a major risk factor for both incidence and severity of

peptides

.

Pathogenesis of autoimmunity

Several mechanisms are thought to be operative in the pathogenesis of autoimmune diseases, against a backdrop of genetic predisposition and environmental modulation. It is beyond the scope of this article to discuss each of these mechanisms exhaustively, but a summary of some of the important mechanisms have been described:

• T-cell bypass – A normal immune system requires the activation of
  super-antigens
  , which are capable of initiating polyclonal activation of B-cells, or even of T-cells, by directly binding to the β-subunit of T-cell receptors in a non-specific fashion.
• T-cell–B-cell discordance – A normal immune response is assumed to involve B and T cell responses to the same antigen, even if we know that B cells and T cells recognise very different things: conformations on the surface of a molecule for B cells and pre-processed peptide fragments of proteins for T cells. However, there is nothing as far as we know that requires this. All that is required is that a B cell recognising antigen X endocytoses and processes a protein Y (normally =X) and presents it to a T cell. Roosnek and Lanzavecchia showed that B cells recognising IgGFc could get help from any T cell responding to an antigen co-endocytosed with IgG by the B cell as part of an immune complex. In coeliac disease it seems likely that B cells recognising tissue transglutamine are helped by T cells recognising gliadin.
• Aberrant B cell receptor-mediated feedback – A feature of human autoimmune disease is that it is largely restricted to a small group of antigens, several of which have known signaling roles in the immune response (DNA, C1q, IgGFc, Ro, Con. A receptor, Peanut agglutinin receptor(PNAR)). This fact gave rise to the idea that spontaneous autoimmunity may result when the binding of antibody to certain antigens leads to aberrant signals being fed back to parent B cells through membrane bound ligands. These ligands include B cell receptor (for antigen), IgG Fc receptors, CD21, which binds complement C3d, Toll-like receptors 9 and 7 (which can bind DNA and nucleoproteins) and PNAR. More indirect aberrant activation of B cells can also be envisaged with autoantibodies to acetyl choline receptor (on thymic myoid cells) and hormone and hormone binding proteins. Together with the concept of T-cell–B-cell discordance this idea forms the basis of the hypothesis of self-perpetuating autoreactive B cells.^[23] Autoreactive B cells in spontaneous autoimmunity are seen as surviving because of subversion both of the T cell help pathway and of the feedback signal through B cell receptor, thereby overcoming the negative signals responsible for B cell self-tolerance without necessarily requiring loss of T cell self-tolerance.
• streptococci
  . Although rheumatic fever has been attributed to molecular mimicry for half a century no antigen has been formally identified (if anything too many have been proposed). Moreover, the complex tissue distribution of the disease (heart, joint, skin, basal ganglia) argues against a cardiac specific antigen. It remains entirely possible that the disease is due to e.g. an unusual interaction between immune complexes, complement components and endothelium.
• Idiotype cross-reaction –
  epitopes
  found in the antigen-binding portion (Fab) of the immunoglobulin molecule. Plotz and Oldstone presented evidence that autoimmunity can arise as a result of a cross-reaction between the idiotype on an antiviral antibody and a host cell receptor for the virus in question. In this case, the host-cell receptor is envisioned as an internal image of the virus, and the anti-idiotype antibodies can react with the host cells.
• Cytokine dysregulation –
  TGF-β
  (to name a few), seem to have a role in prevention of exaggeration of pro-inflammatory immune responses.
• Dendritic cell apoptosis – immune system cells called dendritic cells present antigens to active lymphocytes. Dendritic cells that are defective in apoptosis can lead to inappropriate systemic lymphocyte activation and consequent decline in self-tolerance.^[24]
• Epitope spreading or epitope drift – when the
  immune reaction changes from targeting the primary epitope to also targeting other epitopes.^[25]
  In contrast to molecular mimicry, the other epitopes need not be structurally similar to the primary one.
• Epitope modification or Cryptic epitope exposure – this mechanism of autoimmune disease is unique in that it does not result from a defect in the hematopoietic system. Instead, disease results from the exposure of cryptic N-glycan (polysaccharide) linkages common to lower eukaryotes and prokaryotes on the glycoproteins of mammalian non-hematopoietic cells and organs
  innate immune cell
  receptors to induce a chronic sterile inflammatory state. In the presence of chronic and inflammatory cell damage, the adaptive immune system is recruited and self–tolerance is lost with increased autoantibody production. In this form of the disease, the absence of lymphocytes can accelerate organ damage, and intravenous IgG administration can be therapeutic. Although this route to autoimmune disease may underlie various degenerative disease states, no diagnostics for this disease mechanism exist at present, and thus its role in human autoimmunity is currently unknown.

The roles of specialized immunoregulatory cell types, such as

γδ T-cells

in the pathogenesis of autoimmune disease are under investigation.

Classification

See also: List of autoimmune diseases

Autoimmune diseases can be broadly divided into systemic and organ-specific or localised autoimmune disorders, depending on the principal clinico-pathologic features of each disease.

• Systemic autoimmune diseases include coeliac disease, lupus erythematosus, Sjögren syndrome, scleroderma, rheumatoid arthritis, cryoglobulinemic vasculitis, and dermatomyositis. These conditions tend to be associated with autoantibodies to antigens which are not tissue specific. Thus although polymyositis is more or less tissue specific in presentation, it may be included in this group because the autoantigens
  are often ubiquitous t-RNA synthetases.
• Local syndromes which affect a specific organ or tissue:
  • Endocrinologic:
    diabetes mellitus type 1, Hashimoto's thyroiditis, Addison's disease
  • Gastrointestinal:
    Pernicious anaemia
  • Dermatologic: pemphigus vulgaris, vitiligo
  • Haematologic:
    idiopathic thrombocytopenic purpura
  • Neurological: multiple sclerosis, myasthenia gravis, autoimmune encephalitis, gluten ataxia

Using the traditional "organ specific" and "non-organ specific" classification scheme, many diseases have been lumped together under the autoimmune disease umbrella. However, many chronic inflammatory human disorders lack the telltale associations of B and T cell driven immunopathology. In the last decade^{[clarification needed]} it has been firmly established that tissue "inflammation against self" does not necessarily rely on abnormal T and B cell responses.^[27]

This has led to the recent proposal that the spectrum of autoimmunity should be viewed along an "immunological disease continuum", with classical autoimmune diseases at one extreme and diseases driven by the innate immune system at the other extreme. Within this scheme, the full spectrum of autoimmunity can be included. Many common human autoimmune diseases can be seen to have a substantial innate immune mediated immunopathology using this new scheme. This new classification scheme has implications^{[clarification needed]} for understanding disease mechanisms and for therapy development.^[27]

Diagnosis

Diagnosis of autoimmune disorders largely rests on accurate history and physical examination of the patient, and high index of suspicion^{[clarification needed]} against a backdrop of certain abnormalities in routine laboratory tests (example, elevated C-reactive protein).^{[citation needed]}

In several systemic disorders,^[

autoantibodies can be employed.^{[citation needed]} Localised disorders are best diagnosed by immunofluorescence of biopsy specimens.^{[citation needed}

]

Autoantibodies are used to diagnose many autoimmune diseases.^{[clarification needed]} The levels of autoantibodies are measured to determine the progress of the disease.^{[citation needed}

]

Treatments

Treatments for autoimmune disease have traditionally been

immunomodulatory therapies, such as the TNFα antagonists (e.g. etanercept), the B cell depleting agent rituximab, the anti-IL-6 receptor tocilizumab and the costimulation blocker abatacept

have been shown to be useful in treating RA. Some of these immunotherapies may be associated with increased risk of adverse effects, such as susceptibility to infection.

nematodes (helminths). There are currently two closely related treatments available, inoculation with either Necator americanus, commonly known as hookworms, or Trichuris Suis Ova, commonly known as Pig Whipworm Eggs.^{[29][30][31][32][33]}

T-cell vaccination is also being explored as a possible future therapy for autoimmune disorders.^{[citation needed]}

Nutrition and autoimmunity

Vitamin D/Sunlight

• Because most human cells and tissues have receptors for vitamin D, including T and B cells, adequate levels of vitamin D can aid in the regulation of the immune system.
  vitamin D receptor gene are commonly found in people with autoimmune diseases, giving one potential mechanism for vitamin D's role in autoimmunity.^[35][36] There is mixed evidence on the effect of vitamin D supplementation in type 1 diabetes, lupus, and multiple sclerosis.^[35][36][37]
   

Omega-3 Fatty Acids

• Studies have shown that adequate consumption of omega-3 fatty acids counteracts the effects of arachidonic acids, which contribute to symptoms of autoimmune diseases. Human and animal trials suggest that omega-3 is an effective
  treatment modality for many cases of Rheumatoid Arthritis, Inflammatory Bowel Disease, Asthma, and Psoriasis.^[38]
• While major depression is not necessarily an autoimmune disease, some of its physiological symptoms are inflammatory and autoimmune in nature. Omega-3 may inhibit production of interferon gamma and other cytokines which cause the physiological symptoms of depression. This may be due to the fact that an imbalance in omega-3 and omega-6 fatty acids, which have opposing effects, is instrumental in the etiology of major depression.[38]

Probiotics/Microflora

• Various types of bacteria and microflora present in fermented dairy products, especially Lactobacillus casei, have been shown to both stimulate immune response to tumors in mice and to regulate immune function, delaying or preventing the onset of nonobese diabetes. This is particularly true of the Shirota strain of L. casei (LcS). The LcS strain is mainly found in yogurt and similar products in Europe and Japan, and rarely elsewhere.^[39]

Antioxidants

• It has been theorized that free radicals contribute to the onset of type-1 diabetes in infants and young children, and therefore that the risk could be reduced by high intake of antioxidant substances during pregnancy. However, a study conducted in a hospital in Finland from 1997 to 2002 concluded that there was no statistically significant correlation between antioxidant intake and diabetes risk.^[40] This study involved monitoring of food intake through questionnaires, and estimated antioxidant intake on this basis, rather than by exact measurements or use of supplements.

See also

• Autoimmune disease
• Protective autoimmunity
• Psychoneuroimmunology

References

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External links

• American Autoimmune Related Diseases Association: a nonprofit advocacy
• Immune Tolerance Network: a research-oriented resource
• Nobel Prize – The 1960 Nobel Prize in Physiology or Medicine was awarded to Frank M. Burnet and Peter B Medawar "for discovery of acquired immunological tolerance."
• The Immunology Database and Analysis Portal – an NIAID-funded database resource of reference and experiment data covering the entire immunology domain
• Understanding Autoimmune Diseases - US National Institute of Arthritis and Musculoskeletal and Skin Diseases