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autoimmune diseases

Thursday 3 July 2003

auto-immune diseases; autoimmunity

Definition: Immune reactions against self-antigens-autoimmunity-are an important cause of certain diseases in humans, estimated to affect at least 1% to 2% of the US population.

A growing number of diseases have been attributed to autoimmunity, but in many the evidence is not firm. Autoantibodies can be found in the serum of apparently normal individuals, particularly in older age groups.

Furthermore, innocuous autoantibodies are also formed after damage to tissue and may serve a physiologic role in the removal of tissue breakdown products.

How, then, does one define pathologic autoimmunity? Ideally, at least three requirements should be met before a disorder is categorized as truly due to autoimmunity:

- (1) the presence of an autoimmune reaction;
- (2) evidence that such a reaction is not secondary to tissue damage, e.g., resulting from infection, but is of primary pathogenetic significance;
- (3) the absence of another well-defined cause of the disease.

Similarity with experimental models of proven autoimmunity is also often used to support this mechanism in human diseases.

Autoimmune disorders may result from tissue injury caused by T cells or antibodies that react against self-antigens.

The autoimmune diseases form a spectrum, on one end of which are conditions in which the immune response is directed against a single organ or tissue, resulting in organ-specific disease, and on the other end are diseases in which the autoimmune reaction is against widespread antigens, resulting in generalized or systemic disease.

Examples of organ- specific autoimmunity are type I diabetes mellitus, in which the autoreactive T cells and antibodies are specific for β cells of the pancreatic islets, and multiple sclerosis, in which autoreactive T cells react against central nervous system myelin.

An example of systemic autoimmune disease is SLE, in which a diversity of antibodies directed against DNA, platelets, red cells, and protein-phospholipid complexes result in widespread lesions throughout the body.

In the middle of the spectrum falls Goodpasture syndrome, in which antibodies to basement membranes of lung and kidney induce lesions in these organs.

It is obvious that autoimmunity results from the loss of self-tolerance, and the question arises as to how this happens. Before we look for answers to this question, we review the mechanisms of immunologic tolerance to self-antigens.

See also

- autoimmunity

Classification (Exemples)

- systemic lupus erythematosus
- autoimmune endocrinopathies

- digestive autoimmune diseases

- hepatic autoimmune diseases

  • autoimmune hepatitis
    - autoimmunity with lymphoproliferative syndrome (ALPS)

- autoimmune endocrinopathies


- autoimmune digestive diseases
- autoiimune pulmonary diseases
- autoimmune cutaneous diseases
- autoimmune cerebral diseases
- autoimmune endocrinopathies

  • autoimmune thyroid disease


- primary immune deficiencies


Although it would be attractive to explain all autoimmune diseases by a single mechanism, it is now clear that there are a number of ways by which tolerance can be bypassed, thus terminating a previously unresponsive state to autoantigens. More than one defect might be present in each disease, and the defects vary from one disorder to the other.

- Role of Susceptibility Genes

The development of autoimmunity is related to the inheritance of susceptibility genes, which may influence the maintenance of self-tolerance, and environmental triggers, particularly infections, which promote the activation of self-reactive lymphocytes.

Most autoimmune diseases show a strong genetic predisposition. Among the genes known to be associated with autoimmunity, the best defined are HLA genes. The concept of HLA association with diseases was mentioned earlier. Despite the fact that this association has been well established for many years, the underlying mechanisms remain obscure.

It is postulated that the presence of particular MHC alleles affects the negative selection of T cells in the thymus or the development of regulatory T cells, but there is little actual evidence for either possibility. It should be pointed out that many normal individuals inherit the MHC alleles that are disease-associated in patient populations, and normal MHC molecules are capable of presenting self-antigens.

Therefore, the presence of particular MHC alleles is not, by itself, the cause of autoimmunity. In several autoimmune diseases, such as SLE and type I diabetes, many non-MHC genetic loci have been shown to be associated with autoimmunity.
The story of SLE in a mouse model is particularly interesting-different susceptibility loci are believed to contribute to generalized B-cell activation, the production of anti-DNA autoantibodies, and the severity of nephritis.

A major limitation in these studies is that the susceptibility loci that have been identified so far usually span large segments of chromosome, and the actual disease-associated genes are not known. The relevant genes at such loci may be revealed by modern methods of gene mapping and the availability of genome sequence information.

In mice, mutations of several known genes result in autoimmunity, and many of these are instructive as far as pathogenetic mechanisms are concerned.

The natural mouse mutants of Fas and FasL, which interfere with activation-induced cell death, and knockout mice lacking AIRE, the transcription factor involved in thymic expression of self-antigens, and CTLA-4, the inhibitory receptor involved in T-cell anergy, have been mentioned above.

IL-2, which is a growth factor for T cells, is also required for the development and functions of regulatory T cells, and promotes Fas-mediated apoptosis if present for prolonged periods.

Knockout mice lacking IL-2 or the α or β chain of the IL-2 receptor develop autoimmunity, with inflammatory bowel disease, anti-DNA antibodies, and autoimmune hemolytic anemia.

In these mice, autoimmunity presumably results from a failure of suppression by regulatory T cells and a failure of activation-induced cell death, two of the mechanisms of peripheral tolerance.

B cells express an Fc receptor that recognizes IgG antibodies bound to antigens and shuts off further antibody production (a negative feedback mechanism). Knockout of this receptor results in autoimmunity, presumably because the B cells can no longer be controlled.

Mutations and polymorphisms in the Fas, AIRE, CTLA-4, and Foxp3 genes are also the cause of human autoimmune diseases, as we have mentioned previously.

Although these examples teach us about the mechanisms of autoimmunity, it should be emphasized that most human autoimmune disorders have complex, multigenic patterns of susceptibility and are not attributable to single gene mutations.

- Role of Infections

Many autoimmune diseases are associated with infections, and clinical flare-ups are often preceded by infectious prodromes. Two mechanisms have been postulated to explain the link between infections and autoimmunity.

First, infections may up-regulate the expression of costimulators on antigen-presenting cells. If these cells are presenting self-antigens, the result may be a breakdown of clonal anergy and activation of T cells specific for the self-antigens.

Second, some microbes may express antigens that have the same amino acid sequences as self-antigens. Immune responses against the microbial antigens may result in the activation of self-reactive lymphocytes.

This phenomenon is called molecular mimicry. A clear example of such mimicry is rheumatic heart disease, in which antibodies against streptococcal proteins cross-react with myocardial proteins and cause myocarditis. But more subtle molecular mimicry may be involved in many other, classical autoimmune diseases.

Microbes may induce other abnormalities that promote autoimmune reactions. The tissue injury that is common in infections may release self-antigens and structurally alter self-antigens so that they are able to activate T cells that are not tolerant to these new, altered antigens. Infections may induce the production of cytokines that recruit lymphocytes, including potentially self-reactive lymphocytes, to sites of self-antigens.

Once an autoimmune disease has been induced, it tends to be progressive, sometimes with sporadic relapses and remissions, and the damage becomes inexorable. An important mechanism for the persistence and evolution of autoimmune disease is the phenomenon of epitope spreading.

Infections, and even the initial autoimmune response, may release and damage self-antigens and expose epitopes of the antigens that are normally concealed from the immune system, or cryptic. The result is continuing activation of new lymphocytes that recognize these previously cryptic epitopes; since these epitopes were not expressed normally, the lymphocytes did not become tolerant to them.

Thus, regardless of the initial trigger of an autoimmune response, the progression and chronicity of the autoimmune response may be maintained by continued recruitment of autoreactive T cells that recognize normally cryptic self-determinants.

The induction of such autoreactive T cells is referred to as epitope spreading because the immune response "spreads" to determinants that were initially not recognized.

See also

- molecular mimicry
- dysimmune diseases

  • autoimmune diseases


- The Molecular Pathology of Autoimmune Diseases. by Argyrios N. Theofilopoulos, Constantin A. Bona. Hardcover: 1200 pages ; Dimensions (in inches): 1.92 x 11.26 x 8.50. Publisher: T&F STM ; 2nd edition (January 11, 2002) ISBN: 9057026457


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- Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med. 2002 Sep 19;347(12):911-20. PMID: 12239261

- Zinkernagel RM. Maternal antibodies, childhood infections, and autoimmune diseases. N Engl J Med. 2001 Nov 1;345(18):1331-5. PMID: 11794153

- Nevo U, Kipnis J, Golding I, Shaked I, Neumann A, Akselrod S, Schwartz M. Autoimmunity as a special case of immunity: removing threats from within. Trends Mol Med. 2003 Mar;9(3):88-93. PMID: 12657429