Autoimmunity and autoimmune disease

The principal role of the immune system is to protect the organism from principally two the most dangerous events potentially threatening our life, i.e. infection and malignancy. However, sometimes the immune system instead of reacting against foreign and aberrant self-antigens can attack self-molecules. This inappropriate response of the immune system against self-components is termed autoimmunity.
There are 70 - 80 autoimmune disorders known till now and app. 5% of Caucasoid population suffers from them. Our understanding of autoimmunity has improved greatly during the last two decades, mainly because of the development of a variety of animal models of these diseases and the identification of genes that may predispose to autoimmunity. Nevertheless, the aetiology of most human autoimmune diseases remains still obscure.
The term “autoimmunity” is often erroneously used for a disease in which immune reactions accompany tissue injury; they are “a by-product” of a release of self-antigens to circulation without causing any damage; moreover, these “autoimmune reactions” help to degrade them and to remove them from the body.

   Immunologic tolerance is defined as unresponsiveness to an antigen that is induced by previous exposure to that antigen. When specific lymphocytes encounter antigens, the lymphocytes may be activated, leading to immune responses, or the cells may be inactivated or eliminated, leading to tolerance. Antigens that induce tolerance are called tolerogens, or tolerogenic antigens, to distinguish them from immunogens, which generate immunity. Tolerance to self antigens, also called self-tolerance, is a fundamental property of the normal immune system, and failure of self-tolerance results in immune reactions against self (autologous) antigens. Such reactions are called autoimmunity, and the diseases they cause are called autoimmune diseases.
   Mechanisms of self-tolerance normally prevent an activation of self-reactive lymphocytes; if there are failures, the auto-aggressive reactions result. In the 1960s, it was believed that all self-reactive lymphocytes were eliminated during their development in the thymus and the bone marrow, respectively and that a failure to eliminate these cells led to autoimmune consequences. Since the late 1970s, it was realised that not all self-reactive lymphocytes were deleted during T-cell and B-cell maturation. Instead, normal healthy individuals possess mature self-reactive lymphocytes. Their presence does not under physiological conditions result in autoimmune reactions; they are prevented from the activation by mechanisms of peripheral tolerance. A breakdown in this regulation can cause serious damage to cells and organs, sometimes with fatal consequences.
   Autoimmunity may result from primary abnormalities of B cells, T cells, or both. T cells are, however, more important for two main reasons. First, helper T cells are the key regulators of all immune responses to protein antigens. Second, several autoimmune diseases are genetically linked to the major histocompatibility complex (MHC, i.e. the HLA complex in humans), and the function of MHC molecules is to present peptides to T cells. It should be also pointed out that in healthy individuals failure to produce autoantibodies against self-protein antigens is due from lack of help to B cell by T helper cells rather than of B cell tolerance. Therefore, failure of T cell tolerance is an important mechanism of autoimmune diseases.
   Central tolerance is the mechanism of selection of immature auto-reactive lymphocytes that deletes cells with high-affinity receptors for ubiquitous self-antigens. Therefore it is possible that in some cases autoimmunity results from a failure of these selection processes. The best-known example is a mutation in AIRE (autoimmune regulator) gene resulting in APECED syndrome.
   The central tolerance as a biological phenomenon is not 100% effective; some autoreactive T cells escape to the periphery. In these cases events peripheral mechanisms are adequate for maintaining unresponsiveness to many self-antigens. Peripheral tolerance in mature self antigen-specific T cells is maintained by deletion by apoptosis, and suppression by regulatory T cells, and functional anergy.
   Natural regulatory T cells (Treg) play the principle role in limitations of reactivity of self-reactive T-cells. nTreg-cells mature in the thymus under the regulatory activity of FOXP3 gene that encodes a forkhead transcription factor. A mutation of the FOXP3 gene (Xp11.23-q13.3) results in a recessive autoimmune disorder IPEX.
   Numerous associations between nutrition and the immune system have been made. Leptin, a hormone primarily known for control of appetite and obesity, was recently shown to exhibit immunoregulatory activities, too. I was proved that leptin down-regulated an immunosupressive activity of nTreg cells and up-regulated activity of effector T cells (TH1). nTregs not only express leptin receptors however are its active producers. It is therefore supposed that leptin contributes to the development of autoimmunity too, linking so environmental factors to (auto)immune reactions.
   Exposure of B cells to polyclonal activators such as bacterial lipopolysaccharide (LPS) may activate a large number of these cells, including some that are specific for self-antigens. This mechanism is believed to be important in the pathogenesis of several antibody-mediated disorders such as myasthenia gravis and Graves’ disease.
   Aberrant expression of co-stimulatory molecules (CD80, CD86 etc.) in tissues may result in a breakdown of T cell anergy and tissue specific autoimmune reactions. Cells of tissues and organs under physiological conditions do not express co-stimulatory molecules and therefore are unable to activate self-reactive T cells. Moreover, these are normally not present here, as the recirculation of naïve T cells is restricted to secondary lymphoid organs and they do not enter the tissues. However, an infection and a resulting local inflammation results in aberrant expression of co-stimulatory molecules enabling the activation of auto-reactive T cells, which enter the tissues when previously activated in regional lymph nodes by tissue APCs. As a consequence, self-reactive T cells may proliferate and differentiate into effector cells that cause injurious autoimmune reactions against the tissue.
   Already early studies of autoimmune disorders in both patients and experimental animals have indicated that they have a strong genetic component. For instance, type I diabetes mellitus (DM 1A) shows a concordance of 35% to 50% in monozygotic twins and 5% to 6% in dizygotic twins. Among all the genes that are associated with autoimmunity, the strongest associations are with MHC genes, especially class II MHC genes. HLA typing of large groups of patients with various autoimmune diseases has shown that some HLA antigens/alleles occur at higher frequency in these patients than in the general population. From such studies, one can calculate the relative risk of a disease developing in individuals who inherit various HLA alleles. The strongest such association is between ankylosing spondylitis and HLA-B27. Individuals who are HLA-B27 positive have a 90 to 100-times greater chance of developing ankylosing spondylitis than do individuals lacking HLA-B27.
   Autoimmune processes develop on an intersection of genetic and environmental factors. It is well known fact that autoimmune diseases are often associated with or preceded by infections. However, the infectious microbe is not present in lesions and is not even detectable in the individual when autoimmunity develops. Therefore, the lesions of autoimmunity are not due to the infectious agent by itself but result from host immune responses that may be triggered or dysregulated by the microbe.
   Infections may promote the development of autoimmunity by many possible mechanisms. Infections of particular tissues may induce local inflammation and result in the expression of co-stimulatory molecules on tissue APCs and the breakdown of T cell anergy. Tissue injury caused by infection may lead to alterations in self-antigens that create partially cross-reactive neo-antigens and to release of anatomically sequestered antigens. Furthermore, infectious microbes may contain antigens that cross-react with self-antigens, so immune responses to the microbes may result in reaction against self-antigens. This phenomenon is called molecular mimicry.
   An increase of allergy and autoimmune prevalence has occurred in ”westernized“ societies over the past few decades. This is therefore thought to be primarily due to changes that have taken place in the environment in developed countries as result of reducing infections during early childhood. A consequence may be a bias of the physiological development of the immune system to either to TH2 (allergies) or TH1/TH17 (autoimmune disorders) direction or an insufficient activity of regulatory T cells (a hygiene hypothesis).
   The development of autoimmunity is related to several factors in addition to primary immunologic abnormalities, susceptibility genes, and infections. Anatomic alterations in tissues, such as inflammation (possibly secondary to infections), ischemic injury, or trauma, may lead to the exposure of self-antigens that are normally concealed from the immune system. Such sequestered antigens may not have induced self-tolerance. Therefore, if previously sequestered self-antigens are released, they can interact with immunocompetent lymphocytes (i. e. T and B cells) and induce specific immune responses. Examples of anatomically sequestered antigens include intraocular proteins and sperms. Posttraumatic uveitis and orchitis following vasectomy are thought to be due to autoimmune responses to self-antigens that are released from their normal locations. Tissue inflammation may also cause structural alterations in self-antigens and the formation of new determinants capable of inducing autoimmune reactions. Inflammation may result in macrophage activation by locally produced cytokines, and if these cytokines stimulate the expression of co-stimulatory molecules, the result may be loss of peripheral tolerance.
   Hormonal influences play a role in some human and experimental autoimmune diseases. Many autoimmune diseases have a higher incidence in females than in males. For instance, SLE affects women about ten times as frequently as men. Hormones can affect the function of all cells in the immune system. Estradiol can promote the survival of high-affinity autoreactive B cells. Women also routinely express more TLR7, for which the natural ligand is RNA, thereby permitting more immune activation by microbial or self-RNA. Finally, it is worth remembering that the effect of sex hormones may not be on immune activation, but may in fact be on target-organ display of autoantigen or target-organ response to the production of inflammatory mediators.
   Anti-inflammatory drugs, particularly corticosteroids, are the mainstay of therapy for autoimmune diseases. Such drugs are targeted at reducing tissue injury, specifically, the effector phases of the pathologic immune responses. In severe cases, immunosuppresive drugs such as cyclosporine, tacrolimus and others are used to block T cell activation. Antagonists of proinflammatory cytokines, such as IL-1 and TNF, and agents that block leucocyte emigration into tissues are also being used for their anti-inflammatory effects, e.g. monoclonal antibodies anti-TNF (infliximab, adalimumab) in the treatment of rheumatoid arthritis and m. Crohn, monoclonal antibodies anti-VLA4 in the treatment of multiple sclerosis and others. Other approaches to inhibiting pathologic immune reactions include antagonists against co-stimulators, such as CD80 molecules, CD40 ligand and others. Plasmapheresis has been used during exacerbations of antibody-mediated diseases to reduce circulating levels of antibodies or immune complexes.

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