PREDICTION AND PREVENTION OF AUTOIMMUNE SKIN DISORDERS (LITERATURE REVIEW)

PREDICTION AND PREVENTION OF AUTOIMMUNE SKIN DISORDERS (LITERATURE REVIEW)

Hatem Ghaleb Maabreh

graduate student, Peoples' Friendship University of Russia (RUDN University),

Russia, Moscow

Nadejda Batkaeva

Candidate of Medical Sciences, Peoples' Friendship University of Russia (RUDN University),

Russia, Moscow

Edward Batkaev

Professor, Peoples' Friendship University of Russia (RUDN University),

Russia, Moscow

Nashaat Sultan Al Khateeb

graduate student,  Peoples' Friendship University of Russia (RUDN University),

Russia, Moscow

Ziad Ahmad Alabdallah

PHD, Al Furat University,

Syria, Deirez-or

ABSTRACT

Autoimmune diseases may be preceded by an asymptomatic phase, which is determined by the presence of autoantibodies and can last for many years. These autoantibodies may have a high positive predictive value for disease onset, severity, and organ-specific complications, especially in genetically predisposed individuals. Characteristic autoantibodies and susceptibility genes have been identified in many systemic autoimmune and skin and mucosal diseases such as systemic lupus erythematosus, pemphigus, vitiligo, dermatitis herpetiformis and even psoriasis. Prevention of overt disease can be achieved once individuals at high risk are identified and precipitating factors are eliminated. Numerous environmental factors such as vitamin D deficiency, ultraviolet radiation, smoking, drugs, etc. have been found to cause autoimmunity. Alternatively, even if an autoimmune disease cannot be prevented, it can be delayed or attenuated. Thus, although a large body of data has been accumulated on characteristic autoantibodies, susceptible genes, and environmental factors, many more large-scale studies are needed to evaluate their predictive value, preventive measurements, and means of their application to the clinical management of healthy populations and patients with high levels of morbidity. [1,3,5,7,9]

Introduction:

Autoimmune diseases are the third leading cause of morbidity and mortality in industrialized countries, after heart disease and cancer. These diseases may be preceded by a multi-year preclinical phase in which asymptomatic patients can be identified by the presence of characteristic autoantibodies.[2]

These autoantibodies are not always the direct cause of the disorder, which may be mediated by other immune mechanisms, but they serve as markers that predict the risk of developing the disease and the time of its onset. In many cases, autoimmunity develops over many years as a result of a process that combines immune activation, genetic predisposition, and environmental factors in a particular person at certain points in time. Predicting the disease allows the use of primary prevention methods that can delay or prevent the onset of the disease. Autoantibodies can also predict the clinical manifestations, exacerbations, and progression of diagnosed autoimmune diseases, making it possible to use secondary and even tertiary preventive interventions to improve survival, morbidity, and quality of life. [4,6]

Genetics :

A large body of data confirms the important role of genetic predisposition in the autoimmunity mosaic [10, 8]. Increased concordance in monozygotic twins compared to dizygotic twins, as well as an increased incidence of affected family members, have been reported in many diseases such as psoriasis [11], vitiligo , primary biliary cirrhosis (PBC) [12] and diabetes mellitus (DM) . In lupus, a concordance of 25% among monozygotic twins compared with 2% among dizygotic twins indicates a genetic predisposition, but not sufficient to be the sole cause of the disease [5, 14]. The strongest genetic influence on autoimmunity is through the major histocompatibility complex (MHC). Systemic lupus erythematosus (SLE) is associated with several HLA alleles (Table 1), with a relative risk of 2–12% [13, 10]. The DRB1 and DQB1 alleles are associated with pemphigus vulgaris in Caucasians and have a relative risk of 15% [1]. HLA DQ2 is present in 90% of patients with celiac disease and dermatitis herpetiformis, and HLA DQ8 is present in most of the rest (relative risk 11.6%) [3]. HLA-DR and others are associated with vitiligo [6]. PSORS 1 is associated with psoriasis, while HLA-Cw6 is associated with early disease onset [2]. There are also non-MHC autoimmune susceptible alleles, these genes are difficult to identify, mainly due to extensive genetic heterogeneity . Non-MHC genes can be divided into tissue-specific and immunoregulatory genes. Tissue-specific genes are ADAM33 in asthma, NOD2 in Crohn's disease , and genes on chromosomes 1, 4, 7, 8, etc. in patients with vitiligo [7]. The main non-MHC regulatory gene is CTLA-4, which plays a key role in the interaction between T cells and antigen-presenting cells; defects in CTLA-4 have been found in psoriasis [1], vitiligo , and SLE [4] Graves, diabetes and other diseases .[8]

Environmental factors:

Environmental factors such as ultraviolet light, vitamin D deficiency, infections, vaccines, aduvants, xenobiotics, diet, stress, smoking and different drugs can trigger or exacerbate autoimmunity . Most of these environmental factors are changeable and can be avoided once individual risk of autoimmunity is determined.

A common trigger of autoimmune skin manifestations is sunlight, as Ultra-violet B [UVB] appears to have a pro-autoimmune effect .Low doses of UVB cause apoptosis, which is an anti-inflammatory process, however high doses of UVB can cause abnormal apoptosis and higher doses cause necrosis, a pro-inflammatory process, that may expose auto antigens to antigen presenting cells and exacerbate autoimmunity .Furthermore, a correlation between certain antibodies as anti Ro and sunlight is associated with skin and systemic exacerbations of SLE . Although sunlight exposure is a risk factor for autoimmunity, it also raises vitamin D levels. The skin has the capacity to synthesize the active metabolite of vitamin D as well as be its target tissue. Vitamin D has a multitude of biologic effects that are non-calcemic in nature, mainly interacting with the adaptive and innate immune response via regulating the differentiation of B cells, T cells, Dendritic cells, and expression of Toll like receptors, mainly leading to down regulation of the immune response . Vitamin D-receptor and vitamin D binding protein polymorphisms are associated with autoimmunity and represent an important link between genetics and environmental factor . Evidences for vitamin D deficiency or low levels were reported in animal models of autoimmunity and in humans. Lower levels of vitamin D have been implicated in the etiology of SLE, Rheumatoid arthritis, multiple sclerosis and Diabetes mellitus . Recently vitamin D analogs have been introduced for the treatment of psoriasis [5]. Therefore, although clinical data regarding therapy with vitamin D are lacking, improving vitamin D status in patients with autoimmune diseases should be encouraged.

The relationship between infections and autoimmune diseases has been extensively studied . Infections can break self tolerance and initiate an immune response via several mechanisms such as molecular mimicry, hapten modifications, direct toxic effect etc. A clear proof for a culprit infectious agent as a trigger of autoimmunity is difficult to establish, however, an association was documented in numerous diseases [14] and several infectious agents have been linked to autoimmune skin diseases such as Epstein Barr virus with SLE [11], Herpes virus with pemphigus and streptococcal, staphylococcal and candida albicans infections with psoriasis [3]. Vaccines on one hand protect from infections and might prevent triggering of autoimmunity; on the other hand vaccines were associated with increased prevalence of SLE, dermatomayositis and other diseases [9]. Tobacco smoking is one of the most potent environmental triggers of autoimmunity, which interacts with genetic factors to create a significant up to 21-fold risk of disease [8]. Smoking modulates the immune system through induction of inflammatory response, altered cytokine balance and apoptosis with DNA damage that may result in formation of anti-DNA antibodies [7]. SLE manifestations such as nephritis, serositis, neuro-psychiatric and to some extent dermatologic features are associated with smoking [2].

Thus, although many environmental factors have been identified, many more have yet to be studied so that habitual, lifestyle and therapeutic preventive modification can be successfully employed.

Conclusion :

It has been clearly demonstrated that many autoantibodies have a predictive value, which means that they can be serologically detected long before clinical disease is diagnosed. For muco-cutaneus and other autoimmune diseases, the “multiple hit” hypothesis has been proposed suggesting a synergistic effects of different types of autoantibodies in a certain individual for a certain disease (e.g., accumulation of autoantibodies predict the appearance of SLE). Although not all healthy individuals who are seropositive for autoantibodies will develop autoimmune disease, many of them will, especially those who have the proper genetic background and are further exposed to environmental and other risk factors. Therefore identification of an autoimmune process in the preclinical stage may become feasible and enable the implementation of primary prevention methods. For patients with overt disease, autoantibodies may predict the extent and severity of disease and enable secondary and tertiary preventive interventions.

However, many prospective studies are needed to assess the predictive value of different autoantibodies and combinations, as well as genetic testing and environmental factors in autoimmune skin diseases, in order to apply means of prevention to healthy and diseased populations. Nevertheless, the value of autoantibodies and other component of the autoimmune-mosaic accumulated so far may justify the foundation of serological screening and follow-up programs at least for relatives of patients with autoimmune skin disease as well as avoidance of triggering factors so as to minimize their risk for overt disease.

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