RECENT APPROACHES IN AUTOIMMUNE DISEASES
Prasanna K S
Assistant Professor & Head
Department of Veterinary Pathology, College of Veterinary and Animal Sciences,
Mannuthy, Thrissur, Kerala 680651 prasanna@kvasu.ac.in
Abstract
Auto immune diseases (AIDs) are the result of faulty directions given to immune system, prompted by environmental and genetic factors and the interaction of these two factors. The genetic variations and the influencing factors are found to be increasing day by day and even climatic changes can elicit or enhance these diseases. The influence of pollution and dietary factors have been explored deeply and concept of hygiene, infection and immunisation are revisited in relation to different AIDs. Vitamin D deficiency has come up as a key factor in the pathogenesis. Approximately 10% of the world population suffer from different types of AIDs. In case of animals the definitive diagnosis of such diseases has not gained sufficient importance, may be due to low level of occurrence or misdiagnosis in many such cases. Increasing rate of pet parenting and an upsurge in the number of various risk factors underline the need for discussing AIDs in Veterinary Pathology. This paper is tailored to cater this need by citing recent information on pathogenesis and diagnosis of AIDs in general.
(Key words: Auto immune diseases, environment, genetic, diagnosis)
Introduction
Immune system is considered as a double-edged sword, because it can break or make a detrimental effect to the body. The history of autoimmune diseases starts way back in 1800s when Paul Ehrlich first mentioned a term “horror autotoxicus” which was then interpreted as “autoimmunity can never happen”. Earlier thoughts were such that the immune reactions to self-antigens would reverse nature’s aversion to self-injury. The first spontaneous animal model of autoimmunity, the New Zealand black mouse was discovered in 1959. Description of autoimmune disease in dogs came only later when dog breeding and selection of traits within certain specific dog breeds gained importance. Intensive breeding and selection for specific phenotypic characteristics led to the propagation of a number of autoimmune diseases in dogs such as systemic lupus erythematosus (SLE), myasthenia gravis, diabetes mellitus, autoimmune hemolytic anemia and thrombocytopenia. (Mackey, 2010). Many autoimmune diseases in humans have their counterparts in companion animals.
Autoimmunity
It looks mysterious how or when the immune system starts attacking the self-antigens and cause detrimental effects to the body. T or B cells do not get access to the specific antigens of the target tissues of highly privileged site as in the case of eye lens, brain tissue or testicular cells at any time of its development may develop autoimmunity. It can also occur when there is a distressing incident to exposes the tissues to the active and functional immune system. The shared antigenic epitopes between host tissue and any pathogen can also lead to similar events. The autoantibodies attack the host tissue and elicit inflammation and tissue degeneration as in the case of streptococci induced myocarditis and rheumatic fever. The receptors on the T cells, sense and bind to the foreign antigens and initiate immune reaction for protective purpose. Certain additional proteins known as “accelerators” help in the triggering of immune reaction and some other proteins designated as “brakes” cause opposite effects by checking or controlling the immune reaction. So, autoimmunity develops when there is any change in this balance and immune system gets activated not only against the pathogens but against the healthy cells too.
The immature T cells are ‘‘tested’’ for their ability to bind to self-MHC antigens. Those that do not bind at all, are subjected to induction of apoptosis and are eliminated. Those that bind too strongly are similarly disposed of. The T cells with ability to recognize MHC of self but do not bind strongly enough to elicit a cytotoxic event are retained. These cells become CD4 or CD8 T cells and can bind to MHC class II or MHC class I, respectively, whereas their T-cell receptor (TCR) for antigen has specificity for some foreign epitope. The TCRs are screened for reactivity to the extravagantly expressed tissue antigens on thymic epithelial cells, and those that react with any of these antigens are induced into apoptosis and eliminated from the T-cell pool that enters the periphery to seed the secondary lymphoid organs. Majority of lymphocytes reacting with auto-antigens are deleted in primary lymphoid organs by clonal deletion.
The self-reactive lymphocytes that escape and reach secondary lymphoid tissues are down regulated by clonal anergy, regulatory T cells (Tregs) or other mechanisms and hence normal individuals remain tolerant to autoantigen. Breakdown in this regulation through clonal anergy or clonal suppression leads to activation of self-reactive lymphocytes. The random generation of antigen-binding receptors ensures that many lymphocytes are produced that can bind and respond to self-antigens. It has been estimated that 20-50% of T cell receptors (TCRs) and B cell receptors (BCRs) generated in this way will bind to self-antigens with high affinity. These self-reactive cells are usually rigorously suppressed so that only a few animals develop autoimmune diseases. In some autoimmune diseases, the disease is mediated by auto antibodies alone. In others, the damage may be mediated by T cells alone or by some combination of auto antibodies and T cells. According to Kleinewietfeld and Hafler, (2014), in contrast to effector T cells, Tregs play a central role in immunoregulatory reactions and suppression of autoreactive immune cells. Once get activated, forkhead box P3 (FoxP3) positive Tregs, exert their suppressive functions via the release of anti-inflammatory cytokines like IL-10 and transforming growth factor b (TGF b).
Genetic back up
Immune system itself has certain genetic predisposition that is responsible for the difference in disease susceptibility in individual animals. The specific types of genes responsible for different AIDs have been identified and the diseases develops when these genes get triggered. This trigger is influenced by environmental alterations that lead to genetic variations. There are three types of genetic variations responsible for AIDs: single nucleotide polymorphism which is rare (1%), copy number variants and epigenetic modifications. The polymorphism or mutations that directly result in AIDs is rare and hence the genetic factor underlying the disease is presumed on the basis of position and strength of the genetic signal and the function of the gene. Associations of particular HLA alleles are often specific to a particular autoimmune disease, reflecting that the relevant self-antigen is likely to be different for each form of disease (Cho et al., 2011).
Genome wide association study (GWAS)
Genome-wide association studies (GWAS) are well-established and effective method of identifying genetic loci associated with common diseases or traits. This has explained more than hundred identified loci associated with various autoimmune diseases. These genes belong to distinct functional network groups. For example, PTPN22, CTLA4, PTPN2 genes, to lymphocyte activation and intracellular signalling; IL23R and IL2RA to cytokines and receptors; NOD2 and IRF5 genes to innate immunity and microbial recognition; STAT4 gene belonging to transcription factors. Cotsapas et al (2011) have described the sharing of the genetic effects between different AIDs. According to Sivakumaran et al (2011), diseases like multiple sclerosis and rheumatoid arthritis share genetic factors within the MHC region.
Gender basis
Medical reports confirm that more than 80% of the patients with AIDs are females. The larger number of genes originating from the X chromosome creates a far greater possibility of a larger number of mutations occurring in these genes. This puts females at a higher risk for the development of autoimmune diseases solely due to the double X chromosomes (Anjum et al., 2020). Diseases like systemic lupus erythematosus, dermatomyositis, and Sjogren’s syndrome mainly affect the females. The female hormones, oestrogen and progesterone may also have key roles in such cases. But similar population study to establish the correlation between autoimmune diseases and gender status is yet to be done in case of animals.
Environmental triggers
Climate change
This is a major concern and the main point of discussion globally in all spheres of life. Climate change has initiated an altered response to antigenic exposure by disrupting antigen specific tolerance of immune system. Increased intensity and duration of pollens in the atmosphere are found to enhance respiratory allergy. High prevalence of antibodies is detected in the warmer and moister coastal areas Southern and Eastern Africa. In drier areas, however, seroprevalence is generally lower, with irregular disease outbreaks. Climate change has also been linked to increased concentrations and distribution of air pollutants such as ozone, nitric oxide and other volatile organic chemicals. Another serious outcome, high temperature and CO2, induce biochemical changes in the plant derived proteins (like pea nuts, ground nuts etc.) which constitute major food components in herbivores, leading to gradual changes in the antigenic exposure.
Hygiene theory
Strachan (1989) first formulated this theory stating that allergy and autoimmunity, the two diseases of modern industrialised world are the results of high level of sanitation. When there is too much hygiene, the frustrated immune system will start creating antibodies to self- antigens. So, the decreasing incidence of early life infection may contribute to the increasing incidence of immune disorders such as allergy and other autoimmune diseases.
It is time to reconsider or modify the practice of regular deworming in animals because a low level of parasitism enhances immunity to other types of microbial infection. Relation with irritable bowel syndrome (IBS) and intestinal helminths indicates that the helminths interact with host innate and adaptive immunity to stimulate the Tregs and check effector pathways that drive aberrant inflammation (Weinstock and Elliot, 2009). Experimental studies have shown that parasitic infection or immunisation with Schistosoma manzoni reduced the effect of encephalomyelitis in mice. The transgenic mice (immune deficient, anti-myelin T cell receptors) kept in germ free condition developed severe type of spontaneous demyelination leading to autoimmune encephalitis. Several studies indicated that higher exposure to early life microbial load, has been associated with a reduced risk of diseases like multiple sclerosis (Fleming and Fabry, 2007).
Dietary disposition
“What you eat is what you are”., a diet that modifes the intestinal microbiota has been postulated to influence autoimmune disease. As in the case of medication or stress, dietary factors can cause gut inflammation (Chassaing and Gewirtz, 2014). Studies related to IBS revealed the role of food in the alteration of intestinal immunity. Food with more fat and salt is found to trigger the AIDs in man by promoting the development of Th17 helper T cells, that
are mediators of autoimmune inflammation. Salt intake also matters, because increased NaCl concentrations markedly boosted the induction of murine and human Th17 cells, driving autoimmune diseases. Another study has shown that sodium gets accumulated at the site of skin infections and boost proinflammatory macrophage responses in a p38/MAPK and NFAT5- dependent manner (Jantsch et al. 2015). Studies on type 1 diabetes and multiple sclerosis up stretched the greater role of diet in development of these diseases. The dietary micronutrients exacerbate or suppress murine lupus through genetic–epigenetic interactions by affecting DNA methylation. The role of the gut microbiome in a number of diseases, including gut related and CNS associated autoimmune diseases is exposed by experimental methods. The impact of gut microbiota and its metabolites on the mucosal immune system is carried out by influencing the inflammatory T cell subsets and the balance of pro- and anti-environmental factors in multiple sclerosis and other autoimmune diseases. Promoting the induction of anti-inflammatory Tregs and reducing pathogenic Th17 cell responses might represent the most promising strategy in these conditions.
Vitamin D
Exposure to the sun provides ultraviolet radiation (UVR) and thus assists the generation of UV-derived vitamin D. A study by Disanto et al. (2012) examined the relationship between month of birth and autoimmune diseases like rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. All these diseases showed seasonality and related to season of birth. Lower serum vitamin D levels and some evidence of a positive effect of supplementation were reported in these diseases. Vitamin D inhibits proinflammatory processes by suppressing the enhanced activity of immune cells that are involved in the autoimmune reaction. Though the correlation between 25-hydroxyvitamin D and interferon signature genes (IFI35, OAS1, MX1, IFITM1, STAT2, IFIT3, IFIT1, STAT1, SOCS1) expression are not found significant, the low levels of Vitamin D in patients with autoimmune diseases are well established. It is reported that vitamin D supplementation may be therapeutically beneficial, particularly for Th1-mediated autoimmune disorders such as multiple sclerosis and diabetes type 1. In addition to vitamin D, beneficial effects of supplementation of other nutrients such as vitamin A for autoimmune related skin affections and omega-3 fatty acids for rheumatoid arthritis are also reported.
Diagnostic dilemma
Clinical symptoms, biochemical tests, haematology and histopathology of the biopsy material usually help in conclusive diagnosis of disease conditions, along with the identification of etiology by cultural examination or PCR. A combination of all these diagnostic procedures may not be sufficient to diagnose AIDs, since it is difficult to catch the culprit by any of these methods. So traditional methods in the diagnosis of systemic AIDs include detection of high serum level (>100) of Antinuclear Antibody (ANA) with specificity for nucleic acids and nucleoproteins by indirect fluorescent antibody technique or ELISA. This is to be emphasised that a low level of these Abs may be seen in old age, certain infection and in response to traumatic injury.
Apart from complete blood count (CBC), erythrocyte sedimentation rate (ESR) and detection of complement levels, detection of cell specific auto antibodies is done in case of organ specific diseases. Coomb’s test is the gold standard for diagnosis of immune mediated haemolytic anaemia. There are polyvalent and monovalent Coomb’s reagents. Erythrocytes are screened with anti-IgG, anti-IgM, and anti-C3 Coombs reagents. The presence of antibodies reactive with thrombocytes can be confirmed using the anti-megakaryocyte antibody test on bone marrow or an indirect immunofluorescent evaluation of platelet-bound antibodies (PBAs) in the peripheral blood using flow cytometry. Other different methods used for diagnosis of AIDs include detection of abnormal proteins produced by the immune system, like rheumatoid factor, anti-cyclic citrullinated peptide (anti-CCP) and C reactive proteins.
Recently, electronic health records (systematized collection of electronically stored health information of a patient in a digital format) have been widely used in clinical and genetic association studies which provide extensive access to a repository of longitudinal medical data. With DNA repositories, it is possible to correlate genetic and phenotypic data to understand the immunogenetic architecture in AIDs (Restrepo et al. 2016).
Biopsy examination is an important diagnostic method in different autoimmune diseases. The typical histological features of chronic inflammatory pattern is evident in the affected tissue. There is also predominance of plasma cells, either in aggregates or scattered in the parenchyma. Emperipolesis (intact cells engulfed by other cells and seen in the cytoplasm) is another feature observed in the tissues. The cellular aggregates can be seen as rosette or in pseudo rosette pattern. Autoimmune hepatitis and nephritis characterised by such specific histopathological changes are apparent in multi organ failure in case of dogs. The task is exclusion of other etiological components like viral infection, toxicity or nutritional deficiency and coexistence of different other conditions in such cases.
Conclusion
Many autoimmune diseases in humans have their counterparts in companion animals. Animal disease diagnosis have evolved and got refined from the findings of the medical research data and the reverse perception is also true while considering the data generated from animal experimentations and the use of different animal models in extrapolating different drug discoveries or infectious disease studies. In spite of the fact that main data on autoimmune diseases (AIDs) have been generated based on experimental animal studies, when it comes to the diagnosis of spontaneously occurring diseases in animals, there are some missing links. Autoimmune diseases need additional attention and should be included as a prominent entity in the list of etiological agents. The exact role of genetic propensity, infection, stress, inflammation, medication and environmental factors in the development of autoimmune diseases are yet to be exposed. The multitudes of factors like changing environment, genetic variants, gene-environment interactions, pathogenic microbial population, dietary changes etc., make it favourable for the genesis and sustenance of different types of AIDs. The recent covid related research have emphasised the correlation of autoimmunity and severity of viral infection in certain individuals. Hence it is ideal to give adequate importance by broadening the research on the occurrence and pathology of autoimmune diseases in man and animals.
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