Major types of autoantibodies and their associated antigens in SLE.
Autoantibodies are groups of antibodies that are directed against body’s own antigen. These autoantibodies are generated against different types of antigens in various autoimmune diseases. Clinical symptoms of systemic autoimmune diseases are characterized by the involvement of various organs in addition to the production of non-organ specific autoantibodies. These autoantibodies in autoimmune diseases are associated with a specific clinical symptom within a spectrum . Most of the autoantibodies have diagnostic and prognostic importance with respect to their associated disease and all of these are not involve in the pathogenesis of these diseases. Most autoantibodies are mainly used as biological markers for certain disease but they do not actually reflect the pathophysiological process underwent during the course of the disease,
The history of the autoantibodies goes back to 1940s, when two types of antibodies (anti-nuclear antibodies; ANA and rheumatoid factors; RF) were discovered as the serum factors that bind to nuclear antigen IgG, respectively [7, 8]. ANA and RF considered being a diagnostic feature of SLE but their role in disease pathogenesis remains elusive. In the last two decades, the effects of autoimmune diseases have been gown up to such an extent that it can explains both points of views, as clinically and diagnostically. The pathogenic mechanisms of these autoimmune diseases help to contribute to the discovery of new autoantibodies and new area of research, based on diagnostic and prognostic value, have been developed. Determination of these autoantibodies in the diagnosis of autoimmune disease is important because they are sometime showing nonspecific, unclear character and even shared by different autoimmune diseases . For most of the autoimmune diseases, classification criteria include the determination of autoantibody that helps in final diagnosis. They are important not only for diagnostic perspective but also for prognostic value. Some of these autoimmune have been associated with the clinical manifestation of the disease, therefore estimation of these autoantibodies pattern in the patients might helpful to detect severity of the disease that can be useful for the need of correct therapy .
Several autoimmune diseases show chronic conditions that develop over the period of years and are characterized by the production of autoantibodies that actually present much before the actual onset of the disease. These autoantibodies are called as predictive autoantibodies that are present (or appear) in the blood much before systemic pathological conditions arise during the course of the disease. Detection of specific autoantibodies is the most important clinical and experimental evidence to predict any autoantibodies as biomarker for that autoimmune disease . The levels and variety of autoantibodies may vary according to the disease that may function as predictive biomarker. While the experimental importance of autoantibodies has been well recognized in many clinical conditions, its clinical utilization remains to be short for most of the diseases . Autoimmune diseases are caused by various autoimmune responses, generated during the course of the disease. The generations of immune responses are characterized by the appearance of the autoantibodies in the serum, therefore recognition of a particular autoantibody showed the path to recognize an autoimmune disease. Initially, the clinical symptoms of the disease are not emerges in full flash although these autoantibodies may arises much before these symptoms and actual onset of the disease. So, the symptoms are not visible, so the physician did not think to test these autoantibodies initially . Therefore, test for these autoantibodies could be done in pre-screening on various groups of population to identify the individuals who are susceptible for the development of the disease at an early stages and treatment should be given to prevent the actual occurrence of the disease. Multiple tests have been given for these patients for different autoimmune diseases, and recommendations are given to done multiple test for the patient who are having autoimmune disease . However, disease related autoantibodies cannot develop simultaneously, although they are present much before the actual disease onset, and many of these autoantibodies are antigen specific, so using a panel of different autoantibodies set, might helpful to increase the sensitivity and prediction of the test .
Autoimmunity arises due to the failure of the immune system to be self-tolerance, which is mediated through the involvement of T and B cells . Most of the autoimmune disease involves T cell, which play an important role in dysregulation and autoimmune aggression and during this process large amount of autoantibodies are also produced. These autoantibodies plays not only in key pathogenic role in some diseases including SLE and Graves’ disease but also found in some disease in which they play minor pathogenic role and can act as important biomarker [17, 18]. Cytokines, in addition to the production of autoantibodies, play important role in the generation of autoimmune response (especially pro-inflammatory cytokines: except multiple sclerosis), they are produced in response to the viral invasion and are deeply involved in various autoimmune process. Under normal condition, anti-cytokine antibodies response have been develop in healthy normal individual that is consider to be normal physiological process to control various immune response. These responses are for limited time initially, and then the concentration of these autoantibodies increases, reaching a threshold and then coming up to its normal concentration after few weeks. This process also occurs in some pathological conditions including autoimmunity and autoantibodies develop as a result of these processes might be used as prognostic marker for monitoring the disease .
2. Different types of autoantibodies
2.1. Anti-cytokine autoantibodies
Autoantibodies against various types of cytokines have been described not only in normal individuals but also in patients with different infectious and immuno-inflammatory disease . These include interferon (α, β, and γ), interleukin (α, 2, 4, 6, 8 and 10), nerve growth factor, chemokine (α and β), leukemia inhibitory factor, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor (α and β) and receptor, which are found to be in normal individuals and patients with various disorders. In autoimmune disease, these autoantibodies can function as prognostic biomarkers that may even show negative (autoantibodies against IL-18 and IL-1α in RA) or positive (autoantibodies to IL-6 in systemic sclerosis) results . The autoantibodies against cytokines found to be pathogenic that makes autoimmune patients more susceptible to other diseases. There are various autoimmune diseases including rheumatoid arthritis, multiple sclerosis, systemic sclerosis, SLE, autoimmune polyendocrine syndrome type 1, in which neutralizing autoantibodies against cytokines have been described. The affinity of anti-cytokine autoantibodies may depend on the function of cytokine during various immune responses. For example, pro-inflammatory cytokines such as interleukin-1α, -6, -8, TNF-α and GM-CSF, have more frequently autoantibodies, whereas anti-inflammatory cytokines like interleukin-10 and TGF-β, have autoantibodies that were reported rarely [22, 23, 24]. However, most of these studies does not provide sufficient evidences for the functional effects of these autoantibodies, which might helpful to describe their role in various autoimmune diseases and capitalize them for future therapies. There are few pro-inflammatory cytokines that play important role in joint aggression in rheumatoid arthritis [25, 26]. Autoantibodies against IL-1alpha can be worked as an important prognostic marker for early detection of RA  and several parameters of RA disease activity and severity was found to be significantly lower in those patients who have high levels of anti-IL-1α autoantibodies in comparison to those who have low levels of these autoantibodies. Autoantibodies showed neutralizing effects on the function of IL-1α by inhibiting thymocytes proliferation in the sera of RA patients . These autoantibodies were also detected in the patients with systemic sclerosis. Autoantibodies against IL-1α have been secreted in high amount in the skin . These autoantibodies have also been found in other dermal diseases; for example, psoriasis and pemphigus, that are supposed to be involve in the regulation of inflammation of skin .
2.2. Antinuclear autoantibodies (ANA)
Autoimmune hepatitis is the first disease in which autoantibodies had been clearly associated. In 1960s, these autoantibodies were detected by indirect immunofluorescence assay in the diagnosis and prognosis of autoimmune hepatitis. ANA directed against various nuclear components including single or double stranded DNA (s- or ds-DNA), transfer RNA, histone and other nuclear components [31, 32, 33]. There are various other nuclear components which are targeted by these autoantibodies but are not related with autoimmune hepatitis including s-DNA and ds-DNA, chromatin, histones, hnRNP, A2/B1, cyclin A, and centromere of the chromosomes . These autoantibodies may arise due to the mistake in identifying normal nuclear components as foreign and dangerous. Once this happen, they identify natural occurring protein as foreign and they are called as autoantibodies because they are produce against own antigen. These autoantibodies start chains of reactions causing inflammation and attack itself. So they also start to target normal protein in the nucleus of the cell and they are called antinuclear antibodies. Although, we all have autoantibodies but they are present in very small amount and they remain silent in the body until and unless some factors may trigger these autoantibodies to be active against normal nuclear components. Once these autoantibodies attack on the self nuclear components, they may trigger various diseases including systemic lupus erythematosus, scleroderma, Sjogren’s syndrome, polymyositis/dermatomyositis, etc. Increased level of ANA is seen in almost all the systemic rheumatic disease which either showed sometime high, sometime loose association between a particular type of ANA and a particular type of rheumatic disease. Most of these autoantibodies directed against either nucleic acids or protein close to the nucleic acid. For example, the most common antigen in SLE is nucleosomes. Nucleosomes form the building blocks of chromatin molecule and play an important role in the compaction of DNA in the nucleus. ANA directed against DNA, considered to be as diagnostic maker and hallmark of SLE. Antibodies against histones were also reported in various studies that also proven to be an important marker for SLE. Other important antigen for ANA is small nuclear ribonucleoprotein (snRNP) particles that are formed from a capped small nuclear RNA molecule and polypeptide. In addition, other antigens from the cytoplasmic relevance to ANA binding are ribosomal RNP and aminoacyl tRNA synthetase . ANA play an active role in SLE since these autoantibodies bind to the antigen that may be present in the circulation or their immune complexes are deposited in the tissue that leads to inflammation and subsequent disease features. Either anti-DNA or anti-DNA complexes were involved in the induction of lupus nephritis. In addition, anti-DNA antibodies against various protein molecules are also found in SLE that plays an important role in the etiopathogenesis of this disease [36, 37, 38, 39, 40].
2.3. Anti-citrullinated protein antibodies and anti-CCP antibodies
These are the autoantibodies that are induced against any peptide or protein that are citrullinated. They are present in the majority of the patients suffering from RA. Clinically, this antigen can be frequently used to detect antibodies in the serum of RA patients. It has been assumed that high titers of these autoantibodies are correlated with high risk in the development of RA . These autoantibodies were found to be highly sensitive and specific in comparison to rheumatoid factor. In addition, combined estimation of rheumatoid factor and anti-citrulline antibodies can increase the assessment of both tests . Anti-CCP antibodies can function not only as diagnostic marker but also have prognostic value, they might be used to predict the development of the disease and can be present much before the actual onset of the disease. These autoantibodies are also associated with other diseases such as cardiovascular as well as pulmonary complications. Anti-CCP antibodies can be useful in the diagnosis and prognosis of RA and have been included as one of the major criteria for the classification of this disease .
2.4. Rheumatoid factor (RF)
Rheumatoid arthritis is one of the disease in which the option for diagnosis and prognosis is more advance in the field of autoimmunity . Since RA have nonspecific symptoms, therefore the diagnosis could be difficult but early diagnosis is important to have more option for therapy and cure. However, as this disease is characterized by radiological progression during early phase of the disease, so there might be good opportunity to initiate for early and effective treatment . In early studies, serological diagnostic tool for RA were limited and the only autoantibodies related with the diagnosis of RA was rheumatoid factor that showed low sensitivity and specificity [43, 44]. Some patients can even showed negativity for RF and RF may be positive in various other autoimmune diseases that are showing nonclinical conditions and are positive even with other types of autoantibodies in these diseases. If the RF is falsely positive, it is interesting to mention that the complementary diagnostic test is antistreotolysin O (ASO/ASLO) test. Earlier studies have shown that smoker have elevated incidence of RA because of high RF . Studies also indicated that elevated level of RF was found to be twice in comparison to both current and ex-smokers than nonsmokers and the level of RF was more in these individual . Studies also have shown that smoking somehow effect the progression of RA .
Besides that, there are large groups of autoantibodies that are causing various types of autoimmune diseases including Anti-transglutaminase antibodies-celiac disease, dermatitis herpetiformis; Anti-ganglioside antibodies-Miller-Fisher syndrome, acute motor axonal neuropathy; Anti-actin antibodies-coeliac disease; Anti-thrombin antibodies-SLE; Anti-neutrophil cytoplasmic antibody-polyangiitis; Anti-smooth muscles antibodies-hepatitis; Anti-mitochondrial antibodies-primary biliary cirrhosis; Anti-SRP-polymyositis; Anti-SRP & Anti-AChR-myasthenia gravis; Anti-thyroid antibodies-Hashimoto’s thyroiditis, Graves’ disease; Anti-SLA/LP, perinuclear anti-cytoplasmic antibodies, Anti-LKM, Anti-LC-1, Anti-mitochondrial antibodies, Anti-asialoglycoprotein receptor antibodies-liver disease, etc. (Figure 1).
Autoantibodies are group of antibodies that are directed against self antigen. These antibodies recognized normal molecules in the cells as foreign and dangerous. As a result of that, large group of reactions take place in which these autoantibodies recognized normal molecules and generate various immunological response against them. In consequence, these autoantibodies also interact with other protein molecule in order to generate a series of reactions causing binding to the self molecules. Binding of autoantibodies to self molecules can be recognized by various immune cells that mainly responsible for the damage and excretion of these molecules. For examples, there are various types of autoantibodies and their associated antigens found in in SLE (Table 1). These self damaged molecules are called as auto-antigen and finally treat as foreign molecule and damage by various immune cells.
|Antinuclear autoantibodies (ANA)||Various nuclear components|
|Anti-ds DNA||Double stranded DNA|
|Anti-Sm||Protein with nuclear U1 RNA|
|Anti-RNP||Protein with U1 RNAγ|
|Anti-R○ (SS-A)||Protein with hYRNA|
|Anti-La (SS-B)||Protein with hYRNA|
|Anti-neuronal||Neurons and lymphocytes|
|Anti-ribosomal||Protein in ribosomes|
Wiik AS. Anti-nuclear autoantibodies: Clinical utility for diagnosis, prognosis, monitoring and planning of treatment strategy in systemic immunoinflammatory disease. Scandinavian Journal of Rheumatology. 2005; 34:260-268
Manus MP, Czaja AJ, Gorham JD, Krawitt EL, Micli-Vergani G, Vergani D, et al. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010; 51:2193-2213
Sener AG. Autoantibodies in autoimmune liver diseases. APMIS. 2015; 123:915-919
Kallenberg CGM, Stegeman CA, Bootsma H, Bijl M, Limburg PC. Quantitation of autoantibodies in systemic autoimmune disease: Clinically usefull? Lupus. 2006; 15:397-402
Amoura Z, Koutouzov S, Chabre H, et al. Presence of antinucleosome autoantibodies in a restricted set of connective tissue disease: Antinucleosome antibodies of the IgG 3 subclass are markers of renal oathogenicity in systemic lupus erythematosus. Arthritis and Rheumatism. 2000; 43:76-84
Trouw LA, Groeneveld TW, Seelen MA, et al. Anti-CIq autoantibodies deposit in glomeruli but are only pathogenic in combination with glomeruli C1q-cintaing immune complexes. The Journal of Clinical Investigation. 2004; 114:679-688
Robbin WC, Holman HR, Deicher H, Kunkel HG. Complement fixation with cell nuclear and DNA in lupus erythematosus. Proceedings of the Society for Experimental Biology and Medicine. 1957; 96:575-579
Miescher P, Fauconnet M. Absorption of L.E. factor by isolated cell nuclei. Experientia: Interdisciplinary Journal for the Life Sciences. 1954; 10:252-253
Stinton LM, Fritzler MJ. Clinical approach of autoantibody testing in systemic autoimmune rheumatic disease. Autoimmunity Reviews. 2007; 7:77-84
Avouac J, Gossec L, Dougados M. Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: A systemic literature review. Annals of the Rheumatic Diseases. 2006; 65:845-851
Bizzaro N. Autoantibodies as predictors of disease: The clinical and experimental evidence. Autoimmunity Reviews. 2007; 6:325-333
Lernmark A. Autoimmune disease: Are markers ready for prediction? The Journal of Clinical Investigation. 2001; 108:1091-1096
Rose NR. Prediction and prevention of autoimmune disease: A personal perspective. Annals of the New York Academy of Sciences. 2007; 1109:117-128
Tonutti E, Visentini D, Bizaro N. Interpretative comments on autoantibodies tests. Autoimmunity Reviews. 2007; 6:341-346
Bizzaro N. The predictive significance of autoantibodies in organ-specific autoimmune disease. Clinical Reviews in Allergy and Immunology. 2007; 34:326-331
Kearney JF. Formation of autoantibodies, including anti-cytokine antibodies is a hallmark of the immune response of early B cells. Journal of Interferon Research. 1994; 14:151-152
Ozen S, Berk O, Simsek DG, Darcans S. Clinical cause of Hashimoto’s thyroiditis and effects of levothyroxine therapy on the clinical course of the disease in children and adolescents. Journal of Clinical Research in Pediatric Endocrinology. 2011; 3:192-197
McKee A, Peyer F. TSI assay utilization: Impact on costs of graves hyperthyroidism diagnosis. The American Journal of Managed Care. 2012; 18:e1-e14
Graudal NA, Svenson M, Trap U, Garred P, et al. Autoantibodies against interleukin 1 alpha in rheumatoid arthritis: Association with long term radiographic outcome. Annals of the Rheumatic Diseases. 2002; 61:598-602
Bendtzen K, Hansen MB, Ross C, Svenson M. Detection of autoantibodies to cytokines. Molecular Biotechnology. 2000; 14:251-261
Cappellano G, Orilieri E, Woldetsadik AD, et al. Anti-cytokine autoantibodies in autoimmune disease. American Journal of Clinical and Experimental Immunology. 2012; 1:136-146
Svenson M, Poulsen LK, Fomsgaard A, Bendtzen K. IgG autoantibodies against interleukin 1 alpha in sera of normal individual. Scandinavian Journal of Immunologyl. 1989; 29:489-492
Hansen MB, Svenson M, Diamant M, Bendtzen K. Anti-interleukin-6 antibodies in normal human serum. Scandinavian Journal of Immunology. 1991; 33:777-781
Elkarim RA, Mustafa M, Kivisak P, et al. Cytokine autoantibodies in multiple sclerosis, aseptic meningitis and stroke. European Journal of Clinical Investigation. 1998; 28:295-299
Arend WF, Dayer JM. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor a in rheumatoid arthritis. Arthritis and Rheumatism. 1995; 38:151-160
Le Huu D, Matsushita T, Jin G, et al. IL-6 blockade attenuates the development of Murin sclerodermatous chronic graft-versus-host disease. The Journal of Investigative Dermatology. 2012; 132:2752-2761
Jouvenne P, Fossiez F, Banchereau J, Miossec P. High levels of neutralizing autoantibodies against IL-1alpha are associated with a better prognosisi in chronic polyarthritis: A follow-up study. Scandinavian Journal of Immunology. 1997; 46:413-418
Suzuki H, Kamimura J, Ayabe T, Kashiwagi H. Demosntration of neutralizing autoantibodies ahainst IL-1alpha in cera from patients with rheumatoid arthritis. Journal of Immunology. 1990; 145:2140-2146
Jouvenne P, Fossiez F, Garroue P, et al. Increased incidence of neutralizing autoantibodies against interleukin-1alpha (IL-1alpha) in nondestructive chronic polyarthritis. Journal of Clinical Immunology. 1996; 16:283-290
Mizutani H, Ohmoto Y, Kupper TS, Shimizu M. Endogenous neutralizing anti-IL-1alpha autoantibodies in inflammatory skin disease: Possible natural inhibitor for over expressed epidermal IL-1. Journal of Dermatological Science. 1998; 20:63-71
Bagdanos DP, Chaudhari K, Vergani D. Molecule mimicry and autoimmune liver disease: virtuous intensions, malign consequence. Liver. 2001; 21:225-232
Hennes EM, Zeniya M, Aj C, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008; 48:169-176
Strassburg CP, Manns MP. Autoantibodies and autoantigens in autoimmune hepatitis. Seminars in Liver Disease. 2002; 22:339e52
Johanet C, Beleoken E, Ballot E. Autoantibodies in autoimmune hepatitis: Antinuclear antibodies (ANA). Clinics and Research in Hepatology and Gastroenterology. 2012; 36:394-396
Smeenk RJI, Feltkamp TEW. Antinuclear antibodies. In: Delves PJ, Roitt I, editors. Encyclopedia of Immunology. London: Academic Press; 1998. pp. 125-133
Khan WA, Qureshi JA. Increased binding of circulating systemic lupus erythematosus autoantibodies to recombinant interferon alpha 2b. APMIS. 2015; 123:1016-1024
Khan WA, Moinuddin, Habib S. Preferential recognition of catecholestrogen modified DNA by circulating autoantibodies in cancer patients. Biochemie. 2013; 95:329-335
Khan WA, Moinuddin Khan MWA, Chabbra HS. Catecholestrogen: Possible role in systemic lupus erythematosus. Rheumatology. 2009; 48:1345-1351
Khan WA, Habib S, Khan MWA, Alam K. Moinuddin. Enhanced binding of circulating SLE autoantibodies to catecholestrogen-copper-modified DNA. Molecular and Cellular Biochemistry. 2008; 315:143-150
Khan WA. Binding characteristics of SLE anti-DNA autoantibodies to catechol-estrogen modified DNA. Scandinavian Journal of Immunology. 2006; 64:667-683
van der Linden MPM, van der Woude D, Ioan-Facsinary A, et al. Value of anti-modified citrullinated vimentin and third generation anti-cyclic citrullinated peptide compared with second generation anti-cyclic citrullinated peptide and rheumatoid factor in predicting disease outcome in undifferentiated arthritis and rheumatoid arthritis. Arthritis and Rheumatism. 2009; 60:2232-2241
Gerosa M. Autoantibodies and autoimmune disease: An update. Clinics in Dermatology. 2013; 2:72-76
de Rooy DP, van der Linden MP, Knevel R, et al. Predicting arthritis outcomes-what can be learned from the Leiden early arthritis clinic? Rheumatology. 2011; 50:93-100
vander Woude D, Young A, Vayakumar K, et al. Prevalence of and predictive factors for sustained disease-modifying antirheumatic drug-free remission in rheumatoid arthritis. Results from two large early arthritis cohorts. Arthritis and Rheumatism. 2009; 60:2262-2271
Jonsson T, Thoosteinsson J, Valdimarsson H. Does smoking stimulate rheumatoid factor production in rheumatic individuals. APMIS. 1998; 106:970-974
Heliovaara M, Aho K, Aromaa A, et al. Smoking and risk of rheumatoid arthritis. The Journal of Rheumatology. 1993; 20:1830-1835
Saaq KG, Cerhan JR, Kolluri S, et al. Cigarette smoking and rheumatoid arthritis severity. Annals of the Rheumatic Diseases. 1997; 56:463-469