Journal of Postgraduate Medicine
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Year : 2010  |  Volume : 56  |  Issue : 3  |  Page : 239-242  

PTPN22 gene polymorphisms in autoimmune diseases with special reference to systemic lupus erythematosus disease susceptibility

V Pradhan, V Borse, K Ghosh 
 Department of Autoimmune Disorders, National Institute of Immunohaematology, Indian Council of Medical Research, 13th floor, KEM Hospital, Parel, Mumbai - 400 012, India

Correspondence Address:
V Pradhan
Department of Autoimmune Disorders, National Institute of Immunohaematology, Indian Council of Medical Research, 13th floor, KEM Hospital, Parel, Mumbai - 400 012


Systemic lupus erythematosus (SLE) is a prototype autoimmune disease. SLE is a result of one or more immune mechanisms, like autoantibody production, complement activation, multiple inflammation and immune complex deposition leading to organ tissue damage. SLE affected patients are susceptible to common and opportunistic infections. There are several reports suggesting that Mycobacterium tuberculosis infection precipitates SLE in patients from endemic areas. Genetic factors and environmental factors also play an important role in the overall susceptibility to SLE pathophysiology. Recently, protein tyrosine phosphatase, non-receptor type 22 (PTPN22) gene, has been found to be associated with several autoimmune diseases like SLE, Grave«SQ»s disease and Hashimoto thyroiditis. The missense R620W polymorphism, rs 2476601, in PTPN22 gene at the nucleotide 1858 in codon 620 (620Arg > Trp) has been associated with autoimmune diseases. The PTPN22 locus is also found to be responsible for development of pulmonary tuberculosis in certain populations. The PTPN22 1858C/T gene locus will be ideal to look for SLE susceptibility to tuberculosis in the Indian population. In this review, we focus on human PTPN22 gene structure and function as well as the association of PTPN22 gene polymorphisms with SLE susceptibility

How to cite this article:
Pradhan V, Borse V, Ghosh K. PTPN22 gene polymorphisms in autoimmune diseases with special reference to systemic lupus erythematosus disease susceptibility.J Postgrad Med 2010;56:239-242

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Pradhan V, Borse V, Ghosh K. PTPN22 gene polymorphisms in autoimmune diseases with special reference to systemic lupus erythematosus disease susceptibility. J Postgrad Med [serial online] 2010 [cited 2022 Dec 6 ];56:239-242
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Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the presence of autoantibodies to nuclear constituents and inflammatory lesions in multiple organ systems. The pathogenesis of SLE has a strong and complex genetic base. Molecular genetic studies, both in human and in experimental animal models, have identified important genes that contribute to SLE pathogenesis. Recently, three genome-wide association studies in Caucasian patients with SLE from international collaborations confirmed the known candidate genes for disease susceptibility, including human leucocyte antigen (HLA) like DR3, DR4, Fc gamma receptor IIA, IIIA and IIIB (Fcγ R), protein tyrosine phosphatase, non-receptor type 22 (PTPN22), signal transducer and activator of transcription 4 (STAT4) and interferon regulatory factor 5 (IRF5). [1]

The PTPN22 gene, located on chromosome 1p13, encodes lymphoid protein tyrosine phosphatase (LYP), which is important in negative control of T lymphocyte activation. LYP is expressed on T lymphocytes and associates with C-terminal Src Kinase (CSK) to form a complex that suppresses T cell receptor signaling kinases LCK and FYN. The missense R620W polymorphism in PTPN22 gene at the nucleotide 1858 (1858 C > T) in codon 620 (620Arg > Trp) has been associated with various autoimmune diseases. The disease-associated LYP variant Trp 620 prevents the interaction of LYP with CSK. Consequently, the T cell receptor-associated kinases might exhibit an uncontrolled T cell induction and this may increase the overall reactivity of the immune system thus predisposing an individual to autoimmune disease. [2]

 PTPN22 Polymorphism - Associated Autoimmune Diseases

The first study on the 1858C/T single-nucleotide polymorphism (SNP) in PTPN22 gene and its association with increased risk of type 1 diabetes (T1D) was reported in 2004, which was further confirmed in a large population. [3],[4],[5],[6] The 1858C/T SNP in PTPN22 gene was also reported in rheumatoid arthritis (RA), [7],[8],[9],[10],[11] juvenile idiopathic arthritis (JIA), [11],[12] SLE, [8],[12] Graves disease (GD), [13] Myasthenia Gravis, [14] generalized vitiligo [15] and Wegener's granulomatosis. [16] Interestingly, some autoimmune diseases were demonstrated not to be associated with the 1858T allele, including multiple sclerosis (MS), [17] inflammatory bowel diseases (IBD) such as Crohn's disease [18],[19],[20] and ulcerative colitis, [20],[21] celiac disease, [22] primary biliary cirrhosis, [23] psoriasis and psoriatic arthritis. [11]

In addition to the 1858C/T SNP (rs2476601), there are numerous other SNPs in the human PTPN22 gene. Some of these SNPs are shown in [Figure 1]. An initial investigation of the role of these other SNPs in RA patients confirmed that 1858C/T is the major disease-associated SNP in PTPN22, but also suggested minor involvement of at least one other SNP (rs3789604). [24] Subsequent studies have supported the notion that 1858C/T is the only SNP in PTPN22 associated with RA. [25],[26],[27] Similarly, T1D patients have also been investigated with regard to other SNPs in PTPN22. Kawasaki et al., (2006) had reported that a promoter SNP in PTPN22 (-G1123C, rs2488457) confers increased risk of T1D, supporting a role for 1858C/T as the major T1D-associated SNP in PTPN22.[28] However, it is still possible that additional polymorphisms may be discovered for PTPN22 that may independently relate to different and/or overlapping groups of autoimmune disorders. Huffmeier et al., (2006) reported that 1858C/T SNP was not associated with psoriasis but that there was evidence for a susceptibility locus for this disease somewhere else in PTPN22 or in its vicinity. [29] Studies on PTPN22 gene polymorphism in vitiligo showed that the 1858T allele is significantly overrepresented in vitiligo patients, indicating that LYP missense R620W polymorphism may have an influence on the development of generalized vitiligo, which further provides evidence for the autoimmunity as an etiology factor. [15],[30]{Figure 1}

A metaanalysis has also confirmed the association between the 1858T allele and the diseases T1D, RA, JIA, SLE and GD. [31] Genetic studies with different populations revealed a clear geographic gradient with regard to the frequency of the disease-associated 1858T allele in Europe. Although this allele is relatively rare in southern European populations (2% in Italy, 6% in Spain), the frequency increases northward through Europe (8% in the United Kingdom, 12% in Sweden, 15.5% in Finland). Interestingly, in African-American and Asian populations, the 1858T allele is virtually absent, suggesting a northern European origin and/or selective advantage for the 1858T allele in this region. Nevertheless, an adequate number of studies have now been conducted to demonstrate that an autoimmune disease association with the 1858T allele is population-independent. [32]

 PTPN22 Gene Polymorphism and SLE Susceptibility

Genetic and environmental factors play an important role in the overall susceptibility to a prototype autoimmune disease, SLE and pathophysiology between the affected individuals. SLE has a complex genetic basis that includes many susceptible loci. PTPN22 has been reported as one of the susceptible loci where an SNP 1858C/T in the PTPN22 gene has been found to be associated. SLE patients are susceptible to common and opportunistic infections, which contributes significantly to morbidity and mortality in endemic areas. In many populations, infection is found to be the leading cause of death in SLE. Evidence suggests that in most of the cases opportunistic infections such as candidiasis, cryptococcal meningitis and tuberculosis (TB) leads to mortality. [33],[34],[35],[36] It was reported that the autoimmune disease risk allele of PTPN22 is associated with skewing of the serum cytokine profiles toward higher IFN alpha activity and lower TNF alpha levels in vivo in patients with SLE. This serum cytokine pattern may be relevant in other autoimmune diseases associated with the PTPN22 risk allele. Although, in general, PTPN22 appears to be coupled with the collection of autoimmune diseases that are typically characterized by circulating autoantibodies, the role of PTPN22 in autoantibody response may not necessarily be intrinsic to B cells but rather a consequence of altered T cell help.

An increased susceptibility to infections is due to an abnormal immune response and immunosuppressive therapy used in SLE. Several studies suggest that there is an increasing prevalence of TB infection, especially in the endemic parts of the world such as part of Asia, sub-Saharan Africa and central Europe. A possible role of prior TB infection in precipitating SLE in genetically predisposed patients had been reported. The PTPN22 locus is also found to be responsible for the development of pulmonary TB in certain populations. The PTPN22 1858C/T gene locus will be ideal to look for SLE susceptibility to TB in the Indian population. As Mycobacterium tuberculosis is a strong immunogen, and its product is used extensively as an adjuvant, there is the distinct possibility that in genetically predisposed individuals TB infection may precipitate in SLE. [37],[38],[39]

Lamsyah et al., 2003, had reported on the role for PTPN22 G788A (R263Q) in susceptibility to infectious diseases such as TB. The Q263 enzyme is a loss-of-function variant that is associated with reduced risk of lupus. [35] The association of the two PTPN22 gene variants [R620W(C1878T) and R263Q(G788A)] was found to be relevant in the opposite direction than the ones observed with autoimmunity. The protective effect of the T1858 allele against TB might contribute to the positive selective selection at this locus, which might explain its high frequency in selected populations, despite its role in increasing the risk of autoimmunity. PTPN22 seems to influence the susceptibility to pulmonary TB. The role of PTPN22 in TB and other infectious diseases warrants further investigation. The protective effects of the gain-of-function W620 PTPN22 variant in TB suggest that PTPN22 could be a target for novel pharmacological approaches to the therapy of TB.

 Future Prospects

A candidate biomarker approach is based on the study of known factors that are thought to be involved in disease pathogenesis to identify biomarkers. [ 40],[41] Lack of validated biomarkers for disease activity has been a barrier to drug discovery for the treatment of autoimmune diseases. There is a need to explore the genetic association of PTPN22 1858C/T gene polymorphism with SLE susceptibility to TB in the diverse populations of India. If the PTPN22- Trp620 gain-of-function phenotype has a pathogenic role in human autoimmunity, a specific small molecular inhibitor could be useful to prevent the emergence of autoreactive T-cells. Such a drug could be of broader value for the treatment of autoimmune diseases. [42] Gene therapy is an attractive alternative for systemic protein delivery systems. Gene therapy can be considered as an alternative therapeutic approach to replace the function of the mutant or aberrant gene. This approach of synthesizing therapeutic protein in vivo allows minimizing possible side-effects. Local delivery of PTPN22 gene alone or in association with other SLE-related genes in SLE patients can turn out to become a possible therapeutic approach with several potential advantages over systemic forms of targeted therapy. Several strategies for successful delivery of DNA are available and new techniques are constantly emerging. New vectors (viral and non-viral) continue to become the most promising treatments for a number of autoimmune diseases. However, additional safety studies involving pharmacokinetics, biodistribution and toxicity will need to be accurately evaluated in experimental animal models. [43]


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