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|Year : 2010 | Volume
| Issue : 3 | Page : 242-243
A variant of PTPN22 gene conferring risk to autoimmune diseases may protect against tuberculosis
Otology and Neurotology Group CTS495, Department of Otolaryngology, Hospital de Poniente, El Ejido, Almeria, Spain
|Date of Web Publication||23-Aug-2010|
J A Lopez-Escamez
Otology and Neurotology Group CTS495, Department of Otolaryngology, Hospital de Poniente, El Ejido, Almeria
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Lopez-Escamez J A. A variant of PTPN22 gene conferring risk to autoimmune diseases may protect against tuberculosis. J Postgrad Med 2010;56:242-3
In this issue of JPGM, Pradhan et al. have discussed the role of PTPN22 gene polymorphisms in autoimmunity.  The immune system distinguishes between foreign and self-antigens through the processes of central and peripheral tolerance. Any breakdown in these complex pathways could result in the presence of active T cells with a high affinity for self-antigens. Such self-reactive T cells could initiate an immune response against one or more cellular types of some tissues, leading to an autoimmune phenotype. In addition, foreign antigens that are sufficiently similar to self-antigens can also activate T cells against some tissues.
The PTPN22 gene encodes a lymphoid tyrosine phosphatase (Lyp), which is expressed on T cells and binds to a C-terminal Src kinase (Csk) to form a complex that suppresses T cell receptor activation. Lyp dephosphorylates activating tyrosines Lck, Fyn and ZAP-70, resulting in inhibition of T cell response. 
The substitution of a single nucleotide at position 1858 (1858 C > T) of PTPN22 gene (rs2476601) leads to a change in codon 620 of LYP (620Arg > Trp). This change determines a functional variant of LYP, which has been associated with various autoimmune diseases, including type 1 diabetes, rheumatoid arthritis,  juvenile idiopathic arthritis, systemic lupus erythematosus, autoimmune hypothyroidism, Graves's disease, myasthenia gravis, generalized vitiligo,  Wegener's granulomatosis and Meniere's disease.  Replication studies have shown that the association of the 1858T allele with rheumatoid arthritis is population independent. 
The disease associated with the 1858T allele (LYP variant Trp 620) prevents the interaction of LYP with Csk. Consequently, the T cell receptor-associated kinases might exhibit an uncontrolled T cell response, and this may increase the overall reactivity of the immune system thus predisposing to autoimmune diseases.
Some autoimmune diseases are not associated with this variant of the PTPN22 gene as multiple sclerosis or inflammatory bowel disease and it is suspected that the 1858T allele of PTPN22 is associated with autoimmune diseases with elevated circulating autoantibodies that drive tissue damage and the onset of disease.  Recently, it was demonstrated that the 1858T variant carriers have an impairment of B cell activation, resulting in a deficit in proliferation, decrease in phosphorylation of key signaling proteins of B cells and altered B cell signal transduction. 
What is the evolutive advantage of the 1858T allele of the PTPN22 gene? Gomez et al., suggested the hypothesis that the 1858T allele may protect against some common endemic infections such as tuberculosis. Although the molecular basis of lymphocyte T response in tuberculosis infection is not well known, and as the G788A (R263Q) single nucleotide polymorphism of the PTPN22 gene confers susceptibility to infectious diseases, such as tuberculosis, and the 788A variant of PTPN22 is associated with a reduced risk of lupus, [8,9] it is possible that the 1858T allele may confers protection against tuberculosis.
The association of the two PTPN22 gene variants, 1878C and 788A, has a protection effect against autoimmunity. In contrast, the protective effect of the 1858T allele against tuberculosis may confer a biological advantage and might contribute to a positive selection at this locus, which might explain its high frequency in northern European populations, despite its role in increasing the risk of autoimmunity. Hence, the PTPN22 gene seems to influence the susceptibility to pulmonary tuberculosis in two cohorts of Spanish and Moroccan populations, but this remains to be replicated in other ethnic groups where tuberculosis is endemic, such as the Indian population.
| :: Acknowledgment|| |
Dr. Lopez-Escamez's work has been partially funded by the Research Grants PI07/0035 and INT09/229 from Instituto de Salud Carlos III, Spain.
| :: References|| |
|1.||Pradhan V, Borse V, Ghosh K. PTPN22 gene polymorphisms in autoimmune diseases with special reference to systemic lupus erythematosus disease susceptibility. J Postgraduate Med 2010;56:239-42. |
|2.||Vang T, Miletic AV, Arimura Y, Tautz L, Rickert RC, Mustelin T. Protein tyrosine phosphatases in autoimmunity. Annu Rev Immunol 2008;26:29-55. |
|3.||Plenge RM, Padyukow L, Remmers EF, Purcell S, Lee AT, Karlson EW, et al. Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: Association of susceptibility with PTPN22, CTLA4, and PADI4. Am J Hum Genet 2005;77:1044-60. |
|4.||Jin Y, Birlea SA, Fain PR, Gowan K, Riccardi SL, Holland PJ, et al. Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. N Engl J Med 2010;362:1686-97. |
|5.||Lopez-Escamez JA, Saenz-Lopez P, Acosta L, Moreno A, Gazquez I, Perez-Garrigues H, et al. Association of a functional polymorphism of PTPN22 encoding a lymphoid protein phosphatase in bilateral Meniere`s disease. Laryngoscope 2010;120:103-7. |
|6.||Gregersen PK. Gaining insight into PTPN22 and autoimmunity. Nat Genet 2005;37:1300-2. |
|7.||Arechiga AF, Habib T, He Y, Zhang X, Zhang ZY, Funk A, et al. The PTPN22 allelic variant associated with autoimmunity impairs B cell signaling. J Immunol 2009;182:3343-7. |
|8.||Gomez LM, Anaya JM, Martin J. Genetic influence of PTPN22 R620W polymorphism in tuberculosis. Hum Immunol 2005;66:1242-7. |
|9.||Lamsyah H, Rueda B, Baassi L, Elaouad R, Bottini N, Sadki K, et al. Association of PTPN22 gene functional variants with development of pulmonary tuberculosis in Moroccan population. Tissue Antigens 2009;74:228-32. |
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