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• W2040804037 abstract "Most lymphocytes in the lamina propria of oral lichen planus (OLP) lesions express and secrete interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), whereas they do not secret interleukin-4 and -10 or transforming growth factor-β. We analyzed whether the polymorphisms of several cytokines may influence the susceptibility to OLP. Cytokine typing was performed by a sequence-specific PCR assay. Thirteen cytokine genes with 22 single-nucleotide polymorphisms were studied. IFN-γ UTR 5644 genotype frequencies showed a significant increase in number of T/T homozygotes in OLP patients compared with controls (40.9 vs. 22.9%; p=0.0022). Moreover, in OLP patients, the frequency of the –308A TNF-α allele was higher than in the controls (21.6 vs. 9.3%; p < 0.05) causing a significantly increased frequency of the genotype G/A in OLP (43.2 vs. 14.3%; p=0.0002). Because in patients with mucocutaneous lichen planus (LP), the frequency of the –308A TNF-α allele was more than double the values in the pure OLP patients (40.9 vs. 15.1%; p=0.003), the –308G/A TNF-α genotype showed a significantly higher frequency in patients with mucocutaneous LP than in patients with pure OLP (81.8 vs. 30.3%, p=0.003). In conclusion, we suggest that genetic polymorphism of the first intron of the promoter gene of IFN-γ may be an important risk factor to develop oral lesions of LP, whereas an increase in the frequency of –308A TNF-α allele may best contribute to the development of additional skin involvement. Most lymphocytes in the lamina propria of oral lichen planus (OLP) lesions express and secrete interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), whereas they do not secret interleukin-4 and -10 or transforming growth factor-β. We analyzed whether the polymorphisms of several cytokines may influence the susceptibility to OLP. Cytokine typing was performed by a sequence-specific PCR assay. Thirteen cytokine genes with 22 single-nucleotide polymorphisms were studied. IFN-γ UTR 5644 genotype frequencies showed a significant increase in number of T/T homozygotes in OLP patients compared with controls (40.9 vs. 22.9%; p=0.0022). Moreover, in OLP patients, the frequency of the –308A TNF-α allele was higher than in the controls (21.6 vs. 9.3%; p < 0.05) causing a significantly increased frequency of the genotype G/A in OLP (43.2 vs. 14.3%; p=0.0002). Because in patients with mucocutaneous lichen planus (LP), the frequency of the –308A TNF-α allele was more than double the values in the pure OLP patients (40.9 vs. 15.1%; p=0.003), the –308G/A TNF-α genotype showed a significantly higher frequency in patients with mucocutaneous LP than in patients with pure OLP (81.8 vs. 30.3%, p=0.003). In conclusion, we suggest that genetic polymorphism of the first intron of the promoter gene of IFN-γ may be an important risk factor to develop oral lesions of LP, whereas an increase in the frequency of –308A TNF-α allele may best contribute to the development of additional skin involvement. interferon-γ interleukin lichen planus oral LP tumor necrosis factor-α Lichen planus (LP) is a chronic inflammatory disease that affects skin and mucous membranes of squamous cell origin. LP probably represents a cell-mediated immunologic response to an induced antigenic change in the skin or mucosa, but the etiology is often unknown. The oral form of lichen planus (OLP) seems more common, chronic, and recalcitrant than the cutaneous type, persisting up to more than 20 years without spontaneous remission (Scully et al., 2000Scully C. Eisen D. Carrozzo M. The management of oral lichen planus.Am J Clin Dermatol. 2000; 1: 287-306Crossref PubMed Scopus (105) Google Scholar). OLP is unlikely to be caused by a single antigen, given that studies of T cell receptor-variable region genes from lesional OLP T cells have not revealed the use of a restricted number of different variable region genes (Thomas et al., 1997Thomas D.W. Stephens P. Stephens M. Patten D.W. Lim S.H. T-cell receptor V beta usage by lesional lymphocytes in oral lichen planus.J Oral Pathol Med. 1997; 26: 105-109Crossref PubMed Scopus (17) Google Scholar). Probably, OLP is the common outcome of the influence of a limited range of extrinsic antigens, altered self-antigens, or superantigens. Although the majority of intraepithelial lymphocytes in OLP are CD8+ cytotoxic T cells, most lymphocytes in the lamina propria are CD4+ helper T cells (Matthews et al., 1984Matthews J.B. Scully C.M. Potts A.J. Oral lichen planus: An immunoperoxidase study using monoclonal antibodies to lymphocyte subsets.Br J Dermatol. 1984; 111: 587-595Crossref PubMed Scopus (70) Google Scholar;Ishii, 1987Ishii T. Immunohistochemical demonstration of T cell subsets and accessory cells in oral lichen planus.J Oral Pathol. 1987; 16: 356-361Crossref PubMed Scopus (69) Google Scholar). These subepithelial T cells have been seen to express interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) and contain mRNA for IFN-γ and TNF-α and to secrete these cytokines in vitro (Simark-Mattsson et al., 1998Simark-Mattsson C. Jontell M. Bergenholtz G. Heyden M. Dahlgren U.I. Distribution of interferon-gamma mRNA-positive cells in oral lichen planus lesions.J Oral Pathol Med. 1998; 27: 483-488Crossref PubMed Scopus (36) Google Scholar,Simark-Mattsson et al., 1999Simark-Mattsson C. Bergenholtz G. Jontell M. et al.Distribution of interleukin-2-4-10, tumour necrosis factor-alpha and transforming growth factor-beta mRNAs in oral lichen planus.Arch Oral Biol. 1999; 44: 499-507Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). Contrarily, OLP lesional T cells do not secrete interleukin-4 and -10 (IL-4, IL-10) or transforming growth factor-β (TGF-β) (Simark-Mattsson et al., 1998Simark-Mattsson C. Jontell M. Bergenholtz G. Heyden M. Dahlgren U.I. Distribution of interferon-gamma mRNA-positive cells in oral lichen planus lesions.J Oral Pathol Med. 1998; 27: 483-488Crossref PubMed Scopus (36) Google Scholar,Simark-Mattsson et al., 1999Simark-Mattsson C. Bergenholtz G. Jontell M. et al.Distribution of interleukin-2-4-10, tumour necrosis factor-alpha and transforming growth factor-beta mRNAs in oral lichen planus.Arch Oral Biol. 1999; 44: 499-507Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). The basis of this Th1 cytokine bias in OLP is unclear. A physiologic response to antigens or a dysregulation of the immune response may be responsible. Genetic influence could also play a role in the development of OLP but immunogenetic studies of LP and OLP have given controversial results, possibly owing to the inclusion in the studies of patients heterogeneous for etiology and pathogenesis (Carrozzo et al., 2001Carrozzo M. Francia di Celle P. Gandolfo S. et al.Increased frequency of HLA-DR6 allele in Italian patients with hepatitis C virus associated oral lichen planus.Br J Dermatol. 2001; 144: 803-808Crossref PubMed Scopus (100) Google Scholar). Indeed, cutaneous idiopathic LP is frequently associated with the HLA-DR1 allele particularly the DRB1*0101 allele, whereas idiopathic OLP or LP linked to liver disease is not (La Nasa et al., 1995La Nasa G. Cottoni F. Mulargia M. et al.HLA antigen distribution in different clinical subgroups demonstrates genetic heterogeneity in lichen planus.Br J Dermatol. 1995; 132: 897-900Crossref PubMed Scopus (43) Google Scholar). Recently, hepatitis C virus-associated OLP seems to represent a distinct variant, linked to the HLA-DR6 allele (Carrozzo et al., 2001Carrozzo M. Francia di Celle P. Gandolfo S. et al.Increased frequency of HLA-DR6 allele in Italian patients with hepatitis C virus associated oral lichen planus.Br J Dermatol. 2001; 144: 803-808Crossref PubMed Scopus (100) Google Scholar). Oral mucosal graft-versus-host disease (GVHD) closely resembles OLP both clinically and histologically (Fujii et al., 1988Fujii H. Ohashi M. Nagura H. Immunohistochemical analysis of oral lichen-planus-like eruption in graft-versus-host disease after allogeneic bone marrow transplantation.Am J Clin Pathol. 1988; 89: 177-186PubMed Google Scholar;Mattsson et al., 1992Mattsson T. Sundqvist K.G. Heimdahl A. Dahllof G. Ljungman P. Ringden O. A comparative immunological analysis of the oral mucosa in chronic graft-versus-host disease and oral lichen planus.Arch Oral Biol. 1992; 37: 539-547Abstract Full Text PDF PubMed Scopus (45) Google Scholar). It is likely that graft-versus-host disease and OLP share similar immunologic effector mechanisms, resulting in T cell infiltration, basal keratinocyte apoptosis, epithelial basement membrane disruption, and clinical disease (Sugerman et al., 2002Sugerman P.B. Savage N.W. Walsh L.J. et al.The pathogenesis of oral lichen planus.Crit Rev Oral Biol Med. 2002; 13: 350-365Crossref PubMed Scopus (480) Google Scholar). Although the role of donor T cell activation in the induction of graft-versus-host disease has been confirmed, there is evidence suggesting that several cytokines are also involved (Ferrara, 1994Ferrara J.L.M. Paradigm shift for graft-versus-host disease.Bone Marrow Transplant. 1994; 14: 183-184PubMed Google Scholar). Very recently, a significant association between polymorphism of TNF-α, IFN-γ, IL-10, and IL-6 and the development of severe graft-versus-host disease has been demonstrated (Middleton et al., 1998Middleton P.G. Taylor P.R.A. Jackson G. Proctor S.J. Dickinson A.M. Cytokine gene polymorphisms associated with severe acute graft-versus-host disease in HLA-identical sibling transplants.Blood. 1998: 3943-3948Google Scholar;Takahashi et al., 2000Takahashi H. Furukawa T. Hashimoto S. et al.Contribution of TNF-alpha and IL-10 gene polymorphisms to graft-versus-host disease following allo-hematopoietic stem cell transplantation.Bone Marrow Transplant. 2000; 26: 1317-1323Crossref PubMed Scopus (74) Google Scholar;Cavet et al., 2001Cavet J. Dickinson A.M. Norden J. Taylor P.R. Jackson G.H. Middleton P.G. Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation.Blood. 2001; 98 (1560): 1594Crossref PubMed Scopus (214) Google Scholar). The aim of this study was to analyze whether the polymorphisms of several pro- and anti-inflammatory cytokines may influence the susceptibility to OLP in a Northern-Italian population. No significant difference in the allele or genotype frequencies of IL-1 and 10 cluster, IL-2, IL-6, IL-12, and TGF-α were observed between the OLP subjects taken all together and healthy controls (Table I, Table II). In contrast, IFN-γ UTR 5644 genotype frequencies showed a significant difference between cases and controls (p=0.0022) Table I. This was due to an increased number of T/T homozygotes in OLP patients compared with controls (40.9 vs. 22.9%), although no significant difference was noted in the frequency of the *T allele in OLP and controls (50 vs. 46.4%; relative risk (rr)=0.87, 95% confidence intervals (95% CI) 0.54–1.40, p>0.05). In contrast, in OLP patients the frequency of the –308A TNF-α allele was more than double the value in the controls (21.6 vs. 9.3; rr=2.69, 95% CI 1.41–5.15, p<0.05). This caused a significantly increased frequency of the genotype G/A in OLP compared to controls (43.2 vs. 14.3%, p=0.0002) Table I. Also, we noted that the frequency of the genotype G/G of the IL-4 –1098 is more than sixfold higher in OLP than in controls (6.8 vs. 0.7%, p=0.0427) Table II although no differences in the allele frequencies were noted.Table IIL-1 cluster, IL-12, IFN-γ, TGF-β, and TNF-α polymorphisms in OLP patients and controlsGenotypeOLP, n=44aData are reported as number (%)Controls, n=140aData are reported as number (%)Relative risk95% CIIL1a–889 C/C28 (63.6)73 (52.1)1.610.80–3.23 T/C12 (27.3)54 (38.6)0.600.28–1.26 T/T4 (9.1)13 (9.3)0.980.30–3.17IL-1ß–511 C/C16 (36.4)70 (50)0.570.28–1.15 C/T20 (45.4)58 (42.4)1.180.60–2.33 T/T8 (18.2)12 (8.6)2.370.90–6.24IL-1ß+3962 C/C22 (50)76 (54.3)0.840.43–1.66 C/T21 (47.7)56 (40)1.370.69–2.71 T/T1 (2.3)8 (5.7)0.380.05–3.16IL-1R pst1 1970 C/C19 (43.2)60 (42.9)1.010.51–2.01 C/T19 (43.2)67 (47.9)0.830.42–1.64 T/T6 (13.6)13 (9.2)1.540.55–4.33IL-1RA mspa1 11100 C/C1 (2.3)4 (2.9)0.790.09–7.27 T/C18 (40.9)57 (40.7)1.010.51–2.01 T/T25 (56.8)79 (56.4)1.020.51–2.01IL-12 –1188 A/A24 (54.5)73 (52.1)1.100.56–2.17 C/A18 (40.9)57 (40.7)1.010.51–2.01 C/C2 (4.5)10 (7.2)0.620.13–2.94IFN-? UTR 5644 A/A18 (40.9)42 (30)1.620.80–3.26 A/T8 (18.2)66 (47.1)0.250.11–0.57 T/TaData are reported as number (%)18 (40.9)32 (22.9)2.341.14–4.79TGF-ß1 cdn 10 C/C14 (31.8)32 (22.9)1.580.75–3.32 C/T21 (47.7)63 (45)1.120.57–2.20 T/Tbp=0.0022, p=0.0002.9 (20.4)45 (32.1)0.540.24–1.23TGF-ß1 cdn 25 C/C1 (2.3)4 (2.9)0.790.09–7.27 C/G8 (18.2)14 (10)2.000.78–5.14 G/G35 (79.5)122 (87.1)0.570.24–1.39TNF-a–308 A/A0 (0)3 (2.1)—— G/Abp=0.0022, p=0.0002.19 (43.2)20 (14.3)4.562.13–9.77 G/G25 (56.8)117 (83.6)0.260.12–0.55TNF-a–238 A/A0 (0)1 (0.7)—— G/Acp=0.0022, p=0.0002.3 (6.8)19 (13.6)0.470.13–1.66 G/G41 (93.2)120 (85.7)2.280.64–8.06a Data are reported as number (%)b, c p=0.0022, p=0.0002. Open table in a new tab Table IIIL-2, IL-4 cluster, IL-6, and IL-10 polymorphisms in OLP patients and controlsGenotypeOLP (n=44)aData are reported as number (%).Controls (n=140)aData are reported as number (%).Relative risk95% CIIL-2 –330 G/G5 (11.4)17 (12.1)0.930.32–2.68 T/G19 (43.2)61 (43.6)0.980.50–1.95 T/T20 (45.4)62 (44.3)1.050.53–2.07IL-2 +166 G/G27 (61.4)86 (61.4)1.000.50–2.00 G/T13 (29.5)45 (32.1)0.890.42–1.85 T/T4 (9.1)9 (6.5)1.460.43–4.98IL-4 –1098 G/Gbp=0.0427.3 (6.8)1 (0.7)10.171.03–100.42 T/G5 (11.4)23 (16.4)0.650.23–1.83 T/T36 (81.8)116 (82.9)0.930.38–2.25IL-4 –590 C/C35 (79.5)110 (78.6)1.060.46–2.45 C/T7 (15.9)28 (20)0.760.31–1.88 T/T2 (4.6)2 (1.4)3.290.45–24.04IL-4 –33 C/C37 (84.1)105 (75)1.760.72–4.31 C/T6 (13.6)32 (22.9)0.530.21–1.37 T/T1 (2.3)3 (2.1)1.060.11–10.48IL-4RA +1902 A/A29 (65.9)95 (67.9)0.920.45–1.88 G/A13 (29.5)38 (27.1)1.130.53–2.38 G/G2 (4.6)7 (5)0.900.18–4.52IL-6 –174 C/C6 (13.6)13 (9.3)1.540.55–4.33 C/G17 (38.7)70 (50)0.630.32–1.26 G/G21 (47.7)57 (40.7)1.330.67–2.63IL-6 nt 565 A/A7 (15.9)13 (9.3)1.850.69–4.97 G/A16 (36.4)67 (47.8)0.620.31–1.25 G/G21 (47.7)60 (42.9)1.220.62–2.40IL-10 –1082 A/A16 (36.4)47 (33.6)1.130.56–2.29 G/A23 (52.3)76 (54.3)0.920.47–1.82 G/G5 (11.4)17 (12.1)0.930.32–2.68IL-10 –819 C/C20 (45.4)70 (50)0.830.42–1.64 C/T17 (38.6)62 (44.3)0.790.40–1.58 T/T7 (15.9)8 (5.7)3.121.06–9.17IL-10 –592 A/A7 (15.9)8 (5.7)3.121.06–9.17 C/A17 (38.7)62 (44.3)0.790.40–1.58 C/C20 (45.4)70 (50)0.830.42–1.64a Data are reported as number (%).b p=0.0427. Open table in a new tab As already reported for other diseases (Wilson et al., 1993Wilson A.G. de Vries N. Pociot F. di Giovine F.S. van der Putte L.B. Duff G.W. An allelic polymorphism within the human tumor necrosis factor alpha promoter region is strongly associated with HLA A1, B8, and DR3 alleles.J Exp Med. 1993; 177: 557-560Crossref PubMed Scopus (670) Google Scholar;Rood et al., 2000Rood M.J. van Krugten M.V. Zanelli E. et al.TNF-308A and HLA-DR3 alleles contribute independently to susceptibility to systemic lupus erythematosus.Arthritis Rheum. 2000; 43: 129-134Crossref PubMed Scopus (168) Google Scholar;Werth et al., 2000Werth V.P. Zhang W. Dortzbach K. Sullivan K. Association of a promoter polymorphism of tumor necrosis factor-α with subacute cutaneous lupus erythematosus and distinct photoregulation of transcription.J Invest Dermatol. 2000; 115: 726-730Crossref PubMed Scopus (117) Google Scholar,Werth et al., 2002Werth V.P. Callen J.P. Ang G. Sullivan K. Association of tumor necrosis factor-α and HLA polymorphisms with adult dermatomyositis: Implications for a unique pathogenesis.J Invest Dermatol. 2002; 119: 617-620Crossref PubMed Scopus (74) Google Scholar), we found that only in OLP patients –308A TNF-α exhibit a linkage disequilibrium with HLA-DR3 Table III. A similar linkage disequilibrium was also observed in OLP patients for the allele HLA-DRB*14 Table III. All the OLP patients with at least one HLA-DR3 or DR6 allele also possessed a –308A TNF-α allele. We do not know whether each HLA-DR3 or DR6 allele is on the same chromosomal strand as the –308A TNF-α allele. This finding could indicate linkage disequilibrium or an essential requirement for HLA-DR3 or DR6 to occur with –308A TNF-α for disease to develop. Table III. When stratifying patients and controls according to HLA-DR3 and DR6 status, the frequency of individuals with at least one –308A TNF-α allele was still significantly higher in HLA-DR3- and HLA-DR6-negative OLP patients than in controls (27 vs. 8%; rr=3.48, 95%, CI 1.58–7.69, p=0.002; and 39 vs. 17%, rr=2.22, 95% CI 1.29–3.83, p=0.008, respectively) Table III. Moreover, no significant difference was observed between OLP subjects taken all together and healthy controls Table IV and between the pure OLP or mucocutaneous LP groups compared separately with controls (data not shown) regarding the HLA-DR allele frequency. This was already observed in previous studies (La Nasa et al., 1995La Nasa G. Cottoni F. Mulargia M. et al.HLA antigen distribution in different clinical subgroups demonstrates genetic heterogeneity in lichen planus.Br J Dermatol. 1995; 132: 897-900Crossref PubMed Scopus (43) Google Scholar;Carrozzo et al., 2001Carrozzo M. Francia di Celle P. Gandolfo S. et al.Increased frequency of HLA-DR6 allele in Italian patients with hepatitis C virus associated oral lichen planus.Br J Dermatol. 2001; 144: 803-808Crossref PubMed Scopus (100) Google Scholar).Table IIILinkage disequilibria for TNF-α in OLP patients and controlsGenotypes+/+aData are presented as number (%).+/-aData are presented as number (%).-/+aData are presented as number (%).-/-aData are presented as number (%).χ2ΔrelativeOLP patients –308 A/HLA-DR37 (16)12 (27)0 (0)25 (57)10.951.00 –308 A/HLA-DR6bHLA-DRB1*14.2 (4)17 (39)0 (0)25 (57)2.761.00Controls –308 A/HLA-DR311 (10)9 (8)9 (8)86 (75)23.840.46 –308 A/HLA-DR6bHLA-DRB1*14.0 (0)20 (17)4 (3)91 (79)0.87– 0.0038a Data are presented as number (%).b HLA-DRB1*14. Open table in a new tab Table IVFrequencies of HLA-DR alleles in controls and patients affected by OLPaAll the comparisons were not significant.HLA-DRB geneOLP (n=44)bData are reported as number (%).Controls (n=115)bData are reported as number (%).,cOnly 115 controls were available for HLA analysis.Relative risk95% CIDR0111 (25)20 (17.4)1.580.69–3.65DR0210 (22.7)24 (20.9)1.110.48–2.57DR037 (15.9)23 (20)0.750.29–1.91DR047 (15.9)19 (16.5)0.950.37–2.46DR0518 (40.9)56 (48.7)0.720.36–1.47DR069 (20.4)31 (27)0.690.30–1.61 *13dAsterisk Indicates the splits of the broad antigen.7 (15.9)18 (24.8)1.020.39–2.64 *142 (4.5)4 (3.5)1.320.23–7.48DR0716 (36.4)29 (25.2)1.690.80–3.56DR083 (6.8)8 (7)0.970.24–3.87DR090 (0)0 (0)——DR103 (6.8)3 (2.6)2.730.53–14.08a All the comparisons were not significant.b Data are reported as number (%).c Only 115 controls were available for HLA analysis.d Asterisk Indicates the splits of the broad antigen. Open table in a new tab The –308G/A TNF-α genotype showed a significantly higher frequency in patients with mucocutaneous LP than in patients with pure OLP Table V. This was due to the fact that in patients with mucocutaneous LP, the frequency of the –308A TNF-α allele was more than double the values in the pure OLP patients (40.9 vs. 15.1%, rr=3.88, 95% CI 1.31–11.46, p=0.003). Conversely, we found no significant differences between pure OLP and mucocutaneous LP for any other cytokine (data not shown). Finally, between the OLP subjects with erosive lesions compared with healthy controls, no significant differences were observed in the allele or genotype frequencies for any cytokine analyzed (data not shown).Table VTNF-α polymorphisms in mucocutaneous LP and pure OLP patientsGenotypeMucocutaneous LP (n=11)aData are presented as number (%).Pure OLP (n=33)aData are presented as number (%).Relative risk95% CITNF-a–308 A/A0 (0)0 (0)—— G/A9 (81.8%)10 (30.3)10.351.89–56.80bp=0.003. G/G2 (18.2%)23 (69.7)0.100.02–0.53a Data are presented as number (%).b p=0.003. Open table in a new tab Many studies have suggested a central role for TNF-α and IFN-γ in the pathogenesis of OLP (Yamamoto et al., 1994Yamamoto T. Osaki T. Yoneda K. Ueta E. Cytokine production by keratinocytes and mononuclear infiltrates in oral lichen planus.J Oral Pathol Med. 1994; 23: 309-315Crossref PubMed Scopus (84) Google Scholar;Sugerman et al., 1996Sugerman P.B. Savage N.W. Seymour G.J. Walsh L.J. Is there a role for tumor necrosis factor-alpha (TNF-alpha) in oral lichen planus?.J Oral Pathol Med. 1996; 25: 219-224Crossref PubMed Scopus (70) Google Scholar;Younes et al., 1996Younes F. Quartey E.L. Kiguwa S. Partridge M. Expression of TNF and the 55-kDa TNF receptor in epidermis, oral mucosa, lichen planus and squamous cell carcinoma.Oral Dis. 1996; 2: 25-31Crossref PubMed Scopus (31) Google Scholar;Fayyazi et al., 1999Fayyazi A. Schweyer S. Soruri A. et al.T lymphocyte and altered keratinocyte express interferon-gamma and interleukin 6 in lichen planus.Arch Dermatol Res. 1999; 291: 485-490Crossref PubMed Scopus (49) Google Scholar), but this is the first study showing that genetic variations in expression of both these cytokines contribute to susceptibility to OLP and may influence the course of the disease. Analyzing jointly the polymorphisms of several pro- and anti-inflammatory cytokines, we found that the OLP patients had a significantly higher frequency of the T/T genotype within the first intron of IFN-γ gene promoter and of the A allele at the –308 TNF-α polymorphism. Notably, both the observed polymorphisms are known to increase the production of the respective cytokine (Bouma et al., 1996Bouma G. Xia B. Crusius J.B. et al.Distribution of four polymorphisms in the tumour necrosis factor (TNF) genes in patients with inflammatory bowel disease (IBD).Clin Exp Immunol. 1996; 103: 391-396Crossref PubMed Scopus (148) Google Scholar;Wilson et al., 1997Wilson A.G. Symons J.A. McDowell T.L. McDevitt H.O. Duff G.W. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation.Proc Natl Acad Sci USA. 1997; 94: 3195-3199Crossref PubMed Scopus (2046) Google Scholar;Louis et al., 1998Louis E. Franchimont D. Piron A. et al.Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS) -stimulated whole blood cell culture in healthy humans.Clin Exp Immunol. 1998; 113: 401-406Crossref PubMed Scopus (539) Google Scholar;Perrey et al., 1998Perrey C. Pravica V. Sinnott P.J. Hutchinson J.V. Genotyping for polymorphism in interferon γ, interleukin 10, transforming growth factor β1 and tumour necrosis factor α gene: A technical report.Transpl Immunol. 1998; 6: 193-197Crossref PubMed Scopus (246) Google Scholar;Galbraith et al., 1998Galbraith G.M. Steed R.B. Sanders J.J. Pandey J.P. Tumor necrosis factor alpha production by oral leukocytes. Influence of tumor necrosis factor genotype.J Periodontol. 1998; 169: 428-433Crossref Scopus (83) Google Scholar;Pravica et al., 1999Pravica V. Asderakis A. Perrey C. Hajeer A. Sinnott P.J. Hutchinson I.V. In vitro production of IFN-gamma correlates with CA repeat polymorphism in the human IFN-gamma gene.Eur J Immunogenet. 1999; 26: 1-3Crossref PubMed Scopus (423) Google Scholar;Hoffmann et al., 2001Hoffmann S.C. Stanley E.M. Cox E.D. et al.Association of cytokine polymorphic inheritance, in vitro cytokine production in anti-CD3/CD28-stimulated peripheral blood lymphocytes.Transplantation. 2001; 72: 1444-1450Crossref PubMed Scopus (306) Google Scholar;Braun et al., 1996Braun N. Michel U. Ernst B.P. Metzner R. Bitsch A. Weber F. Rieckmann P. Gene polymorphism at position -308 of the tumor-necrosis-factor-alpha (TNF-alpha) in multiple sclerosis and its influence on the regulation of TNF-alpha production.Neurosci Lett. 1996; 215: 75-78PubMed Google Scholar). Significantly, many other studies demonstrate a high level of IFN-γ and TNF-α in involved oral mucosa (Fayyazi et al., 1999Fayyazi A. Schweyer S. Soruri A. et al.T lymphocyte and altered keratinocyte express interferon-gamma and interleukin 6 in lichen planus.Arch Dermatol Res. 1999; 291: 485-490Crossref PubMed Scopus (49) Google Scholar) and in the serum of patients with OLP (Urata et al., 1986Urata M. Yoshida H. Yanagawa T. et al.Interferon activity and its characterization in the sera of patients with premalignant lesions arising in oral mucosa.Int J Oral Maxillofac Surg. 1986; 15: 134-147Abstract Full Text PDF PubMed Scopus (12) Google Scholar;Yamamoto et al., 1991Yamamoto T. Yoneda K. Ueta E. Hirota J. Osaki T. Serum cytokine levels in patients with oral mucous membrane disorders.J Oral Pathol Med. 1991; 20: 275-279Crossref PubMed Scopus (36) Google Scholar;Karagouni et al., 1994Karagouni E.E. Dotsika E.N. Sklavounou A. Alteration in peripheral blood mononuclear cell function and serum cytokines in oral lichen planus.J Oral Pathol Med. 1994; 23: 28-35Crossref PubMed Scopus (54) Google Scholar). Both infiltrating T lymphocytes and mast cells in OLP contain IFN-γ and TNF-α mRNA (Walsh et al., 1995Walsh L.J. Davis M.F. Xu L.J. Savage N.W. Relationship between mast cell degranulation and inflammation in the oral cavity.J Oral Pathol Med. 1995; 24: 266-272Crossref PubMed Scopus (66) Google Scholar;Zhao et al., 2001Zhao Z.Z. Sugerman P.B. Zhou X.J. Walsh L.J. Savage N.W. Mast cell degranulation and the role of T cell RANTES in oral lichen planus.Oral Dis. 2001; 7: 246-251Crossref PubMed Google Scholar), confirming the hypothesis that a delayed-type hypersensitivity (Th1) reaction is responsible for the development of OLP. Indeed, oral keratinocytes also demonstrate unregulated TNF-α mRNA in a pattern identical to that seen in cutaneous delayed-type hypersensitivity reaction (Sugerman et al., 1996Sugerman P.B. Savage N.W. Seymour G.J. Walsh L.J. Is there a role for tumor necrosis factor-alpha (TNF-alpha) in oral lichen planus?.J Oral Pathol Med. 1996; 25: 219-224Crossref PubMed Scopus (70) Google Scholar). Conversely, OLP lesional T cells did not secrete IL-4 and IL-10 or TGF-β (Simark-Mattsson et al., 1998Simark-Mattsson C. Jontell M. Bergenholtz G. Heyden M. Dahlgren U.I. Distribution of interferon-gamma mRNA-positive cells in oral lichen planus lesions.J Oral Pathol Med. 1998; 27: 483-488Crossref PubMed Scopus (36) Google Scholar,Simark-Mattsson et al., 1999Simark-Mattsson C. Bergenholtz G. Jontell M. et al.Distribution of interleukin-2-4-10, tumour necrosis factor-alpha and transforming growth factor-beta mRNAs in oral lichen planus.Arch Oral Biol. 1999; 44: 499-507Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). Our study suggests that this Th1 cytokine bias could be genetically induced and influence OLP susceptibility. Because the TNF-α gene is located in the class III region of HLA on the short arm of chromosome 6, there was the possibility that the difference observed in this study was due to the linkage disequilibrium of TNF-α with some HLA alleles, despite the inconsistency of the immunogenetic studies on OLP (Carrozzo et al., 2001Carrozzo M. Francia di Celle P. Gandolfo S. et al.Increased frequency of HLA-DR6 allele in Italian patients with hepatitis C virus associated oral lichen planus.Br J Dermatol. 2001; 144: 803-808Crossref PubMed Scopus (100) Google Scholar). We found the less common –308A TNF-α allele associated with HLA-DR3 and DR6 (DRB1*14) in OLP patients. The linkage disequilibrium of the –308A TNF-α promoter polymorphism with HLA-DR3 is well known in Caucasian persons with skin diseases as subacute cutaneous and systemic lupus erythematosus and dermatomyositis (Rood et al., 2000Rood M.J. van Krugten M.V. Zanelli E. et al.TNF-308A and HLA-DR3 alleles contribute independently to susceptibility to systemic lupus erythematosus.Arthritis Rheum. 2000; 43: 129-134Crossref PubMed Scopus (168) Google Scholar;Werth et al., 2000Werth V.P. Zhang W. Dortzbach K. Sullivan K. Association of a promoter polymorphism of tumor necrosis factor-α with subacute cutaneous lupus erythematosus and distinct photoregulation of transcription.J Invest Dermatol. 2000; 115: 726-730Crossref PubMed Scopus (117) Google Scholar;Werth et al., 2002Werth V.P. Callen J.P. Ang G. Sullivan K. Association of tumor necrosis factor-α and HLA polymorphisms with adult dermatomyositis: Implications for a unique pathogenesis.J Invest Dermatol. 2002; 119: 617-620Crossref PubMed Scopus (74) Google Scholar). Notably, in a small study, a significant association between erosive OLP and HLA-DR3 has been reported (Jontell et al., 1987Jontell M. Stahlblad P.A. Rosdahl I. Lindblom B. HLA-DR3 antigens in erosive oral lichen planus, cutaneous lichen planus, and lichenoid reactions.Acta Odontol Scand. 1987; 45: 309-312Crossref PubMed Scopus (28) Google Scholar), whereas hepatitis C virus-associated OLP has been related to HLA-DR6 (Carrozzo et al., 2001Carrozzo M. Francia di Celle P. Gandolfo S. et al.Increased frequency of HLA-DR6 allele in Italian patients with hepatitis C virus associated oral lichen planus.Br J Dermatol. 2001; 144: 803-808Crossref PubMed Scopus (100) Google Scholar). Nevertheless, we found no significant association between HLA-DR and OLP patients without hepatitis C virus infection independently of the presence of erosive or skin lesions. Moreover, the –308A TNF-α association with OLP was still significant in HLA-DR3- and HLA-DR6-negative individuals. Another interesting result of the present study is that cytokine polymorphism may also influence the clinical presentation of the disease. Up to 44% of patients with OLP are prone to develop cutaneous lesions (Eisen, 1999Eisen D. The evaluation of cutaneous, genital," @default.
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