Th1/Th17-Related Cytokines and Chemokines and Their Implications in the Pathogenesis of Pemphigus Vulgaris

Rodolfo Pessato Timoteo, Marcos Vinicius da Silva, Camila Botelho Miguel, Djalma Alexandre Alves Silva, Jonatas Da Silva Catarino, Virmondes Rodrigues Junior, Helioswilton Sales-Campos, Carlo Jose Freire Oliveira, Rodolfo Pessato Timoteo, Marcos Vinicius da Silva, Camila Botelho Miguel, Djalma Alexandre Alves Silva, Jonatas Da Silva Catarino, Virmondes Rodrigues Junior, Helioswilton Sales-Campos, Carlo Jose Freire Oliveira

Abstract

Pemphigus vulgaris (PV) is an autoimmune disease characterized by the presence of IgG autoantibodies against desmoglein-3. Despite the variety of findings, the chemokine and cytokine profiles that characterize the immune response in the disease are still poorly explored. Thus, 20 PV patients and 20 controls were grouped according to gender, ethnicity, place of residence, and clinical parameters of the disease. Then, the levels of chemokines and of Th1/Th2/Th17/Treg/Th9/Th22-related cytokines were assessed in the serum. PV patients had higher levels of inflammatory Th1/Th17 cytokines (IFN-γ, IL-17, and IL-23), as well as higher levels of CXCL8 and reduced levels of Th1/Th2-related chemokines (IP-10 and CCL11). However, no differences in the levels of IL-2, IL-6, TNF-α, IL-1β, IL-4, IL-9, IL-12, TGF-β, IL-33, MCP-1, RANTES, and MIP-1α were found between PV patients and their control counterparts. Furthermore, PV patients with skin lesions had higher serum levels of IL-6 and CXCL8 when compared to PV patients without lesions. Taken together, our findings describe the role of cytokines and chemokines associated with Th1/Th17 immune response in PV patients. Finally, these data are important for better understanding of the immune aspects that control disease outcome, and they may also provide important information about why patients develop autoantibodies against desmogleins.

Conflict of interest statement

The authors declare no conflict of interests.

Figures

Figure 1
Figure 1
Serum profile of T cell-derived cytokines in Pemphigus vulgaris. Levels of (a) IFN-γ, (b) IL-17, (c) IL-10, and (d) IL-22 in Healthy Donors (⬤) and Pemphigus vulgaris patients (■). Error bars represent median ± SD. ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001; ∗∗∗∗p < 0.0001; Mann–Whitney test. (e) Radar plot representation of serum T cell-derived cytokine profile. The lines highlight the fold change in cytokine levels in Pemphigus vulgaris patients (gray line) in relation to Healthy Donors (black line). Data were obtained by calculating the ratio between the median concentration of each cytokine in the Pemphigus vulgaris group and in the healthy group.
Figure 2
Figure 2
Serum profile of other proinflammatory cytokines in Pemphigus vulgaris. Levels of (a) IL-2, (b) TNF-α, (c) IL-12, (d) IL-6, (e) IL-23, (f) IL-13, (g) IL-5, (h) IL-15, and (i) IL-33 in Healthy Donors (⬤) and Pemphigus vulgaris patients (■). Error bars represent median ± SD. ∗p < 0.05; ∗∗p < 0.01; ∗∗∗∗p < 0.0001; Mann–Whitney test. (j) Radar plot representation of serum proinflammatory cytokine profile. The lines highlight the fold change in cytokine levels in Pemphigus vulgaris patients (gray line) in relation to Healthy Donors (black line). Data were obtained by calculating the ratio between the median concentration of each cytokine in the Pemphigus vulgaris group and in the healthy group.
Figure 3
Figure 3
Serum profile of chemokines in Pemphigus vulgaris. Levels of (a) CCL-2/MCP-1, (b) CCL5/RANTES, (c) CCL11/Eotaxin, (d) CXCL8/IL-8, and (e) CCL10/IP-10 in Healthy Donors (⬤) and Pemphigus vulgaris patients (■). Error bars represent median ± SD. ∗∗∗p < 0.001; ∗∗∗∗p < 0.0001; Mann–Whitney test. (f) Radar plot representation of serum chemokine pattern. The lines highlight the fold change in cytokine levels in Pemphigus vulgaris patients (gray line) in relation to controls (black line). Data were obtained by calculating the ratio between the median concentration of each cytokine in the Pemphigus vulgaris group and in the control group.
Figure 4
Figure 4
Skin lesions in Pemphigus vulgaris are associated with higher levels of IL-6 and CXCL8. Levels of (a) IL-2, (b) IL-6, and (c) CXL8 (IL-8) in Pemphigus vulgaris (PV) patients with no skin lesions (⬤) and PV patients with skin lesions (■). (d) Correlation between the frequency of lesions and time of treatment and (e) correlation between the frequency of skin lesions and dosage of glucocorticoids used to treat PV patients. Error bars represent median ± SD. ∗p < 0.05, Mann–Whitney test was used in (a–c). The Spearman correlation test was used to evaluate the strength of association between the variables (d and e).

References

    1. Yeh S. W., Sami N., Ahmed R. A. Treatment of pemphigus vulgaris: current and emerging options. American Journal of Clinical Dermatology. 2005;6(5):327–342. doi: 10.2165/00128071-200506050-00006.
    1. Pisanti S., Sharav Y., Kaufman E., Posner L. N. Pemphigus vulgaris: incidence in Jews of different ethnic groups, according to age, sex, and initial lesion. Oral Surgery, Oral Medicine, Oral Pathology. 1974;38(3):382–387. doi: 10.1016/0030-4220(74)90365-x.
    1. Echigo T., Hasegawa M., Shimada Y., Inaoki M., Takehara K., Sato S. Both Th1 and Th2 chemokines are elevated in sera of patients with autoimmune blistering diseases. Archives of Dermatological Research. 2006;298(1):38–45. doi: 10.1007/s00403-006-0661-5.
    1. Nakashima H., Fujimoto M., Asashima N., et al. Serum chemokine profile in patients with bullous pemphigoid. British Journal of Dermatology. 2007;156(3):454–459. doi: 10.1111/j.1365-2133.2006.07601.x.
    1. Giordano C. N., Sinha A. A. Cytokine networks in Pemphigus vulgaris: an integrated viewpoint. Autoimmunity. 2012;45(6):427–439. doi: 10.3109/08916934.2012.697593.
    1. Giurdanella F., Fania L., Gnarra M., et al. A possible role for CD8+ T lymphocytes in the cell-mediated pathogenesis of pemphigus vulgaris. Mediators of Inflammation. 2013;2013:5. doi: 10.1155/2013/764290.764290
    1. Satyam A., Khandpur S., Sharma V. K., Sharma A. Involvement of TH1/TH2 cytokines in the pathogenesis of autoimmune skin disease—pemphigus vulgaris. Immunological Investigations. 2009;38(6):498–509. doi: 10.1080/08820130902943097.
    1. D'Auria L., Bonifati C., Mussi A., et al. Cytokines in the sera of patients with pemphigus vulgaris: interleukin-6 and tumour necrosis factor-alpha levels are significantly increased as compared to healthy subjects and correlate with disease activity. European Cytokine Network. 1997;8(4):383–387.
    1. Ameglio F., D'Auria L., Cordiali-Fei P., et al. Anti-intercellular substance antibody log titres are correlated with serum concentrations of interleukin-6, interleukin-15 and tumor necrosis factor-alpha in patients with Pemphigus vulgaris relationships with peripheral blood neutrophil counts, disease severity and duration and patients' age. Journal of Biological Regulators and Homeostatic Agents. 1999;13(4):220–224.
    1. D'Auria L., Bonifati C., Cordiali-Fei P., et al. Increased serum interleukin-15 levels in bullous skin diseases: correlation with disease intensity. Archives of Dermatological Research. 1999;291(6):354–356. doi: 10.1007/s004030050421.
    1. Keskin D. B., Stern J. N. H., Fridkis-Hareli M., Razzaque Ahmed A. Cytokine profiles in pemphigus vulgaris patients treated with intravenous immunoglobulins as compared to conventional immunosuppressive therapy. Cytokine. 2008;41(3):315–321. doi: 10.1016/j.cyto.2007.12.007.
    1. Ludwig R. J., Schmidt E. Cytokines in autoimmune bullous skin diseases. Epiphenomena or contribution to pathogenesis? Giornale Italiano di Dermatologia e Venereologia. 2009;144(4):339–349.
    1. Narbutt J., Lukamowicz J., Bogaczewicz J., Sysa-Jedrzejowska A., Torzecka J. D., Lesiak A. Serum concentration of interleukin-6 is increased both in active and remission stages of pemphigus vulgaris. Mediators of Inflammation. 2008;2008:5. doi: 10.1155/2008/875394.875394
    1. Ragab N., Abdallah M., El-Gohary E., Elewa R. Stress and serum TNF-α levels may predict disease outcome in patients with pemphigus: a preliminary study. Cutis. 2011;87(4):189–194.
    1. Mortazavi H., Esmaili N., Khezri S., et al. The effect of conventional immunosuppressive therapy on cytokine serum levels in pemphigus vulgaris patients. Iranian Journal of Allergy, Asthma and Immunology. 2014;13(3):174–183.
    1. Bhol K. C., Rojas A. I., Khan I. U., Ahmed A. R. Presence of interleukin 10 in the serum and blister fluid of patients with pemphigus vulgaris and pemphigoid. Cytokine. 2000;12(7):1076–1083. doi: 10.1006/cyto.1999.0642.
    1. Baroni A., Perfetto B., Ruocco E., Greco R., Criscuolo D., Ruocco V. Cytokine pattern in blister fluid and sera of patients with pemphigus. Dermatology. 2002;205(2):116–121. doi: 10.1159/000063895.
    1. Xue J., Su W., Chen Z., Ke Y., Du X., Zhou Q. Overexpression of interleukin-23 and interleukin-17 in the lesion of pemphigus vulgaris: a preliminary study. Mediators of Inflammation. 2014;2014:5. doi: 10.1155/2014/463928.463928
    1. Hettiaratchy S., Papini R. Initial management of a major burn: II—assessment and resuscitation. British Medical Journal. 2004;329(7457):101–103. doi: 10.1136/bmj.329.7457.101.
    1. Aoki V., Rivitti E. A., Diaz L. A. Update on fogo selvagem, an endemic form of pemphigus foliaceus. Journal of Dermatology. 2015;42(1):18–26. doi: 10.1111/1346-8138.12675.
    1. Cho M. J., Ellebrecht C. T., Payne A. S. The dual nature of interleukin-10 in pemphigus vulgaris. Cytokine. 2015;73(2):335–341. doi: 10.1016/j.cyto.2014.11.002.
    1. Tanaka H., Komai M., Nagao K., et al. Role of interleukin-5 and eosinophils in allergen-induced airway remodeling in mice. American Journal of Respiratory Cell and Molecular Biology. 2004;31(1):62–68. doi: 10.1165/rcmb.2003-0305OC.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir