Increase in Peripheral CD3−CD56brightCD16− Natural Killer Cells in Hashimoto’s Thyroiditis Associated with HHV-6 Infection
Hashimoto’s thyroiditis (HT) is a very common autoimmune disease of the thyroid. In addition to genetic background, several viruses, including herpesviruses, have been suggested to play a role as possible environmental triggers of disease, but conclusive data are still lacking. Previous results showed that HT patients have an increased cellular immune response directed against the HHV-6 U94 protein and increased NK activity directed against HHV-6 infected thyrocytes.
In this study, we characterized the antiviral antibody response and the NK cells activity and subtype in HHV-6 infected HT patients. The results showed that HT subjects have increased prevalence and titer of anti-U94 antibodies and a higher amount of CD3-CD56brightCD16−NK cell percentages compared to controls. Furthermore, the cell activation of CD3−CD56bright NK cells in HT patients significantly correlates with TPO and Tg Ab levels.
The results suggest that HHV-6 might contribute to HT development, increasing NK cell secretion of inflammatory cytokines that could sustain the persistence of an inflammatory status in HT patients.
KeywordsHashimoto’s thyroiditis HHV-6 NK cells
This work was supported by grants from University of Ferrara (FAR).
- Alvarez-Lafuente R, Fernandez-Gutierrez B, de Miguel S, Jover JA, Rollin R, Loza E, Clemente D, Lamas JR (2005) Potential relationship between herpes viruses and rheumatoid arthritis: analysis with quantitative real time polymerase chain reaction. Ann Rheum Dis 64(9):1357–1359. doi:64/9/1357 [pii] 10.1136/ard.2004.033514
- Alvarez-Lafuente R, Martinez A, Garcia-Montojo M, Mas A, De Las Heras V, Dominguez-Mozo MI, Maria Del Carmen C, Lopez-Cavanillas M, Bartolome M, Gomez de la Concha E, Urcelay E, Arroyo R (2010) MHC2TA rs4774C and HHV-6A active replication in multiple sclerosis patients. Eur J Neurol 17(1):129–135. doi:ENE2758 [pii] 10.1111/j.1468-1331.2009.02758.x
- Boccara O, Lesage F, Regnault V, Lasne D, Dupic L, Bourdon-Lanoy E, Pannier S, Fraitag S, Audat F, Lecompte T, Hubert P, Bodemer C (2009) Nonbacterial purpura fulminans and severe autoimmune acquired protein S deficiency associated with human herpesvirus-6 active replication. Br J Dermatol 161(1):181–183. doi:BJD9264 [pii] 10.1111/j.1365-2133.2009.09264.x
- Broccolo F, Drago F, Paolino S, Cassina G, Gatto F, Fusetti L, Matteoli B, Zaccaria E, Parodi A, Lusso P, Ceccherini-Nelli L, Malnati MS (2009) Reactivation of human herpesvirus 6 (HHV-6) infection in patients with connective tissue diseases. J Clin Virol 46 (1):43–46. doi:S1386-6532(09)00191-7 [pii] 10.1016/j.jcv.2009.05.010
- Caruso A, Rotola A, Comar M, Favilli F, Galvan M, Tosetti M, Campello C, Caselli E, Alessandri G, Grassi M, Garrafa E, Cassai E, Di Luca D (2002) HHV-6 infects human aortic and heart microvascular endothelial cells, increasing their ability to secrete proinflammatory chemokines. J Med Virol 67(4):528–533CrossRefPubMedGoogle Scholar
- Caruso A, Caselli E, Fiorentini S, Rotola A, Prandini A, Garrafa E, Saba E, Alessandri G, Cassai E, Di Luca D (2009) U94 of human herpesvirus 6 inhibits in vitro angiogenesis and lymphangiogenesis. Proc Natl Acad Sci U S A 106(48):20446–20451. doi:0905535106 [pii] 10.1073/pnas.0905535106
- Caselli E, Zatelli MC, Rizzo R, Benedetti S, Martorelli D, Trasforini G, Cassai E, Degli Uberti EC, Di Luca D, Dolcetti R (2012a) Virologic and immunologic evidence supporting an association between HHV-6 and Hashimoto’s Thyroiditis. PLoS Pathog 8(10):e1002951. doi: 10.1371/journal.ppat.1002951PPATHOGENS-D-12-01343 [pii]
- Krueger GR, Sander C, Hoffmann A, Barth A, Koch B, Braun M (1991) Isolation of human herpesvirus-6 (HHV-6) from patients with collagen vascular diseases. Vivo 5(3):217–225Google Scholar
- Kubo T SK, Kobayashi D, Motegi A, Kobayashi O, Takeshita S, Nonoyama S (2006) A case of HHV-6 associated acute necrotizing encephalopathy with increase of CD56bright NKcells. Scand J Infect Dis 38(11–12):1122–1125Google Scholar
- Kumagai TYT, Yoshida M, Okui T, Ihira M, Nagata N, Yano S, Shiraki K, Yamada M, Ichihara K, Asano Y (2006) Time course characteristics of human herpesvirus 6 specific cellular immune response and natural killer cell activity in patients with exanthema subitum. J Med Virol 78(6):792–799CrossRefPubMedGoogle Scholar
- Poli A, Michel T, Theresine M, Andres E, Hentges F, Zimmer J (2009) CD56bright natural killer (NK) cells: an important NK cell subset. Immunology 126(4):458–465. doi:IMM3027 [pii] 10.1111/j.1365-2567.2008.03027.x
- Potenza L, Luppi M, Barozzi P, Rossi G, Cocchi S, Codeluppi M, Pecorari M, Masetti M, Di Benedetto F, Gennari W, Portolani M, Gerunda GE, Lazzarotto T, Landini MP, Schulz TF, Torelli G, Guaraldi G (2008) HHV-6A in syncytial giant-cell hepatitis. N Engl J Med 359(6):593–602. doi:359/6/593 [pii] 10.1056/NEJMoa074479
- Rotola A, Ravaioli T, Gonelli A, Dewhurst S, Cassai E, Di Luca D (1998) U94 of human herpesvirus 6 is expressed in latently infected peripheral blood mononuclear cells and blocks viral gene expression in transformed lymphocytes in culture. Proc Natl Acad Sci U S A 95(23):13911–13916CrossRefPubMedPubMedCentralGoogle Scholar
- Scotet E, Peyrat MA, Saulquin X, Retiere C, Couedel C, Davodeau F, Dulphy N, Toubert A, Bignon JD, Lim A, Vie H, Hallet MM, Liblau R, Weber M, Berthelot JM, Houssaint E, Bonneville M (1999) Frequent enrichment for CD8 T cells reactive against common herpes viruses in chronic inflammatory lesions: towards a reassessment of the physiopathological significance of T cell clonal expansions found in autoimmune inflammatory processes. Eur J Immunol 29(3):973–985CrossRefPubMedGoogle Scholar
- Vitale M, Della Chiesa M, Carlomagno S, Romagnani C, Thiel A, Moretta L, Moretta A (2004) The small subset of CD56brightCD16- natural killer cells is selectively responsible for both cell proliferation and interferon-gamma production upon interaction with dendritic cells. Eur J Immunol 34(6):1715–1722. doi: 10.1002/eji.200425100 CrossRefPubMedGoogle Scholar