PDF herunterladen
Semin Respir Crit Care Med 2017; 38(04): 463-476
DOI: 10.1055/s-0037-1602380
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Löfgren's Syndrome: Diagnosis, Management, and Disease Pathogenesis

Bekir Karakaya
1   Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St. Antonius Hospital, Nieuwegein, The Netherlands
*   Both the authors contributed equally to this article.
,
Ylva Kaiser
2   Respiratory Medicine Unit, Department of Medicine, Solna and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Solna, Stockholm, Sweden
*   Both the authors contributed equally to this article.
,
Coline H. M. van Moorsel
1   Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St. Antonius Hospital, Nieuwegein, The Netherlands
**   Shared senior authorship.
,
Johan Grunewald
2   Respiratory Medicine Unit, Department of Medicine, Solna and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Solna, Stockholm, Sweden
**   Shared senior authorship.
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
27. Juli 2017 (online)

    Lizenzen und Reprints

Abstract

Löfgren's syndrome (LS), first described in 1946 by Swedish Professor of Medicine Sven Löfgren, is a clinically distinct phenotype of sarcoidosis. Patients typically experience an acute disease onset, usually with fever, and characteristic symptoms of bilateral hilar lymphadenopathy, erythema nodosum, and/or bilateral ankle arthritis or periarticular inflammation. LS patients are well documented to have a good prognosis, which is especially true for HLA-DRB1*03+ individuals. The presence of this allele correlates closely with an accumulation of clonal CD4+ T-cell populations in the lung, suggestive of local antigen recognition. Moreover, LS differs markedly from “non-LS” sarcoidosis regarding immune cell activation, differentiation, and regulation, which may influence clinical outcome and spontaneous disease resolution.

This review offers an overview of the clinical characteristics, genetic background, and immunological characteristics of LS, as well as patient management, and reflections on future scientific challenges, emphasizing the concept of LS as a disease in its own right.

Keywords

Löfgren's syndrome - HLA-DRB1*03 - erythema nodosum - arthritis - bilateral hilar lymphadenopathy - bronchoalveolar lavage - CD4+ T cells - sarcoidosis
 

  • References

  • 1 Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007; 357 (21) 2153-2165
    CrossrefPubMedGoogle Scholar
  • 2 Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997; 336 (17) 1224-1234
    CrossrefPubMedGoogle Scholar
  • 3 Baughman RP, Lower EE, du Bois RM. Sarcoidosis. Lancet 2003; 361 (9363): 1111-1118
    CrossrefPubMedGoogle Scholar
  • 4 Costabel U, Hunninghake GW. ; Sarcoidosis Statement Committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders. ATS/ERS/WASOG statement on sarcoidosis. Eur Respir J 1999; 14 (04) 735-737
    CrossrefPubMedGoogle Scholar
  • 5 Lofgren S, Lundback H. The bilateral hilar lymphoma syndrome; a study of the relation to tuberculosis and sarcoidosis in 212 cases. Acta Med Scand 1952; 142 (04) 265-273
    PubMedGoogle Scholar
  • 6 Grunewald J, Eklund A. Sex-specific manifestations of Löfgren's syndrome. Am J Respir Crit Care Med 2007; 175 (01) 40-44
    CrossrefPubMedGoogle Scholar
  • 7 Grunewald J, Eklund A. Löfgren's syndrome: human leukocyte antigen strongly influences the disease course. Am J Respir Crit Care Med 2009; 179 (04) 307-312
    CrossrefPubMedGoogle Scholar
  • 8 Lofgren S. Erythema nodosum: studies on etiology and pathogenesis in 185 adult cases. Acta Med Scand 1946; (124) 1-197
    PubMedGoogle Scholar
  • 9 Lofgren S, Lundback H. The bilateral hilar lymphoma syndrome; a study of the relation to age and sex in 212 cases. Acta Med Scand 1952; 142 (04) 259-264
    PubMedGoogle Scholar
  • 10 Lofgren S. Primary pulmonary sarcoidosis. I. Early signs and symptoms. Acta Med Scand 1953; 145 (06) 424-431
    PubMedGoogle Scholar
  • 11 Lofgren S. Primary pulmonary sarcoidosis. II. Clinical course and prognosis. Acta Med Scand 1953; 145 (06) 465-474
    PubMedGoogle Scholar
  • 12 Mañá J, Gómez-Vaquero C, Montero A. , et al. Löfgren's syndrome revisited: a study of 186 patients. Am J Med 1999; 107 (03) 240-245
    CrossrefPubMedGoogle Scholar
  • 13 García-Porrúa C, González-Gay MA, Vázquez-Caruncho M. , et al. Erythema nodosum: etiologic and predictive factors in a defined population. Arthritis Rheum 2000; 43 (03) 584-592
    CrossrefPubMedGoogle Scholar
  • 14 Requena L, Yus ES. Erythema nodosum. Dermatol Clin 2008; 26 (04) 425-438 , v
    CrossrefPubMedGoogle Scholar
  • 15 Bartelsmeyer JA, Petrie RH. Erythema nodosum, estrogens, and pregnancy. Clin Obstet Gynecol 1990; 33 (04) 777-781
    CrossrefPubMedGoogle Scholar
  • 16 Acosta KA, Haver MC, Kelly B. Etiology and therapeutic management of erythema nodosum during pregnancy: an update. Am J Clin Dermatol 2013; 14 (03) 215-222
    CrossrefPubMedGoogle Scholar
  • 17 Jones JV, Cumming RH, Asplin CM. Evidence for circulating immune complexes in erythema nodosum and early sarcoidosis. Ann N Y Acad Sci 1976; 278: 212-219
    CrossrefPubMedGoogle Scholar
  • 18 Spilberg I, Siltzbach LE, McEwen C. The arthritis of sarcoidosis. Arthritis Rheum 1969; 12 (02) 126-137
    CrossrefPubMedGoogle Scholar
  • 19 Caplan HI, Katz WA, Rubenstein M. Periarticular inflammation, bilateral hilar adenopathy and a sarcoid reaction. Arthritis Rheum 1970; 13 (02) 101-111
    CrossrefPubMedGoogle Scholar
  • 20 Visser H, Vos K, Zanelli E. , et al. Sarcoid arthritis: clinical characteristics, diagnostic aspects, and risk factors. Ann Rheum Dis 2002; 61 (06) 499-504
    CrossrefPubMedGoogle Scholar
  • 21 Kremer JM. Histologic findings in siblings with acute sarcoid arthritis: association with the B8,DR3 phenotype. J Rheumatol 1986; 13 (03) 593-597
    PubMedGoogle Scholar
  • 22 Anandacoomarasamy A, Peduto A, Howe G, Manolios N, Spencer D. Magnetic resonance imaging in Löfgren's syndrome: demonstration of periarthritis. Clin Rheumatol 2007; 26 (04) 572-575
    CrossrefPubMedGoogle Scholar
  • 23 Kellner H, Späthling S, Herzer P. Ultrasound findings in Löfgren's syndrome: is ankle swelling caused by arthritis, tenosynovitis or periarthritis?. J Rheumatol 1992; 19 (01) 38-41
    PubMedGoogle Scholar
  • 24 Glennås A, Kvien TK, Melby K. , et al. Acute sarcoid arthritis: occurrence, seasonal onset, clinical features and outcome. Br J Rheumatol 1995; 34 (01) 45-50
    CrossrefPubMedGoogle Scholar
  • 25 Mañá J, Gómez-Vaquero C, Salazar A, Valverde J, Juanola X, Pujol R. Periarticular ankle sarcoidosis: a variant of Löfgren's syndrome. J Rheumatol 1996; 23 (05) 874-877
    PubMedGoogle Scholar
  • 26 Ungprasert P, Crowson CS, Matteson EL. Clinical characteristics of sarcoid arthropathy: a population-based study. Arthritis Care Res (Hoboken) 2016; 68 (05) 695-699
    CrossrefPubMedGoogle Scholar
  • 27 Grunewald J, Eklund A, Olerup O. Human leukocyte antigen class I alleles and the disease course in sarcoidosis patients. Am J Respir Crit Care Med 2004; 169 (06) 696-702
    CrossrefPubMedGoogle Scholar
  • 28 Fischer A, Valentonyte R, Nebel A. , et al. Female-specific association of C-C chemokine receptor 5 gene polymorphisms with Löfgren's syndrome. J Mol Med (Berl) 2008; 86 (05) 553-561
    CrossrefPubMedGoogle Scholar
  • 29 Mañá J, Badrinas F, Morera J, Fité E, Manresa F, Fernández-Nogués F. Sarcoidosis in Spain. Sarcoidosis 1992; 9 (02) 118-122
    PubMedGoogle Scholar
  • 30 Grunewald J, Brynedal B, Darlington P. , et al. Different HLA-DRB1 allele distributions in distinct clinical subgroups of sarcoidosis patients. Respir Res 2010; 11: 25
    CrossrefPubMedGoogle Scholar
  • 31 Sato H, Woodhead FA, Ahmad T. , et al. Sarcoidosis HLA class II genotyping distinguishes differences of clinical phenotype across ethnic groups. Hum Mol Genet 2010; 19 (20) 4100-4111
    CrossrefPubMedGoogle Scholar
  • 32 Baughman RP, Teirstein AS, Judson MA. , et al; Case Control Etiologic Study of Sarcoidosis (ACCESS) research group. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 2001; 164 (10 Pt 1): 1885-1889
    CrossrefPubMedGoogle Scholar
  • 33 Ishimatsu Y, Koyama H, Tomonaga M. , et al. A Japanese patient with Löfgren's syndrome with an HLA-DR12 allele and review of literature on Japanese patients. Tohoku J Exp Med 2014; 234 (02) 137-141
    CrossrefPubMedGoogle Scholar
  • 34 Zhou Y, Shen L, Zhang Y, Jiang D, Li H. Human leukocyte antigen-A, -B, and -DRB1 alleles and sarcoidosis in Chinese Han subjects. Hum Immunol 2011; 72 (07) 571-575
    CrossrefPubMedGoogle Scholar
  • 35 Ziora D, Kornelia K, Jastrzebski D, Labus L, Zieleznik K, Kozielski J. High resolution computed tomography in 2-year follow-up of Stage I sarcoidosis. Adv Exp Med Biol 2013; 788: 369-374
    PubMedGoogle Scholar
  • 36 Idali F, Wikén M, Wahlström J. , et al. Reduced Th1 response in the lungs of HLA-DRB1*0301 patients with pulmonary sarcoidosis. Eur Respir J 2006; 27 (03) 451-459
    CrossrefPubMedGoogle Scholar
  • 37 Heron M, Slieker WA, Zanen P. , et al. Evaluation of CD103 as a cellular marker for the diagnosis of pulmonary sarcoidosis. Clin Immunol 2008; 126 (03) 338-344
    CrossrefPubMedGoogle Scholar
  • 38 Danila E, Norkūniene J, Jurgauskiene L, Malickaite R. Diagnostic role of BAL fluid CD4/CD8 ratio in different radiographic and clinical forms of pulmonary sarcoidosis. Clin Respir J 2009; 3 (04) 214-221
    CrossrefPubMedGoogle Scholar
  • 39 Mota PC, Morais A, Palmares C. , et al. Diagnostic value of CD103 expression in bronchoalveolar lymphocytes in sarcoidosis. Respir Med 2012; 106 (07) 1014-1020
    CrossrefPubMedGoogle Scholar
  • 40 Pettersson T. Sarcoid and erythema nodosum arthropathies. Best Pract Res Clin Rheumatol 2000; 14 (03) 461-476
    CrossrefPubMedGoogle Scholar
  • 41 Johard U, Eklund A. Recurrent Löfgren's syndrome in three patients with sarcoidosis. Sarcoidosis 1993; 10 (02) 125-127
    PubMedGoogle Scholar
  • 42 Brewerton DA, Cockburn C, James DC, James DG, Neville E. HLA antigens in sarcoidosis. Clin Exp Immunol 1977; 27 (02) 227-229
    PubMedGoogle Scholar
  • 43 Smith MJ, Turton CW, Mitchell DN, Turner-Warwick M, Morris LM, Lawler SD. Association of HLA B8 with spontaneous resolution in sarcoidosis. Thorax 1981; 36 (04) 296-298
    CrossrefPubMedGoogle Scholar
  • 44 Gardner J, Kennedy HG, Hamblin A, Jones E. HLA associations in sarcoidosis: a study of two ethnic groups. Thorax 1984; 39 (01) 19-22
    CrossrefPubMedGoogle Scholar
  • 45 Grubić Z, Zunec R, Peros-Golubicić T. , et al. HLA class I and class II frequencies in patients with sarcoidosis from Croatia: role of HLA-B8, -DRB1*0301, and -DQB1*0201 haplotype in clinical variations of the disease. Tissue Antigens 2007; 70 (04) 301-306
    CrossrefPubMedGoogle Scholar
  • 46 Hedfors E, Lindström F. HLA-B8/DR3 in sarcoidosis. Correlation to acute onset disease with arthritis. Tissue Antigens 1983; 22 (03) 200-203
    PubMedGoogle Scholar
  • 47 Price P, Witt C, Allcock R. , et al. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol Rev 1999; 167: 257-274
    CrossrefPubMedGoogle Scholar
  • 48 Sato H, Grutters JC, Pantelidis P. , et al. HLA-DQB1*0201: a marker for good prognosis in British and Dutch patients with sarcoidosis. Am J Respir Cell Mol Biol 2002; 27 (04) 406-412
    CrossrefPubMedGoogle Scholar
  • 49 Swider C, Schnittger L, Bogunia-Kubik K. , et al. TNF-alpha and HLA-DR genotyping as potential prognostic markers in pulmonary sarcoidosis. Eur Cytokine Netw 1999; 10 (02) 143-146
    PubMedGoogle Scholar
  • 50 Seitzer U, Swider C, Stüber F. , et al. Tumour necrosis factor alpha promoter gene polymorphism in sarcoidosis. Cytokine 1997; 9 (10) 787-790
    CrossrefPubMedGoogle Scholar
  • 51 Wilson AG, de Vries N, Pociot F, di Giovine FS, van der Putte LB, Duff GW. 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 (02) 557-560
    CrossrefPubMedGoogle Scholar
  • 52 Somoskövi A, Zissel G, Seitzer U, Gerdes J, Schlaak M, Müller-Quernheim J. Polymorphisms at position -308 in the promoter region of the TNF-alpha and in the first intron of the TNF-beta genes and spontaneous and lipopolysaccharide-induced TNF-alpha release in sarcoidosis. Cytokine 1999; 11 (11) 882-887
    CrossrefPubMedGoogle Scholar
  • 53 Rivera NV, Ronninger M, Shchetynsky K. , et al. High- density genetic mapping identifies new susceptibility variants in sarcoidosis phenotypes and shows genomic-driven phenotypic differences. Am J Respir Crit Care Med 2016; 193 (09) 1008-1022
    CrossrefPubMedGoogle Scholar
  • 54 Kaiser Y, Lepzien R, Kullberg S, Eklund A, Smed-Sörensen A, Grunewald J. Expanded lung T-bet+RORγT+ CD4+ T-cells in sarcoidosis patients with a favourable disease phenotype. Eur Respir J 2016; 48 (02) 484-494
    CrossrefPubMedGoogle Scholar
  • 55 Ostadkarampour M, Eklund A, Moller D. , et al. Higher levels of interleukin IL-17 and antigen-specific IL-17 responses in pulmonary sarcoidosis patients with Löfgren's syndrome. Clin Exp Immunol 2014; 178 (02) 342-352
    CrossrefPubMedGoogle Scholar
  • 56 Grunewald J, Idali F, Kockum I. , et al. Major histocompatibility complex class II transactivator gene polymorphism: associations with Löfgren's syndrome. Tissue Antigens 2010; 76 (02) 96-101
    PubMedGoogle Scholar
  • 57 Spagnolo P, Sato H, Grunewald J. , et al. A common haplotype of the C-C chemokine receptor 2 gene and HLA-DRB1*0301 are independent genetic risk factors for Löfgren's syndrome. J Intern Med 2008; 264 (05) 433-441
    CrossrefPubMedGoogle Scholar
  • 58 Spagnolo P, Renzoni EA, Wells AU. , et al. C-C chemokine receptor 2 and sarcoidosis: association with Lofgren's syndrome. Am J Respir Crit Care Med 2003; 168 (10) 1162-1166
    CrossrefPubMedGoogle Scholar
  • 59 Valentonyte R, Hampe J, Croucher PJ. , et al. Study of C-C chemokine receptor 2 alleles in sarcoidosis, with emphasis on family-based analysis. Am J Respir Crit Care Med 2005; 171 (10) 1136-1141
    CrossrefPubMedGoogle Scholar
  • 60 Kara EE, McKenzie DR, Bastow CR. , et al. CCR2 defines in vivo development and homing of IL-23-driven GM-CSF-producing Th17 cells. Nat Commun 2015; 6: 8644
    CrossrefPubMedGoogle Scholar
  • 61 Spagnolo P, Renzoni EA, Wells AU. , et al. C-C chemokine receptor 5 gene variants in relation to lung disease in sarcoidosis. Am J Respir Crit Care Med 2005; 172 (06) 721-728
    CrossrefPubMedGoogle Scholar
  • 62 Kostrikis LG, Huang Y, Moore JP. , et al. A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation. Nat Med 1998; 4 (03) 350-353
    CrossrefPubMedGoogle Scholar
  • 63 Barmania F, Pepper MS. C-C chemokine receptor type five (CCR5): An emerging target for the control of HIV infection. Appl Transl Genomics 2013; 2: 3-16
    PubMedGoogle Scholar
  • 64 Karakaya B, van Moorsel CH, van der Helm-van Mil AH. , et al. Macrophage migration inhibitory factor (MIF) -173 polymorphism is associated with clinical erythema nodosum in Löfgren's syndrome. Cytokine 2014; 69 (02) 272-276
    CrossrefPubMedGoogle Scholar
  • 65 Pabst S, Fränken T, Schönau J. , et al. Transforming growth factor-beta gene polymorphisms in different phenotypes of sarcoidosis. Eur Respir J 2011; 38 (01) 169-175
    CrossrefPubMedGoogle Scholar
  • 66 Dyskova T, Fillerova R, Novosad T. , et al. Correlation network analysis reveals relationships between microRNAs, transcription factor T-bet, and deregulated cytokine/chemokine-receptor network in pulmonary sarcoidosis. Mediators Inflamm 2015; 2015: 121378
    PubMedGoogle Scholar
  • 67 Wilsher ML. Seasonal clustering of sarcoidosis presenting with erythema nodosum. Eur Respir J 1998; 12 (05) 1197-1199
    CrossrefPubMedGoogle Scholar
  • 68 Demirkok SS, Basaranoglu M, Akbilgic O. Seasonal variation of the onset of presentations in stage 1 sarcoidosis. Int J Clin Pract 2006; 60 (11) 1443-1450
    CrossrefPubMedGoogle Scholar
  • 69 Rossman MD, Thompson B, Frederick M. , et al; ACCESS Group. HLA and environmental interactions in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2008; 25 (02) 125-132
    PubMedGoogle Scholar
  • 70 Grunewald J, Kaiser Y, Ostadkarampour M. , et al. T-cell receptor-HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis. Eur Respir J 2016; 47 (03) 898-909
    CrossrefPubMedGoogle Scholar
  • 71 Fontenot AP, Palmer BE, Sullivan AK. , et al. Frequency of beryllium-specific, central memory CD4+ T cells in blood determines proliferative response. J Clin Invest 2005; 115 (10) 2886-2893
    CrossrefPubMedGoogle Scholar
  • 72 Lecossier D, Valeyre D, Loiseau A. , et al. Antigen-induced proliferative response of lavage and blood T lymphocytes. Comparison of cells from normal subjects and patients with sarcoidosis. Am Rev Respir Dis 1991; 144 (04) 861-868
    CrossrefPubMedGoogle Scholar
  • 73 Moller DR, Forman JD, Liu MC. , et al. Enhanced expression of IL-12 associated with Th1 cytokine profiles in active pulmonary sarcoidosis. J Immunol 1996; 156 (12) 4952-4960
    PubMedGoogle Scholar
  • 74 Katchar K, Eklund A, Grunewald J. Expression of Th1 markers by lung accumulated T cells in pulmonary sarcoidosis. J Intern Med 2003; 254 (06) 564-571
    CrossrefPubMedGoogle Scholar
  • 75 Capelli A, Di Stefano A, Lusuardi M, Gnemmi I, Donner CF. Increased macrophage inflammatory protein-1alpha and macrophage inflammatory protein-1beta levels in bronchoalveolar lavage fluid of patients affected by different stages of pulmonary sarcoidosis. Am J Respir Crit Care Med 2002; 165 (02) 236-241
    CrossrefPubMedGoogle Scholar
  • 76 Schnerch J, Prasse A, Vlachakis D. , et al. Functional Toll-like receptor 9 expression and CXCR3 ligand release in pulmonary sarcoidosis. Am J Respir Cell Mol Biol 2016; 55 (05) 749-757
    CrossrefPubMedGoogle Scholar
  • 77 Idali F, Wahlström J, Dahlberg B. , et al. Altered expression of T cell immunoglobulin-mucin (TIM) molecules in bronchoalveolar lavage CD4+ T cells in sarcoidosis. Respir Res 2009; 10: 42
    CrossrefPubMedGoogle Scholar
  • 78 Facco M, Cabrelle A, Teramo A. , et al. Sarcoidosis is a Th1/Th17 multisystem disorder. Thorax 2011; 66 (02) 144-150
    CrossrefPubMedGoogle Scholar
  • 79 Ten Berge B, Paats MS, Bergen IM. , et al. Increased IL-17A expression in granulomas and in circulating memory T cells in sarcoidosis. Rheumatology (Oxford) 2012; 51 (01) 37-46
    CrossrefPubMedGoogle Scholar
  • 80 Ramstein J, Broos CE, Simpson LJ. , et al. IFN-γ-producing T-helper 17.1 cells are increased in sarcoidosis and are more prevalent than T-helper type 1 cells. Am J Respir Crit Care Med 2016; 193 (11) 1281-1291
    CrossrefPubMedGoogle Scholar
  • 81 Wikén M, Ostadkarampour M, Eklund A. , et al. Antigen-specific multifunctional T-cells in sarcoidosis patients with Lofgren's syndrome. Eur Respir J 2012; 40 (01) 110-121
    CrossrefPubMedGoogle Scholar
  • 82 Whittington HA, Armstrong L, Uppington KM, Millar AB. Interleukin-22: a potential immunomodulatory molecule in the lung. Am J Respir Cell Mol Biol 2004; 31 (02) 220-226
    CrossrefPubMedGoogle Scholar
  • 83 Lee Y, Awasthi A, Yosef N. , et al. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 2012; 13 (10) 991-999
    CrossrefPubMedGoogle Scholar
  • 84 O'Connor Jr W, Kamanaka M, Booth CJ. , et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol 2009; 10 (06) 603-609
    CrossrefPubMedGoogle Scholar
  • 85 Idali F, Wahlström J, Müller-Suur C, Eklund A, Grunewald J. Analysis of regulatory T cell associated forkhead box P3 expression in the lungs of patients with sarcoidosis. Clin Exp Immunol 2008; 152 (01) 127-137
    CrossrefPubMedGoogle Scholar
  • 86 Sakthivel P, Grunewald J, Eklund A, Bruder D, Wahlström J. Pulmonary sarcoidosis is associated with high-level inducible co-stimulator (ICOS) expression on lung regulatory T cells--possible implications for the ICOS/ICOS-ligand axis in disease course and resolution. Clin Exp Immunol 2016; 183 (02) 294-306
    CrossrefPubMedGoogle Scholar
  • 87 Broos CE, van Nimwegen M, Kleinjan A. , et al. Impaired survival of regulatory T cells in pulmonary sarcoidosis. Respir Res 2015; 16: 108
    CrossrefPubMedGoogle Scholar
  • 88 Miyara M, Amoura Z, Parizot C. , et al. The immune paradox of sarcoidosis and regulatory T cells. J Exp Med 2006; 203 (02) 359-370
    CrossrefPubMedGoogle Scholar
  • 89 Broos CE, van Nimwegen M, In 't Veen JC. , et al. Decreased cytotoxic T-lymphocyte antigen 4 expression on regulatory T cells and Th17 cells in sarcoidosis: double trouble?. Am J Respir Crit Care Med 2015; 192 (06) 763-765
    CrossrefPubMedGoogle Scholar
  • 90 Eckert A, Schoeffler A, Dalle S, Phan A, Kiakouama L, Thomas L. Anti-CTLA4 monoclonal antibody induced sarcoidosis in a metastatic melanoma patient. Dermatology 2009; 218 (01) 69-70
    CrossrefPubMedGoogle Scholar
  • 91 Vogel WV, Guislain A, Kvistborg P, Schumacher TN, Haanen JB, Blank CU. Ipilimumab-induced sarcoidosis in a patient with metastatic melanoma undergoing complete remission. J Clin Oncol 2012; 30 (02) e7-e10
    CrossrefPubMedGoogle Scholar
  • 92 Abdi EA, Nguyen GK, Ludwig RN, Dickout WJ. Pulmonary sarcoidosis following interferon therapy for advanced renal cell carcinoma. Cancer 1987; 59 (05) 896-900
    CrossrefPubMedGoogle Scholar
  • 93 Bobbio-Pallavicini E, Valsecchi C, Tacconi F, Moroni M, Porta C. Sarcoidosis following beta-interferon therapy for multiple myeloma. Sarcoidosis 1995; 12 (02) 140-142
    PubMedGoogle Scholar
  • 94 Hoffmann RM, Jung MC, Motz R. , et al. Sarcoidosis associated with interferon-alpha therapy for chronic hepatitis C. J Hepatol 1998; 28 (06) 1058-1063
    PubMedGoogle Scholar
  • 95 Nakajima M, Kubota Y, Miyashita N, Niki Y, Matsushima T, Manabe T. Recurrence of sarcoidosis following interferon alpha therapy for chronic hepatitis C. Intern Med 1996; 35 (05) 376-379
    CrossrefPubMedGoogle Scholar
  • 96 Teragawa H, Hondo T, Takahashi K. , et al. Sarcoidosis after interferon therapy for chronic active hepatitis C. Intern Med 1996; 35 (01) 19-23
    CrossrefPubMedGoogle Scholar
  • 97 Braun NA, Celada LJ, Herazo-Maya JD. , et al. Blockade of the programmed death-1 pathway restores sarcoidosis CD4(+) T-cell proliferative capacity. Am J Respir Crit Care Med 2014; 190 (05) 560-571
    CrossrefPubMedGoogle Scholar
  • 98 Danlos FX, Pagès C, Baroudjian B. , et al. Nivolumab- induced sarcoid-like granulomatous reaction in a patient with advanced melanoma. Chest 2016; 149 (05) e133-e136
    CrossrefPubMedGoogle Scholar
  • 99 Hutloff A, Dittrich AM, Beier KC. , et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 1999; 397 (6716): 263-266
    CrossrefPubMedGoogle Scholar
  • 100 Witsch EJ, Peiser M, Hutloff A. , et al. ICOS and CD28 reversely regulate IL-10 on re-activation of human effector T cells with mature dendritic cells. Eur J Immunol 2002; 32 (09) 2680-2686
    CrossrefPubMedGoogle Scholar
  • 101 Swanson RM, Gavin MA, Escobar SS. , et al. Butyrophilin-like 2 modulates B7 costimulation to induce Foxp3 expression and regulatory T cell development in mature T cells. J Immunol 2013; 190 (05) 2027-2035
    CrossrefPubMedGoogle Scholar
  • 102 Spagnolo P, Sato H, Grutters JC. , et al. Analysis of BTNL2 genetic polymorphisms in British and Dutch patients with sarcoidosis. Tissue Antigens 2007; 70 (03) 219-227
    CrossrefPubMedGoogle Scholar
  • 103 Mitsunaga S, Hosomichi K, Okudaira Y. , et al. Exome sequencing identifies novel rheumatoid arthritis-susceptible variants in the BTNL2. J Hum Genet 2013; 58 (04) 210-215
    CrossrefPubMedGoogle Scholar
  • 104 Orozco G, Eerligh P, Sánchez E. , et al. Analysis of a functional BTNL2 polymorphism in type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Hum Immunol 2005; 66 (12) 1235-1241
    CrossrefPubMedGoogle Scholar
  • 105 Johnson CM, Traherne JA, Jamieson SE. , et al. Analysis of the BTNL2 truncating splice site mutation in tuberculosis, leprosy and Crohn's disease. Tissue Antigens 2007; 69 (03) 236-241
    CrossrefPubMedGoogle Scholar
  • 106 Prescott NJ, Lehne B, Stone K. , et al; UK IBD Genetics Consortium. Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes. PLoS Genet 2015; 11 (02) e1004955
    CrossrefPubMedGoogle Scholar
  • 107 Traherne JA, Barcellos LF, Sawcer SJ. , et al. Association of the truncating splice site mutation in BTNL2 with multiple sclerosis is secondary to HLA-DRB1*15. Hum Mol Genet 2006; 15 (01) 155-161
    CrossrefPubMedGoogle Scholar
  • 108 Simmonds MJ, Heward JM, Barrett JC, Franklyn JA, Gough SC. Association of the BTNL2 rs2076530 single nucleotide polymorphism with Graves' disease appears to be secondary to DRB1 exon 2 position beta74. Clin Endocrinol (Oxf) 2006; 65 (04) 429-432
    CrossrefPubMedGoogle Scholar
  • 109 Berlin M, Fogdell-Hahn A, Olerup O, Eklund A, Grunewald J. HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis. Am J Respir Crit Care Med 1997; 156 (05) 1601-1605
    CrossrefPubMedGoogle Scholar
  • 110 Ying H, Yang L, Qiao G. , et al. Cutting edge: CTLA-4--B7 interaction suppresses Th17 cell differentiation. J Immunol 2010; 185 (03) 1375-1378
    CrossrefPubMedGoogle Scholar
  • 111 Bending D, Pesenacker AM, Ursu S. , et al. Hypomethylation at the regulatory T cell-specific demethylated region in CD25hi T cells is decoupled from FOXP3 expression at the inflamed site in childhood arthritis. J Immunol 2014; 193 (06) 2699-2708
    CrossrefPubMedGoogle Scholar
  • 112 Afzali B, Mitchell PJ, Edozie FC. , et al. CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL-17 in a STAT3-dependent manner. Eur J Immunol 2013; 43 (08) 2043-2054
    CrossrefPubMedGoogle Scholar
  • 113 Pesenacker AM, Bending D, Ursu S, Wu Q, Nistala K, Wedderburn LR. CD161 defines the subset of FoxP3+ T cells capable of producing proinflammatory cytokines. Blood 2013; 121 (14) 2647-2658
    CrossrefPubMedGoogle Scholar
  • 114 Lehmann J, Huehn J, de la Rosa M. , et al. Expression of the integrin alpha Ebeta 7 identifies unique subsets of CD25+ as well as CD25- regulatory T cells. Proc Natl Acad Sci U S A 2002; 99 (20) 13031-13036
    CrossrefPubMedGoogle Scholar
  • 115 McHugh RS, Whitters MJ, Piccirillo CA. , et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002; 16 (02) 311-323
    CrossrefPubMedGoogle Scholar
  • 116 Singh AK, Wilson MT, Hong S. , et al. Natural killer T cell activation protects mice against experimental autoimmune encephalomyelitis. J Exp Med 2001; 194 (12) 1801-1811
    CrossrefPubMedGoogle Scholar
  • 117 Ho LP, Urban BC, Thickett DR, Davies RJ, McMichael AJ. Deficiency of a subset of T-cells with immunoregulatory properties in sarcoidosis. Lancet 2005; 365 (9464): 1062-1072
    CrossrefPubMedGoogle Scholar
  • 118 Tutor-Ureta P, Citores MJ, Castejón R. , et al. Prognostic value of neutrophils and NK cells in bronchoalveolar lavage of sarcoidosis. Cytometry B Clin Cytom 2006; 70 (06) 416-422
    PubMedGoogle Scholar
  • 119 Pardo A, Barrios R, Gaxiola M. , et al. Increase of lung neutrophils in hypersensitivity pneumonitis is associated with lung fibrosis. Am J Respir Crit Care Med 2000; 161 (05) 1698-1704
    CrossrefPubMedGoogle Scholar
  • 120 Ziegenhagen MW, Rothe ME, Zissel G, Müller-Quernheim J. Exaggerated TNFalpha release of alveolar macrophages in corticosteroid resistant sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19 (03) 185-190
    PubMedGoogle Scholar
  • 121 Hunninghake GW, Crystal RG. Mechanisms of hypergammaglobulinemia in pulmonary sarcoidosis. Site of increased antibody production and role of T lymphocytes. J Clin Invest 1981; 67 (01) 86-92
    CrossrefPubMedGoogle Scholar
  • 122 Kamphuis LS, van Zelm MC, Lam KH. , et al. Perigranuloma localization and abnormal maturation of B cells: emerging key players in sarcoidosis?. Am J Respir Crit Care Med 2013; 187 (04) 406-416
    CrossrefPubMedGoogle Scholar
  • 123 Hedfors E, Norberg R. Evidence for circulating immune complexes in sarcoidosis. Clin Exp Immunol 1974; 16 (03) 493-496
    PubMedGoogle Scholar
  • 124 Kulakova N, Urban B, McMichael AJ, Ho LP. Functional analysis of dendritic cell-T cell interaction in sarcoidosis. Clin Exp Immunol 2010; 159 (01) 82-86
    CrossrefPubMedGoogle Scholar
  • 125 Mathew S, Bauer KL, Fischoeder A, Bhardwaj N, Oliver SJ. The anergic state in sarcoidosis is associated with diminished dendritic cell function. J Immunol 2008; 181 (01) 746-755
    CrossrefPubMedGoogle Scholar
  • 126 Munro CS, Campbell DA, Du Bois RM, Mitchell DN, Cole PJ, Poulter LW. Dendritic cells in cutaneous, lymph node and pulmonary lesions of sarcoidosis. Scand J Immunol 1987; 25 (05) 461-467
    CrossrefPubMedGoogle Scholar
  • 127 Ten Berge B, Kleinjan A, Muskens F. , et al. Evidence for local dendritic cell activation in pulmonary sarcoidosis. Respir Res 2012; 13: 33
    CrossrefPubMedGoogle Scholar
  • 128 Lommatzsch M, Bratke K, Bier A. , et al. Airway dendritic cell phenotypes in inflammatory diseases of the human lung. Eur Respir J 2007; 30 (05) 878-886
    CrossrefPubMedGoogle Scholar
  • 129 van Haarst JM, Verhoeven GT, de Wit HJ, Hoogsteden HC, Debets R, Drexhage HA. CD1a+ and CD1a- accessory cells from human bronchoalveolar lavage differ in allostimulatory potential and cytokine production. Am J Respir Cell Mol Biol 1996; 15 (06) 752-759
    CrossrefPubMedGoogle Scholar
  • 130 Prior C, Knight RA, Herold M, Ott G, Spiteri MA. Pulmonary sarcoidosis: patterns of cytokine release in vitro. Eur Respir J 1996; 9 (01) 47-53
    CrossrefPubMedGoogle Scholar
  • 131 Homolka J, Müller-Quernheim J. Increased interleukin 6 production by bronchoalveolar lavage cells in patients with active sarcoidosis. Lung 1993; 171 (03) 173-183
    PubMedGoogle Scholar
  • 132 Foulon G, Wislez M, Naccache JM. , et al. Sarcoidosis in HIV-infected patients in the era of highly active antiretroviral therapy. Clin Infect Dis 2004; 38 (03) 418-425
    CrossrefPubMedGoogle Scholar
  • 133 Johnston A, Gudjonsson JE, Sigmundsdottir H, Love TJ, Valdimarsson H. Peripheral blood T cell responses to keratin peptides that share sequences with streptococcal M proteins are largely restricted to skin-homing CD8(+) T cells. Clin Exp Immunol 2004; 138 (01) 83-93
    CrossrefPubMedGoogle Scholar
  • 134 Grunewald J, Janson CH, Eklund A. , et al. Restricted V alpha 2.3 gene usage by CD4+ T lymphocytes in bronchoalveolar lavage fluid from sarcoidosis patients correlates with HLA-DR3. Eur J Immunol 1992; 22 (01) 129-135
    CrossrefPubMedGoogle Scholar
  • 135 Grunewald J, Olerup O, Persson U, Ohrn MB, Wigzell H, Eklund A. T-cell receptor variable region gene usage by CD4+ and CD8+ T cells in bronchoalveolar lavage fluid and peripheral blood of sarcoidosis patients. Proc Natl Acad Sci U S A 1994; 91 (11) 4965-4969
    CrossrefPubMedGoogle Scholar
  • 136 Grunewald J, Berlin M, Olerup O, Eklund A. Lung T-helper cells expressing T-cell receptor AV2S3 associate with clinical features of pulmonary sarcoidosis. Am J Respir Crit Care Med 2000; 161 (3 Pt 1): 814-818
    CrossrefPubMedGoogle Scholar
  • 137 Planck A, Eklund A, Grunewald J. Markers of activity in clinically recovered human leukocyte antigen-DR17-positive sarcoidosis patients. Eur Respir J 2003; 21 (01) 52-57
    CrossrefPubMedGoogle Scholar
  • 138 Vossenaar ER, Després N, Lapointe E. , et al. Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin. Arthritis Res Ther 2004; 6 (02) R142-R150
    CrossrefPubMedGoogle Scholar
  • 139 Kinloch AJ, Chang A, Ko K. , et al. Vimentin is a dominant target of in situ humoral immunity in human lupus tubulointerstitial nephritis. Arthritis Rheumatol 2014; 66 (12) 3359-3370
    CrossrefPubMedGoogle Scholar
  • 140 Heyder T, Kohler M, Tarasova NK. , et al. Approach for identifying human leukocyte antigen (HLA)-DR bound peptides from scarce clinical samples. Mol Cell Proteomics 2016; 15 (09) 3017-3029
    CrossrefPubMedGoogle Scholar
  • 141 Wahlström J, Dengjel J, Persson B. , et al. Identification of HLA-DR-bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis. J Clin Invest 2007; 117 (11) 3576-3582
    CrossrefPubMedGoogle Scholar
  • 142 Wahlström J, Dengjel J, Winqvist O. , et al. Autoimmune T cell responses to antigenic peptides presented by bronchoalveolar lavage cell HLA-DR molecules in sarcoidosis. Clin Immunol 2009; 133 (03) 353-363
    CrossrefPubMedGoogle Scholar
  • 143 Häggmark A, Hamsten C, Wiklundh E. , et al. Proteomic profiling reveals autoimmune targets in sarcoidosis. Am J Respir Crit Care Med 2015; 191 (05) 574-583
    CrossrefPubMedGoogle Scholar
  • 144 Darlington P, Gabrielsen A, Sörensson P. , et al. HLA-alleles associated with increased risk for extra-pulmonary involvement in sarcoidosis. Tissue Antigens 2014; 83 (04) 267-272
    CrossrefPubMedGoogle Scholar
  • 145 Darlington P, Tallstedt L, Padyukov L. , et al. HLA-DRB1* alleles and symptoms associated with Heerfordt's syndrome in sarcoidosis. Eur Respir J 2011; 38 (05) 1151-1157
    CrossrefPubMedGoogle Scholar
  • 146 Heron M, Grutters JC, van Moorsel CH. , et al. Variation in IL7R predisposes to sarcoid inflammation. Genes Immun 2009; 10 (07) 647-653
    CrossrefPubMedGoogle Scholar