title: Expansion of regulatory T cells in patients with Langerhans cell histiocytosis.
abstract: BACKGROUND
  Langerhans cell histiocytosis (LCH) is a rare clonal granulomatous disease that affects mainly children. LCH can involve various tissues such as bone, skin, lung, bone marrow, lymph nodes, and the central nervous system, and is frequently responsible for functional sequelae. The pathophysiology of LCH is unclear, but the uncontrolled proliferation of Langerhans cells (LCs) is believed to be the primary event in the formation of granulomas. The present study was designed to further investigate the nature of proliferating cells and the immune mechanisms involved in the LCH granulomas.
  
  
  RESULTS
  Biopsies (n = 24) and/or blood samples (n = 25) from 40 patients aged 0.25 to 13 y (mean 7.8 y), were studied to identify cells that proliferate in blood and granulomas. We found that the proliferating index of LCs was low ( approximately 1.9%), and we did not observe expansion of a monocyte or dendritic cell compartment in patients. We found that LCH lesions were a site of active inflammation, tissue remodeling, and neo-angiogenesis, and the majority of proliferating cells were endothelial cells, fibroblasts, and polyclonal T lymphocytes. Within granulomas, interleukin 10 was abundant, LCs expressed the TNF receptor family member RANK, and CD4(+) CD25(high) FoxP3(high) regulatory T cells (T-regs) represented 20% of T cells, and were found in close contact with LCs. FoxP3(+) T-regs were also expanded compared to controls, in the blood of LCH patients with active disease, among whom seven out of seven tested exhibited an impaired skin delayed-type hypersensitivity response. In contrast, the number of blood T-regs were normal after remission of LCH.
  
  
  CONCLUSIONS
  These findings indicate that LC accumulation in LCH results from survival rather than uncontrolled proliferation, and is associated with the expansion of T-regs. These data suggest that LCs may be involved in the expansion of T-regs in vivo, resulting in the failure of the host immune system to eliminate LCH cells. Thus T-regs could be a therapeutic target in LCH.
authors: INSERM, U838, Laboratory of Biology of the Mononuclear Phagocyte System, Necker Enfants Malades Institute, Paris, France.
authors: Brigitte
authors: B
authors: Senechal
authors: Gaelle
authors: G
authors: Elain
authors: Eric
authors: E
authors: Jeziorski
authors: Virginie
authors: V
authors: Grondin
authors: Natacha
authors: N
authors: Patey-Mariaud de Serre
authors: Francis
authors: F
authors: Jaubert
authors: Kheira
authors: K
authors: Beldjord
authors: Arielle
authors: A
authors: Lellouch
authors: Christophe
authors: C
authors: Glorion
authors: Michel
authors: M
authors: Zerah
authors: Pierre
authors: P
authors: Mary
authors: Mohammed
authors: M
authors: Barkaoui
authors: Jean Francois
authors: JF
authors: Emile
authors: Liliane
authors: L
authors: Boccon-Gibod
authors: Patrice
authors: P
authors: Josset
authors: Marianne
authors: M
authors: Debré
authors: Alain
authors: A
authors: Fischer
authors: Jean
authors: J
authors: Donadieu
authors: Frederic
authors: F
authors: Geissmann
mesh_terms: D000293:Adolescent; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D006646:Histiocytosis, Langerhans-Cell / Q000276:immunology*; D006801:Humans; D006968:Hypersensitivity, Delayed; D007223:Infant; D007801:Langerhans Cells / Q000276:immunology / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000502:physiology*
references: Blood. 1999 Dec 15;94(12):4195-201
references: 10590064
references: J Pediatr Hematol Oncol. 1999 Nov-Dec;21(6):554-6
references: 10598673
references: Br J Haematol. 1999 Dec;107(4):883-8
references: 10606898
references: J Cell Physiol. 2000 Mar;182(3):311-22
references: 10653597
references: J Clin Invest. 2000 May;105(9):1317-25
references: 10792007
references: Leukemia. 2000 Jun;14(6):1143-52
references: 10865981
references: Blood. 2001 Mar 1;97(5):1241-8
references: 11222366
references: J Exp Med. 2001 Jan 15;193(2):F5-9
references: 11208869
references: Med Pediatr Oncol. 2001 Feb;36(2):314-6
references: 11452942
references: J Exp Med. 2001 Sep 17;194(6):769-79
references: 11560993
references: Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):351-8
references: 11773639
references: Blood. 2002 Apr 1;99(7):2468-76
references: 11895781
references: Hum Pathol. 2002 May;33(5):555-60
references: 12094383
references: J Exp Med. 2002 Aug 19;196(4):417-30
references: 12186835
references: Science. 2003 Feb 14;299(5609):1057-61
references: 12522256
references: Annu Rev Immunol. 2003;21:685-711
references: 12615891
references: Trends Immunol. 2003 Apr;24(4):190-6
references: 12697451
references: APMIS. 2003 Feb;111(2):300-8
references: 12716386
references: Trends Immunol. 2003 Dec;24(12):646-51
references: 14644138
references: J Pediatr Orthop. 2004 Jan-Feb;24(1):123-9
references: 14676546
references: Hum Pathol. 2003 Dec;34(12):1345-9
references: 14691922
references: J Immunol. 2004 Apr 15;172(8):4676-80
references: 15067041
references: Pediatr Dev Pathol. 2004 May-Jun;7(3):214-25
references: 15022067
references: Hum Pathol. 2004 Jul;35(7):862-8
references: 15257550
references: Eur J Pediatr. 2004 Sep;163(9):536-9
references: 15243808
references: Int Immunol. 2004 Nov;16(11):1643-56
references: 15466453
references: Blood. 1986 Sep;68(3):663-7
references: 2943330
references: J Histochem Cytochem. 1990 Mar;38(3):307-13
references: 1689333
references: Hum Pathol. 1993 Aug;24(8):840-5
references: 7690735
references: Lancet. 1994 Mar 26;343(8900):767-8
references: 7510816
references: J Immunol. 2005 Mar 1;174(5):3067-71
references: 15728521
references: J Exp Med. 2005 Mar 7;201(5):687-93
references: 15753204
references: Acta Paediatr. 2005 Aug;94(8):1073-84
references: 16188852
references: Eur J Cancer. 2005 Nov;41(17):2682-9
references: 16291085
references: Immunity. 2005 Dec;23(6):611-20
references: 16356859
references: Nat Immunol. 2006 Jan;7(1):83-92
references: 16311599
references: Nat Med. 2006 Dec;12(12):1372-9
references: 17143276
references: N Engl J Med. 1994 Jul 21;331(3):154-60
references: 8008029
references: Pediatr Allergy Immunol. 1994 Aug;5(3):162-3
references: 7951757
references: Cancer. 1995 Mar 1;75(5):1162-6
references: 7850715
references: Arch Dis Child. 1996 Jul;75(1):17-24
references: 8813865
references: J Pediatr. 1996 Dec;129(6):836-45
references: 8969725
references: Ann Intern Med. 1997 Feb 1;126(3):210-4
references: 9027271
references: Pediatr Pathol Lab Med. 1997 Sep-Oct;17(5):769-87
references: 9267889
references: Clin Exp Rheumatol. 1997 Nov-Dec;15(6):649-54
references: 9444421
references: Br J Cancer. 1998 Feb;77(4):552-5
references: 9484810
references: Curr Opin Hematol. 1998 Jan;5(1):54-8
references: 9515204
references: Nature. 1998 Mar 19;392(6673):245-52
references: 9521319
references: Am J Pathol. 1998 May;152(5):1143-9
references: 9588881
references: Virchows Arch. 1999 Feb;434(2):109-15
references: 10071244
references: AMA Arch Pathol. 1953 Jul;56(1):84-102
references: 13057466
references: Hum Pathol. 2004 Dec;35(12):1573-4; author reply 1574
references: 15619220