title: FOXP3+ Regulatory T Cells in Hepatic Fibrosis and Splenomegaly Caused by Schistosoma japonicum: The Spleen May Be a Major Source of Tregs in Subjects with Splenomegaly.
abstract: Schistosoma eggs cause chronic liver inflammation and a complex disease characterized by hepatic fibrosis (HF) and splenomegaly (SplM). FOXP3+ Tregs could regulate inflammation, but it is unclear where these cells are produced and what roles they play in human schistosomiasis. We investigated blood and spleen FOXP3+ Tregs in Chinese fishermen with lifelong exposure to Schistosoma japonicum and various degrees of liver and spleen disease. FOXP3+ Tregs accounted for 4.3% of CD4+ T cells and 41.2% of FOXP3+CD4+ T cells; they could be divided into CD45RA-FOXP3hi effector (eTregs) and CD45RA+FOXP3low naive Tregs. Blood Treg levels were high in severe HF (+1.3; p = 0.004) and in SplM (+1.03, p = 0.03). Multivariate regression showed that severe HF (+0.85, p = 0.01) and SplM (+0.97; p = 0.05) were independently associated with the higher proportion of Tregs in the blood. This effect was mostly due to an increase in the proportion of eTregs in the blood of HF+++ (+0.9%; p = 0.04) and SplM (+0.9%; p = 0.04) patients. The proportion of eTregs expressing CXCR3 in the blood was lower in the HF+++ patients (37.4 +/- 5.9%) than in those with milder fibrosis (51.7 ± 2%; p = 0.009), whereas proportion were similar for cells expressing CD25hi, CCR7, and CTLA-4. Splenectomy improves symptoms and was associated with decreases in blood FOXP3+ Treg (-2.5; p<0.001) and eTreg (-1.3; p = 0.03) levels. SplM spleens contained a high proportion of eTregs with CXCR3, CCR5 and CTLA4 upregulation and CCR7 downregulation. This, and the strong expression of ligands of CXCR3 and CCR5 in the liver (n = 8) but not in the spleen suggested that spleen eTregs migrated to Th1-infiltrated liver tissues. Such migration may be attenuated in hepatosplenic patients due to lower levels of CXCR3 expression on Tregs (p = 0.009). Thus, higher blood Treg levels are associated with severe liver disease and splenomegaly. Our data are consistent with the hypothesis that the spleen is a major source of Tregs in subjects with splenomegaly. In most cases, Tregs migrate to the Th1-infiltrated liver and the lower levels of CXCR3+ Tregs in the blood of patients with severe schistosomiasis suggest that decreases in Treg migration sites of inflammation may aggravate the disease.
authors.affiliation: INSERM, UMR-906, Marseille, France.|Université Aix-Marseille, Faculté de Médecine, Marseille, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Romano
authors.affiliation: Hunan Institute of Parasitic Diseases, Yueyang, China.
authors.forename: Xunya
authors.initials: X
authors.lastname: Hou
authors.affiliation: INSERM, UMR-906, Marseille, France.|Université Aix-Marseille, Faculté de Médecine, Marseille, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Sertorio
authors.affiliation: INSERM, UMR-906, Marseille, France.|Université Aix-Marseille, Faculté de Médecine, Marseille, France.
authors.forename: Hélia
authors.initials: H
authors.lastname: Dessein
authors.affiliation: INSERM, UMR-906, Marseille, France.|Université Aix-Marseille, Faculté de Médecine, Marseille, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Cabantous
authors.affiliation: INSERM, UMR-906, Marseille, France.|Université Aix-Marseille, Faculté de Médecine, Marseille, France.
authors.forename: Pablo
authors.initials: P
authors.lastname: Oliveira
authors.affiliation: Hunan Institute of Parasitic Diseases, Yueyang, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: INSERM, UMR-906, Marseille, France.|Université Aix-Marseille, Faculté de Médecine, Marseille, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Oyegue
authors.affiliation: INSERM, UMR-906, Marseille, France.|Université Aix-Marseille, Faculté de Médecine, Marseille, France.
authors.forename: Violaine
authors.initials: V
authors.lastname: Arnaud
authors.affiliation: Hunan Institute of Parasitic Diseases, Yueyang, China.
authors.forename: Xinsong
authors.initials: X
authors.lastname: Luo
authors.forename: Martine
authors.initials: M
authors.lastname: Daujat-Chavanieu
authors.affiliation: INSERM U1040, Hôpital St Eloi, Montpellier, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Chavanieu
authors.affiliation: Institut Curie, Section Médicale, Paris, France.
authors.forename: Odette
authors.initials: O
authors.lastname: Mariani
authors.affiliation: Institut Curie, Section Médicale, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sastre
authors.affiliation: Etablissement Français du Sang, Marseille, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Dombey
authors.affiliation: Hunan Institute of Parasitic Diseases, Yueyang, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: He
authors.affiliation: Hunan Institute of Parasitic Diseases, Yueyang, China.
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Li
authors.affiliation: INSERM, UMR-906, Marseille, France.|Université Aix-Marseille, Faculté de Médecine, Marseille, France.|Assistance Publique, Hôpitaux de Marseille, Marseille, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Dessein
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D002681:China; D015331:Cohort Studies; D051858:Forkhead Transcription Factors / Q000032:analysis*; D006801:Humans; D016130:Immunophenotyping; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure; D012554:Schistosomiasis japonica / Q000473:pathology*; D013154:Spleen / Q000473:pathology; D013163:Splenomegaly / Q000150:complications / Q000473:pathology*; D016176:T-Lymphocyte Subsets / Q000737:chemistry* / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000276:immunology*
chemical_list: D015703:Antigens, CD; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors