title: IL-21-driven neoplasms in SJL mice mimic some key features of human angioimmunoblastic T-cell lymphoma.
abstract: SJL/J mice exhibit a high incidence of mature B-cell lymphomas that require CD4(+) T cells for their development. We found that their spleens and lymph nodes contained increased numbers of germinal centers and T follicular helper (TFH) cells. Microarray analyses revealed high levels of transcripts encoding IL-21 associated with high levels of serum IL-21. We developed IL-21 receptor (IL21R)-deficient Swiss Jim Lambart (SJL) mice to determine the role of IL-21 in disease. These mice had reduced numbers of TFH cells, lower serum levels of IL-21, and few germinal center B cells, and they did not develop B-cell tumors, suggesting IL-21-dependent B-cell lymphomagenesis. We also noted a series of features common to SJL disease and human angioimmunoblastic T-cell lymphoma (AITL), a malignancy of TFH cells. Gene expression analyses of AITL showed that essentially all cases expressed elevated levels of transcripts for IL21, IL21R, and a series of genes associated with TFH cell development and function. These results identify a mouse model with features of AITL and suggest that patients with the disease might benefit from therapeutic interventions that interrupt IL-21 signaling.
authors.affiliation: Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, Maryland.
authors.forename: Shweta
authors.initials: S
authors.lastname: Jain
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Alina
authors.initials: A
authors.lastname: Nicolae
authors.affiliation: Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, Maryland.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, Maryland; Department of Food and Nutrition, Seoul National University, Seoul, Republic of Korea.
authors.forename: Dong-Mi
authors.initials: DM
authors.lastname: Shin
authors.affiliation: Jackson Laboratory, Bar Harbor, Maine; Genetics Program, Tufts University Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts.
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Adkins
authors.affiliation: Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sproule
authors.affiliation: Genetics Program, Tufts University Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts; Department of Animal and Poultry Sciences, College of Agriculture and Life Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Leeth
authors.affiliation: Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, Maryland.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Sakai
authors.affiliation: Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, Maryland.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Kovalchuk
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.affiliation: Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, Maryland.
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Ward
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Jerold E
authors.initials: JE
authors.lastname: Rehg
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.affiliation: Jackson Laboratory, Bar Harbor, Maine; Genetics Program, Tufts University Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts.
authors.forename: Derry C
authors.initials: DC
authors.lastname: Roopenian
authors.affiliation: Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, Maryland. Electronic address: hmorse@niaid.nih.gov.
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D018858:Germinal Center / Q000473:pathology; D006801:Humans; D007119:Immunoblastic Lymphadenopathy / Q000473:pathology* / Q000517:prevention & control; D007074:Immunoglobulin G / Q000097:blood; D053738:Interleukin-21 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008198:Lymph Nodes / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000473:pathology*; D016399:Lymphoma, T-Cell / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D013154:Spleen / Q000473:pathology; D000098546:Interleukin-21
chemical_list: D016207:Cytokines; C508118:Il21r protein, mouse; D007074:Immunoglobulin G; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D000098546:Interleukin-21