title: Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus.
abstract: OBJECTIVE
  In the sanroque mouse model of lupus, pathologic germinal centers (GCs) arise due to increased numbers of follicular helper T (Tfh) cells, resulting in high-affinity anti-double-stranded DNA antibodies that cause end-organ inflammation, such as glomerulonephritis. The purpose of this study was to examine the hypothesis that this pathway could account for a subset of patients with systemic lupus erythematosus (SLE).
  
  
  METHODS
  An expansion of Tfh cells is a causal, and therefore consistent, component of the sanroque mouse phenotype. We validated the enumeration of circulating T cells resembling Tfh cells as a biomarker of this expansion in sanroque mice, and we performed a comprehensive comparison of the surface phenotype of circulating and tonsillar Tfh cells in humans. This circulating biomarker was enumerated in SLE patients (n = 46), Sjögren's syndrome patients (n = 17), and healthy controls (n = 48) and was correlated with disease activity and end-organ involvement.
  
  
  RESULTS
  In sanroque mice, circulating Tfh cells increased in proportion to their GC counterparts, making circulating Tfh cells a feasible human biomarker of this novel mechanism of breakdown in GC tolerance. In a subset of SLE patients (14 of 46), but in none of the controls, the levels of circulating Tfh cells (defined as circulating CXCR5+CD4+ cells with high expression of Tfh-associated molecules, such as inducible T cell costimulator or programmed death 1) were increased. This cellular phenotype did not vary with time, disease activity, or treatment, but it did correlate with the diversity and titers of autoantibodies and with the severity of end-organ involvement.
  
  
  CONCLUSIONS
  These findings in SLE patients are consistent with the autoimmune mechanism in sanroque mice and identify Tfh effector molecules as possible therapeutic targets in a recognizable subset of patients with SLE.
authors.affiliation: Australian National University, Canberra, ACT, Australia.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Simpson
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gatenby
authors.forename: Anastasia
authors.initials: A
authors.lastname: Wilson
authors.forename: Shreya
authors.initials: S
authors.lastname: Malik
authors.forename: David A
authors.initials: DA
authors.lastname: Fulcher
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.forename: Harinder
authors.initials: H
authors.lastname: Manku
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.forename: Giovanna
authors.initials: G
authors.lastname: Roncador
authors.forename: Gavin A
authors.initials: GA
authors.lastname: Huttley
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.forename: Carola G
authors.initials: CG
authors.lastname: Vinuesa
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cook
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015551:Autoimmunity / Q000276:immunology*; D002452:Cell Count; D004195:Disease Models, Animal; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D060889:Inducible T-Cell Co-Stimulator Protein; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014066:Palatine Tonsil / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor; D054380:Receptors, CXCR5 / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000097:blood / Q000276:immunology / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D051017:Apoptosis Regulatory Proteins; C095085:CXCR5 protein, human; C556692:ICOS protein, human; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D054380:Receptors, CXCR5