title: Non-Esterified Fatty Acids Profiling in Rheumatoid Arthritis: Associations with Clinical Features and Th1 Response.
abstract: OBJECTIVE
  Since lipid compounds are known to modulate the function of CD4+ T-cells and macrophages, we hypothesize that altered levels of serum non-esterified fatty acids (NEFA) may underlie rheumatoid arthritis (RA) pathogenesis.
  
  
  METHODS
  Serum levels of NEFA (palmitic, stearic, palmitoleic, oleic, linoleic, γ-linoleic, arachidonic -AA-, linolenic, eicosapentaenoic -EPA- and docosahexaenoic -DHA-) were quantified by LC-MS/MS after methyl-tert-butylether (MTBE)-extraction in 124 RA patients and 56 healthy controls (HC). CD4+ phenotype was studied by flow cytometry. TNFα, IL-8, VEGF, GM-CSF, IFNγ, IL-17, CCL2, CXCL10, leptin and resistin serum levels were quantified by immunoassays. The effect of FA on IFNγ production by PBMC was evaluated in vitro.
  
  
  RESULTS
  Lower levels of palmitic (p<0.0001), palmitoleic (p = 0.002), oleic (p = 0.010), arachidonic (p = 0.027), EPA (p<0.0001) and DHA (p<0.0001) were found in RA patients, some NEFA being altered at onset. Cluster analysis identified a NEFA profile (hallmarked by increased stearic and decreased EPA and DHA) overrepresented in RA patients compared to HC (p = 0.002), being associated with clinical features (RF, shared epitope and erosions), increased IFNγ expression in CD4+ T-cells (p = 0.002) and a Th1-enriched serum milieu (IFNγ, CCL2 and CXCL10, all p<0.005). In vitro assays demonstrated that imbalanced FA could underlie IFNγ production by CD4+ T-cells. Finally, changes on NEFA levels were associated with clinical response upon TNFα-blockade.
  
  
  CONCLUSIONS
  An altered NEFA profile can be found in RA patients associated with clinical characteristics of aggressive disease and enhanced Th1 response. These results support the relevance of lipidomic studies in RA and provide a rationale for new therapeutic targets.
authors.affiliation: Area of Immunology, Department of Functional Biology, University of Oviedo, Oviedo, Asturias, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Rodríguez-Carrio
authors.affiliation: Department of Rheumatology, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Alperi-López
authors.affiliation: Area of Immunology, Department of Functional Biology, University of Oviedo, Oviedo, Asturias, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: López
authors.affiliation: Department of Rheumatology, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Ballina-García
authors.affiliation: Area of Immunology, Department of Functional Biology, University of Oviedo, Oviedo, Asturias, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Suárez
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D002853:Chromatography, Liquid / Q000379:methods*; D016207:Cytokines / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000032:analysis / Q000097:blood*; D005260:Female; D006801:Humans; D020738:Leptin / Q000097:blood; D008297:Male; D008875:Middle Aged; D052243:Resistin / Q000097:blood; D053719:Tandem Mass Spectrometry / Q000379:methods*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D005230:Fatty Acids, Nonesterified; D020738:Leptin; C499624:RETN protein, human; D052243:Resistin