title: Autoantibody-Positive Healthy Individuals Display Unique Immune Profiles That May Regulate Autoimmunity.
abstract: Antinuclear antibodies (ANAs) are detected in ∼18% of females, yet autoimmune disease develops in only 5-8%. Immunologic differences between ANA-positive healthy individuals and patients with systemic lupus erythematosus (SLE) may elucidate the regulatory mechanisms by which ANA-positive individuals avoid transition to clinical autoimmune disease.
  
  
  
  Healthy individuals (n = 790) were screened for autoantibodies specific for 11 antigens associated with lupus, systemic sclerosis, and Sjögren's syndrome. From this screening, 31 European American ANA-positive healthy individuals were selected and demographically matched to ANA-negative controls and SLE patients. Serum cytokine profiles, leukocyte subset frequency, and reactivity were analyzed by multiplex assays, immunophenotyping, and phosphospecific flow cytometry.
  
  
  
  Of 790 individuals screened, 57 (7%) were ANA-positive. The majority of proinflammatory cytokines, including interferon-γ (IFNγ), tumor necrosis factor, interleukin-17 (IL-17), and granulocyte colony-stimulating factor, exhibited a stepwise increase in serum levels from ANA-negative controls to ANA-positive healthy individuals to SLE patients (P < 0.0001). IFNα, IFNβ, IL-12p40, and stem cell factor/c-Kit ligand were increased in SLE patients only (P < 0.05). B lymphocyte stimulator (BlyS) was elevated in SLE patients but decreased in ANA-positive individuals (P < 0.001). Further, IL-1 receptor antagonist (IL-1Ra) was down-regulated in SLE patients only (P < 0.0001). ANA-positive individuals had increased frequencies of monocytes, memory B cells, and plasmablasts and increased levels of pSTAT-1 and pSTAT-3 following IFNα stimulation compared with ANA-negative controls (P < 0.05).
  
  
  
  ANA-positive healthy individuals exhibit dysregulation in multiple immune pathways yet differ from SLE patients by the absence of elevated IFNs, BLyS, IL-12p40, and stem cell factor/c-Kit ligand. Further, severely decreased levels of IL-1Ra in SLE patients compared with ANA-positive individuals may contribute to disease development. These results highlight the importance of IFN-related pathways and regulatory elements in SLE pathogenesis.
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City.
authors.forename: Samantha
authors.initials: S
authors.lastname: Slight-Webb
authors.affiliation: Oklahoma Medical Research Foundation, and University of Oklahoma Health Sciences Center, Oklahoma City.
authors.forename: Rufei
authors.initials: R
authors.lastname: Lu
authors.affiliation: Oklahoma Medical Research Foundation, and University of Oklahoma Health Sciences Center, Oklahoma City.
authors.forename: Lauren L
authors.initials: LL
authors.lastname: Ritterhouse
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City.
authors.forename: Melissa E
authors.identifier: 0000-0002-6933-9745
authors.initials: ME
authors.lastname: Munroe
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Holden T
authors.initials: HT
authors.lastname: Maecker
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Fathman
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City.
authors.forename: Joan T
authors.initials: JT
authors.lastname: Merrill
authors.affiliation: Oklahoma Medical Research Foundation, and University of Oklahoma Health Sciences Center, Oklahoma City.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Guthridge
authors.affiliation: Oklahoma Medical Research Foundation, and University of Oklahoma Health Sciences Center, Oklahoma City. Judith-James@omrf.org.
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000974:Antibodies, Antinuclear / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology; D016022:Case-Control Studies; D051936:Centromere Protein B / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D004264:DNA Topoisomerases, Type I; D005260:Female; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology; D064368:Healthy Volunteers; D006801:Humans; D016130:Immunophenotyping; D016898:Interferon-alpha / Q000276:immunology / Q000494:pharmacology; D016899:Interferon-beta / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D007962:Leukocytes / Q000276:immunology*; D016015:Logistic Models; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D015999:Multivariate Analysis; D009687:Nuclear Proteins / Q000276:immunology; D010750:Phosphoproteins / Q000187:drug effects; D010950:Plasma Cells / Q000276:immunology; D012261:Ribonucleoproteins / Q000276:immunology; D012269:Ribosomal Proteins / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000187:drug effects / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000276:immunology; D012737:Sex Factors; D019089:Stem Cell Factor / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D055815:Young Adult
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; C497926:CENPB protein, human; D051936:Centromere Protein B; D016207:Cytokines; C507763:IL1RN protein, human; D016898:Interferon-alpha; D053590:Interleukin 1 Receptor Antagonist Protein; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; C046750:Jo-1 antibody; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012261:Ribonucleoproteins; D012269:Ribosomal Proteins; C035356:SS-A antibodies; C035357:SS-B antibodies; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C048100:Scl 70 antigen, human; D019089:Stem Cell Factor; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; C538950:anticentromere antibody; D016179:Granulocyte Colony-Stimulating Factor; D016899:Interferon-beta; D007371:Interferon-gamma; D004264:DNA Topoisomerases, Type I