11/8/2011
Interferon-Alpha Activity Levels Increase
Immediately Preceding Clinical
Classification of Systemic Lupus
Nothing relevant to disclose
Julie Robertson, Latisha Heinlen, Timothy
Niewold, Michael Keith, George Tsokos,
John Harley, Judith James
The United States Department of Defense
Serum Repository
Patients Present to
Clinicians
Environmental
Triggers
Pathologic Injury
SLE
Genetic
Predisposition
Onset of
Autoimmunity &
Autoantibodies
Clinical
Disease
Contains over 40,000,000
serum samples collected
on all active duty Military
personnel upon entry into
service and on average
every two years
afterwards.
Demographics
Average Age at
Diagnosis
Sex
Race/Ethnicity
30 ± 5
4 Males, 16 Females
8 EA, 10 AA, 2 Hispanic
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11/8/2011
Establish the temporal relationship between SLE-associated
IFN activity and lupus
• Are IFN levels initially higher than that
observed in matched controls at pre-clinical
disease timepoints?
• When do antigen specific autoantibodies
switch class/subclass?
- Selected 20 individuals with samples at the following
three timepoints: before autoantibodies, at first criterion,
autoantibodies and disease
- Interferon activity measured by a reporter assay
(WISH cell assay)
- Collaboration with Timothy Niewold, MD, University of Chicago
Media
Normal Sera
SLE Patient
Sera:
Before Clinical
Symptom
SLE Patient
Sera:
After
Diagnosis
qPCR for IFN
responsive genes
IFN activity levels increase as the patient
moves toward SLE classification
IFN activity level elevations are most
pronounced at/after diagnosis
Mean IFN Activity Scores at Before 1st/At First/at Dx
Mean IFN Activity Scores
Median IFN Activity Scores at Before 1st/At First/at Dx
p<0.05
N <-4= 9
N-4 to -2= 6
N -2 to 0= 10
N>0= 12
N before 1st= 7
N at 1st criteria= 11
N at diagnosis= 11
With the years to diagnosis categorization, there is a significant positive linear
relationship over time between IFN level and years to diagnosis (p=0.0279).
IFN levels increase as the patient moves toward SLE classification
Levels of IFN are significantly higher at diagnosis compared to 1st criterion
(p<0.05).
Four of these 11 individuals have autoantibodies before detectable
elevations of interferon activity.
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11/8/2011
IFN activity level elevations are most
pronounced at/after diagnosis
Mean IFN Activity Scores at Before 1st/At First/at Dx
Pre-Classification SLE IFN-a Activity Levels are not
Significantly Different based upon
Autoantibody Status in this Preclinical Cohort
Median IFN Activity Scores at Before 1st/At First/at Dx
p<0.05
N before 1st= 7
N at 1st criteria= 11
N at diagnosis= 11
Levels of IFN are significantly higher at diagnosis compared to 1st criterion
(p<0.05).
Four of these 11 individuals have autoantibodies before detectable
elevations of interferon activity.
Ro Specific IgM Antibodies Decrease while
Ro Specific IgG1 and IgG2 Increase toward Dx
• Are IFN levels initially higher than that
observed in matched controls at pre-clinical
disease timepoints?
• When do antigen specific autoantibodies
switch class/subclass?
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11/8/2011
Anti-Sm IgG1, IgG2, and IgG3 Increases Toward Diagnosis;
Anti-nRNP IgA ,IgG1, and IgG2 Increases Toward Diagnosis
Ribo P Specific IgG2 and IgE antibodies are
elevated prior to the presence of 1st criteria
Number of Antibody Classes/Subclasses for Common
Preclinical SLE antibody Responses
Summary
Number of Antibody Classes/Subclasses
• IFN-a Activity Levels are Significantly Different between
before criteria and at SLE diagnosis
• IFN-a Levels Increase as the Patient Moves Toward SLE
Diagnosis
• Ro Specific IgM Antibodies Decrease while Ro Specific IgG1
and IgG2 Increase toward Dx
• Anti-Sm IgG1, IgG2, and IgG3 Increase Toward Diagnosis
• Anti-nRNP IgA ,IgG1, and IgG2 Increase Toward Diagnosis
• Ribo P Specific IgG2 and IgE antibodies are elevated prior to
the presence of 1st criteria
• Interferon activity increases close to the transition to IgG2
in many individuals
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11/8/2011
Acknowledgements
• James Lab:
•
•
•
•
– Julie Robertson, PhD
– Latisha Heinlen MD, PhD
– Jourdan Anderson
Joel Guthridge, PhD
Kenneth Smith, PhD
Timothy Niewold, MD, PhD
John Harley, PhD
• Department of Defense
– Michael Keith, MD
– George Tsokos, MD
• Funding:
– NIH 5U19AI082714
– NIAID Autoimmunity
Center of Excellence
– NIAMS
– NCRR
The opinions and assertions contained herein are private views of the authors and are not to be construed
as official or as reflecting the views of the Department of the Army, Navy, or the Department of Defense.
Systemic Lupus Erythematosus
ACR Criteria
1. Malar Rash
2. Discoid Rash
3. Photosensitivity
4. Oral Ulcers
5. Arthritis
6. Serositis
7. Renal Disorder
8. Neurologic Disorder
9. Hematological Disorder
10. Immunologic Disorder
11. Antinuclear Antibody
CNS Disease
Pleuritis
Pericarditis
Glomerulonephritis
Arthritis
Common Autoantigens
Ro, La, Sm, nRNP, dsDNA, Ribo P
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