Chromatin Binding In SLE Patients Correlates With The Intensity Of Apoptotic Binding By 9G4+ B Cells

Asiya Seema Chida¹, Quan-Zhen Li², Chandra Mohan³, Youliang Wang¹, Scott Jenks⁴, Louise Hartson¹ and Ignacio Sanz⁵, ¹Medicine, Emory University Medical Center, Atlanta, GA, ²Department of Immunology and Microarray Core Facility, University of Texas Southwestern Medical Center, Dallas, TX, ³University of Houston, Houston, TX, ⁴Allergy, Immunology, and Rheumatology, Emory University School of Medicine, Atlanta, GA, ⁵Rheumatology, Emory University, Atlanta, GA

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: apoptotic clearance, autoantibodies, nucleosomes and pathogenesis, SLE

Session Information

Title: Systemic Lupus Erythematosus-Human Etiology and Pathogenesis: Genetics and Genomics

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Systemic Lupus Erythematosus (SLE) is a multi-organ autoimmune disease characterised by production of autoantibodies to multiple nuclear antigens, some of which are highly specific for SLE including anti-ds DNA, anti-Smith and anti-nucleosome antibodies. IgG antibodies expressing the 9G4 idiotype, encoded by the framework-1 hydrophobic patch (HP) of VH4-34, are specifically expanded in SLE and provide a unique model to understand the participation of different autoantigens in the pathogenesis of this disease. 9G4 autoreactivity may be directed against different lupus antigens and accounts for a significant fraction of anti-apoptotic cell binding (APCB), of lupus serum. Here we sought to understand the contribution of anti-nucleosome reactivity to APCB.

Methods:

A panel of 9G4+ monoclonal antibodies was generated from IgD-CD27+ memory cells of SLE patients. APCB was determined by flow cytometry. Positive and negative binders for Apoptotic binding were tested for anti-Chromatin reactivity by ELISA. Three representative antibodies with strong APCB activity were also tested against a glomerular proteome antigen microarray.

Results:

Our preliminary data demonstrate a strong correlation of apoptotic binding with chromatin by ELISA. Out of 37 9G4+ monoclonals tested 10 were positive for apoptotic binding and out of these 10, 9 were positive for chromatin (p=<0.001; fisher exact test). Glomerular microarray analysis identified reactivity with Chromatin, histones H2A, H2B, H3 and H4 in different patterns for the individual antibodies. This assay also identified interesting patterns of polyreactivity against of other lupus antigens including Riboprotein P1, but not P0 or P2, U1-RNP and Sm. Of note, these patterns reflected the reactivity of the patients serum. Levels of reactivity against chromatin, H2A, H2B, H3, and U1-Sn-RNP-68 correlated with disease activity.

Conclusion:

SLE-specific 9G4 antibodies recognize nucleosomal antigens (chromatin and individual histones) and may be polyreactive against components of the snRNP complex. Both these types of antigens are expressed at high density on apoptotic cells which are highly immunogenic sources of self-antigens in SLE at least in part due to deficient clearance. Detailed structural, antigenic and functional studies of our mAbs should shed significant light into the triggering of these autoimmune responses and the role of different antigens in the shaping and selection of the autoimmune B cell memory compartment. Determination of 9G4 antibodies against apoptotic cells and/or nucleosomal antigens might provide a useful test for the diagnosis and monitorization of SLE.

Disclosure:

A. S. Chida,
None;

Q. Z. Li,
None;

C. Mohan,
None;

Y. Wang,
None;

S. Jenks,
None;

L. Hartson,
None;

I. Sanz,

Biogen Idec,

Pfizer Inc,

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