Date of Award

12-2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Microbial Pathogenesis, Immunology, and Inflammation

Research Advisor

Marko Z. Radic, Ph. D.

Committee

Elizabeth A. Fitzpatrick, Ph. D. Terrence L. Geiger, M.D., Ph. D. Fabio C. Re, Ph. D. John M. Stuart, M.D

Keywords

Autoimmunity; Deimination; Felty’s Syndrome; Histone; PAD4; Tolerance

Abstract

Tolerance blocks the expression of autoantibodies, whereas autoimmunity promotes it. How tolerance breaks and autoantibody production begins, thus, are crucial questions for the understanding and treatment of autoimmune diseases. Evidence implicates cell death and autoantigen modifications in the initiation of autoimmune reactions. One form of neutrophil cell death deserves attention because it occurs as a consequence of neutrophil activation, requires the post-translational modification of histones and results in the extracellular release of chromatin. The extracellular chromatin incorporates histones in which arginines have been converted to citrullines by peptidylarginine deiminase IV (PAD4) creating structures that capture or "trap" bacterial pathogens. Neutrophil extracellular traps (NETs), as these structures are known, generate an extracellular complex of deiminated histones and bacterial cell adjuvants. The complex of bacterial antigens and deiminated chromatin may be internalized by host phagocytes during inflammatory conditions, as arise during bacterial infections or chronic autoinflammatory disorders. The uptake and processing of deiminated chromatin together with bacterial adjuvants by phagocytes may induce the presentation of modified histone epitopes and co-stimulation, thus yielding a powerful stimulus to break tolerance. To test the hypothesis that NETs can lead to autoimmunity, we measured autoantibodies to deiminated histones in human autoimmune disorders. We detected autoantibodies to deiminated histones in Felty's syndrome (FS) patients, whereas autoantibodies from Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) patients did not distinguish deiminated from non-deiminated histones. FS autoantibodies colocalized with deiminated histone H3 in LPS-treated neutrophils suggesting activated neutrophils as the source of autoantigens. In addition, we identified and characterized deimination of linker histone H1 and found rare autoantibodies to deiminated H1 in SLE and Sjogren's syndrome patients. We also studied sera of autoimmune lupus prone mice to determine if they would recognize deiminated histones and found that deimination represses binding of murine lupus autoantibodies to histones. The inability of immunoglobin from sera of lupus mice to recognize deiminated histones suggests the presence of effective tolerance to NET components released during innate neutrophil response to infections. Our finding of antibodies to deiminated histones in Felty's syndrome supports the idea that tolerance to deiminated histones is compromised only in exceptional circumstances. Understanding the tolerance mechanism to deiminated histones and how they are compromised in patients could be useful to design strategies for the prevention and treatment of many autoimmune disorders.

DOI

10.21007/etd.cghs.2011.0077

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