Autoantibodies against Modified Histone Peptides in SLE Patients Are Associated with Disease Activity and Lupus Nephritis

Abstract

Persistent exposure of the immune system to death cell debris leads to autoantibodies against chromatin in patients with systemic lupus erythematosus (SLE). Deposition of anti-chromatin/chromatin complexes can instigate inflammation in multiple organs including the kidney. Previously we identified specific cell death-associated histone modifications as targets of autoantibodies in SLE. In this study we addressed, in a large cohort of SLE patients and controls, the question whether plasma reactivities with specific histone peptides associated with serology and clinical features. Plasma from SLE patients with and without lupus nephritis, disease controls, and healthy controls, were tested in ELISA with histone H4 peptide acetylated at lysines 8, 12 and 16 (H4pac), H2B peptide acetylated at lysine 12 (H2Bpac), H3 peptide trimethylated at lysine 27 (H3pme), and their unmodified equivalents. SLE patients displayed a higher reactivity with the modified equivalent of each peptide. Reactivity with H4pac showed both a high sensitivity (89%) and specificity (91%) for SLE, while H2Bpac exhibited a high specificity (96%) but lower sensitivity (69%). Reactivity with H3pme appeared not specific for SLE. Anti-H4pac and anti-H2Bpac reactivity demonstrated a high correlation with disease activity. Moreover, patients reacting with multiple modified histone peptides exhibited higher SLEDAI and lower C3 levels. SLE patients with renal involvement showed higher reactivity with H2B/H2Bpac and a more pronounced reactivity with the modified equivalent of H3pme and H2Bpac. In conclusion, reactivity with H4pac and H2Bpac is specific for SLE patients and correlates with disease activity, whereas reactivity with H2Bpac is in particular associated with lupus nephritis.

Tolerogenic dendritic cell transfer ameliorates systemic lupus erythematosus in mice

“…This result is consistent with previous reports of DC accumulation in cutaneous lupus erythematosus lesions and reinforces the pathological importance of these cells in skin lesions . The selection of histones as target antigens to induce specific tolerance is sustained by the frequent association of anti‐histone antibodies and disease severity in SLE patients . However, we could not rule out a non‐specific tolerogenic effect of self‐antigen‐loaded tolDCs, particularly when considering that tolDCs can induce Treg cells, which in turn could act through linked suppression.…”

“…It is important to note that NZM2410 mice produce several kinds of ANAs (anti‐dsDNA, anti‐chromatin, anti‐histone) and although tolDCs reduce anti‐histones and anti‐DNA, other autoantibodies could be involved in the pathogenicity of the model. For example, although anti‐histone antibodies have been associated with neuropsychiatric lupus (also described in MRL‐Fas lpr mice) and nephritic lupus, the reduced histone‐reactive antibody levels induced in our study by histone‐loaded tolDCs were not able to suppress kidney pathology. Besides, although tolDCs were loaded with histones, NZM2410 mice also reduce anti‐DNA antibody levels.…”

“…34 The selection of histones as target antigens to induce specific tolerance is sustained by the frequent association of anti-histone antibodies and disease severity in SLE patients. 35,36 However, we could not rule out a non-specific tolerogenic effect of self-antigen-loaded tolDCs, particularly when considering that tolDCs can induce Treg cells, which in turn could act through linked suppression. In other words, suppression may spread to different epitopes presented by DCs that are located in the lesion.…”

Acetylated Histones in Apoptotic Microparticles Drive the Formation of Neutrophil Extracellular Traps in Active Lupus Nephritis

“…During the disease course, states of quiescent disease can alternate with periods of active disease, the so-called flares. Although the triggers of these flares are largely unknown, they lead to increased production of autoantibodies and enhancement of inflammatory processes ( 5 – 7 ).…”

Analysis of Histone Antibody Specificity with Peptide Microarrays

“…Indeed, histone peptide microarrays have emerged as an informative discovery platform for chromatin biochemistry research, enabling high-throughput profiling of the writers, erasers, and readers of histone PTMs 15,23,24 , and also for the analysis of histone antibody specificity 17,25 . Beyond their application in chromatin and epigenetics research, histone peptide arrays have potential utility as a diagnostic/prognostic test for systemic lupus erythematosus and other autoimmune diseases where anti-chromatin autoantibodies are generated 26,27 .…”