Guenter Steiner

B and T Cell Responses to the Spliceosomal Heterogeneous Nuclear Ribonucleoproteins A2 and B1 in Normal and Lupus Mice

Autoantibodies directed against spliceosomal heterogeneous nuclear ribonucleoproteins (hnRNPs) are a typical feature of rheumatoid arthritis, systemic lupus erythematosus, and mixed-connective tissue disease. With the aim of investigating a potential pathogenic role of these Abs, we have studied the Ab response to A2/B1 hnRNPs in different murine models of lupus. The specificity of anti-A2/B1 Abs was tested with a series of 14 overlapping synthetic peptides covering the region 1–206 of A2 that contains most of the epitopes recognized by patients’ Abs. A major epitope recognized very early during the course of the disease by Abs from most of MRL lpr/lpr mice but not from other lupus mice and from mice of different MHC haplotypes immunized against B1 was identified in residues 50–70. This peptide contains a highly conserved sequence RGFGFVTF also present in other hnRNPs and small nuclear ribonucleoproteins. Abs reacting with a second A2 epitope identified in residues 35–55 were detectable several weeks later, suggesting an intramolecular B cell epitope spreading during the course of the disease. We identified several T cell epitopes within the region 35–175 that generated an effective Th cell response with IL-2 and IFN-γ secretion in nonautoimmune CBA/J mice sharing the same MHC haplotype H-2k as MRL/lpr mice. None of the peptides stimulated T cells primed in vivo with B1. Because Abs to peptide 50–70 were detected significantly earlier than Abs reacting with other A2 peptides and the protein itself, it is possible that within the protein, this segment contains residues playing an initiator role in the induction of the anti-A2/B1 and antispliceosome Ab response.

Anticarbamylated protein antibodies can be detected in animal models of arthritis that require active involvement of the adaptive immune system

A key characteristic of rheumatoid arthritis (RA), is the occurrence of antibodies against post-translationally modified proteins. Citrullination and anti-citrullinated protein antibodies (ACPAs) have been studied extensively.1 Carbamylation is another type of post-translational modification. During carbamylation, isocyanic acid reacts with the amine group of an amino acid. This mostly results in the conversion of lysine into homocitrulline.2 A subset of patients with RA harbour anticarbamylated protein (anti-CarP) antibodies and the presence of these antibodies is predictive of worse disease progression in ACPA-negative patients.3 Anti-CarP antibodies can be present in patients with arthralgia and their presence predicts the development of RA.4 A cornerstone of biomedical research is the use of animal models to explore basic pathophysiological mechanisms. Therefore, it is important to know whether antibodies against post-translationally modified proteins are present in these models. Although ACPAs were initially reported to be present in collagen-induced arthritis (CIA),5 ,6 this topic is now debated. Little is …

Inhibition of Inflammation and Bone Erosion by RNA Interference-Mediated Silencing of Heterogeneous Nuclear RNP A2/B1 in Two Experimental Models of Rheumatoid Arthritis.

The nuclear protein heterogeneous nuclear RNP A2/B1 (hnRNP A2/B1) is involved in posttranscriptional regulation of gene expression. It is constitutively expressed in lymphoid organs and highly up‐regulated in the synovial tissue of patients with rheumatoid arthritis (RA), who may also generate autoantibodies to this protein. This study was undertaken to investigate the potential involvement of hnRNP A2/B1 in the pathogenesis of autoimmune arthritis, by silencing hnRNP A2/B1 expression in 2 animal models of RA.

Rheumatoid arthritis: an antigenic chameleon

Nowadays, rheumatologists and immunologists have to be absorptive like a sponge—from a breathtaking progress in the basic research field to emerging approaches in diagnosis and treatment of complex disorders like rheumatoid arthritis (RA), there is always exciting and sometimes unexpected news to digest. For those who are particularly interested in the autoimmune response in RA, we have to realise that we are engaged with a true chameleon. Since the discovery more than 15 years ago of humoral autoimmune reactivities to epitopes containing the unusual amino acid citrulline,1 many new autoimmune targets have been discovered and, even more important, also different post-translational modifications to push their antigenic properties. Meanwhile the best understood process represents enzymatic deimination of peptide—or protein-bound arginine to citrulline. In genetically prone individuals, this activity creates highly specific recognition motives for auto-antibodies (anti-citrullinated protein/peptide antibodies, ACPAs), which serve as excellent diagnostic markers, especially in the early phases of disease. Since citrullination, as a physiological process, is also triggered by …

Toll-like receptor dependent autoantigens in animal models and humans in use to improve collagen induced arthritis

This study was conducted with sera from patients with rheumatoid arthritis, systemic lupus erythematosus as well as with arthritis and lupus-like disease animal models to identify identical autoantigens in human and animal models for disease modifying use.