The etiologies of most autoimmune diseases are not completely understood. Aminoacyl-tRNA synthetases (AARS) are a family of heterogenous enzymes responsible for protein synthesis and whose secondary functions include a role in autoimmune myositis. A subset of patients with idiopathic inflammatory myopathies demonstrate autoantibody against specific cytoplasmic AARS and the human asparaginyl-tRNA synthetase (AsnRS) has been shown to be a potent chemokine that interacts with CCR3 chemokine receptors. One way in which a chemotactic cytoplasmic enzyme might contribute to tissue inflammation is if it were abundant in a specific injured tissue and thereby released to the microenvironment at times of cellular damage. To test this hypothesis, the relative levels of AsnRS mRNA were studied in six human tissues. A 1.6 kbF RNA probe identified highly variable levels of the corresponding mRNA in Northern blot analysis of human lung, brain, heart, skeletal muscle, pancreas and liver. The highest levels of signal were noted in muscle and pancreas. Polyclonal antibody raised against recombinant human AsnRS identified abundant antigenic material in the pancreas, in particular in islet cells. Thus, the local abundance of an endogenous pro-inflammatory autoantigen may provide one explanation for perpetuation or exacerbation of tissue specific immune-mediated pathologies.
"Recent reports have shown that expression of some aaRSs can be found specifically in the pancreas (Antonellis et al. 2003, Kron et al. 2005). However, suborganellar localization of aaRSs within the pancreas has not been confirmed. "
[Show abstract][Hide abstract] ABSTRACT: To investigate whether or not antiaminoacyl-tRNA synthetase (aaRS) autoantibodies could be detected in patients with type 1 diabetes mellitus (DM) and be used as a diagnostic marker for type 1 DM, autoantibodies against aaRSs were measured in the plasma of normal subjects, patients with type 1 DM and patients with type 2 DM.
An enzyme-linked immunosorbent assay was performed to detect anti-aaRS autoantibodies in the plasma of normal subjects, and patients with type 1 DM, and patients with type 2 DM.
From the 65 (normal), 58 (type 1 DM) and 57 (type 2 DM) subjects, anti-aaRS autoantibodies were found in 37.9% of patients with type 1 DM compared with 1.54% of the non-diabetic controls, and 5.26% of the patients with type 2 DM (p <0.0001). In addition, anti-aaRS autoantibodies were identified in 30% of patients with type 1 DM without classical type 1 DM autoantibodies.
Anti-aaRS autoantibodies were identified in 37.9% of patients with type 1 DM. The results of this study demonstrate for the first time that autoantibodies against aaRSs are specifically associated with type 1 DM.
"Within a class, each AARS exhibits three highly conserved motifs distributed within a poorly conserved amino-terminal domain and a more highly conserved carboxy-terminal region (Weiner 1999; Ibba et al. 2000). Human cytoplasmic AsnRS is a class II AARS expressed in many human tissues, particularly in the pancreas, skeletal, and cardiac muscle (Kron et al. 2005). A wide range of secondary functions of AARS have been documented in various species, including roles in transcriptional regulation, mitochondrial RNA splicing, control of cell growth, and cytokine-or chemokine-like activity (Martinis et al. 1999). "
[Show abstract][Hide abstract] ABSTRACT: Diagnosis of eukaryotic parasitic infection using antibody-based tests such as ELISAs (enzyme-linked immunosorbent assays) is often problematic because of the need to differentiate between homologous host and pathogen proteins and to ensure that antibodies raised against a peptide will also bind to the peptide in the context of its three-dimensional protein structure. Filariasis caused by the nematode, Brugia malayi, is an important worldwide tropical disease in which parasites disappear from the bloodstream during daylight hours, thus hampering standard microscopic diagnostic methods. To address this problem, a structural approach was used to develop monoclonal antibodies (mAbs) that detect asparaginyl-tRNA synthetase (AsnRS) secreted from B. malayi. B. malayi and human AsnRS amino acid sequences were aligned to identify regions that are relatively unconserved, and a 1.9 A crystallographic structure of B. malayi AsnRS was used to identify peptidyl regions that are surface accessible and available for antibody binding. Sequery and SSA (Superpositional Structural Analysis) software was used to analyze which of these peptides was most likely to maintain its native conformation as a synthetic peptide, and its predicted helical structure was confirmed by NMR. A 22-residue peptide was synthesized to produce murine mAbs. Four IgG(1) mAbs were identified that recognized the synthetic peptide and the full-length parasite AsnRS, but not human AsnRS. The specificity and affinity of mAbs was confirmed by Western blot, immunohistochemistry, surface plasmon resonance, and enzyme inhibition assays. These results support the success of structural modeling to choose peptides for raising selective antibodies that bind to the native protein.
Protein Science 07/2008; 17(6):983-9. DOI:10.1110/ps.073429808 · 2.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent studies have shown that disease-associated self-antigens activate chemokine receptors. This review focuses on the mechanics of autoantigen interaction with select chemokine receptors, how these migratory signals are amplified and discusses the possibility that chemokine receptors can be valuable therapeutic targets in the prevention and treatment of autoimmune disease.
We have recently shown that most autoantigens are chemotactic for immature dendritic cells, suggesting that autoantigens have the potential to bridge the innate and adaptive immune systems. Autoantigens also induce other leukocytes expressing their responsive chemokine receptor to migrate. These newly recruited leukocytes, in response to proinflammatory mediators, simulate the surrounding tissues to release chemokines. Several groups have reported increases in both select chemokines and chemokine receptors in inflamed tissues. Taken together, these studies suggest that autoantigens initiate leukocyte migration into damaged and inflamed tissue that leads to the subsequent amplification of the inflammatory response.
Most autoantigens induce chemokine receptor mediated cell migration, therefore targeting chemokine receptors for either prevention or therapy has great potential to limit autoimmune diseases.
Current Opinion in Rheumatology 12/2006; 18(6):642-6. DOI:10.1097/01.bor.0000245728.40630.27 · 4.89 Impact Factor
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