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Different clinical phenotypes of systemic autoimmune diseases are typically associated with distinct autoantibody profiles. A striking example of this is idiopathic inflammatory myopathy (IIM; myositis), in which the aminoacyl–transfer RNA synthetases are targets of the autoimmune response. Among these antigens, antibodies against histidyl–transfer RNA synthetase (HisRS; also known as Jo-1) are by far the most prominent; these are found in 15–20% of myositis patients, and more strikingly, are detected in ∼70% of patients with myositis and interstitial lung disease.

HisRS belongs to the family of ancient, ubiquitously expressed proteins performing the critical cellular function of translating genetic information into proteins. In 1999, Wakasugi and Schimmel (1) published a seminal study showing that human tyrosyl–transfer RNA synthetase can be secreted under apoptotic conditions and subsequently cleaved by extracellular leukocyte elastase, generating two fragments with distinct cytokine activities. The ability of a molecule that is a target of an adaptive immune response in myositis to initiate an innate immune response suggested to Plotz (2) that activation of the innate immune response might be a critical property that determines whether a specific molecule is selected—from among thousands of possible self antigens—for an autoimmune response. Howard et al (3) demonstrated that the amino-terminal HisRS domain could function as a chemokine, attracting naive lymphocytes and immature dendritic cells through CCR5-mediated interactions. This ability of frequently targeted autoantigens to bridge the innate and adaptive immune responses appears to be a shared feature of many autoantigens in the systemic autoimmune diseases (4, 5).

While immunization of mice with HisRS in adjuvant (which contains signals for activating Toll-like receptors [TLRs] and other innate immune receptors) has previously been shown to cause an immune response to HisRS, along with inflammation of muscle and lung in some mouse strains (6), the intrinsic adjuvant properties of HisRS could not be revealed using this approach. Soejima and colleagues (7) now set out to address this by immunizing a variety of congenic and knockout mouse strains intramuscularly with soluble mouse HisRS (in the form of a fusion protein consisting of amino acids 1–151 of mouse HisRS linked to the C-terminus of maltose binding protein [MBP]) in the absence of adjuvant. Their findings, which are reported in this issue of Arthritis & Rheumatism (7), provide evidence that mouse HisRS without adjuvant can induce sustained muscle inflammation and an adaptive immune response to HisRS. Control immunizations performed with the MBP fusion partner and prepared similarly do not have this effect. The inflammatory response was detected 1 week postimmunization and remained present for 7 weeks (the longest time examined). Similar studies performed in mice lacking recombination-activating gene 2 and in mice lacking TLR-4 showed that the ability of mouse HisRS to produce muscle inflammation did not require TLR-4 signaling, nor was it dependent on recognition of B cell and T cell receptors. It should be noted that in the reported experiments, kinetic characteristics were not addressed, nor were the studies extended beyond 7 weeks; thus, the potential exists for aspects of the induced model to differ if these broader features were studied.

Many interesting questions arise from the data presented in this article. While soluble HisRS induces inflammatory infiltrates and high-titer antibodies to HisRS, the results do not speak to whether other characteristic features of IIM muscle disease are also detected in this model. Additional studies to evaluate and quantify muscle damage functionally, biochemically, and histologically should be very illuminating in terms of how closely this phenotype mimics that of the human disease. For example, the question of whether there are signs of muscle weakness or decreased activity or perhaps evidence of muscle enzyme leakage (such as creatine phosphokinase and aldolase) could be studied, and regenerating and/or necrotic muscle cells present on histologic examination could be quantified.

Another key area to resolve relates to whether the site of initial immunization determines the subsequent phenotype. For example, is the inflammatory response in muscle detected only in local muscle areas at or near the injection site, or is it also found in noninjected muscles as well as other organs? In this regard, lung tissue would be especially interesting to examine, given the strong association of HisRS with interstitial lung disease in humans, and the previous observations by this group in mice immunized with HisRS and adjuvant (6). It would be interesting to evaluate whether muscle inflammation is only induced when mouse HisRS is injected into muscle or whether it also results from subcutaneous immunization or injection into the peritoneum.

Interestingly, when TLR-4–deficient animals were immunized with HisRS, they had a preserved inflammatory response in muscle but failed to generate a HisRS antibody response. This has several important implications. It separates the effects of HisRS on innate and adaptive immune systems—the adaptive response requires the presence of TLR-4. This suggests the presence of TLR-4 ligands in the immunizing mixture, either in the form of contaminating endotoxin or, potentially, the HisRS fusion protein itself. Moreover, it shows that the inflammatory and immune consequences of HisRS immunization can be separated. In this regard, it would be very important to define whether the kinetics and self-sustaining nature of the ongoing muscle inflammation vary in the strains that have TLR-4 compared to those that do not. It is clearly possible that the adaptive immune response plays an important role in driving and amplifying the disease and sustaining this in the longer term.

These studies highlight the possible importance of intrinsic inflammatory functions of phenotype-specific autoantigens in generating a phenotype. Clearly, understanding the implications of these observations to HisRS antibody–associated human disease must focus on defining the source and form of the immunizing HisRS in vivo in humans with myositis. Does this emanate from the muscle, the lung, or another site? Of interest in this regard are the findings reported by Levine et al (8), who described a novel, proteolytically sensitive HisRS conformation in the lung, which led the authors to speculate that the human autoimmune response to HisRS is initiated and propagated in this organ. The amount of antigen that is needed to exert the proinflammatory effects and form it should take are questions that remain to be addressed. As well, investigating whether autoantigen expression in the target tissue changes as the disease amplifies would be informative. Recent findings (9) show that levels of autoantigen expression (including HisRS) are elevated in regenerating muscle cells in damaged muscle, raising the issue that the perturbed tissue is a source of autoantigens, which serve as a feedforward force to both the innate and adaptive immune responses, with the chemokine activity predominating in disease initiation, but also playing a role in sustaining the process once the tissue damage is established. Regenerating muscle cells, which express high levels of HisRS, are particularly important in this regard.

Strategies for regulating the expression of myositis autoantigens in regenerating muscle are therefore emerging as strong contenders for dampening the amplification loop of autoimmunity, possibly providing a way to control disease. Future studies addressing these issues will have therapeutic implications.

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Dr. Casciola-Rosen drafted the article, revised it critically for important intellectual content, and approved the final version to be published.

REFERENCES

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