|Budget Amount *help
¥3,900,000 (Direct Cost : ¥3,900,000)
Fiscal Year 2004 : ¥1,200,000 (Direct Cost : ¥1,200,000)
Fiscal Year 2003 : ¥1,200,000 (Direct Cost : ¥1,200,000)
Fiscal Year 2002 : ¥1,500,000 (Direct Cost : ¥1,500,000)
New profile of myositis-specific autoantibodies (MSAs).
The most common MSAs were anti-aminoacyl-tRNA synthetases (Jo-1:18%, EJ:4%, PL-7:3%, PL-12:1%, OJ:1%) in 118 patients with PM/DM. Anti-SRP (9%) was found only in PM/DM. Anti-Mi-2, not previously reported in Japanese patients, was found in 7 patients with DM and 1 with PM-SSc overlap syndrome, although their titer was very low. All 8 anti-Mi-2 sera strongly recognized a 240 kDa polypeptide (the primary target for all of anti-Mi-2 antibodies), but not the other components of Mi-2 antigen in IPP. In general, the frequency and clinical correlation of anti-synthetase, anti-SRP, and anti-Mi-2 antibodies in Japanese patients appeared similar to those described in North American and European populations. Anti-PMS1 autoantibodies were found in 3 patients with PM/DM and 3 with PM-SSc overlap syndrome, also a similar frequency. In contrast, among this Japanese cohort, anti-PM/Scl antibodies were not found, whereas anti-U2 RNP (15%), anti-Ku (
13%), and anti-DNA-PKcs (3%) antibodies were found in 80 patients with PM-SSc overlap syndrome. We conclude that inflammatory muscle disease in different racial groups leads to somewhat different profiles of autoantibodies. These differences could reflect variation in immunogenetic background or different etiologic mechanisms.
Induction of myositis-specific autoantibodies in normal mice by pristane.
Thirteen non-autoimmune strains of mice (B6, B10, BALB/c, C3H substrains and congenic for MHC, DBA/1, SJL/J, A.SW) were examined. Three month old mice (6-30/group) received a single i.p. injection of 0.5ml of either pristane or saline and sera 6 months later were tested for MSAs. Proteins and RNAs immunoprecipitated by sera were screened using radiolabeled cell extracts, respectively. Autoantibodies to tRNA related proteins including anti-isoleucyl tRNA synthetase antibodies were detected mainly in mice with B6/B10 background (4/63). In contrast, anti-SRP antibodies that immunoprecipitated 7SL-RNA and 54 kDa protein were detected in various strains such as B6 (2/30), BALB/cByJ (1/20), C3H/OuJ (2/8), and DBA/1 (1/15) mice. Anti-7-2RNP antibodies were also common in strains that produce anti-SRP antibodies (6/30 in B6, 2/8 in C3H/HeOuJ, others 4/110). None of these autoantibodies were detected in PBS-treated control. The levels of these antibodies in pristane-treated mice were comparable to those in human myositis sera. These results indicate that normal mice can produce MSA when exposed to certain environmental factors. This new model will facilitate studies of the role of environmental triggers vs. genetic susceptibility in the pathogenesis of MSAs.
Immunogenetic backgrounds of myositis-specific autoantibodies.
Specific diseases are known to exhibit racial differences in their associations with HLA phenotypes and autoantibodies. To further explore these correlations, we examined the immunogenetic associations of MSAs in Japanese patients with inflammatory myopathy. Serum autoantibodies were determined by immunoprecipitation. The HLA-class II (DRB1, DQA1, DQB1, DPB1) alleles were identified from restriction fragment length polymorphism of PCR-amplified genomic DNA. Eight of 10 (80%) patients with anti-Jo-1 had the DRB1^*0405-DQA1^*0302-DQB1^*0401 haplotype, compared to 22% of the controls (odds ratio [OR]=18, P=0.0001). Four of 7 patients (57%) with anti-PL-12 had DRB1^*1501-DQA1^*0102-DQB1^*0602, compared to 9% of healthy controls (OR=14, P=0.006). Seven of 17 patients (41%) with anti-SRP antibodies had DR8. DPB1^*0501 was present in all patients with anti-Ku autoantibodies compared with 59% of control subjects. This association was significant (P=0.0016, OR=30) and remained significant (p = 0.03) even when corrected for the number of alleles examined. Thirteen of the 21 patients (62%) with anti-Ku antibodies, had myositis. Ten of these individuals (77%) had the class II haplotype of DRB1^*0901-DOA1^*0302-DQB1^*0303, compared to 38% of anti-Ku (+) patients without myositis and 28% of Controls (P=0.004, OR=8.5). These results indicate that MSAs in Japanese patients correlate with specific HLA-class II molecules that are different from those associated with the same autoantibodies in North American patients. Less