Hoon Han

Human Cytomegalovirus Gene Products US3 and US6 Down-Regulate Trophoblast Class I MHC Molecules

The epidemiological correlation between human CMV (HCMV) infection and spontaneous fetal loss has been suggested, but the underlying mechanism is not well understood. Fetal cytotrophoblasts, which are in direct contact with the maternal immune system in the uterus during pregnancy, do not express HLA-A and HLA-B, but express the nonclassical class I HLA-G and HLA-C. It has been shown that both HLA-G and HLA-C are capable of inhibiting NK-mediated cell lysis. In our present study, using human trophoblast cell lines as well as other cell lines stably transfected with the human class I genes, we have demonstrated that HCMV US3 and US6 down-regulate the cell-surface expression of both HLA-G and HLA-C by two different mechanisms. HCMV US3 physically associates with both trophoblast class I MHC species, retaining them in the endoplasmic reticulum. In contrast, HCMV US6 inhibits peptide transport by TAP and thus specifically the intracellular trafficking of class I molecules. Therefore, these findings suggest for the first time a possible molecular mechanism underlying HCMV-related spontaneous pregnancy loss.

Genetic risk and protective factors for idiopathic inflammatory myopathy in Koreans and American Whites: A tale of two loci

OBJECTIVE To better understand genetic contributions to autoimmunity, immunogenetic markers were studied in two racially discrete and geographically isolated populations of patients with idiopathic inflammatory myopathy (IIM). METHODS Clinical characteristics, as well as clinical and autoantibody subsets, were defined in 151 American white patients and 50 Korean patients with IIM. HLA-DRB1 and DQA1 genotyping was performed on patients and racially matched controls by standard molecular techniques. Gm allotypes and phenotypes were determined by the hemagglutination-inhibition method. RESULTS HLA-DRB1*0301, the linked allele DQA1*0501, and DRB1 alleles sharing the first hypervariable region motif 9EYSTS13 were major genetic risk factors for the development of myositis in whites (corrected P [Pcorr] < 0.0004, odds ratio [OR] 11.2, 4.5, and 3.1, respectively, for each factor versus controls). Although both the white and Korean patients had a similar distribution of clinical characteristics, autoantibody profiles, and clinical groups, no HLA-DRB1 nor DQA1 allele or motif was found to be a risk factor for IIM in the Korean patients. However, DRB1*14 was a protective factor in Korean patients without myositis-specific autoantibodies (Pcorr = 0.004, OR 0.046). In addition, although no Gm phenotype or allotype was identified as a risk factor in whites, Gm 21 was a protective factor for the development of IIM in Koreans (Pcorr = 0.024, OR 0.3). CONCLUSION Although myositis patients in the US and Korea share similar clinical and serologic features, the immune response genes predisposing to and protecting from myositis in each of these ethnic groups differ at two chromosomal loci. These data suggest that multiple genetic loci should be studied to identify risk and protective factors for some autoimmune diseases in various ethnic populations.

TNFB gene polymorphism in patients with systemic lupus erythematosus in Korean.

Objectives: To elucidate the gene frequency of TNFB Ncol polymorphism and its association with HLA class II antigen in patients with systemic lupus erythematosus (SLE) in Korea. Methods: We investigated the gene frequency of the TNFB alleles using DNA obtained from peripheral mononuclear cells in 141 healthy controls and in 58 patients with SLE. The polymorphisms of TNFB gene (735 bp) were studied by Ncol PCR-RELP. A portion of TNFB gene(735 bp) was amplified by PCR and its products were digested with Ncol restriction enzyme. The digested samples of amplified DNA were analyzed by agarose gel electrophoresis. TNFB*1 and TNFB*2 alleles were identified according to polymorphic fragments on Ncol restriction site in the first intron of the TNFB gene. The generic types of HLA-DRBI were also determined by PCR with sequence specific primers (SSP) using genomic DNA from the same subjects. Results: The genotypic frequency of TNFB*2 homozygote was significantly increased in patients with SLE compared with controls (RR=2.36, P=0.011). The frequency of HLA-DRBI*15 was also significantly increased in patients (RR=2.27, P=0.029). However, the increased frequency of TNFB*2 homozygote was apparently increased in nephritis group (RR=2.79, P=0.035), whereas the significance of TNFB*2 homozygote was weakend in non-nephritis group. Conclusions: Our results suggest that genetic predisposition of TNFB*2 homozygote is another risk factor in Korean SLE, especially in DR2 negative patients. In addition, TNFB*2 homozygote could have a tendency for the development of nephritis in patients with SLE.

Serum Soluble HLA Class I Antigen Levels in Hemodialysis Patients and following Renal Transplantation

We measured the serum levels of soluble HLA class I antigen (sHLA-I) to evaluate the immune status of uremia and following renal transplantation. Twenty-one hemodialysis (HD) patients had serum samples collected for sHLA-I analysis before and after HD and also during the initial posttransplant period. The serum sHLA-I levels in patients undergoing HD were higher than in the normal controls (574.8 +/- 431.1 vs. 415.6 +/- 256.1 ng/ml, p < 0.05). In the HD patients, HD duration was not correlated with serum sHLA-I levels (r = 0.01, p > 0.05), and pre- and post-HD serum sHLA-I levels were not significantly different (574.8 +/- 431.1 vs. 568.3 +/- 398.4 ng/ml, p > 0.05). After successful renal transplantation, the serum sHLA-I levels decreased significantly (574.8 +/- 431.1 vs. 226.7 +/- 202.8 ng/ml, p = 0.0001) but increased significantly during the rejection period as compared to the prerejection period (642.8 +/- 296.1 vs. 305.5 +/- 194.7 ng/ml, p = 0.0002). In conclusion, sHLA-I levels are stable in uremic status and can be used as a parameter for monitoring acute graft rejection in renal transplantation.

RFLP analysis of HLA-DR beta and -DQ beta genes in the Korean patients with insulin-dependent diabetes mellitus.

Human genomic DNA samples from 19 Korean patients and 31 controls of known serological DR antigen specificity were studied for insulin-dependent diabetes mellitus (IDDM)-associated variation in HLA-DRβ and - DQβ restriction fragment length polymorphisms (RFLPs). Genotyping allowed for accurate assignment of HLA-DR types. For HLA-DRw6, a 12kb/DRβ/Taq I fragment was decreased in Korean IDDM (p<0.05). However, we could not find an increased frequency of a 12kb/DQβ/Bam HI fragment or decreased frequency of a 3.7kb/DQβ/Bam HI fragment in Korean IDDM. These results suggest a possible protective role of the HLA-DRw6 specificity in IDDM, irrespective of ethnic background, the absence of a specific DQβ RFLP pattern associated with IDDM in Koreans, and the difference of the Korean population in the genetic of IDDM, compared to the Caucasoid population.

HLA and insulin-dependent diabetes mellitus in Koreans.

Specific allelic associations vary among ethnic groups. We studied the distribution of HLA-A, -B, -C and -DR antigens in 41 patients with insulin-dependent diabetes mellitus (IDDM) and 280 unaffected persons in Korea. HLA typing was performed by the standard microlymphocytotoxicity test using antisera supplied by the Third Asia-Oceania Histocompatibility Workshop Conference (3rd AOHWC, 1986). There was no association between HLA-A, -B, or -C and IDDM. However, the frequencies of HLA-DR3 and HLA-DR4 were increased in the patients as compared with the controls (19.5% vs 4.3%, RR 5.4, corrected p < 0.005 for DR3 and 61.0% vs 36.4%, RR 2.7, corrected p < 0.05 for DR4). Also a decreased frequency of HLA-DR2 was found in the patients with IDDM (9.8% vs 32.1%, RR 0.3, corrected p < 0.05). These results emphasize the differences in HLA-IDDM associations among different ethnic groups.