Genetic association of autoimmune hepatitis and human leucocyte antigen in German patients

INTRODUCTION Autoimmune hepatitis (AIH) is characterized by portal lymphatic infiltrates on liver histology and in most patients with the occurrence of autoantibodies such as antinuclear, smooth muscle antibody-positive (ANA/ SMA, type 1), liver-kidney microsomal antibody-positive (LKM-1), and soluble liver antigen/liver-pancreas antigen (SLA/LP) antibodies. Untreated, the disease usually runs an unfavorable course with 5 year survival rates of 50% and 10 year survival rates between…     

HLA-associated production of anti-DFS70/LEDGF autoantibodies and systemic autoimmune disease

Autoantibodies against DFS70/LEDGF, which is also known as an important partner of HIV-1 integrase, are found in 10% of healthy Japanese people, but in only approximately 2% of patients with systemic autoimmune disease (SAD). We wished to characterize the association of HLA class II alleles with the presence of autoantibodies against this molecule. MHC class II genes (DR, DQ, and DP alleles) were analyzed by the polymerase chain reaction-sequence specific primer method in 24 individuals with anti-DFS70 antibodies. The frequencies of HLA-DRB1*0410, -DQB1*0402, and -DPB1*0301 were increased in anti-DFS70 Ab-positive patients, while HLA-DQB1*0302 was decreased compared to Japanese controls. All anti-DFS70 Ab-positive individuals expressed at least one HLA-DQB1 allele with an aspartic acid at residue 57. The immunogenetic background of Japanese individuals with anti-DFS70 antibodies differs from that of patients with SAD. HLA class II genes influence the production of anti-DFS70 antibodies among individuals with various clinical manifestations.     

Limited allelic diversity of stimulatory two-domain killer cell immunoglobulin-like receptors

Genomic sequencing was used to characterize most of the coding regions of the five two-domain stimulatory killer cell immunoglobulin-like receptor (KIR) loci from 80 unrelated, primarily Caucasian, individuals. Specific loci were present in from 26% (KIR2DS3) to 98% (KIR2DS4) of individuals. The number of known alleles present varied from one (KIR2DS1, KIR2DS5) to five (KIR2DS4). The frequencies of loci and alleles were similar to observations made in populations of European and Asian ethnicities. New alleles were found at 2DS1 (*00202, *00302, *005, *006, *007) and 2DS4 (*008) loci.     

Genetic diversity of HLA system in two populations from Yucatán,Mexico: Mérida and rural Yucatán

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 324 Mexicans from the state of Yucatán living in the city of Mérida (N = 192) and rural communities (N = 132), to obtain information regarding allelic and haplotypic frequencies. We found that the most frequent haplotypes in the state of Yucatán include 16 Native American and one European haplotype. Admixture estimates revealed that the main genetic components in Yucatán are Native American (81.54 ± 4.99% by ML; 62.92% of Native American haplotypes) and European (11.50 ± 15.43% by ML; 23.26% of European haplotypes), and a less prominent African genetic component (6.96 ± 10.47% by ML; 5.93% of African haplotypes).     

Genetic heterogeneity of DR4 in the Old Order Amish and two new HLA-D specificities

Seven Old Order Amish families were D and DR typed using the Eighth International Workshop HTC and Dr antisera. Four different DR4 haplotypes were identified in five families, two of which were negative for Dw4 as well as all other known HLA-D alleles. These two "new" D/DR types reacted with all 8W antisera submitted as anti-DRf4, but could be distinguished by their differential reactivity with three non-DR4 antisera 8W1207, 572, and 1074. We have designated these new specificities as DR-Am4.1 and 4.2 Sera 8W1207 and 572 were positive with DR-Am4.1 cells, while 8W1074 defined DR-Am4.2. The complete haplotypes of the new HLA-D/DR specificities were Aw32, Cw5, Bw44, D-Am4,1, DR-Am4.1 and A2, Cw4, Bw35, D-Am4.2, Dr-Am4.2. Homozygous cells of these new variants stimulated each other strongly in MLC. D-Am4.1/DR-Am4.1 represents a new D region allele possibly showing linkage disequilibrium with Bw4.2/DR-Am4.2, the second new variants, was not found in a screening of 31 non-Amish unrelated subjects. It, therefore, appears to have a low gene frequency in the population.     

Mapping and definition of HLA class I and II serologic epitopes using an unbiased reverse engineering strategy

Current models describing HLA epitopes are both theoretical and empirical. Each has limitations yielding discordant results and increasingly complex modeling. The models make a priori assumptions that epitopes must be present only on the mature protein, solvent accessible, on the ‘top’ (peptide binding surface) of the molecule, restricted to the same class as the antibody, and in the same position on the target allele if reactive to more than one locus. Results obtained counter to these assumptions are routinely discounted. For the 17th International Histocompatibility and Immunogenetics Workshop, we developed a reverse engineering algorithm to define epitopes without these assumptions on a cohort of 332 primary transplant pairs. Complete NGS typing of the transcribed (including leader) genomic DNA for 11 HLA loci of donor and recipient and DSA assignment by single antigen beads was performed. Our results show that, when grouped by 16 class I and II allele specific DSA, uniform clusters and 172 specific amino acid target epitopes are recognized by recipients despite originating from disparate HLA pairs. Data also show that these targets can be in the leader, alpha 3, transmembrane and cytoplasmic domains, thus calling into question current assumptions regarding immunogenic epitopes. Comparisons of amino acid epitopes defined by the Terasaki and Duquesnoy groups (TerEp and EpRegistry) are given.     

不同病理类型及种族恶性黑素瘤遗传学差异

恶性黑素瘤是一种起源于黑素细胞的高度恶性肿瘤,在西方国家的发病率很高,但对于发病率相对较低的黄种人及其他有色人种,黑素瘤的常见病理类型和相应的遗传学改变和分子机制有很大的不同.白种人常见的病理类型是非慢性阳光损伤型恶性黑素瘤,遗传学上以BRAF和NRAS基因突变多见,亚洲人及其他有色人种常见的病理类型是肢端型及黏膜型恶性黑素瘤,以kit变异和CCND1扩增多见.通过对不同病理类型的恶性黑素瘤的遗传学改变的研究,有助于疾病的早期基因诊断和靶向治疗药物的研发.     

妊娠期糖尿病免疫遗传学研究进展

妊娠期糖尿病（GDM）是妇女在妊娠期发生或首次发现的不同程度的糖耐量异常,其是多个基因异常表达与环境因素共同作用引起的临床综合征,其发病率呈逐年上升趋势.因此,探索GDM发病机制及其病理生理对GDM患者进行预测和干预显得尤为重要.与妊娠相关的胰岛素抵抗程度超过了胰岛β细胞功能代偿的极限是目前较为公认的GDM发病原因,但其具体的发病机制尚不完全清楚.近年的研究发现,免疫遗传因素在GDM的发生发展中有重要作用.从免疫遗传角度深入探讨GDM患者T细胞、人类白细胞抗原（HLA）复合体等的变化可为进一步研究GDM发病机制提供新思路.     

Genetic diversity of HLA system in three populations from Sonora,Mexico: Ciudad Obregón,Hermosillo and rural Sonora

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 439 Mexicans from the state of Sonora living in Ciudad Obregón (N = 143), Hermosillo (N = 99), and rural communities (N = 197) to obtain information regarding allelic and haplotypic frequencies. We find that the 13 most frequent haplotypes for the state of Sonora include nine Native American, three European and one Asian haplotypes. Admixture estimates revealed that the main genetic components in the state of Sonora are European (51.25 ± 2.90% by ML; 37.70% of European haplotypes) and Native American (43.35 ± 2.57% by ML; 39.64% of Native American haplotypes), while the African genetic component was less apparent (5.39 ± 2.54% by ML; 11.04% of African haplotypes).     

人类组织相容抗原免疫遗传与妊高征发病关系的探讨

选择４０对妊高征夫妇及正常对照组１００例，对其人类组织相容性抗原中与Ｄ区相关抗原（ＨＬＡ－ＤＲ）频率分布、纯合型频率及夫妇间ＨＬＡ－ＤＲ抗原共享进行了检测。结果显示：与正常对照组相比，妊高征患者ＨＬＡ－ＤＲ＿４频率有极显著的增加（Ｐ＜０．００１），妊高征患者夫妇ＨＬＡ－ＤＲ共享有明显提高（Ｐ＜０．０１），其中尤以ＤＲ＿４抗原共亨率最高（Ｐ＜０．０００１），然而，ＨＬＡ－ＤＲ及ＤＲ＿４纯、杂合型频率两组间无明显差异。结果表明，妊高征的遗传易感性可能与ＤＲ＿４有关，其相关性推测可能是由于ＤＲ＿４与妊高征的疾病易感基因间连锁不平衡所致，但ＤＲ＿４是否直接充当一种免疫缺陷基因尚不能确定。