HLA antigens, psoriasis and acute anterior uveitis in Bechterew's syndrome (ankylosing spondylitis)

One hundred and twenty-two consecutively hospitalized patients with ankylosing spondylitis (AS) were reexamined. Ninety-two per cent were HLA B27 positive. Of the HLA B27 negative patients, 60% were found to have psoriasis, as opposed to 11 % of the HLA B27 positive patients. Acute anterior uveitis (AAU) was found only in HLA B27 positive patients, and more frequently in males than in females. The genetic and clinical heterogeneity of AS, together with the overlapping clinical criteria for AS and psoriatic spondylitis, may make the term "Bechterew's syndrome" preferable. Based on these findings and previous reports, we conclude that (i) AAU is a manifestation of Bechterew's syndrome in HLA B27 positive patients, (ii) HLA B27 negative patients without any obvious accompanying manifestations may suffer from psoriatic spondylitis, and (iii) genetic predisposition to psoriasis in persons who are HLA B13, B17 and B37 negative, may interact with the genetic predisposition to Bechterew's syndrome in HLA B27 positive persons and produce Bechterew's syndrome with psoriasis or psoriasis-like skin eruptions.     

Possible protective role of HLA-B*2706 for ankylosing spondylitis

HLA-B27 is strongly associated with ankylosing spondylitis (AS) but the role of the HLA molecule itself is still unclear. In this study on Singapore Chinese, we have subtyped 50 B27 positive AS patients and 45 B27 positive normals and found that the B*2706 allele has a significant negative association with disease (p=0.047). Together with recent data indicating the existence of AS "protective" B27 alleles, our data shows that the HLA molecule itself plays a crucial role in disease development.     

HISTOCOMPATIBILITY ANTIGENS AND OTHER GENETIC MARKERS IN ANKYLOSING SPONDYLITIS AND INFLAMMATORY BOWEL DISEASES

Of 118 Dutch patients suffering from ankylosing spondylitis (AS) 81.4% were found to be positive for the HLA antigen B27. The B27 frequency proved to be significantly higher in patients in whom the disease had an early onset. In addition to B27, another HLA antigen may be associated with AS; the antigen Bw16 was found to be significantly increased in B27 negative AS patients. HLA phenotype frequencies were also determined in 109 patients with idiopathic inflammatory bowel disease (IBD). In fifty-eight ulcerative colitis (UC) patients a raised incidence of A11 was noticed. In fifty-one patients with Crohn's disease (CD) the antigen B18 showed an increased frequency. Both deviations were statistically significant. In thirty-nine patients suffering from both AS and IBD 50% proved to be B27 positive, which is significantly different from the B27 frequency in patients with AS alone. In the B27 negative patients with AS and IBD an increased frequency of Bw16 was also shown.     

Low frequency of HLA‐B*2706 in Taiwanese patients with ankylosing spondylitis

The presence of HLA‐B27 in patients affected with ankylosing spondylitis (AS) was well established prior to the advent of DNA typing of various genes within the major histocompatibility complex (MHC) in humans. However, molecular typing of the MHC genes revealed that B27 comprises a motley assortment of alleles, some of which are strongly positively associated with the disease and some of which are negatively associated with the disease. B*2706 was reported to have a negative association with AS in the Thai population and in Chinese Singaporeans. We report here our finding of an absence of B*2706 in 184 Taiwanese AS patients.     

中国人HLA-B27、B7、B13和B40的检测及其相互杂合与交叉的分析

目的　检测 1194例初诊怀疑患强直性脊柱炎 (AS)和其它关节性疾病患者的HLA B2 7、B7、B13和B40位点抗原的分布 ,并分析这些位点的相互杂合和其抗原的交叉反应性。方法　微量细胞毒反应法 ,在同一块反应盘上同时检测。结果　 1.在 1194例患者中 ,HLA B2 7抗原阳性率达38 6 % ;B7的抗原阳性率为 7 4% ;B13为 14 6 % ;B40为 13 4%。2 .在HLA B2 7阳性人群中 ,B7抗原的阳性率为 14 3% ,明显升高 ,而在HLA B2 7阴性人群中 ,B7的阳性率仅为 3 2 % ,明显降低 ;3.在44 7例HLA B2 7阳性人群中 ,未检测到HLA B2 7、B7、B13三种抗原皆为阳性者 ,说明B7和B13之间没有交叉 ;4.据此 ,在HLA B2 7阴性人群中 ,查到的HLA B7/B13阳性率 0 5 4%应代表这两个位点的杂合 ;5 .无论在HLA B2 7阳性还是阴性人群中 ,HLA B13/B40的抗原阳性率远高于HLA B7/B40的阳性率 ,说明B13和B40位点的杂合或交叉 ,远大于B7与B40之间的杂合或交叉。结论　检测HLA B2 7及其相关B位点抗原的频度有助于分析这些位点的杂合及其抗原的交叉反应性的特点     

Association of RFLP of HLA class I genes with Chinese ankylosing spondylitis patients

By serum typing, it is indicated that HLA B27 may be associated with the susceptibility to ankylosing spondylitis (AS). We analyzed DNA restriction fragment length polymorphism (RFLP) in 28 Chinese AS patients and 99 healthy controls, using a 1.4 Kb HLA class I cDNA probe. The results showed that the frequencies of the 8.1 Kb EcoRI, 5.2 Kb EcoRI and 21.9 Kb XbaI fragments were found to be significantly increased in affected patients (P less than 0.0001, P = 0.0015, respectively), but that of 19.2 Kb XbaI fragment was decreased (P = 0.0021). The data suggest that AS may be a polygenic disease; furthermore, B27 and 8.1 Kb EcoRI band may be two different factors responsible for the susceptibility or just in linkage disequilibrium with the susceptible gene(s).     

The distribution of clinical findings in Bechterew's syndrome (ankylosing spondylitis) suggests distinct genetic subgroups

One hundred and twenty-two consecutive patients hospitalized for ankylosing spondylitis (AS) were reexamined. The frequency of clinical signs and results of tests for associations are presented. Psoriasis was associated with a distal pattern of peripheral arthropathy. Spinal rigidity was predominantly seen in males. Males with phalangeal arthropathy exhibited preserved spinal mobility. This was the case also when HLA B27 positives and patients who did not have psoriasis were considered separately. HLA B27 positive patients in this group had frequently experienced acute anterior uveitis. It seems possible that the disease in such males is the result of combined predisposition to ankylosing spondylitis and psoriatic arthropathy. Hip arthropathy was frequently present in males with spinal rigidity. The associations observed confirm that AS is a heterogenous group of diseases. The term "syndrome" may be suitable for such a heterogenous group, and we prefer the term "Bechterew's syndrome" as the name of this group. When these new findings are added to the previous observations that acute anterior uveitis probably is a clinical, sex-influenced characteristic of HLA B27 positive Bechterew's syndrome, that HLA B27 negative patients with Bechterew's syndrome frequently had psoriasis and were HLA B13 and B17 negative, and that psoriasis was frequent in HLA B27 positive patients as well, we tentatively conclude that different and interacting genetic mechanisms may be involved in the etiology of Bechterew's syndrome.     

Diminished Mixed Lymphocyte Response in Ankylosing Spondylitis

A diminished mixed lymphocyte response was reported by Nikbin et al. (1976) among patients with ankylosing spondylitis, their asymptomatic relatives and also normal controls carrying the B27 antigen. In the present communication, the responses in 48 ankylosing spondylitis patients and 45 controls were examined in mixed lymphocyte cultures tested against a 'standard stimulator' made up of pooled lymphocytes. A significantly diminished response is confirmed among the ankylosing spondylitis patients, but not in the control group carrying the B27 antigen. The diminished mixed lymphocyte response therefore appears to be more directly associated with the disease than with the B27 antigen, and possibly represents a specific T-cell defect associated with the pathogenesis of the disease.     

HLA-B27 PCR辅助诊断幼年强直性脊椎炎

目的：辅助诊断幼年强直性脊椎炎。方法：用ＰＣＲ技术对２４例临床表现为类风湿关节炎少关节型患儿的ＤＮＡ进行ＨＬＡ－Ｂ２７基因分析。结果：２４份标本中７例ＰＣＲ检测Ｂ２７基因阳性,占分析的２９．２％（７／２４）。７例Ｂ２７基因阳性病例中男５例,女２例,平均年龄１０．４岁。结论：Ｂ２７检测可作为诊断或鉴别诊断幼年强直性脊椎炎的重要指标,利于疾病病鉴别和预后估计。     

Lymphocyte response to IgG in patients with ankylosing spondylitis and their families.

Lymphocyte responsiveness to IgG was measured by an agarose method in nine patients with ankylosing spondylitis (AS), one patient with Reiter's Syndrome (RS), and thirty-six of their family members. Similar studies were also performed in five patients with rheumatoid arthritis (RA) and twenty-nine of their first degree relatives as well as in seven control families (twenty-seven subjects). Lymphocytes from the ten spondylitic patients and twenty-four of thirty-six family members responded in vitro to autologous IgG. Although most of these subjects had the histocompatibility antigen, B27, there was no association between B27 and response to IgG. Four of the five patients with RA and twenty of their twenty-nine first degree relatives responded in vitro to IgG, whereas only six of twenty-seven control family members gave a positive reaction. There was no difference in the incidence of antiglobulins (detected by agglutination tests) in the family members of patients with AS and RA or in control family members. These data indicate that lymphocyte responsiveness to IgG is the only aberrant immune response thus far described which is shared by patients with AS and RA and their family members.     

HLA-B27等位基因和亚型与强直性脊柱炎关系研究进展

大量的研究证明,强直性脊柱炎(AS)是与人类白细胞抗原(HLA)相关性最强的疾病。AS的发病与HLA-B27阳性密切相关,并与B7、B13、B40等几个等位基因有一定关系。HLA-B位点有42个等位基因,其中HLA-B27具有高度多态性,含有22个以上的亚型,不同亚型的碱基序列间只有个别差异。B27亚型在AS患者中的分布因地区和种族上的差别而不同,在中国主要以B2704和B2705为主,但以B2705分布最广。这几年大量的人B27转基因鼠实验证明AS与B27的关联性。     

Higher prevalence of peripheral arthritis among ankylosing spondylitis patients

This study was performed to define the clinical spectrum and disease manifestations of ankylosing spondylitis (AS) in a referral hospital setting. We identified the differences in clinical manifestations according to the sex, the age at onset, the presence of peripheral arthritis and the presence of HLA B27. A total 412 patients (357 males, 55 females) were recruited. Eighty-seven percent were men and 155 out of 412 patients (35%) were juvenile-onset. HLA B27 was detected in 385 patients (93%). Peripheral joint involvement was noted in 287 of total AS cases (juvenile- onset ankylosing spondylitis (JOAS), 82%; adult-onset ankylosing spondylitis (AOAS), 61%), and was more common than those reported in other studies. A greater portion of patients with JOAS had peripheral arthritis and peripheral enthesitis than the patients with AOAS. The patients with peripheral arthritis showed a younger age at onset and an increased tendency of having enthesitis and trauma history. The natural history of Korean AS appears largely similar to those seen in Europe and North America, except a few differences. JOAS was quite common and AS was about nine times more common in men than in women. In addition, the HLA B27 antigen frequency was 93%, which is higher than those reported in other studies.     

HLA-A*9, a probable secondary susceptibility marker to ankylosing spondylitis in Basque patients

HLA-B27 is strongly associated to ankylosing spondylitis (AS). The objective of our study was to analyze HLA-B27 association, B27 subtype distribution and frequency of other HLA class I and DR antigens in a group of Basque AS patients. HLA class I antigens were typed serologically and HLA-B27 and A9 subtypes were determined by DNA typing in samples from 46 patients with AS, 54 B27-positive spondyloarthropathies, 82 healthy subjects and 20 B27-positive controls. A class I HLA 9.2 kb PvuII restriction fragment length polymorphism (RFLP), previously associated with AS, was analyzed in a representative group of patients and controls. We found that HLA-B*2705 conferred a relative risk of 126 for AS in this group. HLA-A9 (A*2402) allele was significantly increased in AS patients compared with healthy controls and B27-positive control group (Pcorr<0.0001) and also increased in patients affected with peripheral arthritis. No association between class I HLA 9.2 Kb RFLP and AS was found. These results suggest that HLA-A*9 allele itself or another linked gene could act as a secondary and independent susceptibility allele to AS.     

采用 PCR-SSP法检测HLA-B27基因

目的：建立顺序特异引物聚合酶链反应（ＰＣＲ－ＳＳＰ）方法检测ＨＩＡ－Ｂ２７基因并与血清学方法比较。方法：设计合成Ｂ２７特异物３个和内源性阳性对照２个,建立ＰＣＲ－ＳＳＰ方法,用于Ｂ２７基因分型。血清学分型为一步法单克隆抗估方法。临床样本１００份,不源于可疑强直性脊柱炎患者。快速酚氯仿法提取模板ＤＮＡ。结果：１００例临床样本ＰＣＲ－ＳＳＰ行Ｂ２７基因分型均获成功。总耗时４ｈ。其中Ｂ２７阴性５８例,阳     

Histocompatibility typing and the counseling of families with ankylosing spondylitis

White individuals who are HLA B27-positive have an increased risk of developing ankylosing spondylitis or related diseases. HLA typing can be used in counseling relatives of persons with spondylitis, if the limitations of presently available data are recognized.     

The effect of LILRB1 but not LILRA3 gene polymorphism in immunopathology of ankylosing spondylitis—A parallel to KIR genes

LILR and KIR receptors recognize HLA‐B27 and may influence immune response in ankylosing spondylitis (AS) development. Purpose of the study was to analyse LILRB1/LILRA3 polymorphisms in AS. We observed a possible protective effect of the T allele of LILRB1 rs1061680:T>C and no association with insertion/deletion polymorphisms of LILRA3 with AS.     

Chlamydial antibody crossreactivity with peripheral blood mononuclear cells of patients with ankylosing spondylitis: the role of HLA B27.

We have previously reported the association of Chlamydia trachomatis with HLA B27+ related diseases. To investigate the possibility that chlamydial antibodies serve to localize the immune response in such diseases, we examined the crossreactivity of chlamydial antibodies (rabbit anti-D and anti-L2 serotypes) with peripheral blood mononuclear cells of patients with ankylosing spondylitis (AS) and anterior uveitis (AU) and with human and bovine ocular tissue and cells in culture. Our results indicate a significantly increased percentage binding of chlamydial antibody (D serotype) to the mononuclear cells of HLA B27+ patients with AS when compared with HLA B27- patients with AS (12.9% +/- 2.2 versus 5.4% +/- 2.2), B27+ controls (5.5% +/- 1.5) and B27- controls (6.1% +/- 1.0). There was no significant difference between controls and HLA B27+ patients with AU (6.6% +/- 1.9) and B27- patients with AU (8.7% +/- 1.1). This crossreactivity could not be blocked by monoclonal HLA B27 antibody. Chlamydial antibodies (D and L2) crossreact with human and bovine conjunctiva but not uvea, tissue culture derived iris fibroblasts or smooth muscle cells. Our results provide additional support for the concept of crossreactivity between antibodies to microbial agents and peripheral blood mononuclear cells of patients with HLA B27+ AS.     

Analysis of HLA B27 in ankylosing spondylitis with human alloreactive cytolytic T lymphocyte clones: failure to detect disease-related T cell epitopes

We have generated several human alloreactive cytolytic T lymphocyte (CTL) clones specific for HLA B27 expressed on cells of normals or of patients with ankylosing spondylitis (AS). These clonal T cell reagents were used to test the recognition of panels of target cells from B27+AS+, B27+AS- and B27- individuals. None of these CTL clones distinguished differences between B27+AS+ and B27+AS- cells. Three clones recognized subtypes of HLA B27 and two of these were cytolytic with group-reactive epitopes of other HLA antigens. The results suggest that there are no immunogenic disease-specific epitopes of HLA B27 in B27-linked spondyloarthropathy.     

Low frequency of HLA-B*2706 in Taiwanese patients with ankylosing spondylitis.

The presence of HLA-B27 in patients affected with ankylosing spondylitis (AS) was well established prior to the advent of DNA typing of various genes within the major histocompatibility complex (MHC) in humans. However, molecular typing of the MHC genes revealed that B27 comprises a motley assortment of alleles, some of which are strongly positively associated with the disease and some of which are negatively associated with the disease. B*2706 was reported to have a negative association with AS in the Thai population and in Chinese Singaporeans. We report here our finding of an absence of B*2706 in 184 Taiwanese AS patients.