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.     

HLA Phenotypes and joint affection in psoriasis, acute anterior uveitis and chronic prostatitis

In a prospective study, 50 patients hospitalized for psoriasis, 34 patients hospitalized for acute anterior uveitis (AAU) and 29 patients hospitalized for chronic prostatitis, were examined. The expected increased frequencies of HLA B13 and HLA B17 in psoriasis and of HLA B27 in AAU over healthy people were found. No unsuspected association between HLA antigens was observed. Psoriatic patients with peripheral joint affection frequently had affected sacro-iliac joints and were HLA B27 negative. Joint affection was frequently seen in HLA B27 positive patients with psoriasis or AAU. In the patients with AAU, 12 out of 22 patients positive for HLA B27 exhibited radiographical sacro-iliitis. This high prevalence of sacroiliitis suggests an interaction between genes predisposing for AAU and sacroiliitis. Asymptomatic sacro-iliitis was found in both HLA B27 positive and negative patients. The low frequency of clinical symptoms in psoriatic sacro-iliitis could not be explained by the absence of HLA B27.     

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     

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.     

Immune function in ankylosing spondylitics and their relatives: influence of disease and HLA B27.

So as to distinguish the separate influences of ankylosing spondylitis (AS) and possible HLA B27 associated immune response genes on immune response patterns, a battery of immunological tests were performed on fourteen patients with AS and their first-degree relatives. Previously unrecognized AS was detected by clinical and radiological means. Individuals with ankylosing spondylitis had significantly higher serum IgG and IgA concentrations than both their B27 positive and B27 negative relatives. B27 positive relatives had significantly lower phytohaemagglutinin (PHA) lymphocyte transformations than B27 negative relatives (P less than 0.01), while there was no difference between the ankylosing spondylitic and B27 positive groups. Antibody titres to Streptokinase/Streptodornase were significantly higher in the B27 positive individuals, with or without AS, than their B27 negative relatives (P less than 0.005 and P less than 0.02 respectively). These results show that serum immunoglobulin differences were associated with disease, while differences in PHA stimulation and varidase antibody titres were associated with the B27 antigen. These findings may indicate the presence of HLA associated immune response genes including those involved with reactions to a particular antigenic component of Streptokinase/Streptodornase.     

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     

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.     

Ankylosing spondylitis is part of a multifactorial syndrome: hereditary multifocal relapsing inflammation (HEMRI)

Complex associations between the different subgroups of seronegative arthritis, acute anterior uveitis, psoriasis and inflammatory bowel disease were found in a series of patients and relatives. Different HLA-B antigens were associated with different clinical signs. The results indicated the existence of a multigenic syndrome whose main clinical manifestations are relapsing innflammations at various sites. The genetic factors appeared to be 1) HLA-B27 associated disease susceptibility, 2) predisposition to psoriatic arthropathy, 3) predisposition to early onset familial psoriasis and, 4) a probable predisposition to inflammatory bowel disease and its associated arthropathy. The results indicated that the different genetic factors may interact and influence each other's penetrance and expression.     

TAP polymorphism is not associated with ankylosing spondylitis and complications with acute anterior uveitis in HLA-B27-positive Japanese

Abstract: HLA-B27 is associated with the etiology of ankylosing spondylitis (AS) and acute anterior uveitis (AAU). Transporter associated with antigen processing (TAP) 1 and TAP2 polymorphism influences the range of peptide presented by HLA class I molecules. In this report, contribution of TAP polymorphism to the susceptibility to AS and AAU was studied in HLA-B27-positive Japanese individuals. Patients were classified into three groups: 16 AS patients, 14 AAU patients and 22 patients with both AS and AAU. Twelve HLA-B27-positive healthy individuals were included as a control. TAP polymorphism was detected by PCR-RFLP methods. Significant differences in frequencies of TAP1 alleles were not found between patient groups. None of the TAP2 frequencies showed increased or decreased frequencies compared with HLA-B27-positive healthy controls. In comparison with a random Japanese control, TAP2D allele frequency was significantly increased in the AAU group, but failed to reach a significant level in a group consisting of the AAU-only patients and the patients with both AS and AAU. All of the patient groups were noted to have a significantly increased prevalence of the TAP2H allele as compared to random controls; however, the higher frequency of this allele was detected in HLA-B27 healthy controls as well. These observations suggest a linkage disequilibrium between TAP2D, TAP2H and HLA-B27 in Japanese.     

HLA-B27基因检定技术

用聚合酶链反应和血清学方法检测ＨＬＡ－Ｂ２７，并进行比较。方法：采用ＰＣＲ技术７８例可疑为强直性脊椎炎患者样本的ＨＬＡ－Ｂ２７基因，并与血清学比较。结果：３６例具有Ｂ２７基因者中２４例同时作血清学试验，５例血清学难以判定结果，并与ＰＣＲ结果不一致。     

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。     

Association of HLA B27 antigen in Indian patients of ankylosing spondylitis and other autoimmune diseases

One thousand three hundred and forty clinically suspected patients of Ankylosing Spondylitis (AS) and other autoimmune diseases and 5000 controls were studied to detect the association of HLA B27 antigen amongst them. Other alleles studied include HLA B7, B40 (B60), B22(B55), B13, etc. Our findings show a considerable and consistent association of HLA B27 with AS irrespective of the community to which the patient, belonged his hygiene or socio-economic conditions. We also found that people in the age group of 21-39 were the most vulnerable, when number of affected individuals or severity of the disease were taken into consideration. Male members showed a preponderance over females in HLA B27 positivity. Detection of HLA B27 could help in the diagnosis of AS. Patients suffering from other autoimmune diseases such as rheumatoid arthritis, psoriasis, Reiter's syndrome and uveitis and patients with inflammatory bowel disease, colitis, eczema, bacillary or fungal infection were also found to be HLA B27 positive. A study of other alleles shows that even they sometimes associate AS and other autoimmune diseases.     

Association of the HLA‐B27 antigen and the CTLA4 gene CT60/rs3087243 polymorphism with ankylosing spondylitis in Algerian population: A case–control study

Ankylosing spondylitis (AS) is a complex inflammatory disease that represents a major health problem both in Algeria and worldwide. Several lines of evidence support that genetic risk factors play a role in AS etiology and the CTLA4 gene has attracted a considerable attention. In this study, we were interested in evaluating the HLA‐B27 frequency and in exploring the CTLA4 gene in a sample of the North African population. The dataset of the current study is composed of 81 patients with AS and 123 healthy controls. All samples were genotyped by TaqMan^®allelic discrimination assay. The genetic risk of the HLA‐B27 specificity and the CTLA4/CT60 polymorphism were assessed by odds ratios (OR) with 95% confidence intervals (CI). High spondylitis risk was detected for HLA‐B27 allele (OR= 14.62, p = 10^?6) in addition to a significant association of the CT60*G allele (OR= 1.89, p = .002). After gender and age stratifications, the association of the CT60*G allele was still significant in females sample (OR= 2.10, p = .001) and when age up to 30 years (OR = 2.21, p = .008). Interestingly, the CT60*G allele revealed an increased spondylitis risk in the B27 negative group (OR= 2.81, p = .006). The present work showed in West Algerian population that the HLA‐B27 antigen and the variation in the CTLA4 3′UTR region played an important role in the ankylosing spondylitis susceptibility. The heterogeneity of this disease is deduced by genetic difference found between B27+ and B27? groups.     

低分子量多肽2 基因多态性与强直性脊椎炎表型的关系

目的研究低分子量多肽（ｌｏｗｍｏｌｅｃｕｌａｒｗｅｉｇｈｔｐｅｐｔｉｄｅ,ＬＭＰ）基因多态性与强直性脊椎炎（ａｎｋｙｌｏｓｉｎｇｓｐｏｎｄｙｌｉｔｉｓ,ＡＳ）表型的关系。方法收集各种类型ＡＳ和单纯虹膜炎（Ａｃｕｔｅａｎｔｅｒｉｏｒｕｖｅｉｔｉｓ,ＡＡＵ）血标本１１８例。应用聚合酶链反应技术对正常人和患者进行ＨＬＡ－Ｂ２７检测以及ＬＭＰ２和ＬＭＰ７扩增,以ＣｆｏⅠ进行限制性酶切图谱分析。结果ＡＳ有ＡＡＵ病史患者ＬＭＰ２基因ＢＢ型频率较正常人以及ＡＳ患者明显增高（Ｐ＜０．０５）,ＯＲ为３．７１。少年型ＡＳ与成年型ＡＳ以及单纯中心型ＡＳ与伴有外周关节炎（ｐｅｒｉｐｈｅｒａｌａｒｔｈｒｉｔｉｓ,ＰＡ）的ＡＳ之间ＬＭＰ２基因型没有明显差异（Ｐ＞０．０５）。ＰＡ＋／ＡＡＵ＋与ＰＡ＋／ＡＡＵ－患者间存在显著差异（Ｐ＜０．０５）,ＯＲ值为４．６３６。ＡＡＵ患者与正常人存在显著差异（Ｐ＜０．０５）,ＯＲ值为５．８３。ＬＭＰ７基因多态性无明显差异。结论ＬＭＰ２基因多态性与有ＡＡＵ病史的ＡＳ以及单纯ＡＡＵ发病存在明显相关,而与ＡＳ发病年龄以及关节类型没有明显关系。     

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.     

Taq I polymorphism of HLA class I genes in an ankylosing spondylitis family

A 3.5-kb HLA class I fragment is polymorphic in an ankylosing spondylitis (AS) family. All B27 AS patients show the 3.5-kb band, which is also present in B12 AS patients in this family. When hybridized with an HLA-B-specific probe, the polymorphic band is revealed in B12 patients, but not in B27 patients.     

HLA B53 is associated with a poor outcome in black COVID-19 patients

A disproportionate incidence of death has occurred in African Americans (Blacks) in the United States due to COVID-19. The reason for this disparity is likely to be multi-factorial and may involve genetic predisposition. The association of human leukocyte antigens (HLA) with severe COVID-19 was examined in a hospitalized population (89% Black, n = 36) and compared to HLA typed non-hospitalized individuals (20% Black, n = 40) who had recovered from mild disease. For additional comparison, HLA typing data was available from kidney transplant recipients and deceased donors. Hospitalized patients were followed for 45 days after admission to our medical center with death as the primary end-point. One HLA allele, B53, appeared to be more prevalent in the hospitalized COVID-19 patients (percent of positive subjects, 30.5) compared to national data in US Black populations (percent of positive subjects, 24.5). The percent B53 positive in non-hospitalized COVID-19 patients was 2.6, significantly less than the percent positive in the hospitalized COVID-19 patients (p = 0.001, Fisher’s exact test) and less than the 8 percent positive listed in national data bases for US Caucasian populations. Significantly greater deaths (73 percent) were observed in HLA B53 positive hospitalized COVID-19 patients compared to hospitalized COVID-19 patients who were B53 negative (40 percent). Multi-variate analysis indicated that HLA B53 positive Black hospitalized COVID-19 patients were at a 7.4 fold greater risk of death than Black COVID-19 patients who were B53 negative. Consideration for accelerated vaccination and treatment should be given to HLA B53 positive Black COVID19 patients.