Mortality in pacemaker-treated patients. A follow-up study of the impact of HLA B27 and associated rheumatic disorders

The mortality in pacemaker-treated patients is due to underlying disorders, and is increased in patients with ischemic heart disease, congestive heart failure, diabetes and renal dysfunction. We have recently shown that the HLA B27-associated inflammatory disease process is the probable underlying cause in 15-20% of permanently paced men. Consequently, we undertook this study to evaluate any impact on mortality of HLA B27 and associated rheumatic disorders. The mortality among pacemaker patients was compared with that of the general population. Comparisons were also made between pacemaker patients with and without HLA B27 and associated disorders. We did not find any influence on mortality associated with the immunogenetic marker HLA B27 or with HLA B27-associated rheumatic disorders.     

Structural homologies between two HLA B27-restricted peptides suggest residues important for interaction with HLA B27

Recently we described an HLA B27-restricted peptide derived from HIV gag p24 protein. In this study we have isolated an HLA B27-restricted peptide from the nucleoprotein (NP) of influenza A virus. The shortest fragment recognized by cytotoxic T lymphocyte (CTL) is eight amino acids long, residues 384-391. Comparison of the sequence of these two HLA B27 restricted peptides reveals homologies which can be aligned from one peptide to the other. Of the eight residues, two are identical: tryptophan and isoleucine. Both peptides have a positively charged residue at the N terminus, lysine at position 265 of gag and arginine at position 384 of NP. Using modified peptides we have shown that lysine or arginine is crucial for the interaction with HLA B27. The wild-type gag peptide blocked CTL recognition of NP peptide by influenza-specific CTL, but removal of the lysine prevented inhibition of NP peptide recognition. The importance of these charged residues was confirmed by the observation that truncated NP and gag peptides where the lysine or arginine was removed were not recognized by specific CTL. Further studies showed that the tryptophan residue influenced the association of the gag peptide with HLA B27, because the affinity of the gag peptide for B27 was strongly increased after replacing this residue with a leucine or a tyrosine. However, these peptides were not recognized by gag-specific CTL, suggesting that the tryptophan may interact with both HLA B27 and T cell receptor. These observations should help in the identification of HLA B27-restricted peptides from other viruses or organisms.     

Atrial fibrillation is associated with cardiac hypoxia

BackgroundAtrial fibrillation (AF), the most common human arrhythmia, is responsible for substantial morbidity and mortality and may be promoted by selective atrial ischemia and atrial fibrosis. Consequently, we investigated markers for hypoxia and angiogenesis in AF.MethodsRight atrial appendages (n=158) were grouped according to heart rhythm [sinus rhythm (SR) or AF]. The degree of fibrosis and microvessel density of all patients were determined morphometrically using Sirius-Red- and CD34/CD105-stained sections, respectively. Next, sections (n=77) underwent immunostaining to detect hypoxia- and angiogenesis-related proteins [hypoxia-inducible factor (HIF)1α, HIF2α, vascular endothelial growth factor (VEGF), VEGF receptor 2 (KDR), phosphorylated KDR (pKDR), carboanhydrase IX, platelet-derived growth factor] and the apoptosis-related B-cell lymphoma 2 protein.ResultsFibrosis progressed significantly from 14.7±0.8% (SR) to 22.3±1.4% (AF). While the positive cytoplasmic staining of HIF1α, HIF2α, VEGF, KDR, and pKDR rose significantly from SR to AF, their nuclear fractions fell (only pKDR significantly). The median CD34/CD105-positive microvessel size increased significantly from SR to AF.ConclusionsAF is closely associated with an atrial up-regulation of hypoxic and angiogenic markers. Whether this is cause, effect, or co-phenomenon of fibrosis remains to be investigated. It is conceivable that fibrosis might lead to an increased O₂ diffusion distance and thus induce ischemic signaling, which, in turn, leads to angiogenesis.     

HLA B27 polymorphism in Western India

We have characterized HLA B27 alleles in a sample population of Maharastra, Western Indians (n = 51), with the aim to investigate the different subtypes present among this population. The study was carried out using polymerase chain reaction with sequence-specific primers (PCR-SSP) and reverse line strip (RLS) techniques. Significant new findings have arisen from this study: B*2704, B*2705, B*2707, B*2708 and B*2714 alleles were found to be present, and two novel B27 alleles, B*2708 and B*2714, were found in this Indian population. In addition, B*2714 was observed in a patient with ankylosing spondylitis. This association has not been previously reported in ethnic groups from India.     

Complete heart block — another HLA B27 associated disease manifestation

An increased prevalence of ankylosing spondylitis and other HLA B27-associated rheumatic diseases has recently been demonstrated in a group of men with permanent pacemaker-treatment. The purpose of the present study was to find out if HLA B27 was associated with severe bradyarrhythmias also in the absence of rheumatic disease.
The frequency of B27 was determined in 83 permanently paced men with complete heart block, in whom presence of radiological or clinical signs of a B27-associated rheumatic disease had been excluded. Eighty-four healthy subjects were HLA typed for comparison.
HLA B27 was found in 17% of the patients and in 6% of the controls, a significant difference with P = 0.017 (Fisher's exact test). The present study suggests that, in a subgroup of patients with complete heart block, the development of heart block is B27-associated, and that the pathophysiological mechanism is similar to that leading to ankylosing spondylitis.
Another B27-associated disease manifestation has been demonstrated.     

强直性脊椎炎病人HLA B27等位基因与HLA A、B 抗原关系分析

目的　调查强直性脊椎炎（ Ａ Ｓ） 病人中 Ｂ２７ 等位基因与其它 Ｈ Ｌ Ａ Ａ、 Ｂ 抗原之间的关系,为 Ａ Ｓ 与 Ｂ２７ 关联机理提供线索。方法　 Ｈ Ｌ Ａ Ａ、 Ｂ 抗原分型采用 Ｎ Ｉ Ｈ 标准微量淋巴细胞毒方法, Ｂ２７ 等位基因的检测采用聚合酶链反应／ 顺序特异的寡核苷酸探针方法。对上海地区６８ 例 Ａ Ｓ 病人和３１８ 例正常对照进行调查。结果　 Ａ Ｓ 病人根据其所检定的 Ｂ２７ 等位基因主要可分为 Ｂ２７０４和 Ｂ２７０５ 二大组, Ｈ Ｌ Ａ Ａ１１ 的频率在 Ｂ２７０４ Ａ Ｓ 组要比正常对照组显著增高（ Ｐ＝ ００００ ９８ , Ｐｃ＜ ０ ．０１） ,在 Ｂ２７０５ Ａ Ｓ 组则比正常对照组稍低（ Ｐ＞ ０ ．０５） , Ｂ２７０４ 与 Ｂ２７０５ Ａ Ｓ 组之间差异也有统计学意义（ Ｐ＜ ０ ．０５） 。结论　上海地区携带 Ｂ２７０４ 的 Ａ Ｓ病人与 Ｈ Ｌ Ａ Ａ１１ 抗原相关,提示 Ｂ２７０４ 与 Ｂ２７０５ 在 Ａ Ｓ 发病中的具体作用可能有所差异,或 Ｂ２７０４ 与 Ａ１１ 之间存在连锁不平衡。     

Soluble HLA-DR molecules in patients with HLA class II versus class I associated disorders

HLA genes have been identified as key genetic factors contributing to many chronic diseases characterized by autoimmune features. The role of HLA encoded molecules in the pathogenesis of these diseases is unresolved. We have now analysed soluble HLA-DR molecules circulating in the serum of patients with different autoimmune diseases and have defined parameters controlling serum levels. Patients with HLA-DR associated diseases were characterized by elevated serum concentrations of HLA-DR molecules and were clearly distinct from patients with HLA-B27 associated disorders. We did not find evidence for a correlation between disease activity, laboratory abnormalities and elevated serum concentrations of soluble HLA-DR molecules. Studies in normal individuals indicated that soluble HLA-DR molecules are at least partially regulated by the HLA haplotype. Highest serum concentrations were found in individuals carrying the HLA-DR3 or HLA-DR4 haplotype raising the possibility that the phenomenon of HLA-disease association reflects differences in the genetic control of soluble HLA-DR molecules. Interferon-gamma treatment caused an increase in serum concentrations of soluble HLA-DR molecules, whereas a decrease of circulating HLA-DR molecules was associated with an immunosuppressive with cyclosporine A. These data suggest that the patient's immunoresponsiveness represents a second important mechanism controlling circulating HLA-DR molecules.     

B27-bearing HLA haplotypes in rheumatoid arthritis: characterization in Finnish patients

The frequency of human leukocyte antigen (HLA)-B27 has been found to be increased in rheumatoid arthritis (RA) in Finland and marginally also in some other populations. In the present study HLA-B27-bearing haplotypes in RA patients were found to carry DR1 and DR4 genes more often than do B27 haplotypes in control population. B27;DR4,DW14;DQw7 was a typical B27-DR4 haplotype whereas DR4 in the majority of other haplotypes occurs with Dw4 and DQw8 genes. The result indicates that the B27 association with RA is not independent of DR1 and DR4, but whether the B27;DR4;DQw7 haplotype subjects a person to a higher disease risk than do other DR4 haplotypes, or is associated with a more severe course of the disease, remains to be investigated.     

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.     

HLA, blood groups and secretor status in patients with established rheumatic fever and rheumatic heart disease

The distribution of HLA-A, -B and -DR antigens as well as blood groups and secretor status was studied in sporadic, North Indian patients of rheumatic fever and rheumatic heart disease. While HLA-Aw33 occurred with an increased frequency in the patient group (X2 = 4.01), no statistically significant differences were observed in the frequency of B-locus antigens. In the DR locus, HLA-DR3 was found to be significantly increased (50% vs 26.1%, X2 = 13.8) and DR2 significantly reduced (21.8% vs 47.0%, X2 = 15.6). Also, there was a preponderance of non-'O' blood group individuals in the patient group as compared to controls. The DR3 association was significant only in those patients of RHD who did not have any previous history of rheumatic fever. These results indicate that susceptibility to rheumatic heart disease is HLA-class II mediated, with HLA-DR3 influencing susceptibility and DR2 conferring protection.     

Arthritis associated with Strongyloides stercoralis infection in a HLA B-27-positive African

A 44-year old West-African living in Germany since 18 years presented because of persistent painful swelling of both ankle joints and diffuse lymphoedema of feet occurring after a trip to Morocco. Laboratory tests revealed inflammation and eosinophilia. HLA-B27 was positive. Antinuclear antibodies and rheuma factors were not found. There was no evidence of an infection with bacteria or viruses known to cause arthritis. Filariasis was excluded. Microscopy of fresh stool revealed larvae of Strongyloides stercoralis. Symptoms resolved after specific antihelminthic therapy with ivermectin 0.2 mg kg⁻¹ day⁻¹ for 2 days and non-steroidal anti-inflammatorials. Reactive arthritis is known to be caused by various bacterial agents. In some individuals, arthritis may be due to helminths, such as S. stercoralis. Patients with strongyloidiasis may respond to non-steroidal anti-inflammatorials but must not undergo treatment with corticosteroids before having received antihelminthic therapy because immunosuppression may result in life-threatening strongyloides hyperinfection syndrome.     

Role of HLA B27 in diagnosis of seronegative spondyloarthropathies

Seronegative Spondyloarthropathies (SSA) is a very common problem in our area. The main aim of present study was (1) to find the HLA B27 positivity in patients presenting with sacroileitis (2) to see the correlation of B27 positivity on haematological, radiological and extra articular manifestations. Total 110 patients of SSA were studied between July 2004 to June 2005. Routine haematological and immunological test were done by standard method. Total positivity of B27 in SSA was 43.63%, HLA B27 positivity was higher in children (68.75%). Sex wise analysis of B27 positive cases showed that 81.81% B27 positive patients were males. In HLA B27 positive cases lower spine, hip, sacroiliac, shoulder and knee joints were more involved (77.08%, 79.16%, 79.16%, 37.50% and 50.00% respectively). Urinary tract infection (UTI), diarrhoea and constipation were more common in B27 positive cases. Leukocytosis of neutrophilic type (33.33%), raised ESR (77.55%)., CRP positivity (63.63%) and anaemia (65.00%) were seen more frequently in B27 positive cases. In bilateral sacroiliitis diagnosed by X-ray, only 69.23% patient were B27 positive. Our study concludes that HLA B 27 positivity is higher in SSA seen in childhood and in young adult males. B27 positive patients have more severe disease and systemic manifestation Hence, male patients specially young adolescent or young adults with sacroileitis must be subjected for B27 typing.     

HLA B-27 subtypes in Turkish patients with spondyloarthropathy and healthy controls

The frequency and the distribution of HLA-B27 subtypes in spondylarthropathy (SpA) patients and controls were investigated in a sample Turkish population. B27 subtyping was performed by PCR-SSP method in two groups: 49 unrelated HLA-B27 positive Turkish patients with the diagnosis of SpA according to the European Spondyloarthropathy Study Group Criteria, and 55 HLA-B27 positive healthy controls. The frequency of HLA-B*27 was 2.6% in the Turkish population, and B*2705 was the predominant allele among patients with SpA. The difference was mainly between male patients and male controls The proportion of B*2705 among B27-positive patients and controls was significantly different (P=0.02). Our study supports other reports from different populations which showed that B*2705 and B*2702 were more frequent in Caucasian patients with SpA.     

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.     

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.     

Interstitial microfibrils in the myocardium of patients with rheumatic and congenital cardiac defects

Electron-microscopic investigation of biopsy specimens of heart tissue from patients with rheumatic and congenital cardiac defects revealed aperiodic microfibrils, the number of which was proportional to the fibrosis of the myocardium, on the basal membranes of the capillaries and muscle fibers and also in the lumen of the T-tubules and their vacuolar expansions. If signs of rheumatic carditis are present the myofibrils are less regular and their number somewhat greater. Microfibrils are rutheniophilic and argyrophilic and consist of elementary fibrils of reticular fibers. Their hyperplasia is the ultrastructural equivalent of the reticular skeleton of the hypertrophied myocardium in patients with cardiac defects.Institute of Rheumatism, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR A. I. Strukov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 82, No. 8, pp. 1011–1014, August, 1976.     

HLA class II antigens are associated with Japanese pemphigus patients

We investigated the HLA class II antigens in 30 Japanese cases of pemphigus, 17 cases of pemphigus vulgaris (PV) and 13 cases of pemphigus foliaceus (PF), by both serologic and restriction fragment length polymorphism (RFLP) analyses. We detected two major haplotypes susceptible to PV, i.e., DRw12-DQw7 and DRw6-DQ5. In contrast, DR2 was absent in PV. RFLP analyses showed that DRw6 PV patients had a disease-associated restriction fragment representing DQw5, the same association as that found in DRw6 Jewish PV patients. However, DRw12 Japanese PV patients had DQw7, whereas DR4 Jewish PV patients had DQw8. On the other hand, all 13 PF patients were serologically typed for DQwl, which could not be further subdivided into DQw5 by RFLP analyses. These results suggest that Japanese and Jewish PV patients may be immunogenetically closely related to each other, but Japanese PV patients appear to be immunogenetically different from Japanese PF patients. (1991).     

Detection of antibodies to streptococcal mucopeptide in patients with rheumatic disorders and normal controls

Bacterial mucopeptide is an integral part of bacterial cell walls and is therefore ubiquitous in our environment. An enhanced degree of humoral immunity has ben detected not only in patients with acute rheumatic fever (ARF), with a known recent response to streptococci, but also in patients with adult and juvenile rheumatoid arthritis (RA and JRA). Our studies confirmed this association with ARF and JRA using a precipitin system as well as a radioimmunoassay to detect IgG anti-mucopeptide antibodies. In those with adult RA, either IgM or IgA rheumatoid factors or IgM or IgA antibodies specific for mucopeptide were responsible for the increased incidence of precipitins to mucopeptide in the RA patients detected in this and other studies. No differences in the specificities of the anti-mucopeptide antibodies were noted between the various patient populations as there were no lines of partial identity or nonidentity when examined by Ouchterlony double diffusion analyses. Additionally, no differences of anti-mucopeptide antibody were observed when the sera from these same patient populations were examined employing inhibition studies utilizing N-acetylglucosamine and rhamnose.