HLA-B27 in Rheumatoid Arthritis and Amyloidosis

To study the role of genetically determined immune responsiveness in the pathogenesis of systemic amyloidosis complicating rheumatoid arthritis the HLA antigens were identified in 26 patients with rheumatoid arthritis complicated by secondary amyloidosis, in 44 patients with rheumatoid arthritis, and in 11 patients with secondary amyloidosis of non-rheumatoid origin. Subjects with ankylosing spondylitis, sacroiliitis without peripheral polyarthritis, Reiter's disease, reactive arthritis, erosive osteoarthritis, psoriatic arthropathy, systemic lupus erythematosus or arthritis associated with a gastrointestinal involvement were excluded from the study. Patients with amyloidosis secondary to rheumatoid arthritis had a high frequency of the HLA specificity B27 and of the haplotype likely to bear A2, B27. The association with B27 was closest in the group of male patients with amyloidosis whose rheumatoid arthritis had begun at an early age and who lacked demonstrable rheumatoid factor in serum. These patients may represent a genetically determined subentity of rheumatoid arthritis.     

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.     

Molecular mimicry in Reiter's syndrome: cytotoxicity and ELISA studies of HLA-microbial relationships.

The pathogenic links between HLA antigens, certain bacterial infections and arthritis have not yet been characterized. The hypothesis of cross-reactivity between HLA B27, the marker of disease susceptibility for these disorders, and the provocative microorganism has been suggested by studies of Klebsiella and ankylosing spondylitis. The present study examines the possibility of molecular mimicry between HLA B27 and two organisms implicated more directly in reactive arthritis, Yersinia enterocolitica and Chlamydia trachomatis. Antibodies against these organisms were obtained both from patients and from antisera raised in rabbits. Neither source of antibacterial antibody was specifically cytotoxic for HLA B27-positive lymphocytes, even when the target cells were derived from patients with recent infections due to these organisms. In addition, monoclonal antibodies against HLA B27 (M1 and M2) showed no reactivity with antigens from these organisms in an ELISA system. These data do not support the notion of molecular mimicry as being the basis of immunogenetic susceptibility to reactive arthritis and Reiter's syndrome following infections with Y. enterocolitica and C. trachomatis.     

HLA profile and Reiter's syndrome

The analysis of the clinical and HLA profiles of 99 patients with Reiter's syndrome is reported. Antigen HLA-B27, which has previously been firmly associated with Reiter's syndrome, predisposes patients to develop disease features which reflect articular involvement. The HLA haplotype A2, B27 was found to be at an elevated frequency in our Reiter's syndrome sample, and the latter two antigens are also associated with a general increase in disease severity. Conversely, antigen BW35 appears to be protective against certain features of the syndrome. Patients with certain antigenic profiles (namely A2 and A3 together with B27) tend to develop certain syndrome manifestations earlier in the course of the disease than those with other antigens.     

beta2-Microglobulin in ankylosing spondylitis and in Reiter's syndrome (author's transl)]

In patients with ankylosing spondylitis (AS) the plasma level of beta2-microglobulin (beta2m) is signficantly higher (1.95 +/- 0.48 mg/l) than in osteoarthritis (1.48 +/- 0.47 mg/l). In Reiter's syndrome the level of beta2m is also higher than in controls, but the paucity of results do not allow definite conclusions. The plasma level of beta2m in AS and in Reiter's syndrome is not related to the presence of HLA B 27 antigen, neither to other biological parameters as sedimentaton rate, blood cell counts, electrophoresis of plasma proteins. In rheumatoid arthritis the plasma level of beta2m is 2,67 +/- 0.84 mg/l, significantly higher than in osteoarthritis or in AS even without any association with Sj?gren's syndrome. In synovial fluid, the beta2m level is closely related to the degree of inflammation, suggesting a local production of this substance.     

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。     

Cellular immunity to autologous IgG in rheumatoid arthritis and rheumatoid-like disorders

Cellular immunity to autologous IgG was determined by a modified agarose leucocyte migration test in twenty-seven patients with rheumatoid arthritis, sixteen patients with ankylosing spondylitis, thirteen patients with Reiter's syndrome, and in a control group consisting of twenty-four healthy, gouty and osteoarthritic subjects. Lymphocytes isolated from peripheral blood were incubated with native and aggregated autologous IgG for 7 days and the supernatants were assayed for the presence of leucocyte migration inhibitory and leucocyte migration enhancement factors. Both factors have been shown to be in vitro correlates of the delayed hypersensitivity reaction. Positive responses to autologous IgG were observed in twenty-three of twenty-seven patients with rheumatoid arthritis, twelve of sixteen subjects with ankylosing spondylitis, five of thirteen individuals with Reiter's syndrome, and four of twenty-four subjects in the control group. Serum antiglobulins to IgG measured by agglutination techniques were present in 77% of patients with rheumatoid arthritis and in none of the subjects with ankylosing spondylitis. There was no correlation between cellular immunity to IgG and the presence of serum antiglobulins. These data indicate that cellular immunity to autologous IgG is an immunological abnormality common to both rheumatoid arthritis and ankylosing spondylitis.     

Cell-mediated immunity in the rheumatoid diseases. I. Skin testing and mitogenic responses in sero-negative arthritides.

Cellular immunity has been investigated in patients with various kinds of sero-negative arthritis. The incidence of cutaneous response to recall antigen streptokinase-streptodornase (SK-SD), and the ability to mount a primary cutaneous response to dinitrochlorobenzene (DNCB) have been examined in patients with ankylosing spondylitis and psoriatic arthritis. The results were not significantly different from normal. In vitro lymphocyte transformation in the presence of phytohaemagglutinin (PHA), concanavalin A (Con A), and pokeweed mitogen (PWM) has been measured using peripheral blood lymphocytes from patients with ankylosing spondylitis, psoriatic arthritis and Reiter's disease. In comparison with a control group, significantly reduced responses were found to a low dose of PHA in the ankylosing spondylitis and Reiter disease patients. Significant increase in response occurred to a high dose of PHA, in patients with psoriatic arthritis and Reiter's disease, and to PWM in Reiter's disease patients. The in vitro results in the ankylosing spondylitis, psoriatic arthritis and Reiter's disease patients suggest some abnormality in the T-cell population in sero-negative arthritis.     

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.     

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.     

Treatment of rheumatoid and degenerative diseases with copper complexes

This review presents a historical account of the treatment of rheumatoid and other degenerative diseases with copper complexes. Clinical data obtained from 1940 to 1971 are provided for about 1500 patients with rheumatoid arthritis (acute or chronic), rheumatic fever, ankylosing spondylitis, staphlococcal spondylitis, gonococcal arthritis, chronic gouty arthritis, polyarticular synovitis, coxitis, disseminated spondylitis, arthritis with psoriasis, Reiter's syndrome, lupus erythematosus, sarcoidosis, arthrosis deformans, erythema nodosum, sciatica (with and without lumbar involvement), cervical spine-shoulder syndrome or lumbar spine syndrome. The drugs used in these studies were Dicuprene, Alcuprin, Cuprimyl, and Permalon, a coppersalicylate preparation. A detailed presentation of toxicities associated with the use of these copper complexes is included.     

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.     

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.     

HLA and Juvenile Chronic Polyarthritis

HLA antigen have been identified in patients with juvenile chronic polyarthritis (J.C.P.) (n = 35). In J.C.P. the incidence of antigen B27 (57%) was found to be higher than in a normal population (n = 1,000). On recent evaluation of the clinical status, serology and x-rays, the patients with juvenile chronic polyarthritis who has been followed up many years, could be subdivided into four groups: Group 1: J.C.P. evolving to ankylosing spondylitis (n = 3); Group 2: J.C.P. with sacroiliitis (n = 17); Group 3: J.C.P. without sacroiliitis (n = 9); Group 4: juvenile rheumatoid arthritis characterised by a positive serology (n = 6). Groups 1 and 2 were characterized by a high incidence of antigen B27 (19/20). Only one subject of groups 3 and 4 had antigen B27. Sex distribution in groups 1 and 2 was found to be similar to that found in ankylosing spondylitis in adults and sex distribution in groups 3 and 4 was found to be similar to that found in rheumatoid arthritis in adults. It is concluded that if B27 positive develop juvenile chronic polyarthritis they have a high risk of developing sacroiliitis and acute uveitis. The authors propose to give the name Still's disease to the total group of children presenting initial symptoms corresponding to the criteria of Ansell & Bywaters (1959). Follow-up of the cases permitted their further classification as juvenile ankylosing spondylitis, as juvenile chronic polyarthritis with or without sacroiliitis or as juvenile rheumatoid arthritis.     

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.     

Diversity of human leukocyte antigen-B27 alleles in Han population of Hunan province, southern China

This study was to investigate the frequency of HLA-B27 and its subtypes in the Han population of Hunan province, southern China. One hundred and sixty-nine healthy unrelated donors were tested for HLA-B27 by polymerase chain reaction-sequence-specific primer (PCR-SSP). One hundred and twenty-eight B27-positive spondyloarthropathy patients and 18 B27-positive healthy controls were subtyped using the high-resolution PCR-SSP. The phenotype frequency of human leukocyte antigen (HLA)-B27 was found to be 2.36% in healthy population. Five B27 alleles were identified: B*2704, B*2705, B*2706, B*2707, and B*2724. No significant difference was found in the distribution of HLA-B27 subtypes between the patients and controls studied. Notably, B*2724 was observed in a juvenile patient with ankylosing spondylitis. This subtype has not been previously reported in Chinese ankylosing spondylitis (AS) patients and other ethnic groups.     

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.     

Abnormal Helper-Inducer/Suppressor–Inducer T-Cell Subset Distribution and T-Cell Activation Status are Common to All Types of Chronic Synovitis

We have previously shown that rheumatoid synovial T cells are virtually all helper-inducer (CD4+4B4+UCHL1+) rather than suppressor-inducer (CD4+2H4+) cells. CD8 cells were also largely 4B4+. In addition, the majority of T cells were HLA-DR+. To investigate whether these findings were specific for rheumatoid disease, we studied the prevalence of these markers in a variety of chronic inflammatory arthropathies such as ankylosing spondylitis, Reiter's syndrome, and psoriatic arthritis. Again, almost 90% of the T cells were 4B4+UCHL1+ and only 11% were 2H4+; 50% expressed the HLA DR antigen. Thus this phenotypic distribution represents a final common pathway of chronic synovitis and may help to explain the immunopathology of the lesion.     

Recognition of HLA-B27 and related antigen by a monoclonal antibody

A monoclonal antibody that binds specifically to HLA-B27, B7, and B22 is described. Binding to B27 appeared to be slightly stronger than to B7 and stronger than to B22 in an indirect binding assay, but no difference in B7 and B27 binding could be detected by Scatchard analysis. No distinction could be made between B27 on cells from normal and from ankylosing spondylitis patients in any assay system. The antibody, which was not cytotoxic, blocked complement-dependent cytolysis mediated by human HLA typing sera specific for B7 and B27. Competitive binding studies with other monoclonal antibodies showed that ME1 could block the binding of antibodies that recognized different antigenic sites on HLA. ME1 did not bind to Klebsiella pneumoniae. This reagent will be useful in further analysis of the relationship between B27 and ankylosing spondylitis.     

Homocysteine modification of HLA antigens and its immunological consequences

Homocysteine-treated cells can be specifically lysed by cytotoxic T lymphocytes (CTL) identifiable in patients with ankylosing spondylitis and reactive arthritis. Sensitization of target cells involves disulfide bonding and the interaction between homocysteine and HLA antigens occurs in a pre-Golgi compartment in the cells. Salmonella-infected B cells are also lysed by homocysteine-specific CTL, suggesting that intracellular invading microorganisms may provide homocysteine which would gain access to the newly synthesized intracellular HLA molecules and modify them inside the cells. Two different mechanisms for homocysteine modification of HLA antigens are proposed: homocysteine could bind directly to the unpaired cysteine residues in HLA antigens, or it could bind indirectly to HLA antigens through cysteine-containing peptides bound to them. Thus, HLA antigens containing unpaired cysteine residues (e.g. HLA B27) could be modified by homocysteine directly or indirectly, while HLA antigens without unpaired cysteine residues (e.g. HLA A68) could only be modified indirectly. The results are discussed in relation to the potential involvement of homocysteine-specific CTL in ankylosing spondylitis and reactive arthritis, both of which are related to bacterial infections, associated with HLA B27, and considered to be autoimmune diseases.