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Abstract
Study of products of genes present on a region on chromosome 6 known as the Major Histocompatibility Complex (MHC) is providing new insight into many chronic diseases of undetermined aetiology, including rheumatic diseases such as ankylosing spondylitis1,2 and rheumatoid arthritis3,4. The human MHC is called HLA, and it contains a tightly linked cluster of genes that encode for cell surface glycoprotein molecules expressed on the cell membrane of virtually all cells5–7. These molecules are involved in cell-to-cell interaction and have been subdivided into two distinct groups called class I and class II molecules6–8. The class I molecules are encoded by the HLA-A, -B, and -C loci of the MHC. These molecules display an exceptional degree of genetic polymorphism and are composed of an MHC-encoded heavy — or α — chain that is non-covalently bound to β2-microglobulin, a smaller and invariant polypeptide chain encoded by a gene located on another chromosome5–8. The class II molecules consist of two glycoprotein chains as well, the larger of the two chains is called α chain and the smaller one is called β chain. These two chains are closer in size than those of the class I molecules. Moreover, both α and β chains are encoded by genes located in the HLA-D region7,8.
... The condition is believed to be more common in males than in females, with the typical age of onset occurring between the ages of 17 and 30 (Khan, 2002). ...
... The condition can be heredity (Hart, 1980;Khan, 2002). In 82% of individuals with ankylosing spondylitis, a fusion of the sacroiliac joint will occur within six years. ...
... This condition is characterized by pitting on the intervertebral surface, along with osteophytes forming along the edge of the marginal surface, resulting in a lipped appearance. The degenerative nature of this condition is believed to be caused by the damage or wear to the intervertebral disc and bony protrusions into the intervertebral foramen are not uncommon (Khan, 2002). These protrusions can damage the nerve connections and arterial passages, causing further degeneration (Kettering et al., 1996). ...
Thesis for completion at the University of Sheffield.
Abstract:
Pathological conditions of the joints are commonplace and incurable, affecting millions of living individuals and yet, surprisingly, there is a great deal that is still unknown about them, including the role and interactions of a variety of risk factors which underpin their development. Much can be learned about joint conditions in the past by marrying clinical and palaeopathological research and by examining patterns of prevalence for joint conditions amongst the living and the trends of the past, the risk factors can be better understood. This thesis aims to utilize palaeopathological evidence of specific joint conditions from past populations in an effort to critically evaluate and analyze the potential risk factors as researched in the clinical literature.
This body of research assessed the joint conditions osteoarthritis, ankylosing spondylitis, sacroiliitis and degenerative disc disease in a sample of skeletal remains from sites across England dating to the 18th-19th centuries. Mature individuals, both male and female, (18+ years) were included. This allowed for the determination and insight into how the lifestyles of each site category affect the development of the joint conditions.
A series of palaeopathological assessments were undertaken to generate a novel dataset that provided skeletal proxies for clinically identified risk factors of the joint diseases to determine whether any relationships/associations existed between the risk factors and joint conditions. Osteological assessments were conducted to create demographic profiles using the pertinent variables (age at death and biological sex), pathologies and the risk factors. These risk factors consisted of body mass (via skeletal height/weight estimation) and activity (via non-imaging cross-sectional geography and entheseal changes), which consisted of five variables, four of which were produced using a method of non-imaging cross-sectional geometry, with the fifth being the scoring of pertinent entheses.
The prevalence rates of the joint conditions fell within the upper ranges of similar sites of post-medieval England and followed sex and age trends also seen in clinical research. These trends showed that the rates increased with age, however statistical testing did not display significance. Body mass and activity did not correspond with joint conditions in the archaeological sample in the same fashion reported in the clinical trials, resulting in a discussion that raised questions about the (1) accuracy and efficacy of currently available osteological methods used to create proxies for these variables from skeletal data, (2) the extent
iii | Mc A f e e IM: J o i n t C o n d i t i o n s i n P o s t -Me d i e v a l E n g l a n d
to which clinical and osteological methods of detecting joint condition offer comparable data and (3) the level which would cause changes to joint function cause a joint condition. However, the body mass of the samples used within this thesis may simply have been too low to have caused sufficient impairment/degradation to the joint, explaining the lack of correlation/association found compared to clinical studies. The variables used as proxies for activity levels did display a significance association with the joint conditions when tested individually. The final binomial logistical regressions found that only a small number of these activity variables were significant factors in the prediction of each joint condition, when all the variables were used in the test. Ankylosing spondylitis was not found to be present in any of the samples used and sacroiliitis was present in only a small percentage of samples and so were unable to be further tested.
Further tests on a larger sample size to test the validity of the results found within this thesis, such as the body mass and activity findings, will need to be conducted. This will help to check the validity of the current data as well as to expand it further so new assumptions/conclusions can be made. The joint conditions conformed to the clinical trends concerning age and sex but differed concerning BMI and activity, offering insights into further avenues to explore. For the spondyloarthropathies, a greater sample size would help to accurately study ankylosing spondylitis and sacroiliitis by increasing the level at which inferential analyses can be made. This research, while concluded in its present form, provides a list of future directions to continue to explore the questions and limitations that have arisen throughout.
... Serologically defined HLA-B27 is associated with a group of idiopathic inflammatory human diseases, including ankylosing spondylitis (AS),' reactive arthritis, and acute anterior uveitis (7,8). The strongest association is with AS; in Caucasian populations, the prevalence of HLA-B27 in the general population is -8%, whereas in patients with primary AS it exceeds 90%. ...
... The strongest association is with AS; in Caucasian populations, the prevalence of HLA-B27 in the general population is -8%, whereas in patients with primary AS it exceeds 90%. Attempts to correlate the incidence of AS with one or more of the B27 subtypes have not been successful; AS apparently is associated with most, if not all, of the B27 subtypes (7,9). ...
... Of particular note is the potential relevance of these findings to the unique association of HLA-B27 with human disease. Although it remains formally possible that this association is due to an allele in tight linkage disequilibrium with HLA-B27, there is now substantial indirect evidence that the HLA-B27 molecule itself is directly involved in disease pathogenesis (7,9). The six B27 subtypes identified by isoelectric focusing have been sequenced at the protein level (5, 6) and shown to display distinctive cytolytic T cell (CTL)-defined epitopes (5,30,31). ...
The HLA class I molecules identified serologically as HLA-B27 are highly associated with ankylosing spondylitis and related human disorders. All known HLA-B27 amino acid sequences contain a cysteine residue at position 67; no other published HLA class I sequence contains a cysteine within the hypervariable region of the alpha 1 domain, which extends from amino acid residues 63-84. To investigate the role of this cysteine residue in the antigenic structure of HLA-B27, we isolated a genomic clone encoding a molecule of the HLA-B27.1 subtype and performed oligonucleotide-directed mutagenesis to convert the cysteine at position 67 to a tyrosine. When transfected into mouse L cells, both the wild-type and Cys67----Tyr67 mutant B27 genes directed the synthesis and surface expression of molecules reactive with the monomorphic anti-HLA class I antibody W6/32. However, only the L cells transfected with the wild-type B27 gene reacted with the anti-B27 antibody ME1; L cells transfected with the mutant B27 were completely unreactive with this antibody. Experiments with hybrid exons created from the HLA-B27 and HLA-A2 genes yielded results consistent with the mapping of the ME1 epitope to the B27 alpha 1 domain. A second anti-B27 antibody, GS145.2, also showed markedly reduced binding to the Cys67----Tyr67 mutant. These studies document the importance of the unique Cys67 residue in the antigenic structure of HLA-B27.
... Moreover it could equally well be argued that in vivo these prebiotics could actually be beneficial, in the absence of fructose malabsorption, due to their inherent bifidogenic effect. Many other studies indeed do not confirm the Klebsiella hypothesis and the topic remains controversial [Amor & Toubert, 1997; Mäki-Ikola et al., 1997b; Spondylitis Association of America, 2009] where it is argued that the evidence for a correlation between Klebsiella and AS is circumstantial so far [Ardicoglu et al., 1996;Khan, 2002a], no infectious trigger has been established [Khan, 2002b] and that the efficacy of low-starch diets like the Ebringer diet [Ebringer, 1996], has not yet been fully scientifically evaluated [ibid Khan, 2002a; ibid Spondylitis Association of America, 2009] although some supporting evidence does exist e.g. elimination of cow's milk products in the diet was shown to improve the symptoms of AS [Appelboom & Durez, 1994]. ...
... Moreover it could equally well be argued that in vivo these prebiotics could actually be beneficial, in the absence of fructose malabsorption, due to their inherent bifidogenic effect. Many other studies indeed do not confirm the Klebsiella hypothesis and the topic remains controversial [Amor & Toubert, 1997; Mäki-Ikola et al., 1997b; Spondylitis Association of America, 2009] where it is argued that the evidence for a correlation between Klebsiella and AS is circumstantial so far [Ardicoglu et al., 1996;Khan, 2002a], no infectious trigger has been established [Khan, 2002b] and that the efficacy of low-starch diets like the Ebringer diet [Ebringer, 1996], has not yet been fully scientifically evaluated [ibid Khan, 2002a; ibid Spondylitis Association of America, 2009] although some supporting evidence does exist e.g. elimination of cow's milk products in the diet was shown to improve the symptoms of AS [Appelboom & Durez, 1994]. ...
The prebiotic inulin is a non-digestible carbohydrate which occurs naturally throughout the normal human diet. Following passage through the gastro-intestinal tract inulin ultimately becomes metabolised to fructose by colonic bacteria, especially the beneficial species, whose growth are also promoted at the expense of the harmful types. There has been much recent attention by industry and the general public in the EU concerning inulin and prebiotics, especially in the marketing of their derived/supplemented products that includes the Central & East European region, (CEE) [Halliday, 2008]. Major benefits to human health have been reported variously worldwide and chiefly consist of maintaining healthy microbial gut homeostasis, reducing gut inflammation and infection, preventing colonic cancer, increasing mineral reabsorption, decreasing cholesterol, improving bowel habits, being of use in diabetic treatments and enhancing immune function. Inulin can thus be of great potential benefit to public health not just through these physiological effects but also in helping to reduce weight by replacing fat and digestible carbohydrate in food products. It is also important however to recognise the likely hazards of inulin arising mainly from fructose intolerance and rare cases of allergy. In addition under certain medical conditions it is possible that the growth of other harmful gut bacterial species may become stimulated with a potential but as yet unproven link to autoimmune disease. This article aims to review and discuss the scientific evidence as well as addressing general concerns raised by consumers and the general public alike. Recommendations based on current knowledge are suggested at the end. © Copyright by Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences.
... These workers reported 96% and 88% of their patients, respectively, to carry the phenotype now designated as HLA-B27. This phenotype is worldwide, especially high in people in the circumpolar regions such as the Haida Indians in British Columbia (Gofton et al 1966) and in the highlands of Papua, New Guinea, but rare in Africans (Khan 1987). Only 25% of Arabs with ankylosing spondylitis have been found to be HLA-B27 positive (Alharbi et al 1996). ...
The spondyloarthropathies are a group of conditions characterised by spinal joint pain and have related clinical, epidemiological and genetic-related features. Ankylosing spondylitis, reactive arthritis, the spinal form of psoriatic arthritis and Crohn’s and colitis enteropathic arthritis are the major clinical entities of the spondyloarthropathies, and principally occur in HLA-B27 positive individuals. Ankylosing spondylitis is much more common in males than females. Patients are usually seronegative for rheumatoid factor, and extra-articular features including iridocyclitis, mucous membrane and skin lesions: aortitis, may occur in some patients. The reactive arthritis form classically occurs following an infection of the gastrointestinal or genitourinary tract. The Crohn’s and colitis enteropathic arthritis forms often have an associated large joint asymmetrical arthritis. Also discussed are acute rheumatic fever and Lyme disease which are conditions where the individual develops arthritis after an infection.
... A comparison of relatives of patients with AS and the general population determined that the risk for AS was 16 times greater among HLA-B27 positive relatives (21% had AS) than among HLA-B27-positive individuals from the general population (1.3% had AS). [21][22][23][24] The HLA-B27-negative relatives did not have any manifestations of AS. AS occurs mostly in men than women. ...
... Incluyen ejercicios de los principales grupos musculares sobre todo la musculatura vertebral y pélvica del plano posterior 29 . En algunos casos se pueden recomendar ejercicios globales que sean además funcionales, tales como sentadillas, levantarse de una silla, etc. Otra alternativa son ejercicios de flexibilidad global que incluyan estiramientos a nivel de espalda, extremidades inferiores y superiores 30 . ...
Objective
To develop expert-based recommendations on physical activity and exercise for patients with spondyloarthritis (SpA).
Methods
Two discussion groups, one of physical therapists, rehabilitation physicians, and professionals of physical activity and sports, and another of rheumatologists interested in SpA, were held to discuss the results of a survey of rheumatologists on exercise and two focus groups with patients on barriers to exercise. Preliminary recommendations were drafted. These were submitted to the opinion of the experts in both groups according to a two round Delphi methodology.
Results
Twenty-one recommendations covering general aspects of exercise, adaptation to patient, how to deliver messages, pain management, and type of exercise and monitoring were issued. The level of agreement varied slightly between expert groups but it was high overall. Items with poor agreement were removed from the consensus.
Conclusions
We present recommendations on when and how to prescribe and monitor exercise in patients with SpA based on the opinion of experts in exercise and in SpA. We must now test whether these recommendations are useful for clinical practice and have an effect on patients with SpA seen by rheumatologists.
... Several structures of some class I molecules have been determined by using crystallography, and it has become clear that the polymorphic residues lie along a groove in which the antigenic peptides are embedded (2)(3)(4). Among the class I alleles, HLA-B27, in particular, has been studied because of its strong association with ankylosing spon-dylitis3 (5). To date, there are seven HLA-B27 alleles known to display few amino acid (aa) differences at positions that, by their location in the peptide binding groove, may significantly affect peptide binding and T cell recognition (6). ...
Seven HLA-B27 alleles are known, which share the same allospecificity, but differ by one to six amino acid substitutions. Herein, we describe a novel HLA-B27 allele, provisionally named B27-ci, which is expressed by an individual from whom a B27-restricted gamma delta T cell clone has been derived. This clone recognizes B cell lines from the proband and all of the other B27-positive members of the family, but does not lyse B cell lines that express other HLA-B27 alleles. The amino acid sequence deduced from three B27-ci cDNA clones was found to differ from the B*2705 sequence by one amino acid substitution (Asp to His) in position 116 of the alpha 2 domain. This position has been shown to lie in the floor of the F pocket, where it plays a key role in determining the nature of the amino acid side chain that will fit into this pocket. Moreover, the fact that the clone described here possesses a TCR-gamma delta indicates that this subset of cells not only can be HLA-restricted, but also can finely discriminate among classical class I molecules.
Ankylosing spondylitis is a progressive, inflammatory, axial, and peripheral arthropathy of unknown etiology. Ankylosing spondylitis is a chronic debilitating disease. It affects the axial spine with pain, loss of mobility, osteoporosis, and increased fracture rate. It may also cause peripheral arthritis, as well as having many extraarticular multisystemic manifestations. The underlying lesion is believed to be enthesitis. Risk factors include being young, male, and a positive HLA-B27 antigen. The role of gut pathogens is less clear. In recent years major advances have occurred in pathogenesis, yet we still do not know the precise natural history or the optimal treatment strategy. A multidisciplinary approach to treatment is recommended, centered around patient knowledge and education as well as exercise and physiotherapy. Simple analgesics and antiinflammatory drugs also play important roles. As outcome is variable, ankylosing spondylitis needs long-term monitoring and management. This has important economic implications.
ZET Ankilozan Spondilit (AS), özellikle vertebral kolonda inflamasyonla karekterize seronegatif spondiloartropati grubunun prototipi olan kronik, sistemik romatizmal bir hastalıktır. Bu hastalık, kalıtsal bir hastalıktır ve tedavisi yoktur. Sadece hastaların yaşam kalitelerini arttırmaya yönelik ilaç ve egzersiz tedavisi önerilir. İlaç tedavisi kadar egzersiz tedavisine önem verilmemektedir ya da egzersiz tedavisi kısıtlı yapılmaktadır. Bu hastalığın tedavisi ile ilgili olarak literatür incelendiğinde; ilaç tedavisi kadar egzersiz tedavisinin de önemi vurgulanmaktadır. Bu makalede, ankilozan spondilit tedavisinde egzersizin önemi tartışılmış ve güncel literatür gözden geçirilmiştir. ABSTRACT Ankylosing Spondylitis (AS) is a chronic, systemic, rheumatic disease that is a prototype of seronegative spondyloarthopathies characterized by inflammation, especially at the spinal column. This disease is hereditary and cannot be treated. The only suggested treatments of which are exercise and drug are for increasing the quality of life in people with AS. The exercise is not considered as important as the drug treatment or the exercise treatment is limited. A growing body of research reveals that exercise is as crucial as drug treatment in the management of AS. In this article, the importance of exercise in treatment of ankylosing spondylitis is discussed with the evaluation of current literature.
This article summarises the available information on seronegative arthritides from South Asian countries, namely India, Pakistan, Bangladesh, Sri Lanka, Nepal, and Bhutan. The diseases described are spondyloarthritides (SpA), including ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA), inflammatory bowel disease-related arthritis (IBDa), enthesitis-related arthritis (ERA) of the paediatric age group, and undifferentiated spondyloarthritis (uSpA). Relevant information on SpA from South Asia is scarce. However, the available publications indicate that these are commonly seen conditions. HLA-B27 is present in approximately 6-8 % of the normal population in the Indian subcontinent. In the SpA group, HLA-B27 has the highest frequency in AS patients (>90 %) and the lowest in PsA patients. Clinical features are similar to those reported in standard textbooks, but with a few exceptions: e.g., in South Asian countries ERA is the most common subset of juvenile idiopathic arthritis (JIA), whereas in the West the most common subset of JIA is oligoarthritis. Poverty is a major challenge in treating these diseases in South Asia; with poor health insurance coverage, only a few patients are able to afford biological treatment. Therefore, rheumatologists have attempted novel treatment strategies for those with an unsatisfactory response to standard non-steroidal anti-inflammatory drugs (NSAIDs) or coxibs.
To assess the incidence of Reiter's syndrome aboard The Golden Venture, a ship carrying illegal immigrants from China to the United States.
After identification of an index case, we conducted telephone interviews with medical staff at immigrant detention centers in Pennsylvania, New York, and Virginia. When a potential case was identified at one facility, we performed a site inspection, reviewing the medical records of all detainees and performing histories and physicals on all those with joint and/or ocular complaints.
We identified two patients, both HLA B27 positive, with Reiter's syndrome. The observed incidence (0.87%) approximated the predicted incidence but may have underestimated the actual incidence. We review the history of shipboard Reiter's syndrome, and discuss the pathogenic roles of HLA B27 and particular infectious agents.
Continued transportation of illegal immigrants from China and other parts of the world is likely to result in occasional clusters of Reiter's syndrome. Physicians treating immigrant populations should remain aware of the possibility of reactive arthritis.
Ankylosing spondylitis is associated with a decreased survival that appears attributable to cardiovascular causes. To determine whether alterations in systolic or diastolic cardiac function precede overt cardiac disease, 20 ankylosing spondylitis patients without clinical evidence of cardiovascular disease and 25 healthy age and gender matched controls were studied by cross-sectional and Doppler echocardiography. Systolic function was assessed by wall motion analysis and ejection velocities. Diastolic function was measured by the peak velocity of early ventricular inflow, peak velocity in late diastole during atrial systole, the ratio of these velocities and the diastolic filling time. Atrial, ventricular and aortic dimensions were similar in patients and controls. Ejection indexes and systolic wall motion were normal in both groups. Diastolic function differed in patients as evidenced by a shorter diastolic filling period [405 +/- 68 ms vs 548 +/- 136 ms, p = 0.0001], a reduced velocity of early mitral inflow [0.55 +/- 0.09 m/s vs 0.63 +/- 0.11 m/s (p = 0.005)], and lower ratios of early/late inflow velocities [1.21 +/- 0.33 vs 1.60 +/- 0.35 (p = 0.0005) for mitral and 1.36 +/- 0.34 vs 1.71 +/- 0.42 (p = 0.016) for tricuspid]. These changes are consistent with impaired ventricular relaxation in some patients with ankylosing spondylitis.
The association of HLA-B27 with ankylosing spondylitis and related spondyloarthropathies has been known for two decades and has provided a great impetus to the epidemiologic studies and also helped broaden the clinical spectrum of these diseases. The etiology of these diseases is likely to be multifactorial and include genetic, immunologic, and environmental mechanisms. The detailed three-dimensional x-ray crystallographic structure of B27 has now been reported. It has revealed electron density compatible with oligopeptides that are nine amino acid-long (nonamers) bound in the antigen-binding cleft of the molecule. Microsequence analysis of 11 peptides eluted from the antigen-binding cleft has confirmed that all are nonamers. The most restricted position in the bound peptide is the second position, where all the 11 peptides contain arginine. The side chain of arginine extends into the B pocket ("45 pocket"), which seems to act as a specificity side pocket in the antigen-binding cleft of the B27 molecule. It is very likely that an understanding of the detailed structure of B27, including the peptide-binding motif and the structural domains recognized by cytotoxic T cells, along with the recent development of the B27 transgenic rat model for spondyloarthropathies, will further enhance our understanding of the immunogenetics of these diseases. It is hoped that this will lead to the source of the arthritogenic triggers and possibly disease prevention by antigen-specific immunomodulation. Because T-cell activation is initiated by the formation of antigen-MHC complexes that are the ligands that are recognized by the antigen-specific T-cell receptor (TCR), it might be possible to inhibit this activation by blocking the antigen-binding cleft of MHC molecules by using high-affinity MHC-binding peptides (MHC blockade) or by a novel, new, and more efficient method of TCR antagonism.
We report a 25-year-old woman presenting with sarcoidosis and bilateral sacroiliitis. Her sarcoidosis related symptoms (malaise, cough and dyspnoea) improved dramatically under treatment with steroids but severe back pain persisted. Only seven similar cases have been described over the last 40 years and the question of a possible association between the two diseases has been raised. However, prevalence data from the literature and the apparent lack of genetic links are better arguments for coincidence than for association.
Cell surface complexes of class I MHC molecules and bound peptide antigens serve as specific recognition elements controlling the cytotoxic immune response. The 2.1 A structure of the human class I MHC molecule HLA-B27 provides a detailed composite image of a co-crystallized collection of HLA-B27-bound peptides, indicating that they share a common main-chain structure and length. It also permits direct visualization of the conservation of arginine as an "anchor" side chain at the second peptide position, which is bound in a potentially HLA-B27-specific pocket and may therefore have a role in the association of HLA-B27 with several diseases. Tight peptide binding to class I MHC molecules appears to result from the extensive contacts found at the ends of the cleft between peptide main-chain atoms and conserved MHC side chains, which also involve the peptide in stabilizing the three-dimensional fold of HLA-B27. The concentration of binding interactions at the peptide termini permits extensive sequence (and probably some length) variability in the center of the peptide, where it is exposed for T cell recognition.
X-ray crystallography reveals electron density in the antigen-binding site of HLA-B27 that is an interpretable image of nonameric peptides in a largely extended conformation. Clear density exists for the main chain and several side chains and is consistent with the sequence of 11 nonameric self-peptides eluted from HLA-B27. Pockets in the antigen-binding cleft bind four side chains and the amino and carboxyl termini of the peptide.
Ankylosing spondylitis and related spondyloarthropathies show a remarkable association with a genetic marker--HLA-B27--and also illustrate the relationship between host and environmental factors. HLA-B27 has revitalized the epidemiology of spondyloarthropathies and has helped to broaden the clinical spectrum of these diseases. These and other aspects of descriptive and genetic epidemiology are reviewed.
Several rheumatic diseases were first shown to be associated with human leukocytic antigen (HLA)-B27 in 1973. Recent developments in understanding this association include the finding that there are at least six variants of HLA-B27 at the molecular level, with no one variant preferentially associated with disease. Detailed studies of the structure of the HLA-B27 molecular family are in progress in several laboratories. Mice expressing HLA-B27 and transmitting it to their offspring (transgenic mice) have been produced and are being studied for their response to bacteria that are known to trigger reactive arthritis in B27+ humans. A particular restriction fragment length polymorphism was recently claimed to be a genetic marker for an additional risk factor in ankylosing spondylitis, but two other laboratories have failed to confirm this finding.
A gene encoding the H chain of the human class I MHC Ag HLA-B27 was introduced into the germ lines of inbred C57BL/6 (B6) and non-inbred (B6 X SJL/J) F2 mice. By immunofluorescence and flow cytometry, the HLA-B27 gene product was expressed on lymphoid cells at levels comparable to the endogenous H-2b and H-2s class I MHC molecules. In both primary and secondary MLC between responder spleen cells from non-transgenic (B6 X SJL/J) F1 mice and transgenic stimulator cells, CTL were generated that specifically lysed mouse L cell (H-2k) or human B cell targets expressing HLA-B27, and this lysis thus appeared largely unrestricted by H-2. These results indicate that transgenic mice express a functional HLA-B27 gene product on cell surfaces in the absence of the human beta 2-microglobulin gene. These transgenic mice promise to be a valuable resource in the investigation of the unique role of HLA-B27 in inflammatory human disease.
This review focuses on various epidemiological aspects of ankylosing spondylitis (AS). Diagnostic criteria currently available are described, and their use in scientific studies as opposed to everyday clinical practice is discussed. Present knowledge of the prevalence of AS is addressed in detail with particular emphasis on discrepancies caused by variations in population frequencies of HLA B27 and those caused by differences in study designs.
This study is the first to assess the prevalence of HLA B27 in Kuwaiti patients with ankylosing spondylitis (AS) or related spondyloarthropathies compared to healthy controls. Positive HLA B27 was found in nine (25.7%) of 35 patients, but only in 22 (4%) of 544 controls (P = 0.000). A significant difference in Cw2 and Cw6 between patients and controls was also found (P < 0.01 and 0.000, respectively), suggesting a linkage disequilibrium between B27 and Cw2 (P < 0.000) in the Kuwaiti population. These findings suggest that B27-positive Kuwaitis are at high risk of developing AS and spondyloarthropathies, especially if they carry Cw2 and Cw6: The importance of HLA Cw loci is becoming increasingly apparent in disease association studies.
The interaction of a series of potent leishmanicidal aromatic diamidines resembling pentamidine, was studied with Leishmania infantum DNA and polynucleotides. The diamidines viz., CGP040215A, CGP033829A and CGP039937A, interacted with leishmania DNA as well as with the polynucleotides poly(dA)-poly(dT), poly(dA-dT) and poly(dG-dC). The thermodynamic analysis to determine the association constants and the binding enthalpy pointed toward binding of the diamidines at AT regions of the DNA. The results also indicate that the diamidines bind at the outside of the DNA double helix, probably to the minor groove regions, with hydrogen bonds connecting the amide nitrogen of the diamidine to carbonyl oxygen atoms of thymidine or adenosine bases. However, CGP040215A and CGP033829A, the bisaryl diamidines, showed higher affinity than CGP039937A, the monoaryl diamidine. The spectrophotometric analysis of the interaction of these diamidines to test their effects on the melting temperature of leishmanial DNA suggests non-intercalating binding. The diamidines also showed potent inhibition of DNA polymerase activity of L. infantum extracts in vitro.
To determine the spectrum and ethnic differences of spondyloarthritis disease patterns in patients attending the Rheumatic Diseases Unit, University of Cape Town, South Africa.
A retrospective survey of case records of 100 patients with spondyloarthritis seen between January 1988 and January 1995.
Of these 100 patients, 71 were male, 53 were Colored [mixed race descendants of Khoisan (Hottentot and Bushmen), Whites, Malays and Black Africans], 40 White, 5 Black and 2 Indian (descendants of immigrants from the Indian subcontinent). Our results show that the prevalence and disease patterns of spondyloarthritis in this South African cohort are comparable to those seen in Europe and North America with respect to clinical and radiological features, as well as therapeutic and orthopedic surgical requirements. No major ethnic differences in disease patterns were observed in White and Colored patients studied.
The spectrum of spondyloarthritis in South Africa is similar to that seen elsewhere in the world. Our study confirmed the rarity of these conditions in Black South Africans.
Reactive arthritis is classically seen following infection with enteric pathogens such as Yersinia, Salmonella, Campylobacter and Shigella. Inflammatory arthritis has also been described following other enteric infection with organisms such as Clostridium difficile, Brucella and Giardia. Furthermore, arthritis is seen in Whipple's disease, caused by the actinomycete Tropheryma whippelii. This chapter reviews the current understanding of these conditions (with the exception of Brucella, which is discussed in a subsequent chapter). The epidemiology is reviewed, and the contribution of both host and organism to the aetiology and pathogenesis is discussed with particular discussion of the role of HLA-B27 in host susceptibility. Recent work exploring evidence for traffic of pathogenic organisms to the joint is highlighted. A practical approach to the diagnosis and management of the condition is then formulated based, where possible, on clinical trial evidence.
Ankylosing spondylitis (AS) is one of a group of disorders characterized by association with HLA-B27 histocompatibility complex, seronegativity for rheumatoid factor, and propensity for inflammation at entheses, synovial articulations, and cartilaginous articulations. The radiographic hallmark of the disease is ankylosis, and the principle sites of involvement are the sacroiliac joints and spine, with less frequent involvement of other joints, including the pubic symphysis, hips, shoulders, knees, hands, feet, and sternoclavicular, acromioclavicular, sternomanubrial, and temporomandibular joints. Following a brief discussion of the basic pathophysiology and typical clinical findings of AS, we describe the typical magnetic resonance imaging features of the disease as it is manifests in the axial skeleton. Finally, a brief mention of special considerations in the radiographic evaluation of the AS patient in the setting of trauma is made.
The Bath Ankylosing Spondylitis Functional Index (BASFI), disease activity index (BASDAI), and Global assessment (BASG) are the most commonly used instruments to assess patients suffering from ankylosing spondylitis (AS). The aim of this study was to translate, adapt, and validate these instruments into the Arabic language. Seventy-three AS patients were included in this study. One question in the BASFI questionnaire was changed to suit the Arabic culture. Also, the VAS in the questionnaires was transformed to numerical rating scales from 0 to 10. After modification, translation, and retranslation of the questionnaires, it was administered and tested for internal consistency, reliability, and construct validity. Magnetic resonance imaging (MRI) of the spine and sacroiliac joints was carried out for 69 patients; scores for disease activity and chronicity were also assessed. The adapted and translated questionnaires demonstrated acceptable comprehensibility scores with a mean of 9.3. Intraclass correlation coefficients for reliability and internal consistency was 0.973 for BASG, whereas standardized alpha ranged between 0.807 and 0.976. The modified item 9 in the BASFI demonstrated a good correlate to the principal component (0.883). When validated, all three questionnaires showed a significant correlation with enthesitis, BAS-radiology index, MRI imaging scores for activity and chronicity, C-reactive protein (CRP), and morning stiffness duration. The Arabic version of the BASFI, BASDAI, and BASG, showed adequate reliability and validity in patients with AS. The measurement properties were comparable to versions in other languages indicating that the questionnaires can be used for evaluation of AS Arabic-speaking patients.
The structure of a variant HLA-B27 antigen, B27.2, that is distinguished from the HLA-B27.1 and HLA-B27.3 subgroups by specific cytolytic T lymphocytes has been established by comparative peptide mapping and sequence analysis. There are only three amino acid substitutions between B27.1 and B27.2: aspartate-77, threonine-80, and leucine-81 in HLA-B27.1 are changed to asparagine-77, isoleucine-80, and alanine-81 in HLA-B27.2. These changes account for their single charge difference detectable by isoelectric focusing. The three clustered substitutions of HLA-B27.2 are identical to the corresponding residues in HLA-A24, so that both molecules become identical in their amino acid sequence between residues 72 and 96. This suggests that gene conversion may have occurred during the diversification of the HLA-B27 antigens. HLA-B27.2 has no changes in the alpha 2 domain and is similar in its pattern of substitutions to the murine bm11 mutant. It is suggested that residues 77-81 are of major significance in determining the specificity of cellular recognition of class I HLA antigens. This study, together with the previous analyses of HLA-B27.1 and HLA-B27.3, completes the structural characterization of the three major HLA-B27 functional subtypes and establishes the molecular basis of their functional and serological differences.
An HLA-B27 positive, Epstein Barr virus-transformed cell line Wewak I was not lysed by Epstein Barr virus-specific cytolytic T lymphocytes restricted by HLA-B27. This line is weakly reactive with a B27-specific monoclonal antibody, M2, which recognizes a majority, but not all, of the HLA-B27-positive cells. To establish the molecular basis for this lack of recognition, the structure of the variant HLA-B27 antigen was compared with the known structure of HLA-B27 from the LG-2 cell line, which is representative of a major subtype of this antigen. Both molecules were almost indistinguishable by isoelectric focusing. However, comparative peptide mapping and sequencing of the difference peptides revealed two amino acid changes: At position 77, Asp in donor LG-2 had changed to Ser in the variant, and at position 152, Val in LG-2 had changed to Glu in the variant. The nature of these substitutions was consistent with the extreme similarity of the isoelectric focusing pattern. An evaluation of these findings in the context of studies on other HLA variants and H-2Kb mutants suggests that both positions 77 and 152 contribute to the determinants recognized by B27-specific cytolytic T lymphocytes. The change at position 152 adds to previous evidence suggesting that the segment 149-156 is critical for cellular recognition. In addition, it is proposed on the basis of structural comparisons that residue 77 may also participate in the epitope recognized by the B27M2 antibody.
Family studies and investigation of the HLA associations have in recent years added to our understanding of the spondyloarthropathies. In regard to ankylosing spondylitis it is likely that B27 itself is the major susceptibility gene but that additional genes may play a secondary role. Heterogeneity of the B27 antigen has been demonstrated but has not yet been shown to be relevant to disease susceptibility. Haplotypes including Cw6 are related to susceptibility to psoriasis and psoriatic arthritis and although the risk for the arthropathy is increased in B27-positive individuals, there is some uncertainty regarding the association with other B locus antigens and further work is needed.
There is also uncertainty as to whether B27-associated disorders occur randomly within families, or whether particular disorders cluster in certain families and further evidence in this field would be of considerable interest.
Genetic studies, as here outlined, have not as yet had a major impact in clinical medicine but it is anticipated that a deeper understanding of the mechanisms of HLA-linked susceptibility genes and in particular of how they interact with environmental agents, will improve our ability to treat and possibly prevent the relevant diseases.
The present study was performed on 61 HLA-B27 positive first-degree relatives and 40 HLA-B27 negative relatives of 20 HLA-B27 positive probands with ankylosing spondylitis (AS). Of 24 HLA-B27 positive relatives 45 years or older, 21% had AS and 38% sacroiliitis. The HLA-B27 negative relatives did not have features of either disease. In the population study of 2,957 individuals 45 years or older, we found 5 cases of HLA-B27 positive sacroiliitis (according to the New York criteria) and 3 of these fulfilled the New York criteria for diagnosis of AS. In 2 of these 3 individuals, the diagnosis was made on clinical grounds. The pheno-type frequency of HLA-B27 in this population is 7.8%, or about 230 HLA-B27 positive individuals in this population sample. Since AS was found in only 3 individuals, 1.3% of the HLA-B27 positive individuals in the population at large have AS; therefore, our data show that among individuals 45 years or older, 21% of HLA-B27 positive relatives of HLA-B27 positive AS patients have AS as compared with 1.3% of the HLA-B27 positive individuals in the population at large. Thus, the risk for AS is 16 times greater in the HLA-B27 positive relatives compared with HLA-B27 positive individuals in the population at large. The discriminatory value of the New York criterion of history of pain or the presence of pain at the dorsolumbar junction or in the lumbar spine was analyzed in the population and family studies and was found to be too nonspecific.
Because of the known association between Gram-negative enteric bacteria and certain seronegative arthropathies, the bowel flora was examined in 59 native Americans: 25 with ankylosing spondylitis, 18 with Reiter's syndrome and 16 healthy controls. Of the 43 ankylosing spondylitis and Reiter's syndrome patients, 35 (81%) were HLA-B27 positive. A significant difference in the isolation of Klebsiella from the stools of ankylosing spondylitis and Reiter's syndrome patients was noted only when the patients were divided on the basis of disease activity. Klebsiella was isolated from 14 of 26 (54%) patients with either active ankylosing spondylitis of active Reiter's syndrome, compared to two of 16 (13%) controls (p = 0.0077) and two of 17 (12%) patients with inactive disease (p = 0.0055). The role of Klebsiella in the pathogenesis of HLA-B27 arthropathies is unknown, but recent literature would suggest an immunologic interaction between the antigens of Klebsiella and those of the histocompatibility complex.
Six variant forms of HLA-1327 were identified among 68 unrelated 1327-positive donors by isoelectric focusing (IEF) gel analysis. Each of the six IEF variants was distinguished by charge heterogeneity of desialated B27 heavy chains immunoprecipitated with specific monoclonal antibody (MAb). Charge differences varied from single to several charge units, indicating that these variants may have substantially different amino acid compositions. Informative family study showed that three B27 variant molecules were genetically determined. The uniqueness of these variant molecules was also demonstrable using a panel of alloantisera and MAbs recognizing 1327-associated epitopes. Six distinct serological reactivity patterns were observed. Five of these serological patterns correlated with four of the IEF-defined variants, two of these patterns being associated with one IEF variant form. The sixth serological pattern was shared by the remaining two IEF variants. Combining the results of the electrophoretic and serological analyses, it is apparent that there are more than six structural variants within the B27 alloantigen family. Some B27 variant forms were found only in individuals of particular racial origin, indicating that unique genetic variations might occur in different racial groups. In a preliminary analysis of patients with ankylosing spondylitis, no apparent correlation was observed between any specific B27 variants and disease susceptibility.
The observed frequency of apparent homozygotes for HLA—B27 (15.5%) was significantly greater than the estimated expected frequency (4.2%) among 58 B27-positive Caucasian patients with ankylosing spondylitis (AS) (P < 0.0005). Search of the literature uncovered four other studies in each of which the frequency of apparent homozygotes was shown by our analysis to be greater than expected. These analyses indicated that B27 homozygotes are more susceptible to developing AS than are B27 heterozygotes. Comparison of the clinical features of AS showed no differences between heterozygotes and apparent homozygotes except for a higher frequency of involvement of peripheral joints in the latter group.
We report 2 independently-conducted family studies of HLA-B27 positive probands with ankylosing spondylitis (AS), both of which support the view that the clinical spectrum of AS is broader than ordinarily assumed, and should include individuals who have symptomatic disease but who do not show radiologic evidence of abnormalities of the sacroiliac joints or the spine. In the Cleveland study of 100 relatives of 30 B27 positive AS probands, 9 relatives did not show radiologic abnormalities of the sacroiliac joints or the spine but had symptoms of chronic inflammatory back pain previously reported to be characteristic of AS. These 9 relatives were all subsequently found to possess B27, in contrast with only 27 of 60 asymptomatic relatives (P < 0.01). In the Leiden study of 101 relatives of 20 randomly chosen B27 positive AS probands, 13 of 86 relatives without radiographic evidence of sacroiliitis reported “thoracic pain and stiffness,” as defined in the Rome criteria for AS. Twelve of these 13 symptomatic relatives were B27 positive. In contrast, among the remaining 73 relatives, only 33 were B27 positive (P < 0.01). The occurrence of these characteristic spondylitic symptoms in B27 positive, but not B27 negative, relatives of AS probands suggests that the spectrum of the clinical manifestations of AS may include individuals with symptomatic disease, but without radiographic evidence of abnormalities of the sacroiliac joints or the spine. The relatively large number of females we found in this group suggests that women are more likely to manifest this variety of disease than are men.
For purposes of genetic comparison, the available HLA data on United States and African Black, together with United States Caucasoid populations, are summarized. Antigen frequencies and pairwise linkage disequilibria are presented for the HLA-A, -B and -C loci in Black populations typed for the 1975 Histocompatibility Testing Workshop. The Black population samples comprise 356 North American Blacks and 411 African Blacks of whom 222 were Bantu. These are compared with a sample of 503 American Caucasoids. All significant linkage disequilibria between the A and B loci found in North American Blacks were also present in the North American Caucasoids. Between the B and C loci, Bw35 and Cw4 were in strong linkage disequilibrium in all groups. Significantly strong association between the A and C loci (Aw28 with Cw3) were observed only in the African Blacks. There were unique disequilibria both in the American Caucasoids and African Blacks. Although the frequencies of many antigens in U.S. Blacks lie between those in Africans and U.S. Caucasoids, there are exceptions such as Aw33, Bw35, Cw4.
An acute, self-limited, asymmetric, polyarthritis is described in 21 Navajo patients, which in all cases affected the knee and, in most, other joints as well. All patients had sterile cultures and negative tests for rheumatoid factor and LE preparations. One patient had multiple bouts without residual defect. We believe that Navajo Arthritis is a distinct syndrome of unknown etiology.
The results of segregation analyses in 75 families where the proband had ankylosing spondylitis, are presented. Of the 278 adult, living first degree relatives, approximately 85% cooperated in the study. Clinical and radiographical examinations were performed and HLA typing was conducted. The results were in agreement with our hypothesis that ankylosing spondylitis is part of a syndrome where different genetic factors interact. Such known factors are HLA B27 associated disease susceptibility, susceptibility to psoriatic arthropathy and susceptibility to entero-arthropathy. Radiographical sacro-iliitis was restricted to HLA B27 positive relatives, and was more frequently found in relatives to probands with psoriasis than in relatives to probands without psoriasis. Environmental factors (intestinal bacteria) are known to trigger the disease at least in some persons, and we have postulated that all or most of them have the predisposition to develop disease. Thus, the syndrome has a multifactorial etiology. The phenotypic expressions of the different genetic predispositions involved, include sacro-iliitis, psoriasis, acute anterior uveitis, peripheral arthropathy and inflammatory bowel disease. We suggest the descriptive name HEREDITARY MULTIFOCAL RELAPSING INFLAMMATION (HEMRI) for this syndrome. Ankylosing spondylitis, psoriatic arthropathy and entero-arthropathy may be regarded as clinical sub-types of the syndrome.
In a study of 34 American black patients with primary ankylosing spondylitis, 18 were found to be HLA-B27-negative. Of these, 10 possessed HLA-B7 (55.6%) compared to 23.7% of 59 B27-negative black controls (P < 0.025, relative risk = 4). On comparing these 10 B7-positive patients (group I) with 16 B27-positive black patients (group II), a difference in mean age at onset of disease was found: 33.6 years in group I and 22.2 years in group II (P < 0.005). In addition, a family history of ankylosing spondylitis was absent in group I patients but present in 6 patients in group II (P = 0.034). These findings indicate an association between HLA-B7 and ankylosing spondylitis in American blacks and suggest that these patients who lack B27 but possess B7 represent a subgroup of patients with this disease.
The frequency of B27 homozygosity was determined in 100 patients with B27 positive ankylosing spondylitis (AS). Six patients appeared to be B27 homozygous. The difference between the observed frequency of homozygosity of 6% and the expected frequency of 2.3% (from results on 725 blood donors) was not significant (p greater than 0.05). All 6 patients had moderate to severe disease. Subsequently, the families of 10 patients with AS were studied. The families were selected because 2 distinct B27 haplotypes were present. No difference was observed between the prevalence of AS in B27 homozygous or heterozygous family members. Although B27 homozygosity may have some influence on the severity of the disease, it does not increase the risk for AS even in families of patients with AS.
HLA-D typing of 44 patients with ankylosing spondylitis (AS) and 31 patients with Reiter's syndrome (RS) did not show increased frequency of any particular Dw allele in either population of patients as compared to controls. Such studies also allowed each patient's general response to be compared with other general responses within each experiment. Contrary to reports of diminished lymphocyte responses in AS patients, hyperresponsiveness in both AS and RS patients was found.
A series of 187 patients with definite ankylosing spondylitis was studied. Seventeen of these lacked the antigen HLA B27, but had signs and symptoms identical to the 170 HLA B27 positive patients. The study provides additional confirmation that other factors besides HLA B27 are involved in the development of ankylosing spondylitis.
Twenty-eight HLA alleles of the A and B loci were determined in 23 American Blacks and 50 Caucasians with primary ankylosing spondylitis (AS). The prevalence of HLA B27 was significantly increased in American Black patients (48 per cent) vs Black controls (two per cent), but was much less than the 94 per cent found in Caucasian patients (controls eight per cent). The lower prevalence of B27 in American Black patients vs Caucasian patients was significant (p less than 0.001), and indicated that susceptibility to AS is not as closely associated with B27 in Blacks as in Caucasians. No other HLA antigen was significantly associated with AS in either racial group. Among B27 positive individuals, the relative risk of developing AS was significantly lower in American Blacks than in Caucasians. These data indicate that for diagnostic purposes, the absence of B27 is less important in ruling out AS in Blacks than in Caucasians.
The effect of homozygosity for HLA-B27 on the clinical expression of rheumatic disease was studied in two families. The 1 homozygous patient in each of two families demonstrated extraordinarily severe peripheral and axial arthritis compared to other affected heterozygous relatives. In addition, predominant peripheral or axial disease appeared to segregate with different B27 haplotypes. The 2 homozygous patients were not homozygous at the hla-a,c, or D loci.
The analysis and precise definition of HLA antigens is still problematical. Adequate characterised monovalent antibodies for the detection of individual HLA antigens are not available in the desired range. It would be desirable if all laboratories involved with HLA typing could use antibodies of identical specificity. It has been possible recently, with the mouse and rat, to produce monoclonal antibodies against MHS antigens, with the help of cell hybridisation.
SUMMARY The clinical, radiological and laboratory data of 50 HL-A B27-positive ankylosing spondylitis (AS) patients were compared
with those of 12 HL-A B27-negative AS patients. The only statistically significant difference (P>0.003) was the association
of acute anterior uveitis (AAU) with HL-A B27-positive patients. The possibility that AS and AAU are two discrete entities
that are independently related to HL-A B27 is discussed.
The association between ankylosing spondylitis and HLA-B27 has been noted in all races that have thus far been studied; it tends to be strongest in whites and relatively weaker in blacks. Reiter's syndrome is also strongly associated with HLA-B27 in whites, but has not been well studied in blacks. Morris and associates have suggested the use of B27 typing in the clinical evaluation of white male patients with suspected Reiter's syndrome and have predicted that the test would be even more helpful in blacks. The results of a study of the diagnostic usefulness of B27 typing in white and black patients with Reiter's syndrome is reported.
The clinical features of ankylosing spondylitis (AS) were compared in 63 HLA-B 27 positive (+) and 15 B27 negative (-) individuals with this disease. There were no differences in age at onset, functional class, degree of deformity, pain, severity of X-ray changes, or frequency of peripheral joint involvement or of reconstructive orthopedic surgery. These data demonstrated that skeletal manifestations of AS were essentially the same in B27(+) and (-) patients, and provide no evidence for the speculation that AS in B27(-) patients is milder or is a different disease from that occurring in B27(+) patients. On the other hand, acute anterior uveitis was found to be significantly more common in B27(+) patients, a fact suggesting that the "uveitis of AS" may in fact be an independent condition occurring in B27(+) individuals, rather than a manifestation of AS per se.
The occurrence of acute anterior uveitis in ankylosing spondylitis was compared in 53 HLA-B 27 positive and 12 HLA-B 27 negative patients with this disease. Uveitis was found in HLA-B 27 positive patients only. These results suggest that uveitis and ankylosing spondylitis are independent diseases occurring on their own and strongly associated with HLA-B 27.
Serologic evidence of Yersinia enterocolitica infection was sought by agglutination testing in serum samples from several populations, including Haida Indians, Red Cross blood donors, and Caucasian patients with rheumatoid arthritis, ankylosing spondylitis, and Reiter's syndrome. No evidence was found to indicate that yersinial infection was etiologically related to Haida spondylitis or Reiter's syndrome. Four of 28 patients with acute arthritis were diagnosed from serologic evidence as having Yersinia-related arthritis.
Proposed mechanisms to explain the association of HLA-B27 with Reiter's syndrome (RS) and ankylosing spondylitis (AS) include abnormal immune response genes linked to HLA or a direct role for HLA antigens in disease pathogenesis. Our studies provide indirect evidence to support the latter hypothesis. Seventy-nine patients (44 with RS, 27 with AS and 8 with idiopathic sacroiliitis [SI]) were evaluated clinically and by HLA phenotyping. Of the 10 patients with RS who were B27-negative, 7 (70%) had another B locus antigen that was immunologically cross-reactive with B27 (B7-group antigen). These included B7 in two, BW22 in four, and BW42 in one. Four of eight patients with sacroiliitis alone had B27, but the remaining four all had B7. Two B27-negative AS patients had no B7-group antigens. Thus, 69% of B27-negative patients had cross-reactive HLA antigens.
A close association between HLA B27 and ankylosing spondylitis has been demonstrated in several studies. A family with 2 siblings affected with both ankylosing spondylitis and iritis and the third affected with iritis only, has been called to attention. The parents, of Jewish Polish origin, were first cousins, who died during the holocaust. The combination of parental consanguinity and the fact that all 3 siblings were affected suggested the possible homozygosity for HLA B27 derived from a common ancestor. Examination of the family revealed that the proposita (IV-4), 52 years of age, had suffered from ankylosing spondylitis and iritis for 30 years. She and her brother (IV-7) and sister (IV-1) are homozygous for HLA B27, all having the same haplotypes (A10, B27 and A28, B27). The proposita's proposita6s husband (IV-5), 61 years old, had suffered from sacroiliitis and back pains since the age of 29, and ankylosing spondylitis was diagnosed; he is heterozygous for HLA B27. Their daughter (V-5), a HLA B27 homozygote, is healthy. The proposita's elder daughter (V-4), heterozygous for HLA B27, suffered from back pains for two years, and sacroiliitis was observed on X ray examination. The brother of the proposita (IV-7), also affected with ankylosing spondylitis, had had back pains since the age of 30, and twice had iritis. Both his children carry HLA B27. The eldest sister (IV-1) has a history of back pains, but ankylosing spondylitis was not diagnosed clinically or radiologically. Since 1965 she has suffered from recurrent iritis. Only her youngest son was examined, and he carries HLA B27. Homozygosity for HLA B27 in the 3 siblings of generation IV cannot be attributed to parental consanguinity since they are not homozygous for a single haplotype. Therefore, homozygosity for B27 may be considered due to chance. The frequency of HLA B27 carriers in various populations is about 7% and consequently about 1.2 in 1000 random persons will be homozygous by chance, or one in about 60 HLA B27 positive persons will be homozygous. Thus, if the population affected with ankylosing spondylitis is regarded as a truncated population the same frequency (one in 60) would be expected among B27 positive patients.
A number of inflammatory disorders have recently been attributed to Yersinia enterocolitica. Among these, polyarthritis is fairly common, though it has not previously been described in any detail in South Africa. The clinical, radiological and laboratory findings in 11 such cases are presented and an attempt is made to differentiate the condition from other types of inflammatory polyarthritis.
HL-A antigens were determined in Haida and Bella Coola native Indians, two communities known to have a high prevalence of ankylosing spondylitis. Tests were conducted on those with x-ray evidence of sacro-iliitis and on a sample of the community at large. Sacro-iliitis was found to prevail in approximately 10 per cent of adult Haida males and in over two per cent of Bella Coola adult males. Of 20 Haidas with sacro-iliitis, 17 were HL-A 27 positive. Fifty per cent of the Haida community at large were HL-A 27 positive. Three Bella Coolas known to have sacro-iliitis were all HL-A 27 positive, while 25 per cent of the community sampled at large were HL-A 27 positive. About one in five adult Haida males who were HL-A 27 positive showed evidence of sacro-iliitis, a proportion close to that ascertained in Caucasian communities. It would appear, therefore that the risk of disease in HL-A 27 positive Bella Coola males is considerably lower.
The complete amino acid sequence of papain-solubilized HLA-B27, an antigen that presents a very strong association to the development of ankylosing spondylitis, has been determined. The overall sequence homology with the cross-reactive allelic products HLA-B7 and HLA-B40 (Bw60) is 93% and 92%, respectively. Half of the differences between HLA-B27 and -B7 are located in segments 63-83 and 113-116. Most of the known HLA class I antigens are different in these segments, and it is suggested that the corresponding residues may be involved in the alloantigenic determinants of HLA-B27. A free cysteine residue is present at position 67, and it is at least partially exposed to solvent. In addition, other differences are found in various areas of the two N-terminal domains. The comparison with available HLA class I sequences allows an evaluation of their contribution to the antigenic polymorphism of these molecules. The relevance of these data is discussed in connection with the mapping of functional sites of HLA class I antigens and with the association between HLA-B27 and ankylosing spondylitis.
Despite major advances in genetic and structural studies of the HLA-B27 antigen, the underlying mechanism responsible for the remarkable association between this antigen and spondylarthropathies remains unknown. At a molecular level, the use of B27M1 and B27M2 monoclonal antibodies has permitted the identification of distinct allospecific epitopes on the B27 molecule. One of these epitopes, B27M2, is polymorphic and has allowed us to define B27 variants: B27M2[+], B27M2[-], and B27M2[int]. The heterogeneity of the B27 antigen correlates well with biochemical and cytotoxic evidence of genetic heterogeneity. These variants exhibit ethnic variation and also appear to correlate, in preliminary studies, with disease susceptibility, especially among Orientals. HLA gene probing is potentially an even more precise tool than monoclonal antibodies for the study of MHC-related disease susceptibilities. Initial work in our laboratory has resulted in the production of probes with specificity for HLA-B locus genes and current efforts are directed toward the derivation of B27 allele-specific probes. It seems likely that, when such probes are applied to B27-positive individuals, complexity in addition to the B27M2 variants will be revealed. Yet to be defined is the mechanism behind the association between B27 and AS. Is the association causal for disease, or is B27 indeed just a marker for other pathogenic factors somehow linked to it? Available evidence points to both causal and linked roles for B27 in ankylosing spondylitis. Products of both HLA and non-HLA gene families may interact with infectious disease pathogens in susceptible individuals to produce a disorder which may not be specific in its association with any one pathogenic factor.
The association between HLA-B27 and ankylosing spondylitis could be explained by a "crosstolerance hypothesis". Experimental studies demonstrate immunological crossreactivity between HLA-B27 and antigens found in Gram-negative bacteria, such as Klebsiella. Clinical studies show that an increased frequency of patients with ankylosing spondylitis and uveitis have Klebsiella in their fecal cultures. Furthermore, antibodies to Klebsiella can be detected in such patients during active phases of the disease. It is suggested that anti-bacterial antibodies bind to cross-reacting self-antigens, activate the complement cascade and produce inflammation which eventually leads to the development of such chronic diseases as ankylosing spondylitis and uveitis.
A chemically synthesized peptide with an amino acid sequence identical to that of the segment spanning residue 63-84 of the major HLA-B27.1 subtype antigen has been obtained. Specific antibodies were raised in rabbits against this peptide, coupled to keyhole limpet hemocyanin carrier. These antibodies lysed lymphoblastoid cell lines expressing HLA-B27.1 in a complement-mediated cytotoxicity assay. They lysed neither B27-negative target cells, nor B27-positive cells expressing other B27 subtype antigens. Complement-mediated lysis of B27.1-positive targets was inhibited by free peptide and by peptide coupled to an unrelated carrier. In addition, the lytic action of the rabbit antiserum was blocked by a monoclonal antibody with no complement-activating capacity that under the conditions of the assay, was specific for HLA-B27. These results indicate that rabbit antibodies against the 63-84 peptide recognize the native HLA-B27.1 antigen; this antiserum is allospecific in character; and it discriminates among B27 subtypes. Thus the data provide direct evidence on the contribution of the hypervariable region spanning residues 63-84 to the alloantigenic specificity of HLA-B27.