No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
The pathogenetic role of HLA-B27
Abstract
The association between HLA-B27 and ankylosing spondylitis, reactive arthritis and acute anterior uveitis is so strong that the molecule itself is thought to play a pathogenetic role. The mechanism is not understood and is the subject of many studies. These were discussed at a recent meeting*.
... 6 It has been suggested that this molecule presents microbial proteins, presumably processed inside the cell, or autologous peptides which are induced during bacterial infections. 7 There is structural homology between HLA B27 and the amino acid sequences of several microbes, but convincing evidence that molecular mimicry is of pathogenic signi®cance is lacking. 7 Due to the nature of the disease as well as to ethical considerations, human tissue is rarely available for the necessary research. ...
... 7 There is structural homology between HLA B27 and the amino acid sequences of several microbes, but convincing evidence that molecular mimicry is of pathogenic signi®cance is lacking. 7 Due to the nature of the disease as well as to ethical considerations, human tissue is rarely available for the necessary research. During acute anterior uveitis, the procedure of anterior chamber paracentesis to collect aqueous may aggravate ocular in¯ammation, and there are also inherent risks of infection and inadvertent trauma to intraocular structures. ...
Acute anterior uveitis is a recurrent inflammatory disease of the eye that occurs commonly, is distressing for the patient, and may have potentially blinding sequelae. The pathogenesis of the disease is poorly understood, and anti-inflammatory treatment is consequently non-specific and may be associated with significant complications. Animal models are a possible key to a better understanding of this disease. In one model, rats and mice develop a relatively short-lived anterior uveal inflammation almost immediately after systemic injection of bacterial endotoxin. Accumulating evidence suggests that cytokine production by resident uveal macrophages initiates endotoxin-induced uveitis which is characterized by an infiltration of neutrophils and mononuclear cells. A second model displays features in keeping with a delayed-type hypersensitivity immune response. Experimental melanin-induced uveitis is an acute recurrent uveitis with delayed onset but extended duration, observed when rats are immunized with bovine ocular melanin. Both animal models have clinical features in common with acute anterior uveitis, although experimental melanin-induced uveitis appears to mimic the human disease more closely. Novel treatment options to target implicated inflammatory cells and molecules are currently under consideration.
... Researchers have long favored the involvement of HLA-B*27 in disease pathogenesis [50][51][52]. In 1992, a significant breakthrough occurred when a three-dimensional structure of HLA-B*27 was resolved at 2.1 A resolution, offering insights into the tight binding of peptide in its Content courtesy of Springer Nature, terms of use apply. ...
Purpose of Review
To commemorate the 50th anniversary of the groundbreaking discovery of a remarkably strong association between HLA-B*27 and ankylosing spondylitis (AS).
Recent Findings
In addition to HLA-B*27, more than 116 other recognized genetic risk variants have been identified, while epigenetic factors largely remain unexplored in this context. Among patients with AS who carry the HLA-B*27 gene, clonally expanded CD8 + T cells can be found in their bloodstream and within inflamed tissues. Moreover, the α and β chain motifs of these T-cell receptors demonstrate a distinct affinity for certain self- and microbial-derived peptides, leading to an autoimmune response that ultimately results in the onset of the disease. These distinctive peptide-binding and presentation characteristics are a hallmark of the disease-associated HLA-B*27:05 subtype but are absent in HLA-B*27:09, a subtype not associated with the disease, differing by only a single amino acid. This discovery represents a significant advancement in unraveling the 50-year-old puzzle of how HLA-B*27 contributes to the development of AS.
Summary
These findings will significantly accelerate the process of identifying peptides, both self- and microbial-derived, that instigate autoimmunity. This, in return, will pave the way for the development of more accurate and effective targeted treatments. Moreover, the discovery of improved biomarkers, in conjunction with the emerging technology of electric field molecular fingerprinting, has the potential to greatly bolster early diagnosis capabilities. A very recently published groundbreak paper underscores the remarkable effectiveness of targeting and eliminating disease-causing T cells in a HLA-B*27 patients with AS. This pivotal advancement not only signifies a paradigm shift but also bolsters the potential for preventing the disease in individuals carrying high-risk genetic variants.
... These include the following conditions: ankylosing spondylitis, reactive arthritis, psoriatic arthritis, enteropathic arthritis, non-radio figure ic spondyloarthritis. ReA is an inflammatory joint disease, which occurs at about 1-4 weeks from a genitourinary or digestive infection, most commonly in HLA-B27 positive patients [8,9]. ...
Reactive arthritis is an inflammatory joint disease which develops after 1-4 weeks following an enteral, genital or ORL infection, with a higher frequency in HLA-B27 positive patients.
Aims:
The objective of this paper is to study the importance of HLA-B27 antigen in the development of reactive arthritis.
Patients and methods:
The transversal, observational study was conducted in the Rheumatology Clinic of the University of Medicine and Pharmacy of Craiova during the period 2012-2015 and included 112 patients. They were divided into three groups, as follows: group I (52 reactive arthritis cases), group II (30 other spondyloarthritis cases), group III (40 osteoarthritis cases). ELISA and PCR techniques were used to determine the antigen.
Results:
Those whom had this genetic marker present, the number of enthesitis almost doubled highlighting a possible correlation between the antigen and these imaging changes. We can confirm the same thing for the erosions as well. Unlike enthesitis, erosions occurred also in group III (37.5%), but if we refer to the first two groups, we will observe a significant relationship regarding HLA-B27. More specifically, in HLA-B27 positive patients (68.97%), erosions were found to be twice as numerous than in HLA-B27 negative patients (31.03%). In group I we identified stage 2 sacroiliitis in 68% of HLA-B27 positive patients and 32% in HLA-B27 negative, which shows another link to this antigen with both joint destruction and a possible unfavorable evolution of reactive arthritis.
Conclusions:
This antigen specific to the seronegative group of spondyloarthritis determines the acceleration of articular destruction, translated by erosion, and the evolution of sacroiliitis to a more advanced stage.
... Comparable affinity changes were found using analogous P2 variants of another B27-binding peptide (sequence GRLTKHTKF; derived from the ribosomal protein L36). The relatively small affinity loss resulting from the arginine to glutamine change observed in these studies is consistent with recent reports that peptides containing glutamine bind to B*2705 (Villadangos et al., 1995), and also consistent with the observation that peptides containing glutamine and valine are presented by B*2705 in transgenic rats (Feltkamp et al., 1996). Previous studies have examined the effect of substitutions of the anchor residues of B27-binding peptides on the stability of B27- peptide complexes, using the half time of p2m dissociation as a measure of stability (Parker et al., 1992). ...
Recognition of self peptides bound to the class I major histocompatibility complex molecule HLA-B27 is thought to trigger proliferation of autoreactive T cells and result in autoimmune arthritic diseases. Previous work from other laboratories established that a predominant feature of endogenous peptides eluted from purified B27 is an arginine at position 2. We studied the binding of peptides containing both natural and unnatural amino acids by the subtype HLA-B*2702, with the goal of gaining insight into peptide binding by this B27 subtype that is associated with susceptibility to arthritic disease. A soluble from of B*2702 was depleted of endogenous peptides. We tested the binding of peptides substituted with cysteine, homocysteine, or an alpha-amino-epsilon-mercapto hexanoic acid side chain (Amh) instead of the naturally occurring arginine at position 2, to determine whether the peptide sulfhydryl residue could be covalently linked to cysteine 67 in the B*2702 binding cleft. Although none of the altered peptide sequences bound covalently to B*2702, the affinities of the homocysteine- and Amh-substituted peptides were close to that of the native peptide sequence. Substitutions at position 2 with other side chains, such as glutamine and methionine, also resulted in peptides that bound with only slightly reduced affinity. These results demonstrate that peptide side chains other than arginine at position 2 can be accomodated within the B*2702 peptide binding site with only minor reductions in affinity. This extended repertoire of permissible B27-binding peptides should be taken into account for a consideration of disease-associated peptide sequences.
... Reactive arthritis is clearly associated with HLA-B27, but how B27 influences susceptibility to arthritis, and whether it is mediated by an effect on the synovial T-cell response to bacterial antigens remains unclear [42][43][44]. The association with B27 is most evident in cases which are considered to require referral to rheumatology clinics because of severity or duration. ...
1.Arthritis can be induced in rodents by priming T-cells to respond to a foreign antigen and then challenging with antigen intra-articularly. This may be a model of the situation in human reactive arthritis in which T-cell responses are induced by antigens from organisms which trigger reactive arthritis (e.g. Chlamydia trachomatis) and antigen finds its way to the joint, most probably within macrophages. Priming by previous exposure to antigens similar to those of the triggering organism could also play a part in pathogenesis. Genetic factors determining the nature and control of the immune response affect the severity and duration of the arthritis.
2.T-cell-dependent arthritis can be induced in rodents by immunization with an antigen known to be expressed in the joint (e.g. Type II collagen). Whether this is an important mechanism in human arthritis is still unclear, even though diseases such as rheumatoid arthritis are conventionally thought of as ‘autoimmune'. No convincing candidate autoantigen has yet been identified in rheumatoid arthritis, and recent experiments in transgenic mice indicate that arthritis can be induced by an autoimmune T-cell response which does not target an antigen confined to the joint.
3.Adjuvant arthritis is a classical T-cell-dependent animal model of human arthritis; recently arthritis has been described as a rare complication in patients receiving adjuvant (intra-vesical live BCG organisms) for bladder cancer. Increasing attention is being paid to the role of adjuvants as ‘danger signals', which allow the immune system to determine whether an antigenic challenge poses a threat. Inappropriate attachment of danger signals to self antigens may result in T-cell-mediated immune responses, which could play a part in the pathogenesis of arthritis.
4.Animal studies indicate that autoimmune/inflammatory diseases can be produced by imbalances within T-cell populations, and that certain T-cells also have the capacity to regulate inflammatory responses. Among the latter are T-cells specific for conserved epitopes within heat shock protein 60. The extent to which T-cells of this kind operate in human disease has yet to be determined.
... HLA-B27 expression in humans has been associated with several inflammatory disorders, [8][9][10] such as ankylosing spondylitis, 8,10-12 reactive arthritis, 12-14 juvenile spondyloarthropathy, 15,16 psoriatic arthritis and psoriasis, 12,17 gastrointestinal inflammation (chronic colitis), 10,12 and anterior uveitis. 13,18 Our hypothesis was that HLA-B27 rats would also be susceptible to inflammatory periodontal disease and therefore to periodontal alveolar bone loss. The purpose of this investigation was to compare the naturally occurring alveolar bone loss in HLA-B27 transgenic and wild type rats. ...
HLA-B27 transgenic rats exhibit generalized, severe inflammatory reactions and spontaneously develop arthritis and chronic gastrointestinal inflammation, as well as inflammatory lesions in other tissues. Our hypothesis was that HLA-B27 rats would also be susceptible to inflammatory periodontal disease, and therefore alveolar bone loss. The purpose of this investigation was to compare the naturally occurring alveolar bone loss in HLA-B27 and wild type rats.
Age- and sex-matched HLA-B27 transgenic (TG) and wild type Fischer 344 (WT) female retired breeders, and their age-matched male WT breeding mates, were examined for alveolar bone loss (ABL). Thirty-eight animals were used: twelve, 20, and 6 animals were 6, 8, and 12 months old, respectively. ABL was measured as the exposed root surface area (mm2) in the defleshed maxilla and mandible.
The coefficient of variation for replicate ABL measurements was 4.4%. For the 6- and 8-month age groups, ABL was significantly greater in TG rats compared to WT rats. The observed difference in ABL between TG and WT animals did not reach statistical significance for the 12-month age group. Within each of the two animal groups (TG and WT), ABL was significantly different between age groups. The ABL rate of TG female rats was 42% to 250% greater than that of WT female rats, depending on the age range examined.
HLA-B27 rats are susceptible to accelerated alveolar bone loss and could serve as an animal model of alveolar bone loss pathogenesis.
Reactive arthritis (ReA) is one of the most frequent inflammatory joint diseases among young people. To be expressed, it is necessary to exist a definite interaction between the factors of the external environment and certain genetic predisposition. Chlamydia trachomatis, Yersinia enterocolitica, Salmonella enteritidis, Shigella flexneri and Campylobacter jejuni are some of the most common agents causing ReA in the individuals, whose susceptibility is connected with the carriage of HLA-B27 antigen. It is found that only 1-3% of the persons who had such an infection develop ReA and of the carriers of HLA-B27 antigen - only 20-40%. This fact shows that the pathogenesis of ReA is very complex and still not quite clear. The survey generalizes the contemporary data about the main factors concerning the beginning and development of ReA: infectious agents and their antigens, cell immunity and HLA-B27 molecules. The role of 60 KD heat shock protein from the external membrane of Gr(-) microorganisms is described as a leading immunodominant antigen, capable to induce immune response in joints. The study presents the experimental results, supporting the main role of the heavy (α) chain of B27-molecule for the expression of some bacterial epitops, having significance for triggering ReA. The basic units of the cellular immune response in patients with ReA are examined.
In 2001, the sequencing of human genome was finished and it was found out, that it contains about 30 000 genes. By this, the long-term and very demanding way has been open to consecutive determination not only function of these genes but also their polymorphism, allele mapping and gene mutation, their significance for carrier, and the relationship to various diseases. Autoimmune diseases belong to those, where some genetic risk factors are already known. This second review article deals with genetic risk factors of four autoimmune rheumatic diseases: juvenile ankylosing spondylitis (JAS), juvenile systemic lupus erythematosus (JSLE), juvenile dermatomyositis (JDM), and sclerodermia in children. In ankylosing spondylitis, the most significant risk factor is histocompatible genes of human leukocyte antigens (HLA), where the HLA-B27 is not only in more than 90 % associated with disease, but its determination has also diagnostic value. HLA but also other risk factors participate in etiopathogenesis of systemic lupus erythematosus, including genes for complement, apoptosis, mannose-binding lectin, and Yaa gene.
Introduction: Human Leucocyte Antigenes (HLA) may play a complementary role in the interaction between tumor and body immunology. In this study, HLA antigens of patients with transitional cell carcinoma (TCC) of the bladder were compared with HLA antigens of the control group and the association between the HLA system and TCC were investigated. Materials and Methods: By using the standard microlymphocytotoxicity method of Terasaki in our study, the HLA A, B, DR and DQ antigen types of 30 patients with TCC of the bladder, were compared with the control group of 30 healthy people who was a donor for kidney transplantation. Histological stage and grade of bladder tumors were established according to the International Union Against Cancer classification. Odds ratio (OR), Fischer's exact test and Chi square tests were used for statistical analysis. Results: the mean age was 64.3±10.8 years in the patients with TCC. Histopathological stage was pTa, pTI (superficial) in 13 patients (43.3%) and pT2, pT3 and pT4 (invasive) in 17 patients (56.7%). A total of 9 patients (30%) low grade and 21 high grade TCC (70%). Carcinoma in situ (CIS) of bladder was determined in 18 patients (60%). HLA-A 10, HLA-B 4, HLA-DR 53 and HLA-DQ 1 antigens were detected significantly higher in the control group compared to the patient group and there was statistically significant (p<0.05). HLA-A 25 (10) was positive in 4 patients with TCC but no observed in the control group. No statistically significant was found (p=0.112), (OR 2.15, 95% confidence interval 1.62 to 2.85) HLA-DQ 6 (1) was detected in 60% and 26.7% of the patients in TCC and the control group, respectively, (p=0.018), (OR 4.12). Similarly, HLA-DQ 7 (3) was found in 63.3% and 33.3% of the patients in TCC and the control group, respectively, (p=0.038), (OR 3.45). In addition HLA-B 51 (5) in patients with low grade was found significantly higher (p=0.02). when the patients with CIS were evaluated only HLA-B 4 was found differently. Conclusion: The results revealed that the people, carrying the antigens that were detected in the patient group, were highly at the risk of TCC and the antigens that were highly detected in the control group, could be accepted as protective for TCC. In the future further researches to be performed in our population will be more illuminating to confirm these results. We have thought that sampling of HLA profiles may be useful for evaluating the people at risk of TCC besides for planning their prognosis and the treatment.
The mechanisms leading to the development of HLA-B27-associated diseases, spondyloarthropathies, are unknown. One of them, reactive arthritis, is clearly caused by an infection, and joint inflammation develops soon after or during an infection elsewhere in the body. In other forms of spondyloarthropathies, such as ankylosing spondylitis, association with infection is suggested but it is not as clear. Pathogenetic mechanisms of reactive arthritis are a focus of great interest as causative infections and strong genetic association are known. How HLA-B27 determines the appearance of joint complications after certain infections is not clear. Several theories have been proposed to explain the association, and they usually include the idea that interaction between microbe and host is abnormal and inefficient in HLA-B27-positive subjects in whom reactive arthritis develops.
Abstract The distinctions between infection, chronic arthritis, and autoimmune diseases have steadily blurred over the past decades. The proposed pathomechanisms underlying these interesting associations include putative pathways from infection to innate and adaptive immunity, molecular mimicry, and certain microbial and host factors. This article further reviews the spectrum of microbial agents implicated in some rheumatic diseases and cites the potential clinical application of this expanding field of knowledge in the prevention and treatment of chronic inflammatory and autoimmune diseases.
Las espondiloartropatías (EPA) agrupan distintas enfermedades cuya lesión elemental es una lesión inflamatoria de las entesis axiales y/o periféricas. Se trata de la espondiloartritis anquilosante (EA), las artritis reactivas (AR), la artritis psoriásica (RP) y las manifestaciones articulares de las enterocolopatías inflamatorias crónicas (enfermedad de Crohn y rectocolitis ulcerohemorrágica). Su prevalencia se aproxima a la de la poliartritis reumatoide, y es del orden del 0,2-0,5% en la población general. Estas enfermedades reumáticas tienen características comunes: casi siempre comienzan en el adulto joven con una base genética predisponente (antígeno leucocítico humano [HLA] B27) y tienen una evolución marcada por frecuentes remisiones espontáneas, aunque también hacia una forma crónica invalidante y discapacitante. Todas las entesis pueden estar afectadas. Las localizaciones más características son las sacroilíacas y la columna vertebral, responsables de la afectación axial, y también el calcáneo, las articulaciones claviculares, la sínfisis púbica y las interfalángicas distales en las afecciones periféricas. Algunas artritis periféricas asimétricas pueden completar el cuadro clínico. Cuando en un adulto joven existe un cuadro de raquialgias inflamatorias o de inflamación de las entesis o articulaciones periféricas, habrá que buscar mediante el interrogatorio y la exploración clínica antecedentes personales o familiares de EPA, así como de psoriasis, acné, pustulosis, enteropatía, trastorno urogenital o digestivo y oftalmopatía. En la exploración física hay que descartar un cuadro pelvirraquídeo, entesítico, articular periférico o extraarticular. Las pruebas de laboratorio sirven sobre todo para descartar los diagnósticos diferenciales. Así, el síndrome inflamatorio puede ser muy leve o estar ausente, sobre todo en las formas axiales. La búsqueda del HLA B27 sólo está justificada en las formas iniciales y/o atípicas de EPA, y debe ser interpretada con prudencia, ya que un 7-10% de la población caucásica es portadora de al menos un alelo HLA B27. Las lesiones radiológicas características aparecen casi siempre en la fase tardía, pero cuando lo hacen permiten confirmar el diagnóstico. La piedra angular del tratamiento de las EPA es la asociación de antiinflamatorios no esteroideos (AINE), cuya eficacia es un criterio diagnóstico clave, y de reeducación funcional. Los analgésicos son eficaces como tratamiento complementario de los AINE. Si los AINE resultan insuficientes, se puede plantear la introducción de un tratamiento de fondo. En las formas periféricas, ciertos tratamientos como la sulfasalazina, el metotrexato, la leflunomida y los antifactores de necrosis tumoral (TNF)-α han mostrado su eficacia clínica, sobre todo en las RP. En cambio, sólo el anti-TNF-α ha demostrado eficacia clínica en las formas axiales. Estos tratamientos sólo se pueden utilizar en las EPA después del fracaso de un tratamiento convencional dirigido de forma óptima y de acuerdo con la opinión de un reumatólogo que tenga una gran experiencia en las EPA y en las bioterapias.
Objectives
This report describes a patient with a mistaken diagnosis of ankylosing pelvospondylitis and illustrates several aspects of the differential diagnosis of this entity, using symptoms, laboratory tests, radiology and magnetic resonance imaging (MRI) and the treatment provided.
Clinical characteristics
A 28-year-old woman consulted for lower back pain and left sacroiliitis. The medical diagnosis was ankylosing spondylitis. Laboratory tests showed the presence of HLA-B27, but the results of the remaining rheumatic tests were negative. The results of x-rays and MRI were also were normal.
Intervention and results
Taking into account these findings, a diagnosis of ankylosing pelvospondylitis was excluded. Manipulative osteopathic treatment in this patient consisted of plantar correction through the use of insoles and an osteopathic manipulative treatment of the patient's somatic dysfunction to modify his postural imbalance.
Conclusion
Diagnosis of pelvospondylitis should be based on several diagnostic factors and cannot be based on a single diagnostic test. After three osteopathic manipulative treatments, the patient's symptoms disappeared.
Reaktive Arthritiden treten infolge einer primär extraartikulären bakteriellen Infektion auf. Charakteristisch ist, daß der auslösende Erreger mit konventionellen Kulturmethoden nicht aus dem Gelenk angezüchtet werden kann. In dieser Übersicht wird aufgrund des aktuellen Forschungsstandes das folgende Modell zur Ätiopathogenese reaktiver Arthritiden vorgestellt: Nach der primären extraartikulären Infektion wird der Erreger via Blutkreislauf in die Gelenke disseminiert. Intraartikulär persistiert der Erreger in der Synovialmembran. Die durch die intraartikuläre Erregerpersistenz initiierte Immunantwort führt zur Arthritis. Wichtige Fragen zur Genese der Persistenz und Relevanz der immunologischen Mechanismen sind jedoch noch ungeklärt. Perspektiven für die weitere Forschung sowie diagnostische und therapeutische Möglichkeiten in der Zukunft werden aufgeführt.
Spondylarthropathies (SpAs) refer to a group of inflammatory arthrites that are characterized by their association with HLA B27 and the development of sacroiliitis and enthesitis. SpAs comprise five subtypes: rheumatoid spondylitis, reactive arthritis, psoriatic arthritis, inflammatory bowel disease associated with arthritis/spondylitis and undifferentiated SpA. The prevalence of the whole group of SpAs has been recently estimated between 0.2 and 0.5 % of the general population. Onset is typically in the third and fourth decades of life. Frequently, spontaneous remission can be observed during the course of this disease that can also result in severe disability and loss of quality of life. The main clinical manifestations of enthesitis include inflammatory back pain, sacroiliitis - axial involvement- and also involve symphysis pubis, insertion of the Achilles tendons, plantar fascia and costochondral joints. Although SpA is traditionally considered a disease of the axial skeleton, arthritis of the appendicular skeleton is also common. In case of a patient with inflammatory low back pain and/or enthesitis, clinical examination must screen for personal or family history of SpAs, psoriasis, acne, inflammatory bowel disease, genital infection, uveitis. Serum acute phase reactant increase and antibodies can be absent in SpAs. Even if SpAs are strongly associated with HLA B27, phenotyping is useful only for recent onset diseases and undifferentiated SpA, because almost 10% of the general population has at least a B27 allele. Characteristic structural damages become apparent lately, confirming the diagnosis. Non-steroidal anti-inflammatory drugs (NSAIDs), exercise and physiotherapy are considered the cornerstone of the treatment for patients with SpAs. Pain killers can be associated. Disease modifying antirheumatic drugs (DMARDs) are considered second line treatment but conclusive evidence for the efficacy of these drugs with respect to spinal manifestations is still lacking.
The end of this century and the dawn of the new millennium are near, and we still don't fully understand the mechanism behind the remarkable association of HLA-B27 with spondy-loarthropathies, although it has been known for more than a quarter of a century. However, there has been a slow but steady progress in the field of spondyloarthropathies. Not all alleles that encode for the HLA-B27 serologic specificity are associated with susceptibility to develop a spondyloarthropathy. The number of known subtypes of HLA-B27 continue to grow; the latest three additions are HLA-B*2713, HLA-B*2714, and HLA-B*2715. It is becoming increasingly clear that the observed synovial and cartilage changes in spondyloarthropathies are mainly the result of an entheseal- rather than a synovial-based pathology, because the initial or primary inflammatory response is located at the enthesis, whereas synovitis is most likely triggered secondarily by locally released cytokines at the adjacent sites in the joint cavity. But we still don't know how ankylosis relates to HLA-B27. The conditions favoring the development of HIV-associated spondyloarthropathy are becoming less of a problem in North America, but this is not the case in some of the other regions of the world, such as Sub-Saharan Africa.
Patients with endogenous uveitis represent 6.5+ of patients in University Hospital Split, which serves most of South Croatia. Within a four-year period 208 patients were treated for endogenous uveitis. Results of clinical-laboratory examinations and treatment of 112 subjects suffering from anterior uveitis are presented and compared. Acute anterior uveitis (AAU) was the commonest form of uveal inflammation. It was present in 49+ of all uveitis cases and in 91.1+ of all anterior uveitis cases (AU). 67.6+ of the subjects with AAU had and 32.4+ did not have the HLA B(27) antigen. The inflammatory pattern in B(27)(+) patients was typical of B(27)(+) AAU. Patients with B(27)(+) AAU exhibited the same inflammatory pattern as those with B(7)(+) AAU. B(27)(+) AAU patients had significantly more systemic/rheumatic diseases (p>0.05), while patients with B(27)(-) AAU had significantly more infectious diseases (p>0.05). Forty percent of the patients with chronic anterior uveitis suffered from juvenile rheumatoid arthritis. The authors observed the rise in peripheral blood IgG, IgA, IgM, CD(2)(+), CD(4)(+) and B cells during the acute phase of AAU. Normalization of B cells (CD(20)(+)) was observed in early remission of anterior uveitis, about eight weeks after the onset of the disease.
Up to one-half of patients with anterior uveitis suffer from related systemic diseases. The common associations are the seronegative arthropathies and, in children, juvenile chronic arthritis. Anterior uveitis may also occur in the context of sarcoidosis or Behçet's disease. Syphilis and tuberculosis remain a significant problem for specific populations and may be the cause of anterior uveitis in these groups. By thorough clinical history and the correct selection and interpretation of simple investigations, it is generally possible for the ophthalmologist to make or exclude a systemic diagnosis, predict the ocular prognosis and direct selected patients to the appropriate physician. Diseases that threaten the patient's wellbeing must certainly be recognized. In the present review we present a method for identifying the systemic associations of anterior uveitis.
HLA-B27 is the major genetic susceptibility factor for ankylosing spondylitis (AS). However, its precise role in the pathogenesis of AS still remains unclear, even though its gene has been cloned and sequenced, and its crystallographic structure has been defined. Arthritogenic peptide and molecular mimicry hypotheses propose mechanisms related to an antigen-presenting function of HLA-B27 to be responsible for disease development. However, peculiar aspects of its immunobiology, such as its misfolding and heavy chain dimerization raise the possibility of involvement of pathogenic mechanisms unrelated to its physiological function. Moreover, HLA-B27 is not a single allele, but a family of 31 different alleles, named HLA-B*2701 to HLA-B*2727. Studies worldwide indicate that the relatively common alleles (subtypes) HLA-B*2705, B*2704, and B*2702 are strongly associated with AS, whereas HLA-B*2706 which is prevalent in South-east Asia and HLA-B*2709 which is prevalent on the Italian island of Sardinia, seem to lack such an association. The distinction between the disease-associated subtypes and those that are not associated, may provide clues to the actual role of HLA-B27 in disease pathogenesis. B*2706 differs from B*2704 by only two residues, and B*2709 differs from B*2705 by only one residue. Moreover, both B*2706 and B*2709 bind an endogenous peptide (derived from vasoactive intestinal peptide type 1 receptor) and also an exogenous peptide (latent membrane protein 2 of Epstein-Barr virus) but in two drastically diverse conformations. These recent X-ray diffraction studies of individual peptides in the context of different HLA-B27 alleles broaden our perception of the possible pathogenetic role of this molecule in the development of AS and related spondyloarthopathies. In summary, the pathogenetic role of HLA-B27 in AS seem to be quite heterogenous, and cannot be explained by a single mechanism, and new ideas have been raised based on the aberrant immunobiologic features of HLA-B27.
Etiologies of Renal Cell Carcinoma (RCC) are not clear despite of the fact that many risk factors have been suggested. Especially in high stages RCC can affect the immune system in various ways. Human Leukocyte Antigens (HLA) may play a complementary role in the activation between the tumor and immunity. Our aim was to determine the existence of the relationship between HLA system and RCC. By using the standard microlymphocytotoxic method of Terasaki in our study, the HLA A, B, DR and DQ antigen types of 20 patients with RCC Stage T1 and T2 were compared with the control group consisting of healthy 30 people. In our RCC patient group, HLA-A23(9) and DQ7(3) antigens were significantly higher than the control group statistically (p=0.005, p=0.0028; respectively). HLA-A10, DQ1, DR10 and B44 antigens were significantly higher in the control group than the patient group (p=0.011; for all).The findings made us suggest that the people, carrying the antigens which were detected in the patient group, were at high risk for RCC and the people, carrying the protective antigens that were detected in the control group were at less risk for RCC. There may be a dramatic regression for the patients who underwent immunotherapy and HLA expression, which is known to play role in tumor biology, may direct the effects of immunotherapeutic agents. Immunologic description and destruction is avoided in case of change or disappearance of HLA expression by cancer cells. Further investigations which will be performed in our population in the future will be more illuminating to confirm those results. We have concluded that, HLA profiles may be evaluated for detection the people at risk of RCC, the prognosis of the patients and their treatments.
Ankylosing spondylitis and reactive arthritis are seronegative spondyloarthropathies, which are strongly associated with HLA-B27. Despite intensive investigation, the basis for this association is not clear. However, in recent years one favored hypothesis to explain this linkage has been that of molecular mimicry, i.e., sharing of linear or conformational epitopes common to microbial antigens and host structures. During the past few years several examples of molecular mimicry between HLA-B27 and microbial antigens have been described. Heat shock proteins, among others, have been considered as target candidates for autoimmune phenomena, because of the high degree of homology between bacterial and mammalian species. Reactive arthritis triggered by Yersinia or Salmonella provides a unique model for studying the pathogenetic mechanisms underlying human inflammatory joint diseases in general, because the arthritogenic microbes are known and well-characterized. We have described two bacterial proteins that share amino acid homology with HLA-B27, namely YadA (Yersinia adhesin) and OmpH, outer surface proteins of Yersinia and Salmonella, respectively. Notably, the area of identity of these amino acid sequences is located in the same place on the HLA-B27 molecule as a hexapeptide identical between Klebsiella nitrogenase and HLA-B27, and a pentapeptide shared by a Shigella flexneri protein and HLA-B27. We have investigated immune responses to a panel of synthetic peptides based on the HLA-B27-homologous portions of pathogen-specific antigens in patients with reactive arthritis and ankylosing spondylitis. One third of the patients have antibodies to the synthetic peptides. However, instead of recognizing the HLA-B27-homologous portion, the antibodies are directed against the flanking sequences of the synthetic peptides. The concept of the role of molecular mimicry between HLA-B27 and microbial antigens in the pathogenesis of spondyloarthropathies is discussed, with a conclusion that no convincing evidence for its significance exists at the present.
B*2703 is an exceptional HLA-B27 molecule in that it differs from the most common B*2705 subtype by a unique amino acid change (His59) altering N-terminal peptide anchorage. To assess how this unusual feature affects the antigenic structure of HLA-B27, TCR usage by alloreactive CTL raised against B*2703 from two individuals was analyzed. Only few CTL recognized B*2703 from two individuals was analyzed. Only few CTL recognized B*2703 but nor ot at a lower level B*2705. Limited heterogeneity of these CTL was revealed by: 1) identity of TCR in two pairs of such CTL clones, 2) identity of beta chains, paired to distinct alpha chains, in two clonotypes, and 3) almost identical fine specificity of these two clonotypes with site-specific HLA-B27 mutants. These results indicate that B*2703 "private" epitopes are rare. TCR usage among anti-B*2703 CTL was analogous as in anti-B*2705 responses in the predominant and donor-independent usage of V beta segments from homology subgroup 4, more moderate and donor-dependent V alpha skewing, N+D beta diversity limited by motifs shared among clonotypes, and restricted J alpha heterogeneity. Homology of N+D beta motifs and J alpha segments of anti-B*2703 with anti-B*2705 TCR suggested significant sharing of peptide-associated epitopes between both subtypes. The results indicate that allospecific TCR are recruited by B*2703 following similar rules as in the anti-B*2705 response, and suggest that the B*2703 change keeps unaltered much of the antigenic structure of the molecule relative to B*2705. Therefore, most of the peptides bound to B*2703 should be the same and keep a similar conformation as in B*2705.
Psoriatic arthritis (PA) is an immune disease associated with HLA-A2 in the Japanese population. To investigate mechanisms the association between HLA-A2 and PA, we examined in vivo immune responsiveness to Streptococcus pyogenes. Recombinant M proteins for the subtype specific N-terminal half (AB region) and conserved C-terminal half (C region) were produced separately. IgG antibody level against each region was measured by ELISA in 31 PA patients, 88 patients with psoriasis vulgaris, 6 patients with rheumatoid arthritis and 77 healthy controls. We found that IgG antibody levels against the C region were markedly higher in the PA patient group than in the other disease groups or controls. Further, IgG antibody levels were higher in PA patients with spondylitis and polyarticular arthritis than in PA patients with rheumatoid-like arthritis and arthritis mutilans. In contrast, no significant difference in the IgG antibody levels against the AB region was observed among the tested groups. HLA-A2 DNA typing showed that HLA-A*0207 was associated with PA (RR = 17.6; pcorr < 0.01) and the IgG antibody responses to the C region correlated well with the presence of HLA-A*0207. These results suggest that streptococcal infection may be involved in the pathogenesis of PA by participating in the HLA-linked immune responsiveness.
Serological typing with the microlymphocytotoxicity test (MLCT) and flow cytometry (FC) using HLA-B27 antisera is commonly used for the determination of HLA-B27. However, in some patients tested more than once, negative results have turned out to be positive at following investigations. We retested by polymerase chain reaction (PCR) samples from 20 randomly selected patients with reactive arthritis or Reiter's syndrome who had now been followed for 20 yr. Ten of the patients were originally tested to be HLA-B27 positive and 10 HLA-B27 negative by the MLCT. All 10 serologically HLA-B27 positive individuals were also positive in the PCR. However, 2/10 patients interpreted as being HLA-B27 negative were positive by PCR. At this time, the same two patients were also positive in the routine MLCT and FC using four different monoclonal antibodies against HLA-B27. PCR is superior to serological techniques to determine HLA-B27 positivity unequivocally, since it is based on the detection of HLA-B27 gene sequences.
The mechanisms leading to the development of HLA-B27-associated diseases, spondyloarthropathies, are unknown. One of them, reactive arthritis, is clearly caused by an infection, and joint inflammation develops soon after or during an infection elsewhere in the body. In other forms of spondyloarthropathies, such as ankylosing spondylitis, association with infection is suggested but it is not as clear. Pathogenetic mechanisms of reactive arthritis are a focus of great interest as causative infections and strong genetic association are known. How HLA-B27 determines the appearance of joint complications after certain infections is not clear. Several theories have been proposed to explain the association, and they usually include the idea that interaction between microbe and host is abnormal and inefficient in HLA-B27-positive subjects in whom reactive arthritis develops.
Human major histocompatibility complex class I allele HLA-B27 is associated with a group of diseases called spondyloarthropathies. In reactive arthritis (ReA), the disease is triggered by certain infections, e.g. gastroenteritis caused by Salmonella. The host/microbe interaction is abnormal in susceptible individuals leading to inefficient elimination of arthritis-triggering bacteria, fragments of them, or both, after the initial infection. Using transfected human monocytic U937 cell lines, we demonstrate that the expression of the HLA-B27 antigen does not influence the uptake of S. enteritidis into U937 cells in vitro. Interestingly, HLA-B27 remarkably impairs the elimination of S. enteritidis within the HLA-B27 transfected U937 cells. The impaired elimination of ReA-triggering microbes by HLA-B27+ monocytes may offer an explanation for the persistence of ReA-triggering microbes in susceptible HLA-B27+ individuals. This modulation of the host/microbe interaction by HLA-B27 may have an important role in the pathogenesis of ReA.
Since intestinal inflammation is correlated with impaired barrier functions, transgenic HLA-B27/human beta 2-microglobulin rats that spontaneously develop intestinal inflammation were used to investigate whether onset of inflammation or impaired barrier function was the initial event.
During the age period of 9-14 weeks, transgenic and non-transgenic (control) rats were gavaged weekly with the marker molecules, 51Cr-ethylenediaminetetraacetic acid, 1-deamino-8-D-arginine vasopressin, and albumin, which were quantified in blood or urine.
At 12 weeks of age the first signs of inflammation appeared with decreased body weight gain, decreased urine production, and onset of diarrhea. By 14-15 weeks of age all transgenic rats had developed intestinal inflammation, as confirmed by histology and increased myeloperoxidase content, whereas no inflammation was observed in controls. Intestinal passage of the markers did, however, not differ between transgenic and control rats over the studied period.
The results suggest that intestinal inflammation precedes altered intestinal barrier function in this inflammation model.
This article discusses the clinical spectrum and characteristics of juvenile-onset spondyloarthropathies and includes a review of the demographic, clinical, radiographic (and other imaging techniques), and laboratory data of conditions, syndromes, and diseases making up this group. The pathogenic role of several factors in the context of adult-onset patients, but also in regards to studies already performed in juvenile-onset patients, is discussed.
Eye is the official journal of the Royal College of Ophthalmologists. It aims to provide the practising ophthalmologist with information on the latest clinical and laboratory-based research.
To investigate the adhesion and extravasation capacity of peripheral blood mononuclear cells (PBMC) and the transport of bacterial antigens within these cells during Salmonella infection.
Thirteen patients who were part of 2 outbreaks of Salmonella enteritidis infection were included in this study. The capacity of PBMC from these patients to bind to vascular endothelium in inflamed synovium was tested using a Stamper-Woodruff-type frozen-section assay. The same cells were studied for the presence of Salmonella antigens by immunofluorescence staining. The transendothelial migration of mononuclear cells containing Salmonella or its components through unstimulated endothelial cell layer was quantified.
The capacity of PBMC to adhere to synovial vessels was significantly increased during Salmonella infection (P=0.0003). Monocytes had a transiently high adhesive state between 2 and 5 weeks after the patients had eaten the contaminated food. The cells containing Salmonella antigens were concentrated in the transmigrated population.
During acute Salmonella infection the increased binding of PBMC to vascular endothelium in inflamed synovium and enhanced transmigration of PBMC containing Salmonella may be the key factors leading to transport of bacterial antigens through the endothelial barrier and initiation of arthritis in susceptible individuals.
This questionnaire survey of 71 patients with ankylosing spondylitis (members of the National Ankylosing Spondylitis Society of the UK) revealed that a substantial proportion of patients were apparently not told of several aspects of their illness by their doctors such as likely cause(s), familial clustering, role of HLA tissue typing and diet (appropriately). Only a small percentage (4.2%) were counselled to actively seek screening for close family members. As HLA B27 presence is not diagnostic of ankylosing spondylitis, and it cannot be prevented or arrested even if diagnosed at onset or early stages, routine screening of close family members cannot be justified at present.
Non-pustular psoriasis consists of two disease subtypes, type I and type II, which demonstrate distinct characteristics. Firstly the disease presents in different decades of life, in type I before the age of 40 years and later in type II. Secondly, contrasting frequencies of HLA alleles are found: type I patients express predominantly HLA-Cw6, -B57, and -DR7, whereas in type II patients HLA-Cw2 is overrepresented. Finally, familial inheritance is found in type I but not in type II psoriasis. The study of concomitant diseases in psoriasis contributes to deciphering the distinct patterns of the disease. Defence against invading microorganisms seems better developed in psoriatics than in controls. This evolutionary benefit may have caused the overall high incidence of psoriasis of 2%. Psoriasis is a multifactorial and heterogenetically inherited disease. The heterogeneity is evident by the diversity of genetically linked markers. The multifactorial component results from the observation of external trigger mechanisms, such as the Koebner phenomenon, stress and the intake of certain drugs. Twin studies have shown that environmental factors contribute to the onset of the disease. In type I psoriasis, special extended haplotypes such as EH57.1 (HLA-Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303) and EH65.1 (HLA-Cw8-B65-DRB1*0102-DQB1*0501) have been found to be increased. The application of microsatellite techniques has identified distinct positions on several chromosomes at which putative psoriasis genes may be located. Disease susceptibility genes are thought to be present on chromosomes 4q, 6p, 16q, 17q and 20p. Moreover, on chromosome 1q, genes regulating epidermal differentiation have been identified. Linkage to this area has been proposed. Furthermore, psoriasis gene loci on chromosomes 2, 8 and 20 have been suggested.
Previous studies indicated the increase of HLA-B39 among HLA-B27 negative patients with spondylarthropathies (SpA). This study was performed to examine whether the natural ligands of HLA-B27 are capable of binding to HLA-B39.
Peptides were synthesized according to the sequences of known natural ligands of HLA-B27 or B39 and were tested for their binding to HLA-B*3901 and B*2705 by quantitative peptide binding assay, using a TAP-deficient RMA-S cell line transfected with human beta2-microglobulin and HLA class I heavy chain genes.
Four of the 10 HLA-B27 binding peptides significantly bound to HLA-B*3901. All 4 peptides had hydrophobic/aromatic amino acids (Leu or Phe) at the C-terminus. In contrast, peptides with basic residues (Lys, Arg) or Tyr at the C-terminus did not bind to B*3901. In parallel experiments, 1 of the 2 natural ligands of HLA-B*3901 was found to bind to B*2705.
A subset of natural HLA-B27 ligands was capable of binding to B*3901. In addition to Arg at position 2 (Arg2), hydrophobic/aromatic C-terminal residues, such as Leu or Phe, seemed to be crucial for the cross-specificity. These results suggested that HLA-B27 and B39 recognize overlapping peptide repertoires, supporting the hypothesis that the peptides presented by both of these class I antigens play a role in the pathogenesis of SpA.
Experimental melanin-induced uveitis (EMIU) is a rodent model of acute anterior uveitis which was described in 1993. We investigated strain susceptibility, and age and gender characteristics of the model, undertook histological and immunohistochemical studies to investigate underlying cellular mechanisms, and examined several treatment options. Rats were immunized with bovine ocular melanin (250 microg), and disease was followed by slit lamp examination. Lewis, Fischer 344 and Porton rats were found to be susceptible to EMIU, whereas Wistar-Furth, DA, and Hooded Wistar strains were resistant. EMIU was neither age- nor gender-dependent. In Fischer 344 rats, EMIU was characterized clinically by florid anterior segment inflammation. Histopathological findings included infiltration of ciliary body and iris with mononuclear cells and neutrophils. Both CD4+ and CD8+ T lymphocytes were prominent. Rats were then treated with intraperitoneal injections of anti-CD4, anti-CD8 or irrelevant isotype-matched MoAb on days -3, 0, 3, 6 and 9 with respect to melanin immunization. Incidence of uveitis was significantly reduced in rats treated with a non-depleting cocktail of anti-CD4 MoAbs (P = 0.007), whereas a depleting anti-CD8 antibody had no effect on the disease. Mannose-6-phosphate inhibits lymphocyte migration in some models of T cell-mediated inflammation. This simple sugar was administered to additional rats via intraperitoneal osmotic pumps for 14 days following disease induction, but did not influence the uveitis. We conclude that EMIU is controlled by CD4+ T cells, and disease may be abrogated by treatment with anti-CD4 MoAbs.
The frequency and severity of ankylosing spondylitis (AS) show a male preponderance, and androgenic steroids have been implicated in its etiology. Some reports have indicated that serum androgen levels are slightly elevated relative to estrogen levels in patients with AS as compared to controls.
In more recent studies, however, serum testosterone, 17β-estradiol, and androstenedione levels did not significantly differ between AS patients and controls. Moreover, testosterone levels measured directly in serum can be spuriously elevated, especially in patients using phenylbutazone. Elevated serum levels of the adrenal steroids 17α-hydroxyprogesterone and dehydroepiandrosterone (DHEA) sulfate have been found in patients with AS. These elevations might be explained by partial 11β- or 21-hydroxylase deficiencies, but may also be secondary to an enhanced stress response. In vitro studies as well as studies in animals and humans indicate that DHEA enhanced, and 17β-estradiol and progesterone inhibit, the cell-mediated immune response, which may play a role in the pathogenesis of AS. Oral estrogen therapy in female patients and human chorionic gonadotrophin injections in male patients with AS, increased the 17β-estradiol/testosterone ratio and resulted in a moderate clinical improvement.
In conclusion, serum testosterone levels are not elevated in patients with AS. Therefore testosterone probably has no role in the perpetuation of long-standing AS and provides no basis for antiandrogenic treatment. Cross-sectional case-control studies, however, cannot clearly distinguish etiological factors from secondary disease effects, especially when blood sampling occurs many years after the onset of AS. Consequently, the role of sex steroids in the pathogenesis is still insufficiently elucidated.
HLA-B*2705 is strongly associated with ankylosing spondylitis (AS) and reactive arthritis. In contrast, B*2709 has been reported to be more weakly or not associated to AS. These two molecules differ by a single amino acid change: aspartic acid in B*2705 or histidine in B*2709 at position 116. In this study, we analyzed the degree of T cell epitope sharing between the two subtypes. Ten allospecific T cell clones raised against B*2705, 10 clones raised against B*2703 but cross-reactive with B*2705, and 10 clones raised against B*2709 were examined for their capacity to lyse B*2705 and B*2709 target cells. The anti-B*2705 and anti-B*2703 CTL were peptide dependent as demonstrated by their failure to lyse TAP-deficient B*2705-T2 transfectant cells. Eight of the anti-B*2705 and five of the anti-B*2703 CTL clones lysed B*2709 targets. The degree of cross-reaction between B*2705 and B*2709 was donor dependent. In addition, the effect of the B*2709 mutation (D116H) on allorecognition was smaller than the effect of the other naturally occurring subtype change at this position, D116Y. These results demonstrate that B*2705 and B*2709 are the antigenically closest HLA-B27 subtypes. Because allospecific T cell recognition is peptide dependent, our results imply that the B*2705- and B*2709-bound peptide repertoires are largely overlapping. Thus, to the extent to which linkage of HLA-B27 with AS is related to the peptide-presenting properties of this molecule, our results would imply that peptides within a relatively small fraction of the HLA-B27-bound peptide repertoire influence susceptibility to this disease.
Major histocompatibility complex (MHC) class I expression is reduced in several viral infections, but it is not known whether the same happens during infections caused by intracellular enterobacteria. In this study, the expression of MHC class I antigens on peripheral blood mononuclear cells (PBMC) from 16 patients with Salmonella, Yersinia, or Klebsiella infection was investigated. During or after the acute infection, the expression of MHC class I antigens was markedly decreased in eight patients, all with genotype HLA-B27, and six out of eight with reactive arthritis (ReA). A significant decrease of monomorphic MHC class I was found in three patients, of HLA-B27 in eight (P<0.05) and of HLA-A2 in two. However, patients negative for the HLA-B27 genotype, or healthy HLA-B27-positive individuals, did not have a significant decrease of MHC class I antigens. During the decreased expression on the cell surface, intracellular retention of MHC class I antigens was observed, whereas HLA-B27 mRNA levels did not vary significantly. This is the first evidence that enterobacterial infection may down-regulate expression of MHC class I molecules in vivo and that down-regulation is predominant in patients with the HLA-B27 genotype.
The MHC class I protein HLA-B27 is strongly associated with susceptibility to spondyloarthropathies and can cause arthritis when expressed in rats and mice, implying a direct role in disease pathogenesis. A prominent hypothesis to explain this role suggests that the unique peptide binding specificity of HLA-B27 confers an ability to present arthritogenic peptides. The B pocket, a region of the peptide binding groove that is an important determinant of allele-specific peptide binding, is thought to be critical for arthritogenicity. However, this hypothesis remains unproven. We show that in addition to its role in peptide selection, the B pocket causes a portion of the pool of assembling HLA-B27 heavy chains in the endoplasmic reticulum to misfold, resulting in their degradation in the cytosol. The misfolding phenotype is corrected by replacing the HLA-B27 B pocket with one from HLA-A2. Our results suggest an alternative to the arthritogenic peptide hypothesis. Misfolding and its consequences, rather than allele-specific peptide presentation, may underlie the strong link between the HLA-B27 B pocket and susceptibility to spondyloarthropathies.
The objectives of this study were to investigate and validate individual variables and to develop a composite score for disease activity measurement in patients with reactive arthritis (REA).
In the first cross-sectional part, the clinical and laboratory evaluation of 45 patients was used to elaborate the most important individual disease activity measures. In the second prospective part, these variables as well as a composite score for disease activity measurement of REA were prospectively validated in 23 patients at two points in time.
The following variables emerged as the most useful for the composite measure: number of swollen and tender joints, patient's pain and global assessment, and C-reactive protein. The score was calculated by simple addition of the individual figures.
DAREA constitutes a reliable score which can easily be assessed on a day-to-day office work basis.
HLA-B27 transgenic rats are a model of spontaneous gastrointestinal inflammation associated with expression of human leukocyte antigen (HLA) B27 and beta(2)-microglobulin. Our goal was to investigate in vitro enteric nerve regulation and contractile activity in isolated longitudinal muscles from the jejunum and colon of HLA-B27 rats. Nontransgenic age-matched Fisher 344 rats were used as controls. Intestinal inflammation and tissue injury, quantified histologically and through tissue myeloperoxidase activity, were evident in both the jejunum and colon of HLA-B27 rats. Although resting tension and spontaneous activity of the jejunal and colonic muscles from HLA-B27 rats did not differ significantly from controls, responses to both enteric nerve stimulation or direct muscle activation were significantly inhibited. In muscles from HLA-B27 rats, electrical field stimulation (0.5 ms, 0.5-20 Hz) induced low-amplitude contractions (maximal reduction 60-65%) compared with respective controls. In the presence of atropine and guanethidine, nonadrenergic and noncholinergic contractile responses to higher frequencies of stimulation (8-20 Hz) were also of lower amplitude. These changes were accompanied by a shift in neurally mediated contractions from predominantly cholinergic in the jejunum and colon of Fisher 344 rats to predominantly nonadrenergic and noncholinergic in HLA-B27 rats. Furthermore, maximal contractions to carbachol or KCl depolarization were reduced (up to 2.7-fold) compared with respective controls. In the jejunum of HLA-B27 rats the EC(50) level for carbachol was decreased. The data indicate that gastrointestinal inflammation induced by expression of HLA-B27 is associated with hypocontractility and inhibition of enteric cholinergic control of the longitudinal muscle in both the small and large intestine.
A role for sex steroids in the pathogenesis of AS is suggested by the male predominance, the peak age of onset in young adults, the increased number of first manifestations and flares after pregnancy, and the fact that sex steroids may modulate immune functions. There is a theoretic possibility that (normal levels of) androgens are indeed relevant in the male sex skew of AS. It has been reported that men with AS have higher than normal androgen levels; however, the evidence that serum testosterone levels are elevated in patients with AS is not robust. Elevated DHEAS and 17 alpha-hydroxyprogesterone levels have been reported in male AS patients; these may be secondary to inflammation and stress but may theoretically also be causally related to AS. These elevations might result from a partial late onset 11 beta- or 21-hydroxylase deficiency. Current data on sex steroid hormones provide no straightforward explanation for the male predominance in AS. It is fair to say that present data in patients with long-standing AS are too limited to suggest a role for androgens in the perpetuation of the disease, but a role in the initiation and the early stages of AS cannot be excluded. Such information can only be obtained from prospective studies. Cross-sectional studies cannot clearly distinguish causal relation from secondary disease effects, because blood sampling to test these hypotheses only takes place many years after the onset of disease. The impact of sex steroids on these features of AS is still unresolved. There is as yet no rationale for the use of medication that modifies sex steroid hormones in the management of AS. Alternative explanations for the higher male prevalence of AS may be found in the different chromosomal configuration and body composition of men and women.
To investigate the role of the class I MHC molecule HLA-B27 in the spondyloarthropathies, we produced rats transgenic for HLA-B27 and human beta 2-microglobulin. Of five lines bearing > 1 copy of each transgene and showing hemizygous expression of both transgenes, two (lines 21-4H and 33-3) developed spontaneous inflammatory disease that closely resembled B27-associated human disease. Two lines, 21-4L and 25-6, remained healthy even when homozygous for the transgene locus, whereas the 21-3 line, bearing the third highest transgene copy number, developed disease similar to that of the 21-4H and 33-3 lines only when homozygous for the transgene locus. The disease-prone lines showed higher expression of B27--thymic mRNA in utero, splenic mRNA by 5 days of age, and splenic cell surface protein by the time of disease onset--than the disease-resistant lines. Disease susceptibility thus appeared to correlate with gene copy number and the quantity of B27 in lymphoid cells. The increase in the amount of B27 protein did not appear to be simply a consequence of the inflammatory disease because 1) there was no similar change in endogenous RT1 class I expression; 2) no alteration of B27 expression occurred in 21-4H rats with adjuvant-induced arthritis; 3) in rats with inflammatory disease transgenic for HLA-A2 and the 21-4H transgene locus, A2 expression was the same as in healthy rats transgenic for A2 but not B27; and 4) the transgenes in disease-prone and disease-resistant lines were equally susceptible to induction by IFN-gamma. Immunocytochemistry of the distal colon, an early site of inflammation, showed that the B27 Ag is expressed at high levels in cells of the lamina propria, but not at all in colonic epithelial cells. Taken together, the data suggest that the B27 transgene is expressed in a copy number dependent, position-independent manner in lymphoid tissue and that disease results from the expression of B27 above a critical threshold level.
Twenty-five years ago, HLA-B27 was recognized as a new HLA specificity. It is present throughout Eurasia but is virtually absent among the genetically unmixed native populations of South America, the Bantus and Sans (Bushmen) of equatorial and southern Africa, and the aborigines of Australia. B27 is a serologically determined specificity that encompasses nine different allotypes (subtypes), B*2701 to B*2709. Ankylosing spondylitis or related spondyloarthropathies thus far have been documented in individuals with any of the following five subtypes: B*2701, B*2702, B*2704, B*2705, or B*2707.
(C) Lippincott-Raven Publishers.
This paper reviews advances in the understanding of the pathogenesis of reactive arthritis that have occurred over the last decade. Inflammatory aseptic joint disease has been linked with prior infection initiated by many different species of microorganisms. The presence of intra-articular bacterial antigens has now been firmly established with the demonstration of bacteria, bacterial fragments, DNA, RNA, and bacterial lipopolysaccharide in joints of patients with reactive arthritis. Chlamydia trachomatis, Salmonella enteritidis, and Shigella flexneri have all been detected in the joint by immunological techniques, although there is still some doubt as to the form in which they reach the joint and whether or not they persist. A number of phlogistic bacterial components could be acting as arthritogens. Negative joint culture results from patients with reactive arthritis make it unlikely that bacteria in the joint are viable, although chlamydial DNA has been shown in the joints of patients with sexually acquired reactive arthritis using the polymerase chain reaction. The use of antimicrobial therapy in the treatment of reactive arthritis is under review; data suggests that long-term antibiotic treatment warrants further study. The role of HLA-B27 in disease pathogenesis is discussed as are possible mechanisms of interplay between germ and gene. HLA-B27 might confer disease susceptibility by affecting immune mechanisms other than classical antigen presentation. The immunopathogenesis of joint inflammation in reactive arthritis is explored with reference to studies of humoral and cellular immune responses. Serological evidence to support the concept of molecular mimicry is far from conclusive; the results of relevant studies are summarized. Lymphocyte proliferation experiments suggest that antigen presenting cells play an important role. Finally, our views on reactive arthritis in the 1990s, and areas of new and potentially fruitful future research are presented.
To obtain information on the rate of concordance for ankylosing spondylitis (AS) in a population-based series of twins.
AS cases were identified by record linkage of the population-based Finnish Twin Cohort and the nationwide registry for fully reimbursed medications. A clinical examination was performed to establish concordance for AS.
There were 6 monozygotic (MZ) pairs and 20 dizygotic (DZ) pairs with at least 1 member affected by AS. Three MZ pairs and 3 DZ pairs were concordant for the disease. All affected subjects were HLA-B27 positive. The pairwise concordance rate was 50% in MZ twins and 20% in HLA-B27 positive DZ twins (95% confidence intervals 11.8-88.2% and 4.3%-48.1%, respectively).
These results indicate that AS disease expression is largely, but not entirely, genetically based, with a gene or genes other than B27 probably playing a role.