HLA-B27 expression and reactive arthritis susceptibility in two patient cohorts infected with Salmonella Typhimurium

Background: Reactive arthritis (ReA) is an inflammatory arthritis triggered by certain gastrointestinal and genitourinary infections. Single source outbreaks of triggering infections provide an opportunity to elucidate host susceptibility factors in this disease. Aim: To determine the role of Major Histocompatibility Complex (MHC) Class I alleles in ReA susceptibility after two large single source outbreaks of Salmonella Typhimurium gastroenteritis. Methods: A questionnaire screening for features of ReA and a request for HLA class I typing were sent to all patients affected by two single source outbreaks of S. Typhimurium gastroenteritis. Individuals with arthritis of recent onset were interviewed, examined and diagnostic criteria for ReA applied. Results: Nineteen cases of reactive arthritis, 11 female, were diagnosed in the 424 respondents with S. Typhimurium gastroenteritis from both outbreaks. Clinical features of the arthritis were similar to those described after other large single source outbreaks of Salmonella infection. HLA‐B27 was expressed by only two of the 19 ReA patients and therefore did not predict susceptibility to this form of arthritis. Caucasians were, however, more likely to develop reactive arthritis than Asians. Conclusions: In this study, susceptibility to ReA was not increased in HLA‐B27 positive individuals or males but was greater in those of Caucasian descent.     

A comparative study of HLA genes in HLA–B27 positive ankylosing spondylitis and HLA–B27 positive peripheral reactive arthritis

Objective. To determine whether HLA–B27 positive patients with ankylosing spondylitis (AS) and reactive arthritis (ReA) share additional HLA factors that confer disease susceptibility. Methods. HLA class I antigens were typed serologically, and class II antigens molecularly, in samples taken from 33 patients with AS, 30 patients with ReA, and 55 healthy HLA–B27 positive controls. Results. There was no major difference between the HLA alleles in AS and ReA patients, but deviations were observed when compared with healthy controls, especially between the antigens that were probably encoded by genes in the non-B27 chromosome. Conclusion. These results suggest that both HLA class I and class II genes may influence the pathogenesis of HLA–B27 positive ReA, whereas class I antigens seem to be the major additional genetic factors in HLA–B27 positive AS.     

Association between reactive arthritis and antecedent infection with shigella flexneri carrying a 2-md plasmid and encoding an hla–b27 mimetic epitope

Objective. To determine whether Shigella flexneri strains that cause enteric infection and are associated with reactive arthritis (ReA) carry a 2-Md plasmid, pHS-2, which encodes an HLA–B27 mimetic epitope. Methods. Plasmid DNA from Shigella isolates was characterized by DNA–DNA hybridization, restriction endonuclease digestion, and sequencing. Results. S flexneri strains associated with ReA carried a 2-Md plasmid homologous to pHS-2. Conclusion. The finding of pHS-2 in additional Shigella strains associated with ReA underscores its potential importance in the etiology of the disease.     

Potential risk factors for reactive arthritis and persistence of symptoms at 2 years: a case-control study with longitudinal follow-up

The objective of the study is to determine the risk factors for the development of reactive arthritis (ReA) and examine the factors associated with the persistence of symptoms. Patients with a new diagnosis of ReA and controls with a gastrointestinal (GI), urogenital, or sexually transmitted infection in the 3–6 months prior to study entry were prospectively enrolled in Guatemala City. ReA patients fulfilled the Assessment in Spondyloarthritis International Society criteria for peripheral spondyloarthropathy (SpA). Patients underwent history, examination, Achilles tendon ultrasound, and blood draw. Human leukocyte antigen (HLA) type and serum biomarkers were measured. t tests and nonparametric equivalents were used to examine the association of clinical, laboratory, and imaging factors with ReA. Patients were contacted 2 years later to assess for persistence of symptoms. Study subjects included patients with ReA (N?=?32) and controls (N?=?32). ReA patients were most frequently infected in April whereas controls were most frequently infected in August. Two ReA patients and two controls were HLA-B27-positive. Serum cathepsin K and C-reactive protein were higher in ReA patients compared to controls (p?=?0.03 for both), while total cholesterol and low-density lipoprotein were lower (p?=?0.008 and 0.045, respectively). Among those with ReA, 15 (47%) patients had continued symptoms at 2 years. These patients had a lower matrix metalloproteinase-3 level at diagnosis than patients for whom ReA resolved (p?=?0.004). HLA-B27 was not associated with development of ReA in Guatemala; however, the month of infection was associated with ReA. The most striking finding was the persistence of arthritis at 2 years in nearly half of the patients.     

Distribution of HLA-B27 and its alleles in patients with reactive arthritis and with ankylosing spondylitis in Tunisia

The purpose of the present study is to investigate the frequency of HLA-B27 and its alleles in reactive arthritis (ReA) and in ankylosing spondylitis (AS) in Tunisia. HLA-B27 alleles were typed by PCR amplification with sequence-specific primers. We studied 17 patients with ReA associated with urethritis or with gastrointestinal infection; 42 HLA-B27-positive patients with AS and 100 healthy controls. Eleven ReA patients (67.7%) were HLA-B27 positive. There was an increased frequencies of HLA-B27 (P = 7.76 × 10⁻¹², OR = 59.30) and a moderate increase of HLA-B51 (P = 0.015; OR = 4.91) alleles in ReA patients when compared with healthy controls. Four B27 subtypes were identified: B*2702, 05, 09 and B*2712. The distribution of these alleles in the ReA patients was 37.5% for B*2702 and B*2705. Only these two subtypes were detected in 18 (42.8%) and 24 (57.1%), respectively, of the AS patients. B*2709 and B*2712 were relatively rare in ReA patients and were identified in one case each. Our results showed a restricted number of HLA-B27 subtypes associated with ReA and AS. B*2702 and 2705 were common in ReA and AS patients.     

Susceptibility to reiter's syndrome is associated with alleles of tap genes

Objective. Although HLA–B27 is strongly associated with susceptibility to Reiter's syndrome (RS), recent data suggest that an additional modifying or susceptibility gene(s) acts in concert with HLA–B27 to contribute to disease pathogenesis. The recently described TAP genes (transporters associated with antigen processing) are potential candidates because they are polymorphic and their function is to transport antigenic peptides to be loaded in HLA class I molecules. Methods. TAP1 and TAP2 alleles were determined for 34 patients with RS (28 HLA–B27 positive, 6 HLA–B27 negative), and their frequencies were compared with those observed for 52 HLA–B27 positive and 80 random disease-free control subjects. Results. The allele frequency of TAP1C was greater in patients with RS (8 of 62, 13%) than in random controls (5 of 160, 3%) (P = 0.009). The frequency of TAP2A was greater in RS patients (51 of 66,77%) than in random controls (88 of 160, 55%) (P = 0.002); likewise, the frequency was greater in HLA–B27 positive RS patients (41 of 54, 76%) than in HLA–B27 positive disease-free controls (49 of 94, 52%) (P = 0.004). Furthermore, the TAP2A allele was present in all RS patients (100%), whereas TAP2A was present in 79% (63 of 80) of the random controls (P = 0.003). Conclusion. The association observed between TAP alleles and RS is independent of the presence of HLA–B27, and despite the physical proximity of TAP and HLA class II genes, linkage disequilibrium does not account for the observed associations between TAP and RS. Thus, TAP genes are genetically separated but functionally linked to class I genes, and both contribute to susceptibility to RS.     

Hla–dr8 and acute anterior uveitis in ankylosing spondylitis

Objective. To identify possible factors in the development of acute anterior uveitis (AUU) in patients with ankylosing spondylitis (AS). Methods. We investigated HLA antigens serologically, and HLA–DRB1^*08 alleles by polymerase chain reaction–restriction fragment length polymorphism, in 42 Japanese AS patients with and without AAU. Results. Thirty-six of the AS patients (85.7%) had HLA–B27. Thirteen (65%) of the 20 patients with AAU had HLA–DR8, whereas only 1 (4.5%) of the 22 patients without AAU had DR8. The difference was statistically significant (P_corr < 0.001). Conclusion. Our data suggest that HLA–B27 is strongly associated with AS in Japanese patients and that HLA–DR8 is important for the development of AAU in Japanese patients with AS.     

Disease-association of different killer cell immunoglobulin-like receptors (KIR) and HLA-C gene combinations in reactive arthritis

Abstract

Background: Reactive arthritis (ReA) is sterile arthritis triggered by bacterial gastrointestinal or urogenital infections. Although the pathogenesis of ReA remains unclear, genetic factors seem to play an important role. Different killer cell immunoglobulin-like receptors (KIRs) and their corresponding specific histocompatibility leukocyte antigen-C (HLA-C) ligand genotypes have been implicated in susceptibility and resistance to infections and autoimmune diseases but have, thus far, not been investigated in ReA.

Methods: This study was conducted in 138 ReA patients (65 females, 73 males); aged 18–69 years (mean, 37 years) and 151 randomly selected healthy control individuals matched for ethnicity, age and sex. These subjects were genotyped for KIR genes and HLA-C alleles by polymerase chain reaction with sequence-specific primers.

Results: The frequencies of inhibitory KIR2DL2 and KIR2DL5 were significantly lower in the ReA patients than in the controls (p?=?.005 and p?=?.033, respectively). The presence of more than seven inhibitory KIR genes was protective (p?=?.016). Moreover, we found that activating KIR2DS1 alone or in combination with the HLA-C1C1 genotype (which indicates the absence of the HLA ligands for their homologous inhibitory receptor KIR2DL1) is associated with susceptibility to ReA (p?=?.039 and p?=?.011, respectively), whereas KIR2DL2 in combination with the HLA-C1 ligand is associated with protection against ReA (p?=?.039).

Conclusion: These observations indicate that high levels of activating and low levels of inhibitory KIR signals may affect the functions of NK cells and T cells. This imbalance enables the innate and adaptive immune responses of the host to be easily triggered by pathogens, resulting in the overproduction of local and systemic cytokines that contribute to the pathogenesis of ReA.     

Cross-reactive epitope with Klebsiella pneumoniae nitrogenase in articular tissue of HLA–B27+ patients with ankylosing spondylitis

Synovial tissues from patients with ankylosing spondylitis or reactive arthritis were examined by an immunoperoxidase technique, using antisera to synthetic peptides representing antigens shared between HLA–B27.1 and Klebsiella pneumoniae nitrogenase. With either antiserum, all HLA–B27+ patients with synovial inflammation showed strong immunoperoxidase staining in synovial lining cells, vascular endothelium, and infiltrating inflammatory cells. These findings indicate that antigens showing cross-reactivity between HLA–B27.1 and Klebsiella nitrogenase epitopes are strongly expressed within inflamed synovial tissues of HLA–B27+ patients.     

Serum antibodies to klebsiella capsular polysaccharides in ankylosing spondylitis

Objective. To measure antibodies to Klebsiella capsular polysaccharides in the sera of HLA–B27 positive patients with ankylosing spondylitis (AS), compared with HLA–B27 positive and HLA–B27 negative healthy control subjects. Methods. Antibodies were detected by means of an enzyme-linked immunosorbent assay specific for each of the 77 known Klebsiella serotypes. Results. Significantly elevated frequencies and titers of antibodies to capsular polysaccharides K26, K36, and K50 were detected in sera from AS patients, compared with controls. Conclusion. These results suggest the predominance of Klebsiella serotypes K26, K36, and K50 in patients with AS.     

KIR2DL3 and the KIR ligand groups HLA‐A‐Bw4 and HLA‐C2 predict the outcome of hepatitis B virus infection

Killer immunoglobulin‐like receptors (KIRs) regulate the activation of natural killer cells through their interaction with human leucocyte antigens (HLA). KIR and HLA loci are highly polymorphic, and certain HLA‐KIR combinations have been found to protect against viral infections. In this study, we analysed whether the KIR/HLA repertoire may influence the course of hepatitis B virus (HBV) infection. Fifty‐seven subjects with chronic hepatitis B (CHB), 44 subjects with resolved HBV infection and 60 healthy uninfected controls (HC) were genotyped for KIR and their HLA ligands. The frequency of the HLA‐A‐Bw4 ligand group was higher in CHB (58%) than subjects with resolved infection (23%) (crude OR, 4.67; P<.001) and HC (10%) (crude OR, 12.38; P<.001). Similar results were obtained for the HLA‐C2 ligand group, more frequent in CHB (84%), than subjects with resolved infection (70%) (crude OR, 2.24; P<.10) and HC (60%) (crude OR, 3.56; P<.01). Conversely, the frequency of KIR2DL3 was lower in CHB (81%) than in subjects with resolved infection (98%) (crude OR, 0.10; P<.05). These results suggest a detrimental role of HLA‐A‐Bw4 and HLA‐C2 groups, which are associated with the development of CHB, and a protective role of KIR2DL3. A stepwise variable selection procedure, based on multiple logistic regression analysis, identified these three predictive variables as the most relevant, featuring high specificity (90.9%) and positive predictive value (87.5%) for the development of CHB. Our results suggest that a combination of KIR/HLA gene/alleles is able to predict the outcome of HBV infection.     

Association of tumor necrosis factor microsatellite polymorphisms with HLA-DRB1*04–bearing haplotypes in rheumatoid arthritis patients

Objective. To investigate 1) tumor necrosis factor (TNF) microsatellite allele frequencies in rheumatoid arthritis (RA), and 2) associations between TNF microsatellites and RA-associated HLA specificities in order to build up extended HLA haplotypes. Methods. Eighty-five caucasoid patients with RA and 109 healthy caucasoid controls were typed for TNF microsatellites a-d using fluorescent-labeled primers and semiautomated genotyping. A further 56 RA patients who were selected for having certain HLA-DRB1 types were also typed for these TNF microsatellites. Linkage disequilibria between TNF and HLA alleles were calculated, and extended haplotypes were established. Results. The TNFa6 allele frequency was significantly increased in the RA patients compared with the controls (P = 0.0019, odds ratio [OR] 2.5, 95% confidence interval [95% CI] 1.3–4.6), an increase that was further evident in patients who were HLA–DRB1*0401 homozygous (P =0.0003, OR 7.3, 95% CI 2.2–24.4). This increase was found to be due to association with HLA–DRB1*0401. No TNF microsatellite allele was found to be associated with HLA-DRB1*0404. Three HLA extended haplotypes were identified in the RA group: 1) HLA–DRB1*0401;TNFd4;TNFa6;TNFb5;HLA–B44;HLA–Cw5;HLA–A2, 2) HLA–DRB1*0301;TNFd2;TNFa2;TNFb3;HLA–B8;HLA–CW7;HLA–A1, and 3) TNFd5;TNFc2;TNFa2;TNFb1;HLA–B62;HLA–Cw3. Conclusion. TNF microsatellites found to be associated with RA do not appear to be independent of class II HLA associations.     

HLA–B27 modulates nuclear factor κB activation in human monocytic cells exposed to lipopolysaccharide

Objective

To study whether HLA–B27 modifies some key factors controlling inflammatory responses on lipopolysaccharide (LPS) stimulation in human monocytic cells.

Methods

U937 human monocytic cells were stably transfected with either HLA–B27 genomic DNA, HLA–B27 complementary DNA, HLA–A2 genomic DNA, or with the resistant vector pSV2neo (mock) alone. The cells were stimulated with LPS. Electrophoretic mobility shift assay was performed to determine nuclear factor κB (NF‐κB) and heat‐shock factor 1 activities, Western blotting was performed to detect the expressions of inhibitory κBα (IκBα) and heat‐shock proteins (HSPs), and enzyme‐linked immunosorbent assay was performed to measure tumor necrosis factor α (TNFα) secretion.

Results

The expression of HLA–B27 modulated the response to LPS in U937 human monocytic cells. Stimulation with LPS led to faster degradation of IκBα regulatory proteins, accompanied by faster and prolonged activation of NF‐κB in HLA–B27–expressing cells compared with HLA–A2 and mock transfectants. The secretion of TNFα upon LPS stimulation correlated well with the activation of NF‐κB. No activation of the heat‐shock response was observed.

Conclusion

Our data indicate that HLA–B27 has effects on host responses to LPS that are unrelated to antigen presentation. Two crucial events in the development of arthritis, the activation of NF‐κB and the secretion of TNFα, were found to be enhanced in HLA–B27–expressing cells upon LPS stimulation. Because LPS is known to be present in the inflamed joints of patients with reactive arthritis (ReA), the enhanced inflammatory response of HLA–B27–positive cells upon LPS stimulation offers an attractive explanation for the role of HLA–B27 in the development of ReA.

     

Association of human leukocyte antigen polymorphism with outcomes of hepatitis B virus infection

Background and Aim: Host genetic and environmental factors are viewed as a common basis of the different outcomes of hepatitis B virus (HBV) infection. Human leukocyte antigen (HLA) plays an important role in immunological reaction to HBV infection. In this study, we aimed to determine the association between HBV infection and HLA‐A, B, and DRB1 alleles in northern Iran. Methods: HLA‐A, B, and DRB1 alleles in 33 patients with chronic hepatitis B (CHB) and 31 healthy carriers as the persistent group, and 30 subjects who had spontaneously recovered from HBV infection were analyzed by using the polymerase chain reaction (PCR)–sequence‐specific primer (PCR‐SSP) technique. Results: The frequency of the HLA‐A*33 allele was higher in the persistent group than in the recovered group (10.16% vs 0%, P < 0.008); the frequency of the DRB1*13 allele was lower in the persistent group than in the recovered group (3.13% vs 11.67%, P < 0.03). The frequency of the B*52 allele was higher in CHB patients than healthy carriers (7.58% vs 0%, P < 0.05). The logistic regression model showed that the presence of the HLA‐DRB1*13 allele was the significant factor associated with protection against the persistency of HBV. There were significant differences between the HBV recovered group, CHB patients, and healthy carriers regarding age, hepatitis B e antigen, and anti‐hepatitis B e positivity. Conclusion: HLA‐A*33 was closely related with susceptibility to persisting hepatitis B infection, and HLA‐DRB1*13 was closely related with protection against persisting hepatitis B in an Iranian population. These findings emphasized that the host HLA polymorphism is an important factor in determining the outcome of HBV infection.     

Clinical correlations with HLA type in Japanese patients with connective tissue disease and anti–U1 small nuclear RNP antibodies

Objective. To elucidate the roles of HLA genes in the clinical presentation of patients with connective tissue disease and serum anti–U1 small nuclear RNP antibody. Methods. HLA class I antigens and HLA class II alleles were determined in 43 Japanese patients with anti–U1 RNP antibody alone, by microcytotoxicity testing and DNA typing, respectively. Prospectively recorded clinical and laboratory features were analyzed in relation to HLA class I and class II types. Results. DQB1*0303 was associated with lupusrelated symptoms including fever, malar rash, oral ulcers, hypocomplementemia, and high-titer anti–double-stranded DNA antibody. Other HLA–clinical associations included DR2 with pleuritis, DR4 with hand swelling, and DRB1*0405 with arthritis. Conclusion. These HLA–clinical associations explain, in part, the heterogeneous clinical presentation in patients with anti–U1 RNP antibody.     

Infections preceding early arthritis in southern Sweden: a prospective population-based study

OBJECTIVE: To detect evidence of infections preceding early arthritis in Southern Sweden and to compare the clinical outcome of remission during a 6-month followup for patients with and without signs of prior infection. METHODS: Adult patients with arthritis of less than 3 months' duration were referred from primary health care centers to rheumatologists. All patients were systematically screened for infections caused by Salmonella typhimurium and Salmonella enteritidis, Yersinia enterocolitica, Campylobacter jejuni, Borrelia burgdorferi, Chlamydia trachomatis, Chlamydia pneumoniae, and parvovirus B19. RESULTS: Seventy-one patients were included in this study. Twenty-seven (38%) patients had reactive arthritis (ReA), 17 (24%) undifferentiated arthritis, 15 (21%) rheumatoid arthritis (RA), 4 (6%) psoriatic arthritis, and the rest (11%) other diagnoses. Of all the patients, 45% had evidence of a recent infection preceding the arthritis, as indicated by laboratory tests and/or disease history. C. jejuni dominated the ReA group. The occurrence of recent C. trachomatis, B. burgdorferi, C. pneumoniae, and parvovirus B19 infections was low. Overall, 58% of the patients went into remission during the 6-month followup. Of the patients with a preceding infection, 69% went into remission as compared to 38% of the patients without a preceding infection (p = 0.011). Thirty-three percent of the patients with RA were in remission after 6 months. CONCLUSION: In this population-based cohort, 45% of the patients presenting with a new-onset arthritis had had a prior infection. Campylobacter ReA dominated the ReA group. There were only a few cases preceded by infections by C. trachomatis, B. burgdorferi, C. pneumoniae, and parvovirus B19 infections. Remission during the first 6 months was especially frequent in the group of patients with a prior infection, but the remission rate was relatively high even for arthritis without prior infection.     

The role of infection in the pathogenesis of spondyloarthropathies with special reference to human leukocyte antigen-B27

Spondyloarthropathies consist of many inflammatory diseases that are closely associated with human leukocyte antigen (HLA)-B27. One of these diseases is reactive arthritis (ReA), which is a joint inflammation that occurs after infections that are caused by certain gram-negative bacteria. The importance of these infections as causative agents of ReA has been clearly established. It is not clear, however, whether these infections contribute to the development of other forms of spondyloarthropathies. The exact mechanism by which HLA-B27 influences disease susceptibility in spondyloarthropathies remains to be determined. The role of HLA-B27 as an antigen-presenting molecule is certainly important in the pathogenesis of these diseases; however, recent data indicate that this molecule may exhibit other functions unrelated to antigen presentation, which may be important in the pathogenesis of ReA. In this paper, the authors summarize the current knowledge of the role of infection in the spondyloarthropathies.     

Juvenile spondyloarthropathies associated with Mycoplasma pneumoniae infection

Background Reactive arthritis (ReA) has been sporadically reported as triggered by Mycoplasma pneumoniae. This study examined the potential relationship between the acute M. pneumoniae infection and juvenile spondyloarthropathy (jSpA) in children.Patients and methods Twelve patients with ReA secondary to acute M. pneumoniae were examined. M. pneumoniae-specific IgM, IgG and IgA antibodies were serologically confirmed by enzyme-linked immunosorbent assay (ELISA) tests (Savyon Diagnost., Israel). Due to the early appearance and relatively short life time of M. pneumoniae-specific IgM antibodies, their detection allowed the diagnosis of acute infection using single serum sample, confirmed by parallel serum in 7 of 12 patients. Specific IgM and IgG titers higher than 10 U/l were considered positive and those higher than 50 U/l as highly positive. Specific IgA antibodies were detected in only one patient.Results Four patients were female and eight were male. The mean age at onset was 9 years, and the mean duration of follow-up was 24.1 months (range 18–32). The mean number of involved joints was 2.8, and the knee joints were involved in 7 of 12 patients. The mean recovery time was 4.5 weeks (range 1–28) in eight reactive arthritis (ReA) cases; three patients developed enthesitis-related arthritis, and in one patient, genuine juvenile ankylosing spondylitis (jAS) was diagnosed. Two patients were HLA-B27-positive, and one patient was HLA-B7/B27-positive. Six patients had preceding respiratory symptoms, and five were treated with antibiotics.Conclusions Our findings provide clear evidence of ReA diagnosis following an acute M. pneumoniae infection that in four patients progressed to chronic jSpA. Our results suggest that detecting M. pneumoniae-specific antibodies in serological screening of jSpA patients might be useful. It is presently unclear whether antibiotic treatment would change the disease course in those patients.     

Association of major histocompatibility complex determinants with the development of symptomatic and asymptomatic genital herpes simplex virus type 2 infections

The clinical spectrum of herpes simplex virus (HSV) infections, ranging from asymptomatic to frequently distressing outbreaks, suggests that there may be immunologic determinants of disease severity that are associated with human leukocyte antigen (HLA) expression. A controlled, prospective study identified several major histocompatibility complex (MHC) class I and II antigens whose frequencies are associated with HSV-2 infection or with frequent symptomatic genital recurrences. Previous studies were hampered by the inability to serologically identify patients with asymptomatic HSV-2 infection. Clinical evaluation and Western blot assay were used to identify 3 subject cohorts: 1 with no prior HSV infections, 1 with HSV-2 antibodies but no recognized symptoms, and 1 with HSV-2 antibodies and frequent genital recurrences. Statistical comparisons of HLA frequencies among these cohorts showed associations of HLA-B27 and -Cw2 with symptomatic disease. Also, HLA-Cw4 was significantly associated with HSV-2 infection. These associations indicate that immunologic factors linked to the MHC influence the risk of HSV-2 infection and disease expression.