Role of HLA-DQ in rheumatoid arthritis susceptibility: comment on the article by de Vries et al.
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Arthritis, Rheumatoid↗
Biomedical subjects
E Zanelli
Publications and source records attributed to E Zanelli.
HLA class II association with rheumatoid arthritis: facts and interpretations.
We have reviewed the literature on the association of HLA class II with rheumatoid arthritis (RA). Strong linkage disequilibrium among DQB1, DQA1 and DRB1 alleles makes it difficult to evaluate the individual contribution of each locus. Nonetheless, there is a strong case for the role of DQB1*03 and *04 combined with DQA1*03 in susceptibility to severe RA while DQB1*0501 combined with DQA1*0101 and *0104 weakly predisposes to a mild form of RA. However, it is also clear that DRB1*0401 has a particular role in predisposition to the most severe form of the disease while other DRB1 alleles might provide protection. We would like to propose that in RA, as in type I diabetes, both DQ and DR loci contribute to predisposition to the disease.
Alleles↗
A dual function for CD40 agonists.
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Animals↗
HLA association with autoimmune disease: a failure to protect?
That certain HLA specificities are associated with predisposition to autoimmune disease does not necessarily imply that self-reactive T cells restricted to particular HLA alleles are eliciting the disease. In the present essay, we argue that HLA can be a major genetic factor in the development of autoimmune diseases without T cells being primarily involved in its initiation or perpetuation. There is now ample evidence that self-reactive, regulatory T cells can protect against pernicious autoimmunity. Hereafter, we propose that extended HLA haplotypes, such as DQ3-DR4, DQ3-DR9, DQ5-DR1 and DQ5-DR10 in the case of rheumatoid arthritis, predispose to impaired T-cell-mediated immune regulation. The haplotypes associated with impaired regulation are the combination of certain class II alleles and a yet unknown 'amplifier'. In this model, products of the HLA class II region are not involved in the presentation of particular organ-specific autoantigens. Therefore, HLA does not predispose to autoimmune disease per se, but rather fails to provide efficient protection.
Animals↗
[Appropriateness of referral to the emergency department through a telecardiology service. "Boario Home-Care" researchers].
BACKGROUND: The use of telemedicine appears particularly promising in cardiovascular diseases; it may reduce the decisional time during an acute myocardial infarction, which is the greater part of the so-called "avoidable delay" and the inappropriate admission to the Emergency Department with the possibility of ruling out an acute pathology. The aim of our study was to show the diagnostic accuracy of a telecardiology service in the daily activity of general practitioners. METHODS: From February 1998 to February 1999, 150 general practitioners received a portable electrocardiographer (Card-Guard 7100) transferring, by a mobile or fixed telephone, a 12-lead ECG to a receiving station, where a cardiologist was available for the reporting and interactive teleconsultation. RESULTS: During 1 year 3456 calls took place. At the time of the ECG recording 44% of patients were symptomatic. Chest pain was present in 669 patients (44%), dyspnea in 21%, palpitation in 18%, dizziness in 7%, and asthenia in 13%. ECG and teleconsultation solved all the problems for 2452 patients (71%) and further diagnostic tests were requested in 862 patients (25%); 142 patients (4%) were sent to the Emergency Department. Cardiological diagnosis was confirmed in 95 patients (73%), while anxiety or gastritis were presumed in 35 patients (27%). In the group of patients (n = 3314) for whom the cardiologist solved the problem without admission to the Emergency Department, there were 5 patients who were admitted to the Emergency Department for myocardial ischemia in the following 48 hours after the teleconsultation. Telecardiology service showed versus Emergency Department admission a sensitivity of 95%, a specificity of 97.5%, and a diagnostic accuracy of 92.5%. CONCLUSIONS: These data confirm a good diagnostic value to the service and a useful support to the general practitioners' activity.
Electrocardiography↗
HLA-DQ-associated predisposition to and dominant HLA-DR-associated protection against rheumatoid arthritis.
We have recently proposed a new hypothesis to explain the association of Human Leukocyte Antigen (HLA) with rheumatoid arthritis (RA) predisposition. In this model, which challenges the Shared Epitope (SE) hypothesis, HLA-DQ predisposes while HLA-DR protects. In the present study, we have compared these two models in an Early Arthritis Clinic started in 1993 in the Department of Rheumatology at the Leiden University Medical Centre. Out of 524 patients who enrolled this programme in the period 1993-1998 and completed the one year follow-up, 155 have been classified as RA. These patients along with 306 consecutive cadaveric renal organ donors have been typed for HLA-DR and -DQ. The distributions of predisposing DR alleles according to SE, and predisposing DQ and protective DR according to our model were analysed. We found that two doses of predisposing DQ alleles strongly predisposed to RA, even in individuals with a single dose of SE while DRB1 alleles carrying the motif DERAA confered a dominant protection in DQ5-positive individuals. We conclude that the present findings are consistent with our previously described model of HLA and RA association. Using this new model, we have been able to characterise two novel groups of individuals on the basis of their HLA typing: one strongly predisposed to RA and one protected. Knowing the mechanism of HLA-related dominant natural protection may help in designing novel treatment modalities for RA.
Alleles↗
Association of the TNF +489 polymorphism with susceptibility and radiographic damage in rheumatoid arthritis.
Multiple genetic factors contribute to susceptibility to rheumatoid arthritis (RA). The extent of variability in disease presentation in RA may be related to genetic heterogeneity. In this study we investigated the association of the TNF gene polymorphism at position +489 with susceptibility to and severity of RA. Analysis of the frequency of the +489 A and G alleles in a group of 293 consecutive RA patients and 138 healthy controls revealed a significant decrease of the A allele. The +489 GA patients had a 3.9 times decreased chance of having erosive disease than +489 GG patients. These results were confirmed in a prospective study using a cohort of 112 patients who were followed for 12 years. The progression rate of the erosion score over 12 years expressed as Sharp score for X-rays of hands and feet was 3.4 per year for the GA-genotyped patients and 12.1 for the GG-genotyped patients. These associations were independent of rheumatoid factor and HLA-shared epitope positivity. In conclusion, these data suggest that the intron TNF +489 polymorphism is associated with susceptibility to and disease severity of RA independently of HLA-shared epitope-positive alleles.
Adult↗
Effects of oxygen on autonomic nervous system dysfunction in patients with chronic obstructive pulmonary disease.
Chronic hypoxaemia can play a pathological role in abnormalities of the autonomic nervous system (ANS). In patients with chronic obstructive pulmonary disease (COPD), chronic hypoxaemia is associated with increased mortality and only long-term oxygen therapy is able to improve their survival. Normoxaemic COPD patients have been shown to suffer from abnormalities in ANS function. The aims of this study were to evaluate ANS function in COPD patients with chronic hypercapnic respiratory insufficiency and to test whether oxygen supplementation could reverse any ANS dysfunction. Eleven stable COPD patients with chronic hypercapnic respiratory insufficiency underwent evaluation of ANS by analysis of variability in cardiac frequency at rest and during both vagal (controlled breathing) and sympathetic (tilting) stimuli breathing with and without oxygen supplementation. Thirteen male, healthy, nonsmoking volunteers served as controls. Evaluation of ANS in COPD patients during hypoxic conditions showed alterations both at rest and in response to vagal and sympathetic stimuli. Oxygen supply reversed hypoxaemia without significant changes in arterial carbon dioxide tension and, therefore, ANS alterations were corrected during sympathetic stimulus only. Breathing room air and oxygen, the resting low-frequency (LF) powers were 45+/-15 and 148+/-55 ms2 x Hz(-1), respectively, and controlled breathing LF were 107+/-41 and 141+/-113 ms2 x Hz(-1), respectively. In stable patients with chronic obstructive pulmonary disease with chronic respiratory insufficiency, hypoxaemia is associated with derangements in the autonomic nervous system which may be partially reversed by oxygen administration.
Aged↗
Telecardiology community: a new approach to take care of cardiac patients. "Boario Home-Care" Investigators.
BACKGROUND: Cardiovascular diseases are the leading cause of morbidity and mortality in Western countries and represent, in terms of diagnostic and treatment measures, a large amount of health care expenses. A telecardiology service may offer to general practitioners, in real time, a useful diagnostic tool and the possibility of an accurate screening of patients with suspected ischemic heart disease. METHODS: From February to July 1998, in the provinces of Bergamo and Brescia (Italy), 178 general practitioners received a portable Card Guard 7100 electrocardiographer transferring, by a mobile or fixed telephone, a 12 lead ECG to a receiving station, where a cardiologist was available for the reporting and interactive teleconsultation. RESULTS: During the first 6 months a total 2800 calls took place. Due to incompleteness of requested data only 2254 traces, corresponding to 2254 subjects (mean age 63 +/- 18 years) were entered in the study. In 27% of patients (n = 609) there was a history of systemic hypertension, in 12.5% (n = 283) there was a history of coronary artery disease, and in 38% (n = 834) there was no history of cardiovascular diseases. At the time of ECG recording, 42% of patients (n = 949) were symptomatic: more common symptoms were chest pain (39%), dyspnea (23%), palpitation (19%), dizziness or faint (10%), and asthenia (9%). No action was suggested by cardiologists in 74% of cases. Of the remaining patients, 16% (n = 92) were referred to the Emergency Department, 27% (n = 158) were offered further diagnostic tests as an out patient, and 56% (n = 328) were started on medication or had their treatment changed. CONCLUSIONS: A telecardiology system provides a useful support to general practitioners in the management, in real time, of patients with cardiovascular conditions, and possibly contributes to optimization of health care costs in terms of appropriateness of hospital admissions and diagnostic tests.
Aged↗
Is heart rate variability a reliable method to assess autonomic modulation in left ventricular dysfunction and heart failure? Assessment of autonomic modulation with heart rate variability.
Autonomic dysfunction seems to be involved in the progression and prognosis of congestive heart failure. Measurement of heart rate variability (HRV) provides a noninvasive method to obtain reliable and reproducible information on autonomic modulation of heart rate, but there is a difficulty in using HRV as a quantitative estimate of autonomic dysfunction in heart failure. This study was aimed at testing the hypothesis that abnormal modulation of heart rate assessed by power spectrum analysis may be present also in asymptomatic patients with left ventricular dysfunction and progress in patients with overt symptoms of congestive heart failure. HRV was measured in three groups of subjects: Group 1: 30 patients with chronic heart failure; Group 2: 21 patients with asymptomatic left ventricular dysfunction; and Group 3: 25 healthy volunteers as control group. HRV was evaluated by autoregressive spectral analysis with 600-beat ECG samples, while subjects were quietly recumbent (BSI), in conditions of controlled breathing (15 acts/min) (RSC) and passive orthostatism after tilting (80 degrees) (TLT). Patients in group 1 showed a reduction in the standard deviation of the R-R intervals (SDRR) (p<0.0003) and in the low frequency component (LF) (p<0.0001) compared to normal subjects. Low frequency component was not detectable in 11 patients of group I (p<0.0008). On RSC and TLT, group 1 failed to show any modification in the low frequency and high frequency components (HF) under any stimulation. Group 2 showed no modification at baseline evaluation, no increase in the high frequency component on RSC and in LF during TLT compared to controls (p<0.01 and p<0.0001 respectively). At baseline, group 1 had a lower SDRR (p<0.03) and LF (p<0.0001) vs. group 2, whereas during stimulation the two groups exhibited the same behaviour. In conclusion, reduced heart rate variability is specific for both asymptomatic and symptomatic post-ischemic left ventricular dysfunction. Our results suggest that frequency domain analysis of heart rate variability during a stimulation test allows a more accurate definition of the degree of autonomic control of heart rate.
Autonomic Nervous System↗
Identification of HLA class II-restricted determinants of Mycobacterium tuberculosis-derived proteins by using HLA-transgenic, class II-deficient mice.
T helper 1 cells play a major role in protective immunity against mycobacterial pathogens. Since the antigen (Ag) specificity of CD4(+) human T cells is strongly controlled by HLA class II polymorphism, the immunogenic potential of candidate Ags needs to be defined in the context of HLA polymorphism. We have taken advantage of class II-deficient (Ab0) mice, transgenic for either HLA-DRA/B1*0301 (DR3) or HLA-DQB1*0302/DQA*0301 (DQ8) alleles. In these animals, all CD4(+) T cells are restricted by the HLA molecule. We reported previously that human DR3-restricted T cells frequently recognize heat shock protein (hsp)65 of Mycobacterium tuberculosis, and only a single hsp65 epitope, p1-20. DR3.Ab0 mice, immunized with bacillus Calmette-Guérin or hsp65, developed T cell responses to M. tuberculosis, and recognized the same hsp65 epitope, p1-20. Hsp65-immunized DQ8.Ab0 mice mounted a strong response to bacillus Calmette-Guérin but not to p1-20. Instead, we identified three new DQ8-restricted T cell epitopes in the regions 171-200, 311-340, and 411-440. DR3.Ab0 mice immunized with a second major M. tuberculosis protein, Ag85 (composed of 85A, 85B, and 85C), also developed T cell responses against only one determinant, 85B p51-70, that was identified in this study. Importantly, subsequent analysis of human T cell responses revealed that HLA-DR3+, Ag85-reactive individuals recognize exactly the same peptide epitope as DR3.Ab0 mice. Strikingly, both DR3-restricted T cell epitopes represent the best DR3-binding sequences in hsp65 and 85B, revealing a strong association between peptide-immunodominance and HLA binding affinity. Immunization of DR3.Ab0 with the immunodominant peptides p1-20 and p51-70 induced T cell reactivity to M. tuberculosis. Thus, for two different Ags, T cells from DR3.Ab0 mice and HLA-DR3+ humans recognize the same immunodominant determinants. Our data support the use of HLA-transgenic mice in identifying human T cell determinants for the design of new vaccines.
Amino Acid Sequence↗
Critical residues on HLA-DRB1*0402 HV3 peptide for HLA-DQ8-restricted immunogenicity: implications for rheumatoid arthritis predisposition.
Recently, we have proposed that the combination of HLA-DQ and -DR alleles is responsible for the association of the HLA class II region with rheumatoid arthritis (RA). According to this model, some HLA-DQ alleles, namely DQ4, DQ7, DQ8, and DQ9, predispose carriers to severe RA, but a self peptide of sequence KDILEDERAAVDTYC from the third hypervariable (HV3) region of some DRB1 alleles, including DRB1*0402, can protect from the disease if presented by DQ molecules. This model implies that DQ4, DQ7, DQ8, and DQ9 should be able to present a set of common peptides, despite polymorphisms in their Ag binding groove. In the present study, we have further analyzed the immunogenicity of the DRB1*0402 HV3 peptide in DQ8-transgenic mice. We found that the motif DERAA guarantees DQ8-restricted immunogenicity, and that R is the main anchor residue for binding of the DRB1*0402 peptide to DQ. Interestingly, the p1 pocket that probably controls binding of the R residue is identical in all four RA-associated DQ molecules. Our results imply that the association of RA with some DR subtypes can be explained by their linkage with DQ alleles displaying a binding site for similar "arthritogenic" peptides.
Amino Acid Sequence↗
Contribution of left atrial pressure and dimension to signal-averaged P-wave duration in patients with chronic congestive heart failure.
In a group of patients with chronic heart failure, a longer P-wave duration on signal-averaged electrocardiogram was found in those patients with higher pulmonary capillary wedge pressure, whereas the left atrium end-systolic diameter was not significantly different. Furthermore, an acute reduction in pulmonary capillary wedge pressure induced by sodium nitroprusside infusion was associated with a reduction in P-wave duration.
Adult↗
Human leukocyte antigen-DRB1*1502 (DR2Dw12) transgene reduces incidence and severity of arthritis in mice.
A strong correlation exists between susceptibility to RA in humans and some DRB1 alleles of the MHC region, such as DRB1*0401 and DRB1*0101. Meanwhile, incidences of other DR specificities, such as DR2, DR5, or DR7 have often been found reduced among RA patients. Like RA, susceptibility to mouse CIA is influenced by the MHC class II loci. To analyze the effect of a DRB1 molecule associated with low incidence of RA on mouse CIA, a human DRB1*1502 (DR2Dw12) transgene was introduced into CIA-susceptible B10.RQB3 (H2Aq) mice. Transgene-positive DRB1*1502 mice showed a significant reduction in the incidence and severity of arthritis. Moreover, the clinical reduction of arthritis correlated with the T-cell proliferative response of B10.RQB3-DRB1*1502 mice against a self-derived DRB1 peptide from the third hypervariable region. Our results suggest that the DRB1*1502-mediated protection against CIA can be explained by the DRB1 molecule acting as a source of self-antigenic peptide which interferes with the T-cell response against immunodominant regions(s) of the arthritogenic type II collagen molecule. By analogy, a similar mechanism might play a critical role in influencing the class II-associated predisposition to RA.
Animals↗
Immune response of HLA-DQ8 transgenic mice to peptides from the third hypervariable region of HLA-DRB1 correlates with predisposition to rheumatoid arthritis.
The major histocompatibility complex class II genes play an important role in the genetic predisposition to many autoimmune diseases. In the case of rheumatoid arthritis (RA), the human leukocyte antigen (HLA)-DRB1 locus has been implicated in the disease predisposition. The "shared epitope" hypothesis predicts that similar motifs within the third hypervariable (HV3) regions of some HLA-DRB1 alleles are responsible for the class II-associated predisposition to RA. Using a line of transgenic mice expressing the DQB1*0302/DQA1*0301 (DQ8) genes in the absence of endogenous mouse class II molecules, we have analyzed the antigenicity of peptides covering the HV3 regions of RA-associated and nonassociated DRB1 molecules. Our results show that a correlation exists between proliferative response to peptides derived from the HV3 regions of DRB1 chains and nonassociation of the corresponding alleles with RA predisposition. While HV3 peptides derived from nonassociated DRB1 molecules are highly immunogenic in DQ8 transgenic mice, all the HV3 peptides derived from RA-associated DRB1 alleles fail to induce a DQ8-restricted T-cell response. These data suggest that the role of the "shared epitope" in RA predisposition may be through the shaping of the T-cell repertoire.
Amino Acid Sequence↗
H2-A polymorphism contributes to H2-Ebeta-mediated protection in collagen-induced arthritis.
Collagen-induced arthritis (CIA) is an animal model of auto-immune inflammatory polyarthritis which has features similar to rheumatoid arthritis (RA). Much like RA, susceptibility to mouse CIA is influenced by the major histocompatibility complex (MHC) and is restricted to the H2 haplotypes q and r. In previous experiments, we have found that the introduction of an H2-Ebd transgene in H2-Aq CIA-susceptible mice was able to protect these mice against disease development. More recently, we have proposed that the polymorphism of the first domain of the Ebeta molecule modulates this protection, and that the presentation of a peptide from the third hypervariable region of the Ebeta chain by the H2-Aq molecule plays an important role in this mechanism. In the present report, we investigated whether the H2-E-mediated protection is H2-Aq-specific and whether the source of collagen has any influence. While the source of collagen had no effect on the protection, our results showed that the H2-E molecule failed to protect B10.RIII (H2(r)) mice against CIA. Further, the H2 haplotype r exerted a negative effect on the Ebetad-mediated protection in H2-Aq-restricted disease. Our results provide additional proof that self-MHC-derived peptides, such as Ebeta peptides, may play an important role in the T-cell repertoire education and/or modulation of the T-cell response in the periphery.
Amino Acid Sequence↗
Polymorphism of the MHC class II Eb gene determines the protection against collagen-induced arthritis.
Collagen-induced arthritis (CIA) is an animal model of auto immune polyarthritis, sharing similarities with rheumatoid arthritis (RA). Paradoxally, susceptibility to mouse CIA is controlled by the H2A loci (DQ homologous) while RA is linked to HLA.DR genes (H2E homologous). We recently showed that the E beta d molecule prevents CIA development in susceptible H2q mice. We addressed the question of whether H2Eb polymorphism will influence CIA incidence as HLA.DRB1 polymorphism does in RA. In F1 mice, only H2Ebd and H2Ebs molecules showed protection. Using recombinant B10.RDD (Ebd/b) mice, we found that CIA protection was mediated by the first domain of the E beta d molecule. Using peptides covering the third hypervariable region of the E beta chain, we found a perfect correlation between presentation of E beta peptides by the H2Aq molecule and protection on CIA. Therefore, the mechanism by which H2Eb protects against CIA seems to rely on the affinity of E beta peptides for the H2Aq molecule.
Amino Acid Sequence↗
Genetic polymorphism of the mouse major histocompatibility complex-associated proteasome subunit Lmp7.
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Alleles↗