Low and stable prevalence of rheumatoid arthritis in northern France.

OBJECTIVES: Few data are available on the prevalence of rheumatoid arthritis (RA) in France. Results of the Epidémiologie des rhumatismes inflammatoires (EPIRHUM-2) study suggest a lower prevalence in northern France (0.13%) than nationwide (0.31%) or in southern France (0.66%). Here, our objective was to confirm the lower prevalence of RA in northern France than in the rest of the country or in Europe. METHODS: We used the universal health insurance database to identify patients with RA in northern France (Nord-Pas de Calais region) in 2005. RESULTS: Seven thousand one hundred and twenty-eight patients of the 3,617,224 individuals receiving health insurance under the plan for salaried workers in the Nord-Pas de Calais region (89.3% of the population in the region) were listed as receiving free care for RA, yielding a prevalence of 197.1/100,000 population (female-to-male ratio, 2.99:1; mean age, 60.8 years). DISCUSSION: The prevalence of RA in northern France (0.197% in 2005) is lower than in southern France and northern Europe; thus, the prevalence gradient in France is in the opposite direction to the decreasing north-to-south gradient previously described in Europe. Although environmental and genetic factors involved in the pathogenesis of RA may be involved, the main explanation to the low prevalence in northern France may be the young age of the population.

Prediction of desmoglein-3 peptides reveals multiple shared T-cell epitopes in HLA DR4- and DR6-associated pemphigus vulgaris.

BACKGROUND: Pemphigus vulgaris (PV) is a severe autoimmune blistering skin disorder that is strongly associated with major histocompatibility complex class II alleles DRB1*0402 and DQB1*0503. The target antigen of PV, desmoglein 3 (Dsg3), is crucial for initiating T-cell response in early disease. Although a number of T-cell specificities within Dsg3 have been reported, the number is limited and the role of T-cells in the pathogenesis of PV remains poorly understood. We report here a structure-based model for the prediction of peptide binding to DRB1*0402 and DQB1*0503. The scoring functions were rigorously trained, tested and validated using experimentally verified peptide sequences. RESULTS: High predictivity is obtained for both DRB1*0402 (r2 = 0.90, s = 1.20 kJ/mol, q2 = 0.82, s(press) = 1.61 kJ/mol) and DQB1*0503 (r2 = 0.95, s = 1.20 kJ/mol, q2 = 0.75, s(press) = 2.15 kJ/mol) models, compared to experimental data. We investigated the binding patterns of Dsg3 peptides and illustrate the existence of multiple immunodominant epitopes that may be responsible for both disease initiation and propagation in PV. Further analysis reveals that DRB1*0402 and DQB1*0503 may share similar specificities by binding peptides at different binding registers, thus providing a molecular mechanism for the dual HLA association observed in PV. CONCLUSION: Collectively, the results of this study provide interesting new insights into the pathology of PV. This is the first report illustrating high-level of cross-reactivity between both PV-implicated alleles, DRB1*0402 and DQB1*0503, as well as the existence of a potentially large number of T-cell epitopes throughout the entire Dsg3 extracellular domain (ECD) and transmembrane region. Our results reveal that DR4 and DR6 PV may initiate in the ECD and transmembrane region respectively, with implications for immunotherapeutic strategies for the treatment of this autoimmune disease.

Human leukocyte antigens and prognosis in patients with head and neck cancer: results of a prospective follow-up study.

BACKGROUND: Prognostic information is essential for optimal treatment of patients with head and neck cancer. We studied the relationship of class I and class II human leukocyte antigens (HLA) on prognosis in patients with head and neck cancer. METHODS: HLA-A, -B, -C and -DR antigens were determined in 209 patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. The patients were subjected to follow-up investigations for a period of 5 years. RESULTS: Five-year survival rates in relation to tumor stage varied between 86% for stage I tumors and 28% for stage IV tumors (P <.0001, log-rank trend test). The EBA-A11 antigen showed a significant negative correlation with survival. While the 5-year survival of 124 HELA-A11-negative patients was 58%, none of the 17 HLA-A11-positive patients survived 5 years (P = .0002). A significant negative correlation with survival was also observed for HLA-DR6. While the 5-year survival rate of 106 HLA-DR6-negative patients was 60%, it was only 40% in 35 HLA-DR6-positive patients (P = .0313). CONCLUSIONS: If the findings of our study can be confirmed, HLA-A11 and HLA-DR6 might become clinically important supplemental prognostic markers in head and neck cancer.

HLA-A33/B44/DR6 is highly related to intrahepatic cholestasis induced by tiopronin.

In order to elucidate the immunogenetic predisposition of tiopronin (mercaptopropionylglycine)-induced intrahepatic cholestasis, human leukocyte antigen (HLA) was analyzed in patients with tiopronin-induced liver injury. HLA-A, -B, -C, and -DR loci of 14 patients (10 males and 4 females) with tiopronin-induced liver injury were compared with those of control subjects. The mean duration of tiopronin administration was 26 days and that of jaundice was 4.5 months. The elevation of biliary enzymes lasted from 2 months to up to 10 years. Most of the cases manifested intrahepatic cholestasis on liver biopsy. Lymphocyte transformation test with tiopronin was positive in 6 of 8 (75%) tested cases. Thirteen patients (92.9%) had HLA-A33, 10 (71.4%) had B44, and 9 (64.3%) patients had DR6. These are statistically higher in the patients with tiopronin-induced cholestasis than in the general population. Ten of those with tiopronin-induced liver dysfunction (71.4%) had A33/B44 and 8 (57.1%) had A33/B44/DR6 in their haplotype. In conclusion, long-lasting tiopronin-induced intrahepatic-cholestasis is highly linked to specific HLA-A33, -B44 and -DR6.

Analysis of HLA antigens in Mycobacterium avium-intracellulare pulmonary infection.

Mycobacterium avium-intracellulare (MAI) pulmonary infection may occur in subjects with no preexisting lung disease and no known immunodeficiency, showing radiologically nodular bronchiectasis. There have remained some unresolved problems in the pathogenesis of the disorder, including the predominance in elderly women and the presence of not deteriorated or deteriorated disease. In the present study, we examined whether immunogenetic susceptibility is present in the disorder. We evaluated 64 cases of MAI disease and analyzed their short-term natural history by assessing symptoms, sputum bacteriology, and chest computed tomographic findings. The frequencies of human leukocyte antigen (HLA) alleles in patients were compared with those in 100 healthy Japanese control subjects. We assayed the HLA-A, -B, -C, -DR, and -DQ antigens serologically. Among 64 patients, 37 (35 females) did not show deterioration, whereas 27 (24 females) showed deterioration after an interval of 30 +/- 15 mo. There was no significant frequency of HLA-B and -C alleles in either group. In 37 not deteriorated patients, DR-6 was positive in 14 (37.8%) patients but in only 16 (16%) control subjects (p = 0.0061, odds ratio [OR] = 3.20). DQ-4 was positive in 10 (27.0%) patients but in only 10 (10%) control subjects (p = 0. 0122, OR = 3.33). In 27 deteriorated patients, HLA-A26 was positive in 14 (51.9%) patients but in only 21 (21.0%) control subjects (p = 0.0015, OR = 4.05). MAI pulmonary infection with nodular bronchiectasis shows two types of outcome, deteriorated and not deteriorated. The subjects with A-26 antigen might indicate the deterioration of MAI infection.

Hypoxia-induced pulmonary blood redistribution in subjects with a history of high-altitude pulmonary edema.

BACKGROUND: Pulmonary hypertension has been suggested to play an important role in development of high-altitude pulmonary edema (HAPE), and individual susceptibility has been suggested to be associated with enhanced pulmonary vascular response to hypoxia. We hypothesized that much greater pulmonary vasoconstriction would be induced by acute alveolar hypoxia in HAPE-susceptible (HAPE-s) subjects and that changes in pulmonary blood flow distribution could be demonstrated by radionuclide study. METHODS AND RESULTS: We performed ventilation-perfusion scintigraphy in 8 HAPE-s subjects and 5 control subjects while each was in the supine position and acquired functional images of pulmonary blood flow and ventilation under separate normoxic and hypoxic (arterial oxygen saturation, 70%) conditions. We also measured acceleration time/right ventricular ejection time (AcT/RVET) with Doppler echocardiography under each condition in both groups. Moreover, we assayed human leukocyte antigen (HLA) alleles serologically in the HAPE-s group. Pulmonary blood flow was significantly shifted from the basal lung region to the apical lung region under hypoxia in HAPE-s subjects, although no significant change in regional ventilation was observed. With Doppler echocardiography, HAPE-s subjects showed increased pulmonary arterial pressure during hypoxia compared with control subjects. The magnitude of cephalad redistribution of lung blood flow was significantly higher in the HLA-DR6-positive than in HLA-DR6-negative HAPE-s subjects. CONCLUSIONS: These findings suggest that acute hypoxia induces much greater cephalad redistribution of pulmonary blood flow that results from exaggerated vasoconstriction in the basal lung in HAPE-s subjects. Furthermore, pulmonary vascular hyperreactivity to hypoxia may be associated with HLA-DR6.

Association of insulin-dependent diabetes mellitus and celiac disease: a study based on serologic markers.

BACKGROUND: The association of celiac disease and insulin-dependent diabetes mellitus has been known for some time. In an attempt to clarify this association, the prevalence of celiac disease among diabetic children was determined, and the risk of insulin-dependent diabetes mellitus was defined in pediatric patients with celiac disease. METHODS: Ninety-three children with diabetes were analyzed for the presence of celiac disease-related markers (antigliadin and antiendomysial antibodies) and characteristic alterations in the intestinal mucosa. In another group, 93 children with celiac disease were screened for pancreatic autoantibodies and pancreatic beta-cell function. RESULTS: Among children with insulin-dependent diabetes mellitus, a 6.45% prevalence of celiac disease was observed, a value significantly higher than that found among healthy controls. In contrast, only three celiac disease patients showed potential autoimmunity toward the pancreatic beta cell, a proportion not significantly different from that in the general population. Additionally, no alteration of glucose metabolism was observed in the antibody-positive patients. CONCLUSION: The increased risk of celiac disease among patients with diabetes requires a long follow-up to determine the presence of celiac disease markers among patients with diabetes, to avoid potential malignant disease derived from untreated celiac disease. In contrast, there is no evidence to support an increased risk of insulin-dependent diabetes mellitus among children with celiac disease. In accordance with the accepted influence of diet in the development of autoimmune diabetes, a hypothetical mechanism of protection against insulin-dependent diabetes mellitus that is mediated by environmental factors related to restricted diet is suggested in this population.

Bilateral iridocyclitis with retinal capillaritis in juveniles.

PURPOSE: The authors present clinical features of 18 juvenile patients with a new type of uveitis termed bilateral iridocyclitis with retinal capillaritis (BIRC). METHODS: The authors reviewed medical records of 18 consecutive patients who showed bilateral iridocyclitis with retinal capillary leakage but no systemic manifestations during an 11-year period from January 1985 to December 1995. RESULTS: Twelve of the 18 patients were female and the age at onset ranged from 9 to 17 years old. All patients had many cells in the anterior chamber and anterior vitreous, together with mutton fat keratic precipitates. Fluorescein angiography showed leakage from the optic disc and retinal capillaries, mainly in the midperiphery, which corresponded to retinal cloudiness. Macular edema was minimal, and all patients maintained good vision. The inflammation responded well topical, oral, and intravenous administration of corticosteroids, the choice of which was based on the extent of retinal inflammation. Human leukocyte antigen (HLA)-DR6 and HLA-Cw7 were associated significantly with the presence of BIRC (chi square test, P < 0.0001). CONCLUSIONS: Bilateral retinal capillaritis affecting capillaries in various areas of the retina and overlying retinal cloudiness with no distinct lesions are unique to these patients. Fluorescein angiography is essential for diagnosis of BIRC.

[Study of HLA-II antigens in chronic hepatitis C and B and in acute hepatitis B]. / Estudio de los antígenos HLA-II en las hepatitis crónicas C y B y en las hepatitis agudas B.

The aim of this study was to analyze the variability of the HLA-II system in a series of patients with chronic hepatitis B, chronic hepatitis C and acute hepatitis B to know whether there is any relationship between the polymorphism of the HLA system, the different types of hepatitis and the evolution of the infection. HLA-II antigens were determined by a PCR technique in serum samples of 24 controls, 22 cases of chronic hepatitis C, 38 cases of chronic hepatitis B and 11 with acute hepatitis B. The prevalence of the HLA-DR4 antigen was lower in the cases of chronic hepatitis B (10.5%) and C (13.6%) than in the controls (33.3%), particularly the DRB1*0401 allele (p = NS). The prevalence of HLA-DR6 was similar in chronic hepatitis B (42.1%) and acute hepatitis B (45.5%). Predominance of the DRB1*1301 and DRB1*1302 alleles were, however, observed in acute hepatitis B (36.4%) versus chronic hepatitis B (13%). These data suggest that immunologic factors such as HLA antigens may influence in the susceptibility to infection by HBV and HCV. The use of PCR techniques which discriminate between the different alleles of the HLA antigens may provide better knowledge of the immune response.

Human leukocyte antigens in occupational allergy: a possible protective effect of HLA-B16 in laboratory animal allergy.

Human leukocyte antigens (HLA-A, -B, -C, and -DR loci) and possible associations with occupational allergy to laboratory animals and atopy indicators were studied in laboratory animal workers with airway symptoms (n = 92) and in those who were symptom free (n = 27), as well as in a population reference group of blood donors in good health (n = 123). The laboratory animal workers, but not the population reference group, were allergologically examined with skin prick testing to common environmental and animal allergens together with measurement of total serum IgE levels. Seven HLA antigens, i.e., HLA-A9, -B5, -B12, -B16, -DR4, -DR5, and -Drw6, suggested possible associations with symptoms and/or atopy indicators. When correcting the p-values for the number of studied antigens, only the HLA-B16 differences remained statistically significant. HLA-B16 was elevated in symptom-free subjects compared to the population reference group and in subjects with serum IgE < 10 kU/L. Subjects with serum IgE > 100 kU/L and sensitized against environmental and/or laboratory animals, including LAA asthmatics, lacked HLA-B16. It is suggested that HLA-B16 or an immunosuppressive gene linked to HLA-B16 reduce the risk of producing IgE antibodies against animal protein allergens. However, our a priori hypothesis of a possible risk associated with HLA B15-DR4 could not be confirmed.

Decreased frequency of HLA-DR13DR6 in Wegener's granulomatosis.

The pathogenesis of Wegener's granulomatosis, microscopic polyangiitis and idiopathic rapidly progressive glomerulonephritis (RPGN) is still unclear; in vitro data support both humoral and cellular autoimmune mechanisms. An association of Wegener's granulomatosis with HLA antigens has been described, with conflicting results concerning the antigens involved. We have performed serological HLA typing of patients at two different laboratories within the Netherlands (N = 118 and N = 106,N respectively). A significant decrease in the frequency of HLA-DR13DR6 was present in both patient groups in comparison to controls (chi 2 = 21.9; corrected P value < 0.004 for both groups together). There were no differences in the distribution of HLA-antigens between patients with Wegener's granulomatosis and microscopic polyangiitis, between cANCA (cytoplasmic anti-neutrophil cytoplasmic antibodies) and pANCA (perinuclear ANCA, anti-MPO) positive patients, and between patients with and without relapsing disease.

Human leucocyte antigen phenotypes and gold-induced remissions in patients with rheumatoid arthritis.

To assess possible associations between human leucocyte antigens (HLA) and the achievement of remission during gold treatment, HLA typing was performed in 67 rheumatoid arthritis (RA) patients with a gold-induced remission and in 25 control RA patients who discontinued gold therapy because of lack of efficacy. Both groups of RA patients showed a significantly higher frequency of DR4 antigen and lower frequency of DR6 than a control population. There were no significant differences in HLA antigens between remission-responders and non-responders. It is concluded that HLA typing is not helpful in predicting the therapeutic response to parenteral gold therapy.

Pemphigus vulgaris in siblings: HLA-DR4 and HLA-DQw3 and susceptibility to pemphigus.

BACKGROUND: The association of pemphigus vulgaris with the HLA serotypes, DR4 and DRw6, and with the DQ-beta chain alleles, DQw1 and DQw3, suggests that there is a genetic predisposition to this disease. However, familial cases of pemphigus vulgaris are exceedingly rare. OBJECTIVE: We studied two siblings with pemphigus vulgaris and three unaffected family members to determine whether an HLA allele was associated with the development of pemphigus vulgaris in this family. METHODS: We utilized restriction fragment length polymorphism methods using the HLA-DR beta 1, HLA-DQ alpha, and HLA-DW beta 1 genes as cDNA probes. RESULTS: We found that the affected siblings share the haplotype HLA-DR4 and the DQw.3.2 allele. CONCLUSION: Our findings of gene sharing among siblings with pemphigus vulgaris lend support to previous studies of unrelated Caucasian patients, which implicated DQw3 allele polymorphisms in conferring susceptibility to pemphigus.

HLA associations in patients with polycystic ovaries and in patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency.

Ninety-nine Caucasian patients with ultrasonically detected polycystic ovaries (PCO) were typed for human leucocyte (HLA) antigens. Fifty patients with congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency were similarly typed. Among the patients with PCO, there was a significant increase in the frequency of HLA DRW6 (P = 0.0027) compared with that found in a control population, which remained significant (P = 0.027) when corrected for the number of antigens tested. This difference was reduced, but remained significant (P = 0.006), when the patients with CAH and PCO were added. There was also a significant decrease in the frequency of HLA DR7 (P = 0.017) among the patients with PCO compared with a control population, but there was no distortion of the frequencies of HLA A, B or Cw antigens. Among the patients with CAH, previously well documented associations of HLA B14 and DR1 with non-classical disease were confirmed. The frequency of HLA Bw47 was increased among the whole group of CAH patients (P = 0.05) but was not increased among those with classical salt-wasting (SW) or simple virilizing (SV) disease. Family studies were performed in close female relatives of 16 of the PCO patients and 21 of the CAH patients but no evidence for genetic linkage between HLA and PCO status could be found. These data suggest that there is no significant component of disturbed adrenal steroid 21-hydroxylase activity to account for the PCO morphology, although there may be some other genetic factor, more proximal to the centromere on chromosome 6, affecting the development of polycystic ovaries.

HLA-A, B, C and DR antigens in nickel contact sensitivity.

The relationship between HLA antigens (A, B, C and DR) and nickel contact sensitivity was examined in 54 patients with contact allergy, as confirmed by an unequivocal positive patch-test reaction only to nickel. A control group was 320 healthy blood donors from the same geographical area as the patients. The HLA-A, B, C and DR antigens were typed using standard serological methods. HLA typing revealed a significant increase of HLA-DRw6 antigen in the patient group (corrected P less than 0.025) and the relative risk for patients with DRw6 to develop nickel sensitivity was 3.32.

Vitiligo is associated with HLA-DR4 in black patients. A preliminary report.

We have determined the HLA-DR and HLA-DQ phenotypes of 24 black patients with vitiligo and compared these with phenotypes of 143 local black controls. HLA-DR4 was significantly increased in patients, 38% vs 11% for controls. HLA-DQw3 was also increased in patients, 58% vs 32% for controls and may be explained in part by linkage disequilibrium with HLA-DR4. When patients were subgrouped according to family history of autoimmune disease and compared with controls, the increase in HLA-DR4 and HLA-DQw3 segregated with a positive family history. HLA-DRw6 in patients with a negative family history of autoimmune disease (64%) was significantly greater than the 10% in patients with a positive family history. When patients were subgrouped according to age at onset of disease, HLA-DR4 was increased in those with early onset of disease (younger than 20 years) while HLA-DRw6 was greater in patients who were older at onset of disease. These findings support the hypothesis of an immunogenetic influence on the expression of vitiligo in black patients with vitiligo.