Behçet Disease and the HLA System

Seventy-three unrelated patients with Behçet disease together with 33 members of seven families with at least two patients per family were tissue typed for 26 antigens of the HLA system. The patients with the complete type of Behçet disease were found to have HLA-B5 more significanth than healthy individuals. Family studies suggest that the genes closely linked to HLA locus influence the degree of severity of Behçet disease.     

Association of HLA class I antigens with Behçet disease in South Tunisia

Purpose

To study antigen HLA class I association with different clinical forms of Behçet's disease in South Tunisian population.

Patients and methods

We retrospectively reviewed 129 clinical case patients. All of the patients fulfilled the criteria of the international study group for Behçet's disease, and were followed at the department of internal medicine of the university hospital of Sfax. HLA class I phenotyping was performed by microlymphocytotoxicity complement dependent for our 129 patients and for 123 healthy controls. We used the program SPSS 11.0 to analyse clinical data and to compare HLA class I antigen distribution between these two populations.

Results

The study group concerned a total of 129 patients (81 males and 48 females). The mean age at disease onset was of 32 years. HLA-B51 antigen was the only antigen significantly more frequent among patients (24.81%) than controls (9.76%, p = 0.002). HLA-B44 was significantly more frequent among patients having familial history of recurrent buccal aphthosis or Behçet disease. HLA-A11 antigen was associated with early disease onset, and HLA-A1 was negatively associated with severe form of the disease (neurological, vascular or ocular manifestations).

Conclusion

Our study confirmed the HLA-B51 association with Behçet disease. Nevertheless, B51 frequency in South Tunisian patients was lower than that found in other studies regardless of the clinical manifestation.     

HLA-Cw*1602: a new susceptibility marker of Behçet's disease in southern Spain

Abstract: Genotyping of the HLA-C locus by PCR-SSP in Behçet's disease patients from southern Spain reveals a statistically significant association with Cw*1602 (OR 20.15, corrected ρ<0.05). This is an uncommon allele absent from the healthy control group, which seems to confer higher relative risk than B51 in this study (OR 1.85). Stratified frequencies do not show statistically significant differences but suggest that the Cw*1602-B51 haplo-type could be the main HLA marker of Behçet's disease in the analyzed population.     

A strong association between HLA-B*5101 and Behçet's disease in Greek patients

Behçet's disease is known to be associated with HLA-B51, one of the split antigens of HLA-B5, among many different ethnic groups. In a Greek population, an increased incidence of HLA-B5 in the patient group also been reported. Because the B51 antigen has been recently identified to comprise seven alleles, B*5101-B*5107, we performed HLA-B51 allele genotyping by the PCR-SSP method as well as serological HLA-A and -B typing among 31 Greek patients with Behçet's disease to investigate whether there is any correlation between one particular B51-associated allele and Behçet's disease. The frequency of B51 was remarkably high (80.6%) in the patient group as compared to the ethnically matched control group (26.7%). In addition, HLA-A26 was also increased in the patients (29.0%) as compared with the healthy controls (3.3%). B51 allele genotyping revealed that all these B51-positive patients carried B*5101. This study revealed a strong association of Behçet's disease in Greeks with one of B51 subantigens, providing insight into the molecular mechanism underlying an HLA association with Behçet's disease.     

HISTOPATHOLOGY OF BEHÇET DISEASE

An autopsy case of Behçet disease which was considered to be typical both clinically and histopathologically was reported. Cerebral abscess was also noted. Consequently it was presumed that some of the findings which had been called softening, demyelination, cavitation among others as the lesions of Neuro-Behçet might be closely related to abscess. Besides suppurative endoaortitls which was thought to be of interest as the lesions of Vascular-Behçet was observed. In order to substantiate the above, a general review of the literature of Behçet disease was made.     

BEHÇET SYNDROME ASSOCIATED WITH NASAL MALIGNANT LYMPHOMA – REPORT OF AN AUTOPSY CASE –

The present case deals with a patient who was suffering concurrently from malignant lymphoma of the nasal cavities and Behcet disease accompanied with colitis ulcerosa.
A possibility that Behçet syndrome might be accompanied with malignant tumor is discussed. Moreover, it may be possible to point out the presence of such a type of Behçet syndrome as a "tumoral Behcet".     

Behçs Disease: Lack of Correlation of Clinical Manifestations with HLA Antigens

It has been suggested that certain tissue types are associated with different clinical manifestations of Behçet's disease in Japan and England. Regional differences in the associations between HLA antigens and Behjet's disease have been established. We tissue typed 119 patients with Beliefs disease in Istanbul and attempted to correlate various clinical manifestations with HLA antigens. The frequency of only one tissue antigen, HLA-B5, was found to be increased in these series. HLA-B5 was present in 94 of 119 patients (77%) compared to 89 of 268 controls (33%), P < 0.0001, ARR = 6.79. Age of onset, sex, incidences of ocular disease, arthritis, thrombophlebitis and erythema nodosum did not show any positive or negative associations with any of the alleles tested.     

Neuronal Hyaline Inclusions Observed in an Autopsy Case of Behçet's Disease

An autopsy case of Behçet's disease is reported. The patient, a 59 year old Japanese woman, died of intestinal bleeding after a 34 year clinical course of Behçet's disease. She also suffered from recurrent oral aphthous ulcers, erythema nodosum like cutaneous lesions and genital ulcerated lesions. Autopsy revealed marked atherosclerosis of the aorta and multiple deep ulcerations in the terminal ileum with no significant vascular lesions. Lewy bodies and globular hyaline inclusions in the neurons of the central nervous system were noted, although there were no clinical symptoms of Parkinson's disease throughout the clinical course. These findings appear to suggest that the patient was probably in the preclinical or early stage of Parkinson's disease. However, the presence of Lewy bodies in the 6th decade without any accompanying symptoms is very rare. This case seems to draw attention to the presence of these neuronal inclusions in Behçet's disease.     

Twenty-six new polymorphic microsatellite markers around the HLA-B, -C and -E loci in the human MHC class I region

Abstract: The human major histocompatibility complex (MHC) class I region is believed to contain a large number of disease-related loci for diseases such as Behçet's disease and psoriasis vulgaris. Although many novel genes have recently been identified in this region, it still appears to be difficult to relate any of these new genes to MHC class I-associated diseases as causative genetic factors. During the course of large-scale genomic sequencing of the human MHC class I region, we identified 262 microsatellite sequences with dinucleotide to pentanucleotide repeats around the HLA-B, -C and HLA-E genes. Of these, 26 microsatellites were investigated for repeat polymorphism using 60 HLA homozygous B-cell lines and 60 healthy random individuals. The average number of alleles at these microsatellite loci was 9.6 with a PIC (polymorphism content value) of 0.69. These new polymorphic microsatellite markers will probably be very useful for precise mapping of disease-related genes within the HLA class I region in linkage analysis. Moreover, they will provide a powerful tool to study recombination events in this region, which contributes to haplotypic diversification.     

HLA Class I in Egyptian patients with Behçet’s disease: new association with susceptibility,protection, presentation and severity of manifestations

Introduction: Behçet’s disease is an autoimmune disease with diverse clinical manifestations with vasculitis being the hallmark of the disease. The aim of this work is to study the genetic association between human leukocyte antigen (HLA) class-I molecules of Egyptians with Behçet’s disease and the disease susceptibility and clinical patterns.

Methods: Fifty-seven patients diagnosed with Behçet’s disease according to the 1990 International Study Group (ISG) criteria for Behçet’s disease coming from Egyptian origin up to the third grandfather were included in the study. Healthy controls were taken from HLA Class-I case control studies in Egyptian population yielding a pool of 221 healthy controls. HLA Class-I typing for patients was done using Reverse Sequence specific oligonucleotide probes (rSSO).

Results: Male patients represented 89% of the sample. Mean age of onset was 25.81 (± 6.7) years and mean disease duration was 9.47 (± 7.4) years. Behçet’s disease was associated with HLA-A*24 and HLA-B*42 (p = 0.001) and highly associated with HLA-A*68 and B*15 and B*51 (p < 0.001). While HLA A*03 and B*52 were protective for Behçet’s (p = 0.002 and 0.007). Interestingly, HLA-B*51 and HLA-A*68 (p = 0.005 and 0.023) were associated with the blinding eye disease. HLA-B*51 was protective from Neurological and vascular involvement (p = 0.005 and 0.032, respectively).

Conclusion: Behçet’s disease is associated with HLA Class-I A*24, A*68 and B*15, B*42 and B*51 in Egyptian patients while A*03 and B*52 were found to be protective. Interestingly, HLA B*51 and A*68 could be considered as poor prognostic factor for eye involvement.     

Lack of Association of HLA-A and B Locus Antigens with Relapsing Polychondritis

Relapsing polychondritis is a systemic disease of unknown cause in which various inflammatory reactions recur in the cartilage structures of the ears, nose, and trachea (Kaye & Sones 1964). Although the cause of this disease is unknown, several immunologic abnormalities have been noted which explain some of the pathogenic mechanisms involved (Dolan et al. 1966, Herman & Dennis 1973, Rajapakse & Bywaters 1974, McKenna et al. 1976, Bergfeld 1978, Foidart et al. 1978). To ascertain if the frequency of HLA antigen is increased among patients with this disease, we performed HLA-A and HLA-B locus typing in Caucasian patients with well documented disease. Serologically defined HLA antigens at the A and B loci were determined by the microcytotoxicity assay of Mittal et al. (1968). No statistically significant increase in the frequency of any of the HLA-A or B locus antigen type was found between the patient group and the control group (Table 1). These findings suggest that no correlation exists between HLA-A and B locus antigens and relapsing polychondritis. HLA-DRw antigen typing was not done, although such typing would be of interest.     

Immunoglobulin allotypes and the immune response to wheat gliadin in a Finnish population with celiac disease

Several immunoglobulin allotypes were determined for 42 Finnish children with celiac disease (CD) and for 42 normal controls. The CD patients had been previously HLA typed; all but 2 were positive for HLA B8, DR3 or both. The incidence of HLA B8, DR3 and DR7 was found to be significantly higher in patients than in a control group. No significant association was found between any of the immunoglobulin allotypes and CD either when patients were grouped as a whole or when grouped according to sex. In addition, no association was found between levels of antigliadin antibody and the G2m(23) allotypic marker. This latter finding is in sharp contrast with the report of a significant association in American Caucasians between G2m(23) and the level of antigliadin antibodies by Weiss et al. [J. clin. Invest. 72: 96-101, 1983].     

Cytokine profiles in aqueous humor of patients with different clinical entities of endogenous uveitis

We assayed aqueous humor (AH) samples from patients with Behçet's disease (BD), Vogt–Koyanagi–Harada (VKH) disease, and HLA-B27-associated uveitis and control patients for the proinflammatory cytokines IL-15, IL-17, interferon-γ and tumor necrosis factor-α and the immunosuppressive cytokine IL-10. Cytokine levels were significantly higher in the three disease groups than in controls. In patients with similar disease activity, levels of IL-15 and IFN-γ were significantly higher in BD patients than in VKH and HLA-B27-associated uveitis groups. Logistic regression identified a significant negative correlation between BD and high levels of IL-10 and a significant positive correlation between VKH disease and high levels of IL-10. The proinflammatory cytokines versus IL-10 ratios were significantly higher in BD compared with other groups. These data suggest that both T helper (Th) 1 and Th17 cells are involved in endogenous uveitis immunopathogenesis. BD is characterized by extensive Th1 polarization, severe proinflammatory conditions and a low immunosuppressive status.     

Association of goitrous autoimmune thyroiditis with HLA-DR3 in eastern Hungary

An association of HLA-DR5 and goitrous autoimmune thyroiditis has been reported elsewhere (Farid et al., 1981; Weissel et al., 1980). Recently, the disease was found to be associated with HLA-DR4 in Newfoundlanders (Farid & Thompson, 1986). In order to find out whether different HLA associations with the disease may be found in different ethnic groups, we have now typed 68 patients with autoimmune goitrous thyroiditis from Eastern Hungary for HLA-A, -B, -C, and -DR antigens; 66 of these patients were also typed for IgG heavy-chain markers (Gm). A significant increase in DR3 (OR = 3.30) and a non-significant increase in DR4 (OR = 1.67) were found in the patients when compared with controls. The Gm3 allele, g, interacted with DR3 to enhance the risk for goitrous autoimmune thyroiditis. Hashimoto's disease may show different associations in different ethnic groups, and indeed within the same ethnic group, when newly diagnosed patients are typed several years apart.     

HLA typing in classical and African Kaposi's disease

HLA A, B, C, typing have been done in 39 patients with clinically and histologically documented classical Kaposi's sarcoma. Thirty three were also typed for HLA DR antigens. Twenty seven were males, 12 were females and three ethnic groups were represented: european caucasoids 41%, north african caucasoids 38.5% and negroids 20.5%. The only statistically significant abnormality is an increase of HLA DR5 frequency (60.6 vs 26. p less than 0.001 et RR = 4.2). Such an increase has been evidenced also in AIDS patients, with or without Kaposi's sarcoma and then is not discriminant between all this different types of the disease.     

New insights of HLA class I association to Behçet's disease in Portuguese patients

Human leukocyte antigen (HLA)-B*51 is a well-known genetic factor associated with Beh?et's disease (BD). To analyse the influence of HLA-B*51 and other HLA class I alleles in BD susceptibility in a Portuguese population and its association with disease severity, we studied 78 BD patients and 208 healthy controls. The patients were classified into two severity groups as described by Gul et al. As expected, a higher frequency of HLA-B*51 was found. The frequency of HLA-Cw*16 alleles was significantly higher in patients. Regarding severity, HLA-B*27 frequency was higher in the severe group compared with controls and with the mild group. Thus, HLA-B*51 and HLA-Cw*16 seem to confer susceptibility to BD in this patients. HLA-B*27 may be important as a prognostic factor.     

HLA-B*51 allele analysis by the PCR-SBT method and a strong association of HLA-B*5101 with Japanese patients with Behçet's disease

Abstract: Behçet's disease (BD) is known to be associated with human leukocyte antigen (HLA) B51 in many different ethnic groups. An increased incidence of HLA-B51 in the patient group has also been reported in a Japanese population. Recently, the B51 antigen has been identified to comprise 21 alleles, B*5101–B*5121. Further, not only HLA-B*5101 but also HLA-B*5108 were found to be relatively increased in the patient groups among Italian and Saudi Arabian populations. Therefore, we performed HLA-B*51 allele genotyping by the polymerase chain reaction-sequencing based typing (PCR-SBT) method in order to investigate whether there is any correlation of one particular B51-associated allele with Japanese BD. Ninety-six Japanese patients with BD and 132 healthy Japanese volunteers were enrolled in this study. As a result, the phenotype frequency of the B51 antigen was confirmed to be remarkably increased in the patient group as compared to the ethnically matched control group (59.4% in patients vs. 13.6% in controls; P c=0.0000000000098, R.R.=9.3). In the B*51 allele genotyping, 56 out of 57 B51-positive patients were defined as B*5101 and the remaining one was B*5102. In contrast, all of 18 B51-positive normal controls were B*5101. None of the Japanese patients and healthy controls carried the HLA-B*5108 allele. This study revealed that B*51 allelic distribution in Japanese was different from those in Italian and Saudi Arabian populations, and that the significantly high incidence of the HLA-B51 antigen in the Japanese BD patient group was mostly caused by the significant increase of the HLA-B*5101 allele.     

HLA-Dw2 as a Marker of Resistance Against Juvenile Diabetes Mellitus

Juvenile-onset diabetes mellitus (JDM) is one of the human diseases shown to be associated with histocompatibility antigens. The occurrence of serologically defined HLA antigens B8 Bw15, B18 and Cw3 is increased among these patients (Singal & Blajchman 1973, Nerup et al. 1974, Cudworth & Woodrow 1975). However, lymphocyte defined HLA-D antigens Dw3 and Dw4 (LD 8a and LD w15a), positively associated with these serologically defined antigens, seem to be even stronger markers of susceptibility to this disease (Thomsen et al. 1975).     

Human lymphocyte antigens (HLA) and Graves' disease in Turkey

To evaluate the association of HLA types with Turkish patients with Graves' disease, HLA typing, clinical findings, and thyroid antibodies were correlated. The HLA types, clinical findings (ophthalmopathy and age at onset), and thyroid stimulating hormone (TSH) receptor (TRAb) and antithyroid microsomal antibodies (MAb) were analyzed. Seventy Turkish patients with Graves' disease and 306 control subjects were assessed. Serological HLA typing was performed in HLA A, B, C, DR, and DQ loci. There was a significantly increased prevalence of HLA B8, B49, DR3, DR4, and DR10 in Graves' disease. The association of Graves' disease with HLA DR3 was found to be less strong than previously described. The HLA DR4 antigen may contribute to the predisposition of Graves' disease in Turkey. The results suggest that HLA B7, B13, DR7, DQw2, and DQw3 may confer a protective effect for Graves' disease in Turkey. Patients carrying HLA B12, B18, and B44 haplotypes had a tendency to develop the disease at a later age. The difference from the other studies may be the result of the selection of the controls; in part, of the variability in serological typing reagents; and, also, of the rather weak HLA associations with the disease.This study was presented in part at the Annual Meeting of the National Endocrinology and Diabetes Association, Bursa, Turkey, May 25–28, 1992.     

Serum antibodies to human leucocyte antigen (HLA)‐E,HLA‐F and HLA‐G in patients with systemic lupus erythematosus (SLE) during disease flares: Clinical relevance of HLA‐F autoantibodies

T lymphocyte hyperactivity and progressive inflammation in systemic lupus erythematosus (SLE) patients results in over‐expression of human leucocyte antigen (HLA)‐Ib on the surface of lymphocytes. These are shed into the circulation upon inflammation, and may augment production of antibodies promoting pathogenicity of the disease. The objective was to evaluate the association of HLA‐Ib (HLA‐E, HLA‐F and HLA‐G) antibodies to the disease activity of SLE. The immunoglobulin (Ig)G/IgM reactivity to HLA‐Ib and β2m in the sera of 69 German, 29 Mexican female SLE patients and 17 German female controls was measured by multiplex Luminex^®‐based flow cytometry. The values were expressed as mean florescence intensity (MFI). Only the German SLE cohort was analysed in relation to the clinical disease activity. In the controls, anti‐HLA‐G IgG predominated over other HLA‐Ib antibodies, whereas SLE patients had a preponderance of anti‐HLA‐F IgG over the other HLA‐Ib antibodies. The disease activity index, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)‐2000, was reflected only in the levels of anti‐HLA‐F IgG. Anti‐HLA‐F IgG with MFI level of 500–1999 was associated with active SLE, whereas inactive SLE revealed higher MFI (>2000). When anti‐HLA‐F IgG were cross‐reactive with other HLA‐Ib alleles, their reactivity was reflected in the levels of anti‐HLA‐E and ‐G IgG. The prevalence of HLA‐F‐monospecific antibodies in SLE patients was also associated with the clinical disease activity. Anti‐HLA‐F IgG is possibly involved in the clearance of HLA‐F shed from lymphocytes and inflamed tissues to lessen the disease's severity, and thus emerges as a beneficial immune biomarker. Therefore, anti‐HLA‐Ib IgG should be considered as a biomarker in standard SLE diagnostics.