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.     

Recurrent erythema multiforme: tissue typing in a large series of patients

Previous reports have shown an increased frequency of certain HLA antigens in association with erythema multiforme, including HLA-B15(B62), HLA-B35, HLA-A33, HLA-DR53 and, more recently, HLA-DQB1*0301. A strong association with HLA-DQ3 has been documented in patients with recurrent erythema multiforme. We have performed HLA typing in 39 patients with recurrent erythema multiforme, of whom 33 were associated with herpes simplex virus infection. The results were compared with 309 controls. In the recurrent erythema multiforme patients there was a statistically significant increase in HLA-B62 and HLA-B35. An increase in HLA-DR53 was also found, although this did not reach statistical significance. There was no increase in HLA-A33. The presence of HLA-DQ3 in the study population approached that in the controls. Finally, the study population demonstrated a trend towards a reduction in the HLA antigens A1, B8, and DR3. The study confirms the previously reported associations with HLA-B62 (B15), HLA-B35 and HLA-DR53. We have been unable to confirm an association of HLA-A33 or HLA-DQ3 with erythema multiforme. The HLA antigens A1, B8, and DR3 are associated with autoimmune disease, reflecting an increased host response to tissue self antigens. Their absence in patients with recurrent erythema multiforme (REM) may be an indicator of a poor host response to an antigen, which in the case of REM is the herpes simplex virus.     

HLA antigens and Langerhans cell density in contact dermatitis

We studied 67 patients with multiple contact allergies to determine whether there was an association of this state with any particular HLA antigen. HLA-A, -B and DR antigens were typed by standard serological methods. There was no significant HLA association, although there was an increased frequency of DR4 in those patients who included nickel as one of their sensitivities (64% compared with 33% in controls), and an increase in DR6 in those patients who included sensitivity to a rubber accelerator (45% compared with 16% in controls). However, when the probabilities were corrected for the number of HLA antigens tested and the number of substances in the patch test battery, these associations were no longer statistically significant. We also examined the morphology and numbers of Langerhans cells in epidermal sheets from six subjects with multiple allergies. There were no differences in appearance or numbers of Langerhans cells stained for ATPase, compared with 20 non-allergic controls.     

HLA antigens in Arabs with lichen planus

We have HLA typed 50 Arab patients with cutaneous lichen planus who were resident in Kuwait and then compared the antigen incidence with 100 normal controls. There were no significant differences in the antigens of the HLA-ABC loci but there was a significant increase in HLA-DR1 (P= 0.0018, RR = 3.68) and HLA-DRH) (P. corr. = 0.00096, RR=8.27) and a significant decrease in HLA DR5 (P. corr. = 0.0396, RR = 0.18.) The relevance of these findings to earlier reports on lichen planus in which HLA-DR1 (but not DR10) is increased is discussed. This is the first report of HLA antigen frequency in Arab patients with lichen planus, and would support the fact that HLA DR1 is universally associated with the disease, although the more significant association appears to be with HLA-DR10.     

HLA-class 1 and class 2 antigens in Turkish patients with pemphigus

BACKGROUND: Pemphigus is an autoimmune disease which is more frequently seen in certain ethnic groups such as Jews. It is thought that exogenous factors may induce pemphigus in genetically predisposed individuals. Recent reports on HLA antigens indicate an increased frequency of HLA-class II antigens particularly HLA-DR4 among Jewish patients. Herein we investigated the antigen frequencies of HLA-A, B, C, HLA-DR and DQ in Turkish patients with pemphigus. METHODS: HLA class I and II antigens were typed by microdroplet lymphocyte cytotoxicity test in 33 patients with pemphigus and 100 healthy individuals. RESULTS: HLA-B35, B44, CW4, DR4, DR14, DQ8 and DQ4 antigens were significantly high in the study group whereas HLA-DR11, DQ7 and DQ2 antigens were high among the controls. The most striking differences were observed in HLA class II antigens. HLA DR14-DQ8 and HLA B35-DR14 haplotypes were the most frequently observed ones in the study group. CONCLUSIONS: We postulate that HLA-B35, B44, CW4, DR4, DR14, DQ4 and DQ8 antigens may be responsible for susceptibility to pemphigus while HLA-DR11, DQ7 and DQ2 antigens may have a protective role in the Turkish population.     

Analysis of HLA antigens in Croatian patients with psoriasis

In common with most autoimmune diseases, psoriasis is associated with some HLA antigens. We studied the distribution of HLA antigens in Croatian patients with psoriasis: 108 patients were divided into groups according to family history and age of disease onset. HLA antigens were analyzed serologically and HLA-C alleles were analyzed using polymerase chain reaction. We found significant increases in HLA-A2, -B17, -B37 and -B13 antigens and highly significant increases in HLA-Cw*0602 and DR7 antigens in psoriatic patients compared with controls. Patients with type I psoriasis (early onset, positive family history) showed highly significant associations with Cw*0602 [p < 0.00001; relative risk (RR) = 14.45] and DR7 (p < 0.00001; RR = 15.09) antigens. Patients with type II psoriasis (late onset, no family history) had a significant association with Cw*03 antigen (p = 0.008; RR = 0.17). In conclusion, HLA-B13, -B17, Cw*0602 and -DR7 antigens are associated with a significant risk of psoriasis in the Croatian population and the Cw*0602 allele has the strongest association, especially for type I psoriasis.     

Fixed drug eruption induced by trimethoprim-sulfamethoxazole: evidence for a link to HLA-A30 B13 Cw6 haplotype

BACKGROUND: Recent reports indicated a significant association between fixed drug eruption (FDE) and HLA class I antigens. A strong correlation was found between B22 antigen and feprazone-induced FDE. OBJECTIVE: Our aim was to investigate the association between HLA class I antigens and FDE in Turkey, a country where feprazone is not on the market and trimethoprim-sulfamethoxazole is most often the offending drug. METHODS: HLA class I typing was performed by lymphocytotoxicity assay in 67 unrelated patients with FDE, all established by oral provocation. The frequencies are compared with those of 2378 control subjects. RESULTS: Significantly higher (P <.001) frequencies of the A30 antigen and A30 B13 Cw6 haplotype were found in 42 patients with FDE induced by trimethoprim-sulfamethoxazole. HLA-B55 (split of B22) was present exclusively in trimethoprim-sulfamethoxazole-induced FDE, and in higher frequency than in control subjects. CONCLUSION: To our knowledge, ours is the first report indicating a link between A30 B13 Cw6 haplotype and trimethoprim-sulfamethoxazole-induced FDE. In addition, HLA-B22 was increased in patients with FDE caused by a drug other than feprazone.     

Class II MHC typing in pemphigoid gestationis

Pemphigoid gestationis (PG) is a rare, autoimmune skin disease associated with pregnancy or the immediate postpartum period, previously shown to be associated with the HLA class II antigens DR3 and DR 4. Advances in molecular analytical techniques now allow the identification of HLA alleles previously difficult to define by serological assays. Unsuspected polymorphism within the HLA-DR 3 and DR 4 classes can, therefore, be identified. The aim of our study was to apply these newer techniques to the question of genetic predisposition in PG by re-evaluating the association with DR 3 and by studying a possible link with DQ. We have investigated by restriction fragment length polymorphism, the DQA, and by sequence specified oligonucleotide probing the DQB and DRB 1 (HLA DR) specificities of 41 women with immunofluorescence-confirmed PG. The principal finding of this study is that there is an association between PG and DRB 1*0301 (DR3) and DRB 1*0401/040X (DR4). Although there is also an increase (P= 0.06) in the concurrent presence of both antigens, this appears to be due to the association with either antigen alone. We also found an increase in the frequency of DQA1*2 (P= 0.016 vs. control) and a decrease in frequency of DQB 1*0201 (P= 0.022 vs. controls) and DQB1*0602 (P= 0.026 vs. controls).     

HLA Antigens and Linkage Disequilibrium Patterns in Turkish Behçet's Patients

Behçet's disease (BD) is a multisystem disorder featuring mucocutaneous, ocular, articular, vascular, intestinal, pulmonary, and neurologic involvement. Although the pathogenesis of the disease is still unknown, most studies have proposed that immunologic factors may play a major role in its development in genetically predisposed individuals. Seventy-one Turkish patients with BD, diagnosed according to the International Study Group for Behçet's Disease criteria, were studied and compared with 600 healthy controls to determine not only frequencies of HLA-A, B, and DR antigens but also whether BD shows any distinct linkage disequilibrium (LD) patterns. In addition, three-point linkage disequilibrium and relative risk (RR) values were determined. Of the HLA-A, B, and DR antigens examined, only B5 (51) was significantly increased in the patient group (X²=55.4; p<0.05; RR=6.44). DR7 was significantly decreased in the patient group (X²=6.9; p>0.05; RR=0.31). HLA haplotype B5-DR5 was found to be in negative LD in the control group, but Behçet's patients showed a strong positive LD between these two antigens. HLA haplotypes A2-B12, B5-DR2, and B12-DR4 showed negative LD in the patients; A1-B5 and B5-DR5 had positive LD in the patients. HLA haplotype A2-B5-DR5 was found to be more frequent than expected in both patients and control gorups. A2-B12-DR4 showed a negative LD in the patients. The strong LD patterns between HLA-B and DR antigens in BD suggest that the susceptibility gene to BD could reside between the these two antigens.     

A preliminary report on the role of some immunologic factors in persistence of chronic tinea pedis

The phenotypic distribution of HLA antigens was investigated in 29 patients with chronic dermatophyte infections and 558 age controls using a microcytoxicity assay. Statistical analysis of data indicated that there was an increased frequency of HLA antigen A26, and AW33. A26 was present in 24% of the patients and 6% of the controls (P= 0·0006). AW₃₃ was present in 14% of the patients and 2% of the controls (P= 0·0002). Intercellular substance (ICS) antibody and IgE assay were performed on these patients. Thirty-four per cent of the patients produced an ICS antibody and had an increased incidence of A26 (P= 0·002). Sixty-six per cent of the patients who did not produce an anti-ICS antibody had an increased frequency of HLA antigen AW₃₃ (P= 0·0002). DR antigens were studied in 26 patients. DR4 was found in 46% of patients but this was not statistically significant. The frequency of the antigen increased to 83% (corrected P value 0·049) in patients with a personal and/or family history of atopy and increased to 86% in patients with high IgE levels (corrected P value 0·016). It appears that several host factors may play an important role in determining and/or perpetuating chronic tinea pedis infection.     

Positivity for HLA DR1 is associated with basal cell carcinoma in renal transplant patients in southern Brazil

Background Renal transplant patients have a higher incidence of non‐melanoma skin cancer (NMSC). Previous studies hypothesized that human leukocyte antigen (HLA), especially types DR1, DR4, and DR7, may influence the incidence of these tumors. This study investigates the association between NMSC and the presence of HLA DR1, DR4, and DR7 in renal transplant patients in southern Brazil. Methods In a historical cohort study, 1032 patients who underwent renal transplantation during the period from January 1993 to December 2006 were examined to identify occurrences of NMSC and HLA status prior to transplant. Results Of the 1032 patients examined, 59 (5.71%) developed NMSC (squamous cell carcinoma [SCC]: 2.42%; basal cell carcinoma [BCC]: 1.74%; both: 1.55%). The presence of HLA DR1 was associated with a higher probability of developing any NMSC and particularly with developing BCC (P < 0.05). There was no statistically significant association between the presence of HLA DR4 or DR7 and the occurrence of NMSC in this sample. Conclusions HLA DR1 appears to be associated with the development of BCC, as well as with the higher number of NMSC lesions in renal transplant patients. This study supports the trend to associate the DR1 allele with BCC and not with SCC.     

Locus B HLA antigens in psoriatic patients. Population and family studies and clinical relationship

Summary The HLA gene and haplotype frequencies in psoriatic population (N=136) and families (N=47) were estimated. The significant association with HLA-B17 and B13 was found. The relative risk for these antigens was 4.4 and 2.4, respectively. The most frequent haplotypes carrying the psoriatic antigens was HLA-A1, B17 and HLA-A10, B17, with significant relative risk, equalled 8.24 and 5.75. The distribution of HLA-B13 and B17 phenotypes according to the three groups of clinical activity and four groups of extent of skin lesions were considered. The strong association between HLA-B17 and psoriasis with large skin involvement (more than 50%) was observed. The possible role of antigen B17 in pathomechanism of psoriasis is discussed.Supported by The Polish Academy of Sciences, grant no. 10.5     

HLA antigens in Omani patients with vitiligo

Fifty native Omanis with vitiligo were studied to compare the incidence of HLA ABC and DR antigens with a control population. HLA Bw6 was found in 82% of patients compared with 49% controls (P_c= 0.0009 RR = 4.56) and HLA DR7 occurred in 40% of patients and 9% in controls (P_c= 0.00075 RR = 6.17). HLA DR7 was significantly increased in those patients with acrofacial, compared to focal disease (57% vs. 24%P= 0.038). Sixty-six per cent of the patients in this study had parents who were consanguineous and a positive family history was only found in this group with an incidence of 32%. HLA Bw4 segregated 100% with patients with a positive family history compared with 48% in consanguineous patients without a positive family history (P_c= 0.011 RR = 23). Vitiligo appears to be associated with different HLA antigens in different ethnic groups.     

Vitiligo is associated with a significant increase in HLA-DR6 and a decrease in DQw2 antigens in Northern Italian patients.

Background Pathogenesis of vitiligo is still unclear; although the mechanism of melanocyte destruction is not know, reports of abnormalities in immunoregulation and immune reactivity in these patients support the autoimmune theory of the disease. A wide variety of autoimmune disorders have been associated with HLA antigens, and at the present time there are conflicting results about the association between vitiligo and HLA phenotypes. Objective and methods To determine if some increases in certain HLA antigens in the Northern Italian population suffering from vitiligo exist, we studied 33 patients, and we compared the results obtained with those observed in 443 control subjects of the same geographical area. Results HLA-DR and DQ typing showed a statistically significant increase of DR6 antigen and a statistically significant decrease of DQw2 type. The comparison of the phenotype frequencies of the loci A,B and C observed in the patients and in the control group showed no statistically significant differences after the p correction. Conclusion This study showed that genes in or closely linked to the HLA-DR and DO regions of the major histocompatibility complex could influence susceptibility to vitiligo in Northern Italian patients.     

Long-lasting allergic patch test reactions to nickel sulfate: analysis by nickel quantification and immunocytochemistry

We previously showed the median duration of positive patch test reactions to nickel sulfate(5% pet) was 9 days, and defined as long-lasting (LLAPTR) the 14.3% of reactions that persisted for 17 Days or longer. The pathomechanisms of LLAPTR are unclear, but may involve either localized antigen persistence or abnormal down regulation of the cellular immune response. In this study, we compared (a) the nickel concentration and (b) the immunocytochemical nature of the local immune reaction, between biopsies from LLAPTR ( n = 8) and normally resolving allergic patch lest reactions (NRAPTR) ( n = 8) to nickel sulfate. The concentration of nickel in LLAPTR (median 0.8μg/g, μg/g, range 0.25–3.87 μg/g, mean 0.83μg/g, 95% CI 0 35–1.31) and NRAPTR (median 0.58 μg/g, range 0.2 1.85 μg/g, mean 0.88 μg/g, 95% CI 0.02 1.74) was similar. Activated T lymphocytes, expressing surface IL-2 receptor, HLA DR, DR alpha 1, DP, DQ, and CD2>CD8>CD4 antigens, were seen throughout the dermis and occasionally infiltrating the suprabasal layer of the epidermis in all biopsies. CDI and HLA DR, DR alpha 1, DP, and DQ-expressing Langerhans cells were present throughout the epidermis and occasionally seen in the papillary dermis. HLA DR, DR alpha 1, DP, and DQ antigen expression were also seen on the surface of non-dendritic cells in the epidermis (probably either keratinocytes or T lymphocytes) and vascular endothelial cells in the papillary dermis. There were no significant qualitative or quantitative differences in the immuno-cytochemical nature of the localized immune reaction between LLAPTR and NRAPTR. These findings suggest that the pathomechanism of LLAPTR to nickel sulfate is unlikely to be explained simply on the basis of nickel concentration or the nature of the localized immune reaction at the patch test site.     

系统性红斑狼疮(SLE)与HLA抗原

SLE被认为是一种具有遗传倾向的自身免疫性疾病,作者利用微量淋巴细胞毒方法研究了22例系统性红斑狼疮与人类遗传学多态性标志HLA的相关,发现HLA—A_3、B_8、B_(35)、DR_2明显高于对照组,校正P值后,HLA—DR_2仍明显高于对照组,本文认为SLE患者与HLA—DR_2明显相关。     

Histocompatibility antigens in discoid and systemic lupus erythematosus

A Study of histocompatibility (HLA) antigens in 6₉ patients with discoid lupus erythematosus (DLE) showed an increased incidence of HLA-B7 and HLA-B8 related to the age at onset and sex of the patient. Young females and males aged 15–39 years at onset were associated with HLA-B₇and females aged over 40 years with HLA-B8. This supports previous studies concerning sex and age specific onset rates in DLE which suggested that there is more than one genotype in this disorder. Female patients with systemic lupus erythematosus (SLE) at all ages of onset showed a significant association with HLA-B8. Female patients, with onset 15–39 years, with either SLE or DLE which has transformed to SLE, show a significant increase in HLA-B8 compared with the females in the same age at onset group who have the discoid disease. The presence of HLA-B8 in a young female with DLE may represent a risk factor for the development of the systemic disease.     

HLA-A31 strongly associates with carbamazepine-induced adverse drug reactions but not with carbamazepine-induced lymphocyte proliferation in a Japanese population

Carbamazepine (CBZ) is the most frequent culprit drug for severe cutaneous adverse drug reactions (ADR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS). A strong association between human leukocyte antigen (HLA)-B*1502 and CBZ-induced SJS/TEN has been reported in Han Chinese, Thai, Malaysian and Indian populations, but not in Caucasian or Japanese populations. Recent studies showed an association between HLA-A*3101 and CBZ-induced ADR in Caucasian and Japanese populations. We conducted a case-control study to determine HLA genotyping of patients with CBZ-induced ADR in a Japanese population. Fifteen patients with CBZ-induced ADR and 33 subjects who had taken CBZ for more than 3 months without evidence of any ADR as a control were enrolled. In addition, the results of a CBZ-induced lymphocyte stimulation test were compared between the groups. A strong association was found between HLA-A31 and CBZ-induced ADR (P < 0.001), and a weak association was found between HLA-A11 and HLA-B51 with CBZ-induced ADR. No HLA-B*1502 was found in either patients or control subjects. The mean CBZ-induced lymphocyte stimulation index was significantly high in patients with CBZ-induced ADR compared with CBZ-tolerant patients (P < 0.001); however, no significant difference was seen between HLA-A31-positive subjects and HLA-A31-negative subjects in either group. These findings suggest that HLA-A31 is strongly associated with CBZ-induced ADR in the Japanese, but does not determine CBZ-induced lymphocyte proliferation.     

HLA antigens in allergic contact dermatitis.

The relationship between HLA factors and allergic contact dermatitis was examined in a series of 149 patients with unequivocal positive reactions to one or several allergens on epicutaneous testing. Nine statistically significant associations involving 6 different HLA antigens and 6 different allergens were found. Four allergens (chromium, formalin, balsam of Peru and wool alcohol) were positively associated with the B7 antigen. Furthermore chromium allergy was associated with A3, formalin allergy with A2 (negative association) and A9, nickel allergy with B8 and colophony allergy with B27. The B7 antigen and the combination A3+B7 showed significant regressions on number of allergies. The results fit the hypothesis that some HLA factors (like B7) may predispose for multiple contact allergy and others for allergen specific reactions.     

Lack of association between allergic contact dermatitis and HLA antigens of the A and B series

A previous study of patients with allergic contact dermatitis yielded results which supported the hypothesis that the presence of certain HLA antigens led to a predisposition to allergen-specific reactions and others to multiple contact sensitivity. The present study was performed to test this hypothesis. 129 patients sensitive to one allergen only (either chromium, nickel, formalin or balsam of Peru) and 83 patients sensitive to two or more allergens were HLA typed regarding the A and B loci. A series of 368 persons matched with regard to sex, age and place of residence were used as controls. A tendency towards an association between HLA B7 and contact allergy was observed. No other data confirming the hypothesis mentioned above were obtained. Among 37 patients who also had atopic diathesis a decreased frequency of HLA B7 was found.