Association of fatal aneurysmal subarachnoid hemorrhage with human leukocyte antigens in the Finnish population.

Human leukocyte antigens (HLA) have been reported to associate with the risk of aneurysmal subarachnoid hemorrhage (SAH) and poor outcome after SAH. Our aim was to identify HLA antigens that associate with the risk of fatal SAH in the Finnish population. Medical records of 600 cadaveric organ donors were reviewed to find organ donors that succumbed to SAH (n = 232) or brain trauma (n = 151). HLA antigen frequencies in these groups were compared with HLA frequencies in a reference population of 10,000 bone marrow donors. Chi-Square test with Bonferroni correction and multiplicative logistic regression models were used and false positive result probabilities (FPRP) were calculated. Alpha-level was 0.01. HLA-A3 associated with fatal SAH (p = 0.0014, OR 1.3 and 95%CI 1.1-1.6) and HLA-DR7 inversely associated with fatal SAH (p = 0.0040, OR 0.3 and 95%CI 0.2-0.6). HLA-A3 but not HLA-DR7 showed also a positive trend in donors with brain trauma. FPRP was below 0.5 for HLA-A3, but clearly above 0.5 for HLA-DR7. HLA-A3 seems to associate with fatal SAH in the Finnish population. Further studies are needed to reveal the pathobiologic mechanisms for how HLA-A3 associates with the risk of fatal SAH in Finns.

Relation between HLA antigens and skin cancer in renal transplant recipients in Queensland, Australia.

On the basis of previous studies that showed a negative association between HLA-A11 and skin cancer in renal transplant recipients and a positive association with HLA-B27 and HLA-DR7, we performed a study in Queensland with 1098 recipients to address the question of whether the same associations could be found. The influence of HLA mismatching and HLA homozygosity on the risk of skin cancer was also studied. In contrast to earlier studies, HLA-A11 was associated with an increased risk of skin cancer. On the other hand, we confirmed that the HLA-B27 antigen was associated with the development of skin cancer, but only when the development of basal cell carcinomas alone was considered, and we confirmed that there is a weak but not statistically significant association with HLA-DR7. No association between HLA mismatching or HLA homozygosity and the development of skin cancer was observed. Environmental factors such as different levels of exposure to sunlight and infection with human papillomaviruses are factors that are most likely to be involved. We hypothesize that human papillomavirus-induced antigens prevail in the skin cancers in the recipients living in the Netherlands, whereas antigens induced by solar radiation, the so-called "photo-antigens," may be more common in the skin cancers of the recipients living in Queensland. Exposure to sunlight can also induce immunologic unresponsiveness, and excessive exposure to sunlight in Australia may, therefore, simply override the risk factors that are important in countries with a more temperate climate.

All patients with persistent polyclonal B cell lymphocytosis present Bcl-2/Ig gene rearrangements.

The bcl-2 gene belongs to a class of oncogenes involved in the inhibition of apoptosis. Most follicular lymphomas are associated with the t(14;18) translocation that juxtaposes the bcl-2 gene located on chromosome 18 to the immunoglobulin gene locus located on chromosome 14. Consequently, the bcl-2 gene is overly expressed and leads to an accumulation of mature clonal B cells. Prolonged survival of the B cell clone appears to be the early event in tumorigenesis, creating an increased risk of cumulative mutations. Interestingly, bcl-2/Ig gene rearrangements may be identified in nearly 50% of normal individuals but the outcome of normal individuals carrying high levels of t(14;18) is not well defined. Persistent polyclonal B cell lymphocytosis (PPBL) is a unique polyclonal lymphoproliferative disorder mostly restricted to women. We have recently demonstrated that PPBL is also associated with multiple bcl-2/Ig gene rearrangements. In this report, we have extended our analysis to additional patients and demonstrated that all patients presented multiple detectable t(14;18) translocated clones. In addition, Bcl-2 protein expression was increased. Our findings, along with the clinical features of PPBL, make this disorder an exceptional model for the study of B-cell homeostasis.

Anticardiolipin antibodies in a patient with Crohn's disease and thrombosis.

Thrombosis is an uncommon though well recognized complication of inflammatory bowel disease, for which various coagulation alterations have been described as possible causes. Antiphospholipid syndrome (APS) is defined as the association of thrombosis, fetal loss and thrombocytopenia with anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LA). We describe a case of a 21-year-old female with recurrent thrombosis associated with aCL who went on to develop Crohn's disease. Tissue typing done in this patient revealed the presence of the HLA-DR7, DRw53, which previous studies have shown to be found in increased frequencies in APS patients. To our knowledge, this is the first report of an association between these two clinical conditions and, in this particular case, aCL may be implicated in the thrombotic events.

HLA antigens in alkaptonuric patients.

BACKGROUND: In alkaptonuric patients a disabling ochronotic arthropathy develops, due to the deposit of a pigmented polymer of homogentisic acid. Since in inherited diseases the clinical expressions may be multifactorial, involving genetic and environmental factors, where the HLA system may play a role, we studied HLA antigens in ochronotic patients. METHODS: The study was carried out in 21 members of three families of six ochronotic patients and in two isolated ochronotic patients. The HLA typing has been done testing for antigens from loci A, B and C, by international standard microlymphocytotoxicity method, and for loci DR and DQ, by fluorescence method on immunologically isolated cells by means of antibody-coated microspheres. The chi square test was used for statistical analysis, with Yates correction due to the low number of observations. RESULTS: Despite the limited number of subjects, due to the rarity of the disease, a significantly higher prevalence of HLA-DR7 antigen was found in the alkaptonuric patients when compared to a general population (p<0.02), suggesting a possible association, while the prevalence of HLA A, B, C and DQ showed no significant differences. CONCLUSIONS: It might play a role in the pathophysiology and in the clinical expression of the disease.

Dental enamel defects in celiac patients.

OBJECTIVE: The incidence and distribution of enamel defects among patients with celiac disease were examined. STUDY DESIGN: The oral cavity was explored in 137 patients with celiac disease (mean age 16.2 years; age range 5 to 68 years) and in 52 control patients (mean age 19.8 years; age range 5 to 64 years). Permanent dentition enamel defects were recorded, along with their number and locations. The decayed, missing, and filled teeth index rates were also established, and an investigation was made of the human leukocyte antigens among the patients with celiac disease. The results obtained were analyzed with the chi-squared test, statistical significance being regarded for p < or = 0.05. RESULTS: Enamel defects were observed in 72 (52.5%) of the patients with celiac disease (52 patients had systematic defects) and in 22 (42.3%) of the control patients (9 patients had systematic defects). Systematic defects were significantly more common in the celiac disease group. In the patients with celiac disease, 72.2% were symmetrical, compared with 40.9% of the defects in the control patients. The incisors were the most frequently affected teeth, the extent of involvement being significantly greater in the celiac disease group. In patients with celiac disease, DR7, DR3, and DQ2 were the most commonly observed human leukocyte antigens. The mean decayed, missing, and filled teeth index rates were 4.8 and 6.2 in the celiac disease group and the control group, respectively. CONCLUSIONS: Enamel defects are common among patients with celiac disease. They tend to be bilateral and symmetrical, and they are chronologically distributed. The lesions affect mainly the incisors and the molars. Patients with such characteristics should be evaluated for possible celiac disease.

Strong association of antiepithelial cell antibodies with HLA-DR3 or DR7 phenotype in patients with recurrent oral ulcers.

BACKGROUND: Previous studies showed that antiepithelial cell antibodies (anti-ECA) were present in 71% (15/21) of patients with recurrent oral ulcers (ROU) and that there was a strong association of human leukocyte antigen (HLA)-DRw9 with ROU in Chinese patients. In this study, we assessed anti-ECA in a larger group of Chinese patients with ROU (n = 88) in order to further investigate the association of anti-ECA with HLA-DR and -DQ antigens. METHODS: The anti-ECA in the sera of ROU patients were detected by an indirect immunofluorescence technique with rat esophagus as the substrate, and the HLA-DR and -DQ antigens in ROU patients were typed by a standard microcytotoxicity assay using Terasaki's oriental tray. RESULTS: The rate of anti-ECA positivity was significantly higher (p < 0.0001) in ROU patients (68%) than in healthy control subjects (0%). Furthermore, the rate of anti-ECA positivity in patients with major or minor oral ulcers (72%) was significantly higher (29%) than that in patients with herpetiform ulcers (p < 0.05). There was a significant increase in the frequency of DR3 or DR7 antigen expression (p < 0.0001, pc [p corrected] < 0.001, relative risk [RR] = 4.3, etiologic fraction = 0.41) in anti-ECA-positive ROU patients compared with the corresponding frequencies in healthy control subjects. There was also a significant increase in the frequency of DR7 or DRw9 antigen expression (p < 0.005, pc < 0.05, RR = 4.7, etiologic fraction = 0.45) compared to healthy controls. CONCLUSIONS: Because only DR3 or DR7 antigen occurred more frequently in anti-ECA-positive than in anti-ECA-negative ROU patients (p < 0.0007, pc < 0.05, RR = 19.6, etiologic fraction = 0.51), we concluded that the gene coding for DR3 or DR7 antigen may contribute to the presence of anti-ECA in Chinese patients with ROU.

[HLA DR7 as a protective factor against gold salt toxicity in rheumatoid arthritis]. / HLA DR7 como factor de protección frente a la toxicidad por sales de oro en la artritis reumatoide.

We performed a study of antigens HLA type I and II (specificity DR) in 90 patients with diagnosis of Rheumatoid Arthritis (RA) treated with Sodium Aurothiomalate (SATM) in order to detect the presence of an antigen HLA which could act as a protective factor against toxicity by SATM. Our results demonstrated a decrease in the frequency of the antigen DR7 in patients with toxicity by SATM, which suggests a protective factor of this antigen against the development of toxic reactions due to gold salts.

[Class II human leukocyte antigens in minimal change nephrotic syndrome and focal segmental glomerulosclerosis--preliminary study]. / Antygen zgodnosci tkankowej klasy II w submikroskopowym klebuszkowym zapaleniu nerek oraz w ogniskowym segmentalnym szkliwieniu klebuszków--doniesienie wstepne.

The aim of research was to compare the frequencies of HLA class-II antigens between children with minimal change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS). The two morphological courses of glomerulosclerosis were considered: FSGS as a progressive state of minimal lesions (shown by renal rebiopsy results in a given patient), and primary (idiopathic) FSGS. The study group consisted of 38 children observed at least for four years. 15 patients were diagnosed as MCNS, 17 children had minimal lesions shown in the initial biopsy findings, but later progressed to glomerulosclerosis and 6 children had idiopathic FSGS. The control group consisted of 51 healthy unrelated individuals. HLA class II antigens were typed with the microlymphocytotoxicity test and with the method of sequence specific oligonucleotide DNA probes hybridisation (PCR-SSO). In minimal change nephrotic syndrome and glomerulosclerosis which followed the formerly found minimal lesions, the significant associations with HLA-DR3, DR7, and HLA-DQ2 were found. HLA-DQ1 was significantly rare in these groups. Differently idiopathic focal segmental glomerulosclerosis associates with the presence of HLA-DR4.

CD8dim and NKG2D expression defines related subsets of CD4+ T cells in HIV-infected patients with worse prognostic factors.

CD4 T lymphocytes expressing CD8dim (DP: CD4 CD8dim) or NKG2D represent cytotoxic effector populations, which have been involved in viral infections and chronic diseases. The frequency of DP cells was analyzed by flow cytometry in 300 consecutive HIV-infected patients and 50 healthy controls. NKG2D expression and memory/effector markers in CD4 T cells were also studied, in addition to virologic and genetic factors involved in DP T-cell expansion. HIV-infected patients showed a significantly higher frequency of DP cells than controls, mainly in patients with advanced disease. Expansion of DP cells was related to NKG2D appearance in CD4 T cells and was predicted by CD4 CD28null T-cell levels. Cells expressing CD8dim and NKG2D cells are closely related populations with a similar pattern of surface markers, perforin expression, and responses to activation. We also found that these subsets seem to share an ontogenic relationship and TcR oligoclonality. In this way, cytomegalovirus infection and certain HLA alleles, such as DR7, conditioned the expansion of DP cells. Their common ontogenic origin and oligoclonality, possibly due to repeated encounters with the same antigen, could result in a limitation of the repertoire of responder cells and in a worse prognosis of HIV infection.

HLA Bw57 and DR7 association with psoriasis vulgaris in south India.

Eighty-three south Indian patients with psoriasis vulgaris were studied for HLA antigen frequencies and compared with 77 controls studied simultaneously. HLA Bw57, a split of B17 was found elevated in the patients. The two sexes differed in their age-at-onset curves: females had a preponderance to early onset of the disease, while the males had late onset. Among these patients, major group 3, a Western Brachycephal Armenoid group, revealed the highest risk for B17 & Bw57 but not major group 2, a Mediterranean one.

Unfavorable response to cyclophosphamide in steroid-dependent nephrotic syndrome.

Development of steroid dependency represents a significant therapeutic challenge in steroid-sensitive nephrotic syndrome. Previous studies have shown conflicting results concerning the benefit of a 12-week treatment with cyclophosphamide (CPO), with 24%-67% of patients achieving long-term remission. We therefore analyzed the clinical response of 20 consecutive children with steroid-dependent nephrotic syndrome (SDNS) (12 male, median age at start of treatment 5.9 years, range 3.2-14.7 years) treated at our institution with CPO (2 mg/kg per day) for 12 weeks since 1989. Median duration of follow-up was 5.8 (range 1.1-9.25) years. Only 6 of 20 children (30%) showed a long-term remission of >2 years, while 14 of 20 (70%) developed relapses again. Of these, 12 patients (86%) again developed steroid dependency, requiring further alternative treatment. Our data show that a 12-week course of CPO leads to unfavorable results in the majority of patients with SDNS. We therefore conclude that there is a need for further optimization of therapy in SDNS.

Destructive arthritis, rheumatoid factor, and HLA-DR4. Susceptibility versus severity, a case-control study.

In response to the continuing debate as to whether seronegative rheumatoid arthritis (RA) and seropositive RA are part of the same disease spectrum or are distinct disorders, we evaluated 720 patients with definite and classic RA, of whom 53 subjects had definite persistently seronegative destructive disease. For all but 1 seronegative RA patient, a seropositive RA case control was identified and matched for age, disease duration, degree of destruction on hand radiographs, and disease-modifying drug therapy. DR typing was undertaken on these 105 patients, together with scoring of hand radiographs. The frequency of DR4 was 69% in seropositive RA patients and 60% in seronegative RA patients (P = 0.22), versus 36% in 318 healthy controls (P = 0.008 and P = 0.007 versus seropositive and seronegative RA, respectively). Patients were matched and rematched with different controls in a series of subanalyses in order to make comparisons of hand radiograph scores. We found that HLA-DR4 was associated with destructive RA in both seropositive and seronegative RA patients. In general, DR4+ patients had more severe disease by radiologic criteria than did DR4- patients. Thus, HLA-DR4 may be an additive factor to the serologic status and may be more closely related to disease severity than to disease susceptibility.

Specificity and T cell receptor beta chain usage of a human collagen type II-reactive T cell clone derived from a healthy individual.

Collagen type II (CII) is a cartilage-specific matrix compound well known as an inducer of an experimental, T cell-dependent autoimmune arthritis, a disease which shows some similarities to human rheumatoid arthritis. Here we report on an HLA-DR7-restricted human CD4 T cell clone (TC9), which was isolated from a healthy donor and recognizes human CII. After screening CNBr fragments of CII and tryptic fragments derived thereof, the T cell epitope could be mapped to amino acid residues 271-285 of the triple helical region of CII that are located within CNBr fragment 11 [alpha 1 (II) CB11]. This epitope was confirmed by a synthetic peptide stimulatory for TC9. The T cell receptor beta chain of TC9 was cloned using the polymerase chain reaction; it comprises V beta 6.7 and contains besides J beta 2.3 and C beta 2 an as yet undescribed sequence for the D segment.

Skin cancers and HLA frequencies in renal transplant recipients.

An association between HLA DR7 and the development of multiple non-melanoma skin cancer was detected in immunosuppressed patients in southern Australia. The relative risk was 2.6 which was lower than for immunocompetent patients with the same skin cancers. HLA frequencies of renal transplant recipients with multiple skin cancers were determined. The types HLA B27 and HLA Dr7 were found in significantly higher frequency, and there was no absence of HLA A11.

HLA association of anti-IgA antibody production.

We have HLA typed 46 unrelated IgA deficient blood donors in our region. A weak association to DR3 (RR = 2.07) was observed. However, owing to the heterogeneous nature of this group, we found DR7 may be associated with those who developed class-specific anti-IgA antibodies (RR = 2.94), whereas DR1 may be associated with those who did not (RR = 2.42).

An association between mesial temporal lobe epilepsy with hippocampal sclerosis and human leukocyte antigens.

PURPOSE: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is one of the medically intractable epilepsies that may be remediable with surgery. Although the pathogenesis of HS still remains obscure, genetics may play a role as a predisposing factor, with the genetically controlled immune system as one of its aspects. Our aim in this study was to investigate whether there is any association between human leukocyte antigens (HLAs) that are related to chromosome 6 and this specific type of epilepsy. METHODS: HLA class I and II typing were performed with the microlymphocytotoxicity method on 65 Turkish patients with MTLE-HS and on 184 healthy controls. RESULTS: Our study revealed a significantly high frequency of class II antigens HLA-DQ2, -DR4, and -DR7 alleles and the combination of HLA-DR4-DQ2, and DR7-DQ2 alleles. CONCLUSIONS: The HLA alleles that occur with increased frequency in many HLA- associated conditions appear to serve as risk factors that increase susceptibility but are not essential for disease expression. Our data support the role of genetic factors in the development of HS, possibly related to early childhood events that may act as a trigger factor to initiate the cascade in genetically prone patients with specific HLA types to give rise to MTLE eventually.