Expression of TRAIL, DR4, and DR5 in kidney and serum from patients receiving renal transplantation.

Renal transplantation is the best treatment of some end-stage renal diseases. Unfortunately, not every transplant is successful due to the rejection or dysfunction of the transplanted kidney. Many cytokines participate in rejection by inducing inflammation or apoptosis. In this study, the expressions of TRAIL, DR4, and DR5 in rejected renal tissue and of serum soluble TRAIL (sTRAIL) in patients with kidney rejection were investigated by immunohistochemical staining and sandwich enzyme-linked immunosorbent assay, respectively. The results showed that the expression of TRAIL, DR4 and DR5, and serum sTRAIL levels were markedly upregulated among renal transplant patients. Since both membrane and soluble forms of TRAIL can induce apoptosis of DR4/DR5-expressing cells via recruiting FADD and caspase 8, elevated TRAIL and its receptors may participate in renal graft rejection.

Persistent polyclonal B-cell lymphocytosis: further evidence for a genetic disorder associated with B-cell abnormalities.

Persistent polyclonal B-cell lymphocytosis (PPBL) is an intriguing disorder diagnosed predominantly in women, usually cigarette smokers, characterized by an increase in the number of polyclonal B lymphocytes. Abnormality of the B-cell population is also evidenced by the presence of multiple bcl-2/Ig gene rearrangements and the finding of an additional long arm chromosome 3q+ (i3)(q10) within a significant proportion of B cells. The physiopathology of PPBL is unknown but its association with the HLA DR7 phenotype suggests a possible genetic disorder. To further determine whether PPBL has a genetic predisposition, we have undertaken an extensive study in a large family of a patient diagnosed with PPBL. Three individuals among the first-degree relatives presented all the criteria for a diagnosis of PPBL. A slight increase in serum IgM without evidence of B-cell proliferation was shown in two additional siblings. Multiple bcl-2/Ig gene rearrangements, a typical feature of PPBL, were identified in 8/10 individuals among first-degree relatives. A statistically significant association was found between the presence of these rearrangements and of a paternal HLA haplotype. We conclude that PPBL has a familial occurrence suggesting an underlying genetic defect. The development of the complete syndrome probably relies on unidentified additional co-factors.

Additive effect of Apo2L/TRAIL and Adeno-p53 in the induction of apoptosis in myeloma cell lines.

OBJECTIVE: We have previously shown that Adenovirus-p53 (Ad-p53) is a potent inducer of apoptosis in myeloma cells expressing nonfunctional p53 and low levels of bcl-2 and that Apo2L/TRAIL is a potent inducer of apoptosis, independent of bcl-2. A study was designed to test the synergy between Ad-p53 and Apo2L/TRAIL in the induction of apoptosis in relation to the expression of DR4/DR5 and DcR1, in cells undergoing Ad-p53-induced apoptosis. METHODS: Replication deficient Ad-p53 and human recombinant Apo2L/TRAIL were used. Myeloma cells with mutated/w.t. p53 and varying expression of bcl-2 were used to test the effect of Ad-p53, Apo2L/TRAIL, or both, on apoptosis, measured by annexin V. RESULTS: Treatment with Ad-p53 resulted in a dose-dependent apoptosis concomitant with a dose-dependent increase in the expression of DR4/DR5 and a decrease in the expression of DcR1, in Ad-p53-sensitive cell lines. In these cells, addition of Apo2L/TRAIL to cells treated with Ad-p53 resulted in a dose-dependent increase in apoptosis. Myeloma cells resistant to Ad-p53 had high levels of DR4/DR5 and high levels of DcR1 and treatment with Ad-p53 did not reduce the expression of DcR1. Also, addition of Apo2L/TRAIL to Ad-p53 did not affect the level of apoptosis beyond the level of apoptosis observed with Apo2L/TRAIL alone. CONCLUSIONS: 1) Cotreatment with Ad-p53 and Apo2L/TRAIL resulted in additive apoptosis in myeloma cells expressing nonfunctional p53 and low levels of bcl-2. 2) Resistance to Ad-p53 or to the combination of Ad-p53 and Apo2L/TRAIL was not due to the lack of adenovirus receptor (CAR) or low expression of DR4/DR5 but rather due to the relatively high expression of DcR1 receptor.

Familial Kaposi's sarcoma and Paget's disease of bone.

Familial Kaposi's sarcoma and familial Paget's disease of bone have not previously been reported to occur in the one patient or the one family. We report on an 82-year-old female of Lebanese descent who was recently diagnosed with Kaposi's sarcoma and Paget's disease. Of the patient's eight siblings, seven had Paget's disease and two of these also had Kaposi's sarcoma. Histocompatibility leucocyte antigen (HLA) class I and II typing of the patient showed: A2, A3; B35, Bx; Bw6; Cw4; DR beta 1*1101 (an HLA-DR5 subtype), DR beta 3 and DQ beta 1*0301. Previous reports have described possible associations of familial Kaposi's sarcoma with HLA-DR5 and Paget's disease with DR2. DR beta 1*1104, DP beta 1*04 and DQw1. Genetic factors and possible viral aetiologies for each condition are reviewed.

Clinical hepatitis after transplantation of hepatitis C virus-positive kidneys: HLA-DR3 as a risk factor for the development of posttransplant hepatitis.

BACKGROUND: Exposure to hepatitis C virus (HCV) and subsequent infection after renal transplantation lead to significant clinical hepatitis in approximately 50% of graft recipients. METHODS: One hundred thirty-two consecutive renal allotransplant patients, who underwent transplantation of kidneys from HCV-positive cadaveric donors, were studied to investigate the relationship between donor and recipient HLA type and the risk of developing clinical hepatitis. Specific attention was directed toward the DR3 and DR4 alleles, as these had previously been associated with worse prognoses in autoimmune and viral hepatitis. RESULTS: Overall, 42% of patients receiving kidneys from donors seropositive for HCV developed clinical hepatitis. This was unrelated to preoperative recipient HCV serum reactivity (P=0.65). Patients receiving kidneys from seropositive donors with HCV RNA as detected by PCR were more likely to develop hepatitis than those receiving kidneys from PCR-negative donors (56% vs. 11%; P=0.005). The presence of the DR3 allele was associated with a significant risk of clinical hepatitis (P=0.025); 80% of DR3-positive recipients (n=34) progressed to hepatitis compared with 42% of DR3-negative patients. No other recipient HLA type was significantly related to prognosis. All patients receiving a donated kidney that expressed the B41 allele developed hepatitis, compared with 55% of recipients of non-B41 grafts (P=0.039). No association between the development of clinical hepatitis and HLA compatibility was found. CONCLUSIONS: These results suggest that both HLA type and viral presence as assayed by polymerase chain reaction, influence the risk of disease progression after transplantation of HCV-positive kidneys. Application of these associations may decrease the relative risk of a recipient contracting HCV hepatitis after cadaveric renal transplantation.

[Is mixed connective tissue disease a distinct rheumatic disease].

Mixed connective tissue disease (MCTD) as a distinct clinical entity is still controversial. To address the issue, the authors observed the evolution of 50 patients diagnosed as MCTD at our clinic, evaluated the reliability of three different diagnostic criteria proposed by Sharp, Alarcon-Segovia and Kasukawa respectively and performed HLA-A, -B and -DR antigen typing in 38 of the patients. The results showed that: (1) 13 (26.9%) of the 50 MCTD patients subsequently developed other connective tissue disease (OCTD) including 7 systemic lupus erythematosus (SLE), and 6 progressive systemic scleroderma (PSS). (2) among 23 of the MCTD patients fulfilling Sharp's criteria, 1 (4.3%) developed PSS, but among 23 of the patients fulfilling Kasukawa's, not Sharp's, 7 (30.4%) developed OCTD and among 27 of the patients fulfilling Alarcon-Segovia's, not Sharp's, 12 (44.4%) developed OCTD. (3) in the frequencies of DR, and DR5, there were significant differences between patients fulfilling Sharp's (60.9%, 56.5%) and the normal controls (24.3%, P < 0.005, RR = 4.7 and 21.4%, P < 0.005, RR = 4.6%), but no significant differences between the patients not fulfilling Sharp's and normal controls (P > 0.05). We concluded that: (1) MCTD is a distinct rheumatic disease. (2) Sharp's criteria is the most reliable for diagnosis of MCTD.

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.

Update on lymphoid interstitial pneumonitis.

Lymphoid interstitial pneumonitis (LIP) involves a clinicopathologic pattern of pulmonary disease characterized by diffuse interstitial reactive lymphoid infiltrates. In adults, it occurs most commonly in autoimmune diseases, such as Sjögren's syndrome (0.9% of these patients) and primary biliary cirrhosis, whereas in children it is usually seen in HIV infection. Dysproteinemias (hyper- and hypogammaglobulinemia) are found in more than 60% of patients. Children can show CD8-lymphocytosis in bronchoalveolar lavage fluid, lung tissue, peripheral blood, and salivary gland, associated with HLA-DR5 haplotype. Radiographically, most patients with LIP have reticulonodular infiltrates, with or without patchy areas of consolidation. CT scans can show both small nodular and ground glass patterns, patterns that are diagnostically nonspecific. Reduced lung volumes and diffusing capacities are consistent and sensitive indicators of disease in LIP. In an experimental model, diffusing capacity was the single most sensitive functional index of disease progression. Microscopically, LIP is part of a spectrum of pulmonary lymphoid proliferations, ranging from follicular bronchitis-bronchiolitis and pulmonary lymphoid hyperplasia (the latter in AIDS patients), proliferations largely limited to airways, to low-grade malignant lymphoma. These patterns may be difficult to differentiate from each other. It appears that LIP sometimes evolves to lymphoma; the frequency of this evolution is probably low but is difficult to assess because low-grade lymphomas may mimic LIP. A relatively high frequency of LIP patients have Epstein-Barr virus DNA in their lungs but not all patients with LIP show this finding, suggesting other possible etiologies.

HLA in familial and nonfamilial Mediterranean Kaposi's sarcoma in Greece.

Fifty-four (54) unrelated patients with Mediterranean Kaposi's sarcoma (MKS) and 8 patients members of 4 unrelated families with familial MKS were serotyped for HLA-A,B and DR antigens. The diagnosis was histologically confirmed and all patients were negative for anti-HIV antibodies. An increased frequency of HLA-B18 (44.4% vs 14.2% in the controls, p < 0.001, RR = 4.8) and HLA-DR5 (57.6% vs 37.2% in the controls, p < 0.025, RR = 2.29) was observed in the group of patients with MKS. Seven (7) of the 8 family members with FMKS possessed HLA-DR5, and the affected members in the 3 families shared a common haplotype which included HLA-DR5. These findings support the hypothesis that genetic factors linked to HLA-DR5 antigen may contribute to the pathogenesis of MKS.

[Clinical and immunogenetic aspects of children with local and multiple forms of primary tuberculosis]. / Klinicheskaia i immunogeneticheskaia kharakteristika detei s lokal'nymi i mnozhestvennymi formami pervichnogo tuberkuleza.

Immunogenetic examination of 146 preschool children with local and multiple tuberculous lesions and 148 controls found out the key role of unfavourable premorbid background (low-quality BCG vaccine, family contacts, associated diseases) in the disease onset. General trends in systemic immunity shifts are characterized. These depend on the age, inflammation phase, severity of clinical symptoms. Representation of antigens HLA DR2, DR5, Cw2, Cw4 indicates that a child has a 5-9 times greater risk to develop tuberculosis. These data should be allowed for in forming groups of higher risk among children.

Association of HLA-DR5 (DR11) with systemic sclerosis (scleroderma) in Mexican patients.

OBJECTIVE: To study the association between Major Histocompatibility Complex (MHC) haplotypes and systemic sclerosis (SSc) in Mexican mestizo patients. METHODS: Class I, II and III MHC antigens were determined in 41 Mexican mestizo patients with SSc, 113 of their first degree relatives, and 85 ethnically matched controls. The significance of differences between patients and controls was tested by chi-square analysis with Yates' correction. RESULTS: Frequencies of HLA-DR5 and HLA-DRw52 were found to be higher in SSc patients compared to ethnically matched healthy controls (p = 0.007, RR = 3.31; 95% confidence interval: 1.3-8.3 and p = 0.04, RR = 2.4; 95% confidence interval: 1.0-5.7, respectively). Sequence-specific oligotyping in DR5 positive individuals showed that 10 out of 41 patients had the DRB1*1104 subtype (24.3%) as compared to only 6 of the 85 healthy controls (7.0%) (p = 0.01, RR = 4.25). Subdividing patients according to their clinical features showed a significant increase of HLA-DR5 in diffuse (p = 0.013, RR = 3.89, 95% confidence interval: 1.27-12.0) and limited scleroderma (p = 0.0008), but not in the CREST syndrome. Segregation analysis obtained from the families showed that in the patients, DR5 was mostly part of the [HLAB35;DR5] haplotype as opposed to healthy controls. CONCLUSION: These data support the role of DR5 (DRB1*1104) in the genetic susceptibility to develop scleroderma in Mexican patients and also sustain the notion of genetically determined clinical subgroups of SSc.

HLA associations in end-stage renal disease due to membranous glomerulonephritis: HLA-DR3 associations with progressive renal injury. Southeastern Organ Procurement Foundation.

Membranous glomerulonephritis (MGN) is the most common cause of idiopathic glomerulonephritis in American adults. African-Americans develop end-stage renal disease (ESRD) due to chronic glomerulonephritis four times more often than whites. To determine whether HLA phenotype associations existed in the subset of MGN patients with ESRD we analyzed HLA frequencies, by race, in patients with MGN entered in the Southeastern Organ Procurement Foundation registry between 1982 and 1992. HLA frequencies from 250 renal transplant patients with MGN (190 whites and 60 African-Americans) were compared with 4,506 race-matched cadaveric kidney donor controls (4,039 whites and 467 African-Americans). Race-specific odds ratios (ORs) were calculated and fitted into a log-linear model to determine associations between MGN and HLA frequencies. The reported values were considered significant (P < 0.05) after Bonferroni correction for multiple comparisons. HLA-DR3 and HLA-DR5 frequencies were increased in cases of both races compared with race-matched controls (race-combined ORs, 2.22 and 1.61, respectively; all P < 0.02). Interracial analyses revealed that HLA-DR7 frequency was decreased solely in whites with MGN (OR, 0.53; P < 0.04). The results of this study indicate that HLA-DR3 and HLA-DR5 are positively associated with ESRD due to MGN in patients of both races and that HLA-DR7 is negatively associated with MGN in whites. These analyses confirm the published reports of HLA-DR3 association with MGN in Chinese, French, British, Chilean, and American white populations. The novel association of HLA-DR5 may reflect the fact that the MGN cases in this study all had ESRD.(ABSTRACT TRUNCATED AT 250 WORDS)

Association of HLA-DR5 with mucocutaneous lesions in patients with rheumatoid arthritis receiving gold sodium thiomalate.

OBJECTIVE: To investigate the possible association between HLA antigens and adverse reactions to gold sodium thiomalate therapy (GSTM). METHODS: Ninety consecutive patients with rheumatoid arthritis (RA) were studied for possible association between HLA antigens and adverse reactions to GSTM therapy. RESULTS: HLA-DR5 was significantly increased in patients who developed gold induced mucocutaneous lesions. On the other hand, patients with RA carrying B8 and DR3 antigens are of a high risk of developing proteinuria after gold therapy. A very interesting finding was the low incidence of DR7 antigen in patients who developed adverse reactions to GSTM. We also report the relationship between B27 antigen and chrysiasis due to gold therapy. CONCLUSION: Our results support suggestions that the DR7 antigen provides a protective effect against gold toxicity. We also found a strong association between DR5 and mucocutaneous lesions in patients with RA treated with GSTM.

Serologic HLA typing in cryptogenic Lennox-Gastaut syndrome.

Serologic HLA typing was performed on 12 patients with cryptogenic Lennox-Gastaut syndrome and compared to a normal control group of 1661 Caucasians. In the Lennox-Gastaut group we found a significant increase in the frequency of DR5 antigen (55%, chi 2 = 5.6), and an indication of a decrease in the frequency of DR4 antigen (0%, chi 2 = 3.0) as compared with controls (20% and 28%, respectively). No significant differences existed in the frequencies of HLA-A, B, and C antigens between the Lennox-Gastaut group and the controls. These findings contribute to the hypothesis that immunogenetic mechanisms may play a role in triggering or maintaining cryptogenic Lennox-Gastaut syndrome.

[Ecological immunodeficiency: immunogenetic aspects of its etiology and correction]. / Ekologicheskii immunodefitsit: immunogeneticheskie aspekty ego razvitiia i korektsii.

The examinations of auto-transport Kazakh drivers have indicated that there is a significant reduction in some immunological parameters HLA-B5 and HLA-DR5-proliferative responses of lymphocytes to mitogens, production of interleukin-1 and interleukin-2, activity of NK and LAK-cells. It is suggested that these impairments occur with their long-term exposure to automobile transport effluents (ATE), since the same changes in immunological parameters were found previously in the experiments with animals exposed to ATE for a long time. Some of the detected immunoresponsive disorders are associated with the availability of definite HLA antigens, such as HLA-B5 and HLA-P5. The new immunomodulating agents thymohexin (TH) and phyto-extraction drugs C4 and C6 used in vitro substantially restored the lower functional activity of immunocompetent cells and production of cytokines (thymohexin was particularly effective). The most marked recovery was observed in the drivers with the phenotype HLA-B6+ and HLA-P5+, i.e. in persons with maximally ATE-reduced immunological parameters.

HLADR5 and C4BQO high frequency and antinuclear antibodies positivity in patients with 21 hydroxylase deficiency from Campania region.

HLA haplotypes, complement C4 factor and factor B immunochemical concentrations and autoantibodies titer have been studied in six patients with mild congenital adrenal hyperplasia (MC-AH), in two patients with classical congenital adrenal hyperplasia (CCAH) and in their parents. A high frequency of DR5 and C4BQO alleles have been found in MCAH patients. Moreover, C4BQO allele is carried out in three out of four cases associated with DR5. In the two CCAH patients we found a B51 and a B14 allele, the last one usually described in the non classical form of the disease in population of different ethnic origin. Signs of autoimmunity in some patients and parents have been found. C4 null alleles were several-fold more frequent among our patients with respect to the same ethnic control group and the autoantibody positivity could be the result of an altered immune regulation. The presence of a positive correlation between cortisol basal levels and C4 and Bf concentrations in the six MC-AH patients suggests an interrelationship between hormonal factors and immunological findings in this disease. Our finding about HLA antigens not previously described in this syndrome may stimulate more profound studies by genomic and cDNA probes.

Idiopathic dilated cardiomyopathy: lack of association between circulating organ-specific cardiac antibodies and HLA-DR antigens.

Organ-specific cardiac antibodies are serological markers of autoimmunity in dilated cardiomyopathy (DCM). HLA-DR4 and possibly DR5 are immunogenetic markers of susceptibility in DCM, but it is not known whether they are associated with autoantibody production. We studied the frequency of HLA-DR antigens and the presence of organ-specific cardiac antibodies in 80 DCM Caucasian patients from Northern Italy. HLA-DR typing was performed by serology; 289 healthy blood donors from the same region were tested as controls. HLA-DR frequencies in DCM were also compared with VIII International Workshop control data for Italy. Cardiac antibodies were detected by indirect immunofluorescence on human heart. Skeletal muscle was used to identify cross-reacting antibodies. The prevalence of cardiac antibodies in DCM was: organ-specific 34% and skeletal muscle cross-reactive 30%. The previously reported positive association between DCM and HLA-DR4 was confirmed using either the controls from the same region (21.25% vs 10.73% p = 0.02, relative risk = 2.30) or from all of Italy (21.25% vs 12.3%, p = 0.03). HLA-DR5 frequency was slightly but not significantly higher in DCM than in controls from the same region (46.25% vs 31.49% p = 0.02, relative risk of 1.87, p corrected = NS) or from all of Italy (46.25% vs 35.8% p = NS). HLA-DR3 frequency was lower in DCM than in controls from the same region (12.50% vs 29.41% p = 0.003, relative risk of 0.36, p corrected = 0.03). This negative association was not confirmed using the control data from the whole of Italy (12.50% vs 16.5% p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

HLA-DR antigens in children with mumps meningitis.

The frequency of HLA-DR antigens was studied in 54 patients with mumps meningitis, and in two control groups. The first control group comprised 333 randomly chosen subjects while the second group was composed of 46 subjects who have passed mumps without meningitis. The DR5 antigen was more frequent in patients than in the second control group with relative risk of 2.4 and significance at the level of p < 0.05. The p value became insignificant after the correction for the number of antigens investigated.