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E J Yunis

Publications and source records attributed to E J Yunis.

At least 19 recordsLinked to original sources
PubMed1992

DNA content and other prognostic features in childhood medulloblastoma. Proposal of a scoring system.

The authors reviewed clinical features, surgical extent of resection, histologic parameters, and DNA content in 55 children with medulloblastomas and found that complete or near total resection, absence of tumor dissemination, tumor DNA aneuploidy, and low proliferative index correlated with a favorable clinical outcome. A scoring system was developed based upon these features to identify patients who, in the future, may benefit from more aggressive or novel therapeutic regimens. Patient age and sex and adjuvant chemotherapy did not significantly correlate with long-term survival. The data also suggest that tumors that have been designated as cerebellar neuroblastomas may be a distinct group of posterior fossa tumors, which may have a better prognosis.

Adolescent↗
PubMed1992

The immune response to hepatitis B vaccine in humans: inheritance patterns in families.

We have recently shown that the human antibody response to the hepatitis B virus surface antigen (HBsAg) vaccine is major histocompatibility complex (MHC) associated. In studies of nonresponders to the vaccine, we found an increased incidence of individuals homozygous for human histocompatibility leukocyte antigen (HLA) proteins associated with the extended (conserved) haplotype [HLA-B8,SC01,DR3]. In later prospective vaccination trials, we showed that none of five individuals homozygous for this haplotype developed more than 1,300 radioimmunoassay (RIA) units of antibody (mean, 467 RIA units), while all heterozygotes made at least 2,500 RIA units (mean antibody level, 15,608 units). Our results suggested that [HLA-B8,SC01,DR3] lacks an immune response gene for HBsAg, and that response is inherited in a dominant fashion. To provide further evidence for this hypothesis, we have now analyzed the results of HBsAg immunization in families. 43 members of 10 families were immunized with the hepatitis B vaccine, including seven families where at least one member bore the haplotype [HLA-B8,SC01,DR3], and three families where one member had already received, but failed to respond to, the vaccine. In two of these three families, the presence of [HLA-B8,SC01,DR3] was subsequently found. Of nine MHC-identical sibling pairs in the study, both members of eight pairs had similar antibody responses (five nonresponder and three responder pairs). In all families with such sibling pairs, including the discordant pair, rank-ordering members by antibody level demonstrated that no relative's value came between the sibling pair values. Furthermore, of nine [HLA-B8,SC01,DR3]-haplotype-homozygous individuals, six were nonresponders, and two others had only low-normal responses. [HLA-B8,SC01,DR3]-heterozygous family members always had higher levels of antibody than their homozygous relatives. Linkage analysis of nonresponse to HLA haplotypes revealed a maximum likelihood LOD (logarithm of the odds) score of 6.3 at a recombination fraction of 0.1. The MHC association with lack of antibody response to HBsAg was not seen with tetanus immunization, where 1 of 20 HBsAg responders and 1 of 21 poor or nonresponders had tetanus titers of less than 1:512; both tetanus nonresponders were [HLA-B8,SC01,DR3] heterozygotes. Our results indicate that: (a) response to the HBsAg vaccine is MHC linked, and inherited in a dominant fashion; (b) an abnormal or missing immune response (Ir) gene for HBsAg is a characteristic of most examples of the extended haplotype [HLA-B8,SC01,DR3]; and (c) other haplotypes also have abnormal or missing Ir genes for HBsAg.

Female↗
PubMed1992

HLA-DR2, [HLA-B7, SC31, DR2], and [HLA-B8, SC01, DR3] haplotypes distinguish subjects with asthma from those with rhinitis only in ragweed pollen allergy.

MHC haplotypes were determined for 52 patients with ragweed pollen allergy, with and without asthma, and 27 non-atopic controls. Total IgE levels were unimodally distributed in all study groups and were higher in atopic patients in general compared with non-atopics. There was no difference in total IgE levels in patients with rhinitis only compared with those with rhinitis and asthma. IgE anti-Amb a V was detected (after subtraction of values representing the means + 2 SD of the non-atopics) in 9 of 20 asthmatics but only 3 of 32 patients with only rhinitis and was thus associated with asthma. Mean anti-Amb a V was much higher in the antibody-positive asthmatics (1710 U/ml) than in the positive patients with rhinitis only (469 U/ml). The extended MHC haplotype [HLA-B7, SC31, DR2] and its possible DR-containing fragment (SC31, DR2), were found almost exclusively among the patients with IgE anti-Amb a V and were significantly elevated in patients with asthma. DR2 in general, but not DR2 without SC31, was significantly increased in frequency in patients with anti-Amb a V. In contrast, the extended haplotype [HLA-B8, SC01, DR3] and DR3 in general were increased among patients with rhinitis only and patients without IgE anti-Amb a V compared with general controls. Thus, [HLA-B8, SC01, DR3] and DR3 appear to be "protective" for the production of this antibody and the occurrence of asthma. The findings are consistent with an MHC-linked gene or genes on [HLA-B7, SC31, DR2] (but not necessarily DR2, Dw2, or DQw6 in general) controlling the IgE immune response to Amb a V and associated with asthma in ragweed pollen-sensitive subjects. In patients with rhinitis alone and generally undetectable levels of IgE anti-Amb a V, the increase in [HLA-B8, SC01, DR3] and DR3 may mark a response to an as yet unidentified Ag associated with ragweed allergy and rhinitis only.

Asthma↗
PubMed1992

Phospholipase C-gamma 1 association with CD3 structure in T cells.

Recently, we and others have reported tyrosine phosphorylation of phospholipase C-gamma 1 (PLC gamma 1) enzyme after CD3 activation of T cells, and have proposed that PLC gamma 1 mediates signal transduction through the T cell receptor (TCR/CD3). Here, using immunoblotting and immune complex PLC assays, we show that CD3 stimulation of Jurkat cells induces the association of PLC gamma 1 enzyme with CD3 complex. PLC activity is also found to co-precipitate with the CD3 zeta chain from activated cells. In addition, in vitro PLC assays show that CD3 activation leads to about 10-fold stimulation of PLC gamma 1 activity. These results, along with the observation that Jurkat cells preferentially express PLC gamma 1, indicate that PLC gamma 1 participates in CD3 signaling.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1992

Functional deficiency of antigen-presenting cells in the synovial fluid of rheumatoid arthritis.

In our study of rheumatoid arthritis (RA) patients, we observed a decrease of tetanus toxoid antigen-presenting capacity of synovial fluid (SF) adherent cells to autologous T cells of either SF or peripheral blood. Additionally, we found a higher capacity of adherent synovial cells to stimulate autologous T-lymphocytes. Our results suggest that antigen-presenting cells of the SF of RA patients have defects that may play a role in defective presentation of antigens in joints and may account for other abnormal functions important in the pathogenesis of RA.

Adult↗
PubMed1992

Gastrointestinal microvillus inclusion disease.

A 3-year-old girl of Navajo heritage had intractable diarrhea beginning at 4 days of age and resulting in long-term hyperalimentation. Investigation before multivisceral transplantation included biopsies of the rectum, stomach, duodenum, and liver. The diagnosis of microvillus inclusion disease was established by documentation of microvillus inclusions in duodenal epithelial cells. A trial of somatostatin therapy was ineffective in controlling the diarrhea. Subsequently, a multivisceral organ transplant provided a unique opportunity to establish the gastrointestinal extent of involvement of this disease. Ultrastructural microvillus inclusions were identified in the duodenum, jejunum, ileum, and colon, but not in the gallbladder. A few inclusions also were documented in gastric antral epithelial cells. Alkaline phosphatase stains performed on paraffin-embedded material showed a few inclusions in the antrum of the stomach and many inclusions throughout the small intestine, primarily in surface epithelial cells but also in upper crypt cells.

Diarrhea, Infantile↗
PubMed1992

Traits that influence longevity in mice: a second look.

Analysis of genetic interactions in the F2 of an intercross of (C57BL/6 x DBA/2) F1J revealed influences of genetic factors on life span. Females lived longer than males. Dilute brown females died sooner than females of other colors. H-2b/H-2b males died sooner than H-2b/H-2d or H-2d/H-2d males, except that among dilute brown males those of typeH-2b/H-2d died sooner. Cluster analysis suggested that male and female genotypes each fall into two groups, with female dilute brown mice having shorter lives than other females, and male H-2b/H-2b mice except dilute brown and dilute brown H-2b/H-2d mice having shorter lives than other males. The association of heterozygosity with life span was clearer in females than in males, yet the longest-lived female genotype was homozygous H-2d/H-2d, of dominant Black phenotype at the Brown locus of chromosome 4, and homozygous dd at the Dilute locus of chromosome 9. The shortest-lived females were dilute brown H-2b/H-2b. The longest-lived and shortest-lived male genotypes were dilute brown H-2d/H-2d and dilute brown H-2b/H-2d, respectively. Although histological findings at postmortem differed between the sexes, there was no association of particular disorders with other genetic markers. The importance of H-2 in males was confirmed, but the allelic effects were perturbed, possibly by the absence of Sendai infection in this experiment. Overall our studies suggest that genetic influences on life span involve interactions between loci, and allelic interactions may change with viral infections or other environmental factors.

Animals↗
PubMed1992

Predictability of alloreactivity among unrelated individuals.

Extended haplotypes are specific HLA-B, BF, C2, C4A, C4B and DR allelic combinations that occur at high frequencies and show positive linkage disequilibrium among these highly polymorphic MHC markers. About 30% of all normal caucasian haplotypes are extended, and the matching of two extended haplotypes in unrelated individuals has been shown to match for the determinants of primary mixed lymphocyte reactivity (MLR-I). In this work we report that the matching of one extended haplotype and a serologically defined HLA-DR generic type on the second chromosome in unrelated individuals is associated with the absence of mixed lymphocyte reactivity in 15 to 30% of the cases studied. Our results suggest that, for those individuals who carry either one or two extended haplotypes, it is relatively easy to identify an unrelated MLR-I-matched subject. However, for individuals lacking at least one extended haplotype, it should be difficult to find an MLR-I-matched unrelated subject.

Alleles↗
PubMed1992

HLA-DQA1 and MLC among HLA (generic)-identical unrelated individuals.

We modified a previously published PCR-RFLP for DQA1 typing (1) and examined the predictive value of HLA-DQA1 in mixed lymphocyte cultures (MLC) among matched (HLA generic types) pairs of unrelated individuals. There were 61/102 (60%) pairs with positive MLC, one-third of which could be predicted by DQA1* typing alone. DQA1 matching and MLC reactions were classified into 3 groups: 1) DQA1 mismatches showing positive MLC: 19/102 (19%); 2) DQA1 matches showing negative MLC: 41/102 (40%); 3) DQA1 identical showing positive MLC: 42/102 (41%). Five different HLA haplotypes that result from non-random association of HLA generic types (high delta haplotypes) were overrepresented in the individuals tested. One of these haplotypes carrying HLA-B7, DR2 was found associated with three different DQA1 alleles (*0201, *0103, *0102). The remaining four high delta haplotypes were associated with one DQA1 allele in all independent examples tested: HLA-A1, B8, DR3 with DQA1*0501; HLA-A26, B38, DR4 with DQA1*0301; HLA-A2, Bw62, DR4 with DQA1*0301 and HLA-A1, Bw57, DR7 with DQA1*0201. Forty per cent of the negative MLC were explained in part by the excessive number of individuals carrying two of these four haplotypes, which probably carry determinants in linkage disequilibrium with HLA. Nineteen per cent of HLA-identical (generic types) unrelated pairs show positive MLC reactions and all of them are DQA1* mismatched, suggesting that DQA1* allele typing should be used to screen samples prior to performing MLC.

Alleles↗
PubMed1992

HLA-DPB1 allele mismatches between unrelated HLA-A,B,C,DR (generic) DQA1-identical unrelated individuals with unreactive MLC.

We have used a PCR-RFLP method with one generic amplification of HLA-DPB1 second exon and 6 endonucleases to differentiate the 19 HLA-DPB1 alleles and 171 heterozygous combinations. The set of primers used in our studies produced fragment sizes different from those published before (1). The HLA-DPB1 alleles in Caucasians showed a higher frequency of DPB1*0401 and DPB1*0402, when compared to a small group of Colombians who showed a higher frequency of DPB1*0402 and DPB1*0201. We found three HLA-DPB1 alleles associated with two HLA haplotypes that result from non-random association of alleles: DPB1*0401 with HLA-A26, B38, DR4, DQA1*0301 and DPB1*0101 and DPB1*0401 with HLA-A1, B8, DR3, DQA1*0501. We also report that 70% of combinations between HLA (generic A,B,C,DR) and DQA1-identical MLC-unreactive cell mixtures showed HLA-DPB1 mismatches, suggesting that HLA-DPB1 differences are not important in MLC reactivity.

Alleles↗
PubMed1992

HLA-DQB1 allele typing by a new PCR-RFLP method: correlation with a PCR-SSO method.

We have developed a new PCR-RFLP method for HLA-DQB1 typing. This method was easy to follow, requiring only one DQB1 generic amplification and 5 endonucleases to assign 14 out of 15 HLA-DQB1 alleles. In addition, we determined that by using one generic amplification and two enzymes (Sau96 I and Hae III) it was possible to type the generic specificities: DQw2, DQw4, DQw5, DQw6, and DQw7, DQw8-9, providing a practical alternative for serological HLA-DQ generic typing. We also performed a side-by-side correlation with a PCR-SSO typing method and found an almost 100% concordance between the methods. The limitations of these methods were: 1) the PCR-RFLP method did not allow the differentiation between the HLA-DQB1*0602 and *0603 alleles; 2) the PCR-SSO method gave crosshybridization signals in the detection of *0302 or *0303 alleles. Our results suggested that both methods, PCR-RFLP and PCR-SSO, are useful alternatives for HLA-DQB1 typing.

Alleles↗
PubMed1992

Major histocompatibility complex associations with clozapine-induced agranulocytosis. The USA experience.

In order to determine associations between the major histocompatibility complex (MHC) and the development of clozapine-induced agranulocytosis, HLA typing was performed in a group of 42 clozapine-treated patients, of whom 11 had developed this adverse reaction. Among the patients with agranulocytosis, 7 (63%) were of Ashkenazi Jewish background and 4 (37%) were non-Jewish. An association between the HLA-B38, -DR4, -DQw3 haplotype and clozapine-induced agranulocytosis was found in all Jewish cases (7/7; 100%); in contrast only 4 of 21 (19%) Jewish control (nonagranulocytic) patients carried this haplotype. Among non-Jewish patients the HLA-DR2, -DQw1 haplotype was present in 4 of 4 (100%) patients with clozapine-induced agranulocytosis and in only 3 of 10 (30%) ethnically matched control patients. Our results indicate that gene products within the MHC could be involved in clozapine-mediated haematological toxicity.

Agranulocytosis↗
PubMed1992

No independent association between HSP70 gene polymorphism and IDDM.

A role for heat shock proteins (HSPs) in autoimmunity has recently been suggested by several authors. Autoantibodies against HSPs have been associated with such autoimmune diseases as systemic lupus erythematosus, polymyositis, and the NOD mouse model of diabetes. Moreover, genes for the major 70,000-M(r) HSP (HSP70) are located within the MHC. To investigate a potential association of an HSP70-2 gene polymorphism with insulin-dependent diabetes mellitus (IDDM), we analyzed restriction-fragment-length polymorphism (RFLP) of this gene in 29 families with one or more member affected by IDDM. With the enzyme PstI, as reported previously, two HSP70-2 alleles of 8.5- and 9.0-kb were found. The 8.5-kb allele was found more frequently on diabetic haplotypes compared with control haplotypes (41 of 66 [62%] vs. 20 of 46 [43%], P = 0.03). This association was due to the conservation of alleles on extended haplotypes we previously reported to be associated with diabetes on initial analysis of families. Twenty-three of 26 diabetic DR3 haplotypes and 3 of 3 normal DR3 haplotypes and all instances of [HLA-B8, SC01, DR3] and [HLA-B18, F1C30, DR3] had the 8.5-kb allele, whereas 0 of 9 normal DR2 haplotypes and 0 of 2 diabetic DR2 haplotypes had the 8.5-kb allele (P = 8 x 10(-7) DR3 vs. DR2 haplotypes). The alleles were equally distributed among DR4 haplotypes.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1992

Conserved, extended MHC haplotypes.

Extended major histocompatibility complex (MHC) haplotypes are fixed conserved regions of the short arm of the sixth human chromosome defined by their HLA-B, complotype (BF, C2, C4A, C4B), HLA-DR alleles. The regions of conservation may extend further. At least a third of normal MHC haplotypes in Caucasians are extended, and they are largely responsible for previously observed linkage disequilibrium in the region. They are relatively population-specific. Their presence has major implications for tissue transplantation, and particularly for the identification of unrelated donor-recipient pairs, since matching for extended haplotypes probably optimizes engraftment in individuals who have them. Even for those who do not, extended haplotypes provide the means for identifying likely MLR-I-negative donor-recipients, and for identifying the genes involved in this function. Extended haplotypes provide most of the markers for HLA-associated autoimmune diseases; like the MHCs of inbred and inbred recombinant strains of mice, they have aided in the analysis of the contribution of specific genes in this region to disease susceptibility and immune functions, particularly the antibody response. Finally, extended haplotypes must be taken into account when considering population genetic questions and when using HLA markers to identify individuals in forensic applications.

Asthma↗
PubMed1991

Association of DQw7 (DQB1*0301) with ocular cicatricial pemphigoid.

Ocular cicatricial pemphigoid (OCP) is an autoimmune blistering disease that affects the conjunctiva and multiple mucous membranes. Class I and II and complement genetic markers of the major histocompatibility complex were studied in 20 Caucasian OCP patients and members of their families. Frequencies of individual alleles and common fixed or extended haplotypes in the patients were compared with those in normal family control haplotypes and with overall normal Caucasian haplotypes. The most striking increase compared with overall controls was noted in HLA-DQw3 (P = 0.006), unassociated with any extended haplotype. All but 1 of the 20 patients carried DQw3 in linkage with HLA-DR4 (increased significantly with P = 0.042 compared with overall normal genotype controls) or DR5. The DQw3, on analysis by restriction fragment length polymorphism in genomic DNA, was, in every instance, DQw7 (3.1, DQB1*0301). The frequency of DQB1*0301 in patient haplotypes compared with overall normal DR4 and DR5 DQw3-bearing haplotypes was statistically significantly increased (P less than 0.003, relative risk = 9.6). The distribution of homozygotes and heterozygotes for DQB1*0301 among the patients was consistent with dominant but not recessive inheritance of DQB1*0301 or a gene, probably a class II allele, in linkage disequilibrium with it as the major histocompatibility complex susceptibility gene for OCP.

Eye Diseases↗
PubMed1991

Major histocompatibility complex haplotypes and class II genes in non-Jewish patients with pemphigus vulgaris.

Previous studies demonstrated that HLA-DR4 was markedly increased among Ashkenazi Jewish patients with pemphigus vulgaris (PV), almost entirely as the common Jewish extended haplotype [HLA-B38, SC21, DR4, DQw8] or as the haplotype HLA-B35, SC31, DR4, DQw8, and that HLA-DR4, DQw8 was distributed among patients in a manner consistent with dominant expression of a class II (D-region or D-region-linked) susceptibility gene. In the present study of major histocompatibility complex (MHC) haplotypes in 25 non-Jewish PV patients, DR4, DQw8 was found in 12 of the patients and DRw6, DQw5 was found in 15. Only 3 patients had neither. Only 1 of the DR4, DQw8 haplotypes was [HLA-B38, SC21, DR4, DQw8] and 2 were HLA-B35, SC31, DR4, DQw8; most were the presumed fragments (SC31, DR4, DQw8) or (SC21, DR4, DQw8) or DR4, DQw8 with some other complotype. Of the patients with DRw6, DQw5, all were DRw14, DQw5, and 6 had a rare Caucasian haplotype, HLA-Bw55, SB45, DRw14, DQw5. Four of 6 of these were found in patients of Italian extraction, as was the 1 normal example. The non-Jewish patients were of more Southern European extraction than our controls. This suggests that there are two major MHC susceptibility alleles in American patients with PV. The more ancient apparently arose on a haplotype in the Jews, HLA-B38(35), SC21(SC31), DR4, DQw8, and spread to other populations largely as D-region segments. The other arose in or near Italy on the haplotype HLA-Bw55, SB45, DRw14, DQw5 and has also partially fragmented so that many patients carry only DRw14, DQw5. The available data do not permit the specific localization of either the DR4, DQw8- or the DRw14, DQw5-linked susceptibility genes.

Alleles↗