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Biomedical subjects

N E Goeken

Publications and source records attributed to N E Goeken.

At least 19 recordsLinked to original sources
PubMed1995

A description of a new DR allele, DRB1*1113.

We have discovered a previously unpublished HLA-DRB1 allele, observed in a patient (SB), his mother, and one sibling. The undefined allele gave sporadic positive reactions with sera in the DR52-associated group. SSOPH analysis utilizing both generic and group specific primers and probes also gave ambiguous results. SB typed clearly as a DRB1*0301 (paternal allele) but the DNA from SB also bound probes specific for DRB1*14 and DRB1*11. Sequencing revealed that the undefined allele was similar to a DRB1*14 allele with a segment of sequence found in DRB1*11 alleles. The patient was MLC reactive with donors who express DRB1*0301, *1401 and *0301, *11 and was nonreactive solely to DRB1*0301 (Dw3) homozygous typing cells.

Alleles↗
PubMed1994

Bw4-reactive and Bw6-reactive antibodies recognize multiple distinct HLA structures that partially overlap in the alpha-1 helix.

Bw4 and BW6 epitopes are expressed by mutually exclusive sets of HLA-B alleles and some HLA-A and HLA-C alleles. To test whether antithetical structures are required to express Bw4 and Bw6 epitopes, we measured binding of Bw4-reactive and Bw6-reactive alloantibodies and mAbs to HLA-B7 variants. A triple substitution of HLA-B7 alpha-1 helix residues 80, 82, and 83 created Bw4 and destroyed Bw6 epitopes detected by alloantibodies and mAbs. Both Bw4-reactive and Bw6-reactive mAbs competed for binding to HLA-B7 variants with single substitutions at residues 82 and 83. Substitutions of residues H93 and D119 which form a salt bridge in HLA-A2 also permitted binding by both Bw4-reactive and Bw6-reactive mAbs, suggesting that Bw4 and Bw6 epitopes are conformationally dependent. Six Bw4-reactive mAbs showed four distinct patterns of binding to HLA-B7 variants. Detailed analysis of 74 HLA-B7 single-residue variants showed that Bw6-reactive SFR8-B6 binding was prohibited by mutations altering the distal end of the alpha-1 helix and the nearby connecting loop. In contrast, Bw6-reactive BB7.6 binding required both alpha-1 and alpha-2 helix residues. Thus, Bw4-reactive and Bw6-reactive Abs recognize multiple distinct HLA structures that partially overlap in the alpha-1 helix. As both Bw4 and Bw6 epitopes are expressed by some HLA-B7 variants, mutually exclusive expression of Bw4 and Bw6 epitopes in naturally occurring HLA class 1 molecules may reflect evolutionary pressure.

Antibodies, Monoclonal↗
PubMed1993

The association of HLA-B8, B51, DR2, and multiple sclerosis in pars planitis.

PURPOSE: To establish a human leukocyte antigen (HLA) association in a homogeneous population of patients with pars planitis. METHODS: A strict set of inclusion parameters was established for the diagnosis of pars planitis. Forty patients with pars planitis who met these criteria underwent HLA analysis of class I and II phenotypes. RESULTS: HLA-B8 was present in 15 (37.5%) of 40 patients versus 85 (19.7%) of 431 controls (relative risk, 2.44; P = 0.011). HLA-B51 was present in 9 (22.5%) of 40 patients versus 51 (11.8%) of 431 controls (relative risk, 2.16; P = 0.049). HLA-DR2 was present in 27 (67.5%) of 40 patients versus 121 (28.0%) of 431 controls (relative risk, 5.32; P < 0.0001). HLA-DR2 has been associated with multiple sclerosis (MS). Exclusion of five patients with pars planitis in whom MS subsequently developed did not change the significance of these findings. CONCLUSIONS: The strongest association of pars planitis with HLA-DR2 and the temporal development of MS in some patients with pars planitis further supports an association between pars planitis and MS.

Case-Control Studies↗
PubMed1993

The relationship between HLA-A, B, DQ, and DR antigens and asbestos-induced lung disease.

To evaluate the relationship between human leukocyte antigen (HLA) and both asbestos-induced pulmonary fibrosis and pleural fibrosis, we obtained HLA-A, B, C, DQ, and DR phenotypes in 42 long-term asbestos-exposed workers. Among these exposed workers, 15 had asbestosis (ILO > or = 1/0) on the chest radiograph and 18 had asbestos-induced pleural fibrosis. We found that there was an increased percentage of HLA-A29, HLA-B44, and HLA-Bw4 in the subjects with asbestosis. In addition, we observed a marginally positive relationship between HLA-A29 and the severity of pulmonary fibrosis. Similarly, there was a higher prevalence of HLA-DRw53 and DQ2 in the subjects with asbestos-induced pleural fibrosis. The presence of HLA-DQ2 was significantly related to the extent and type of asbestos-induced pleural fibrosis while HLA-DRw53 was not consistently related to the type or extent of pleural disease. Importantly, we observed that HLA-A29, HLA-B44, HLA-Bw4, HLA-DRw53, and HLA-DQ2 do not have a significantly shorter duration or latency of asbestos exposure. Moreover, none of the HLA haplotypes (A29, B44, Bw4, DRw53, and DQ2) that we found to be associated with radiographic manifestations of asbestos-induced lung disease were associated with the physiologic abnormalities that have been traditionally associated with asbestos-induced lung disease. The only exception was an isolated decrease in the residual volume associated with the presence of HLA-A29. These results suggest that the HLA-A29 phenotype may be associated with the development of asbestosis and the HLA-DQ2 phenotype may be associated with the development of asbestos-induced pleural fibrosis. However, these associations are not particularly strong, physiologic correlation is lacking, and previous studies do not support our findings.

Asbestosis↗
PubMed1993

Salsalate-induced pancytopenia in a patient with systemic lupus erythematosus.

After a patient with a history of systemic lupus erythematosus in remission was given salsalate, all of her hematologic elements, especially leukocytes, profoundly decreased within hours, although the patient was receiving steroids. She had been challenged with salsalate at an earlier date, with a similar but less impressive drop in blood counts. Granulocytotoxic antibodies persisted during this episode in contrast to declining lymphocytotoxic and anti-native DNA antibodies that accompanied a remission of systemic lupus. This is the first case of this kind occurring with salsalate therapy and may have represented preformed antibodies induced by salsalate.

Adolescent↗
PubMed1992

Critical role of HLA-DR beta 1 residue 58 in multiple polymorphic epitopes recognized by xenogeneic and allogeneic antibodies.

In a previous study, we identified glutamic acid at position 58 in DR (beta 1*1101) as critical for the epitopes recognized by the DRw11-specific mAb GS88.2, as well as the I-LR1 mAb that recognizes a polymorphic epitope on DR(alpha,beta 1*1101) and some DP molecules. The purpose of this study was to determine whether other polymorphic residues contribute to these epitopes and whether DR beta glutamic acid or alanine 58 and DP beta glutamic acid 56, the analogous position in DP beta, contribute to epitopes recognized by other anti-class-II mAb and allosera. Site-directed mutagenesis and transfection were used to produce cells bearing wild-type or mutant class II molecules that were analyzed with mAbs by flow cytometry and with human allosera by absorption and subsequent microcytotoxicity assays. These studies demonstrate that the residue at DR beta position 58 plays a central role in at least three different mAb epitopes and an epitope recognized by anti-DRw11 allosera. Substitution of glutamic acid for alanine at position 58 of eight DR beta chains caused gain of binding of four mAbs to all of the mutant molecules, except DR(alpha,beta 4*0101). These data suggest that the side chains of DR beta 58 and DP beta 56 point outward from the alpha-helix and directly contact antibody.

Alanine↗
PubMed1991

Biological mothers may be dangerous blood donors for their neonates.

Premature neonates require blood transfusions, and biological parents may wish to be directed donors. Biological mothers pose a potential danger because their plasma may contain antibodies that will react with blood cell antigens inherited by the infant from the father. We studied 25 healthy, pregnant women at the time of delivery for the presence of antibodies against red blood cell, leukocyte and platelet antigens. Mothers known to have red cell antibodies earlier in pregnancy were excluded, and no new red cell antibodies appeared at delivery. Antileukocyte and antiplatelet antibodies were found in 16 and 12% of mothers, respectively. Because these antibodies have the potential to cause adverse reactions when transfused passively, we suggest that either biological mothers not provide blood components containing plasma for their neonates or that maternal red cells and platelets be given as washed products.

Blood Donors↗
PubMed1990

HLA-B7 and HLA-DR2 antigens and acute posterior multifocal placoid pigment epitheliopathy.

Acute posterior multifocal placoid pigment epitheliopathy is a chorioretinal inflammatory disease occurring in young, healthy adults. Its cause is unknown, although it frequently follows a flulike illness. We reexamined 30 patients with documented acute posterior multifocal placoid pigment epitheliopathy to determine their HLA class I antigen (A and B) and class II antigen (DR and DQ) distribution. The HLA class I antigen B7 was found in 12 patients (40.0%) compared with 63 controls (16.6%) (relative risk, 3.38). The class II antigen DR2 was present in 17 patients (56.7%) compared with 107 controls (28.2%) (relative risk, 3.34). The specific role of HLA antigens in uveitis is unknown, but the finding of an increased prevalence of HLA-B7 and HLA-DR2 antigens in patients with acute posterior multifocal placoid pigment epitheliopathy suggests an immunogenetic predisposition to acquiring this disease.

Chorioretinitis↗
PubMed1989

Monocyte suppressor factor is plasminogen activator inhibitor inhibition of membrane bound but not soluble IL-1.

Human monocytes cultured in monolayer for 6 days were found to secrete a factor that suppressed the T cell proliferative response to soluble Ag and to alloantigens. The elaboration of this monocyte suppressor factor (MSF) was not inhibited by indomethacin. It has an apparent Mr of 50 to 60 kDa. It does not inhibit soluble IL-1 in the murine thymocyte costimulator assay but does inhibit the activity of membrane bound IL-1, which we observed to be almost exclusively IL-1 alpha. MSF contains elevated amounts of plasminogen activator inhibitor (PAI) when measured either as bioactivity or in an ELISA. Its immunosuppressive properties are inhibited by anti-PAI antibody. Furthermore, the eluate but not the effluent of an anti-PAI immunoabsorbent column contains all of the immunosuppressive activity. Based on these data we suggest that MSF is, in fact, PAI and postulate that the mechanism of action is inhibition of the plasmin cascade, thereby preventing the release of membrane bound IL-1. This suggests that monocytes possess an autoregulatory circuit that may have implications for the kinetics of the inflammatory response.

Binding, Competitive↗
PubMed1988

Is secreted IL-1 necessary for normal human T-cell activation?

The role of secreted and membrane-bound IL-1 in the activation of human T cells by monocyte-associated, processed antigen was examined. The IL-1 is secreted from antigen-pulsed plastic-adherent monocytes for only 24 h after isolation. After extensive washing, however, these monocytes are fully capable of stimulating T cells to proliferate. The T cells require less than 24 h of exposure to the monocytes to become activated and can then be cultured alone in fresh media. Addition of exogenous IL-1 does not enhance T-cell responsiveness in this model. Anti-IL-1 beta antibody does not inhibit the response, although we observed that pulsed monocytes have significant membrane-bound IL-1 assayed as biologic activity in the murine thymocyte costimulator assay. These studies suggest that secreted IL-1 is not required for the activation of human T cells and that membrane-bound IL-1 serves this function. The data further suggest that these two forms of IL-1 may be functionally distinct and that IL-1 beta is not the major component of membrane-bound IL-1. The possible relationship of these findings to the clinical efficacy of IL-1 inhibitors, such as corticosteroids, is discussed.

Antigen-Antibody Reactions↗
PubMed1988

Allogeneic marrow grafting with partially mismatched, unrelated marrow donors.

Forty patients with advanced hematologic malignancies or severe aplastic anemia received marrow grafts from partially mismatched, unrelated marrow donors. All patients were administered conventional prophylaxis for acute graft-v-host disease (GVHD) consisting of methotrexate and low-dose glucocorticoids. All but two patients who survived at least 30 days showed durable engraftment. Six patients survive 17+ to 36+ months following transplantation. Severe acute GVHD was seen in 47% of the patients; however, no direct correlation between GVHD and the degree of mismatching could be determined. Fatal infections were seen in 29 patients, and in the majority the infection occurred after the granulocyte count had risen to greater than 500 cells/microL. We conclude that the problems encountered in this pilot study can potentially be solved, and that further studies with this type of marrow grafting are warranted.

Adolescent↗
PubMed1986

Alteration of human accessory cell function by heat treatment: role of IL-1 and class II MHC antigens.

Heat-treated monocytes (1 hr, 45 degrees C) cannot present soluble antigen or mitogen to purified autologous T cells. This is despite normal viability and normal expression of class II MHC antigens. They do not secrete IL-1 nor stimulate secretion of IL-2 by T cells. Addition of exogenous IL-1 or IL-2 does not, however, reconstitute the response to soluble antigen. Furthermore, even after overnight pulsing with antigen prior to heat treatment under circumstances in which the antigen is known to be appropriately processed, stimulation of T-cell proliferation still does not occur. Thus there appear to be at least two discrete lesions produced by heating: failure of IL-1 production, per se, and intrinsic failure to present previously processed antigen. It is also hypothesized that heat treatment may produce alterations in Ia molecules which specifically disallow transduction of the proliferation signal to T cells.

Antigen-Presenting Cells↗
PubMed1986

Resistance to suppression and acquisition of memory by human T cells.

Human memory cells acquire resistance to several types of suppressor cells, including MLR generated suppressor cells. These data suggest one possible mechanism of that resistance, namely retention of IL-2 receptors in the resting state. Cells from a 7-day MLR were separated on a single step percoll gradient. All proliferating cells were found in the interface. Pellet cells were nondividing. Interface and pellet cells had equivalent memory function in a secondary MLR. Thus, there appear to be at least two subpopulations of memory cells, including one that is primed without undergoing division. These subpopulations are functionally distinct. Interface memory cells were 30-50% more resistant than pellet memory cells to MLR generated suppressor cells. On culture day 10, neither pellet nor interface cells displayed significant spontaneous proliferation but exogenous Interleukin 2 (IL-2) produced up to five times as much proliferation in interface cells as in pellet cells. Further, FACS analysis with an anti-TAC equivalent antibody also showed that significantly more interface cells have surface receptors for IL-2. Thus, cells that had previously divided continue to have more and/or higher affinity receptors for IL-2 even after return to the resting state. If a mechanism of suppression in the mixed lymphocyte reaction is to reduce the synthesis/release of Il-2, memory cells may acquire their relative resistance to this suppression by virtue of the increased IL-2 sensitivity of this discrete subpopulation.

Cell Communication↗