New variant of MHC class II deficiency with interleukin-2 abnormality.
Explore the source record for details and available documents.
Female↗
Biomedical subjects
M Fotino
Publications and source records attributed to M Fotino.
Presence of a non-HLA B cell antigen in rheumatic fever patients and their families as defined by a monoclonal antibody.
Numerous investigators have suspected that there is a genetic predisposition to rheumatic fever (RF). In this context we have recently produced a series of monoclonal antibodies directed against B cells obtained from RF patients one of which, labeled D8/17, identifies a B cell antigen present in 100% of all RF patients studied. While the highest percentage of positive cells were exhibited by RF probands (33.5% +/- SE), the percentage of cells in unaffected siblings and parents was 14.6 and 13%, respectively. The percentage of positive cells in APSGN probands, unaffected siblings, and parents was 2.96, 3.86, and 2.8%, respectively. A low level of B cells (5-7%) bearing the D8/17 marker was seen in control patients. The segregation pattern of the phenotypes defined by the percentage of D8/17 positive cells within HLA-typed RF families are consistent with an autosomal recessive mode of inheritance not associated with the human MHC system. We postulate that these phenotypes indicate the presence of at least one necessary genetic factor for susceptibility to RF.
Analysis of Variance↗
OKT3-associated adverse reactions: mechanistic basis and therapeutic options.
OKT3, a prototypic monoclonal antibody directed at the lineage-specific CD3 antigen expressed on mature T cells, is an effective immunosuppressant in organ graft recipients. Unfortunately, a variety of adverse reactions are observed following the first and second doses of OKT3. In a series of experiments designed to examine the signaling repertoire of OKT3, it was found that (1) OKT3 is an effective substitute for the alloantigen stimulus in the activation of antigen-specific memory T cells; (2) OKT3 is a potent inducer of cytolytic activity (secondary cytotoxic T-cell activity as well as natural killer-cell activity); (3) OKT3 is also an inducer of interleukin-2 and interferon gamma production; and (4) of the immunosuppressants currently in clinical use, cyclosporine greater than methylprednisolone greater than 6-mercaptopurine (an in vivo cleavage product of azathioprine) in curtailing T-cell activation with OKT3. Collectively, these observations suggest a potential mechanistic basis for the adverse reactions associated with OKT3 and provide experimental support for therapeutic strategies that include the use of cyclosporine and/or methylprednisolone before OKT3 administration.
Antibodies, Monoclonal↗
Isolated pulmonary hypertension in the grandchild of a kindred with scleroderma (systemic sclerosis): "neonatal scleroderma"?
We report a small kindred in which the father and daughter with positive antinuclear antibodies (ANA) (proband) had diffuse cutaneous and visceral scleroderma (systemic sclerosis, SSc), antitopoisomerase autoantibodies and shared the HLA-A23 C- B- DR5 DRw52 DQw3 haplotype. The ANA- granddaughter (daughter of the proband) was noted to have severe isolated pulmonary hypertension within the first 6 months of life, and had the other maternal HLA-A1 Cw8 B14 DR1 DQw1 haplotype, which included a B1, B2 duplication of the C4B allele. All 3 members shared DRw52. The possibility that neonatal pulmonary hypertension represents an isolated autoimmune disease or a hitherto undescribed neonatal syndrome is proposed and the immunogenetic autoantibody implications are discussed.
Antibodies, Antinuclear↗
Marked increase in the frequency of psoriatic arthritis in psoriasis patients with HLA-DR+ keratinocytes.
Immunocytochemical studies with a monoclonal anti-HLA-DR antibody were performed on skin sections and keratinocyte (KTC) suspensions obtained from suction blisters of active psoriatic plaques. HLA-DR+ KTCs were found in the plaques of 23 of 38 patients with active psoriasis. Of these 23, 16 had clinical findings typical of psoriatic arthritis (PA); none of the 15 patients who lacked HLA-DR+ KTCs had PA. Although KTC HLA-DR expression was more prevalent in patients with severe skin disease, 7 of the 23 patients with HLA-DR+ KTCs in active psoriatic plaques had mild skin disease; 4 of these 7 had PA. Nail pitting or duration of skin disease did not account for increased incidence of PA in patients with HLA-DR+ KTCs. All psoriasis patients with arthritis received nonsteroidal antiinflammatory drug therapy; 14 received additional therapy directed primarily to the cutaneous manifestations of psoriasis. Nine of these noted arthritis improvement with concurrent skin response; however, in 5 patients, arthritis activity increased, despite improvement of the cutaneous disease. Two other patients, treated with methotrexate, also had concurrent skin and joint improvement. These data suggest that psoriasis patients with HLA-DR+ KTCs are at increased risk for the development of associated arthritis.
Anti-Inflammatory Agents, Non-Steroidal↗
A double determinant immunoassay for HLA class I typing using serum as an antigen source.
We have applied a double determinant immunoassay (DDIA) to HLA-A2,A28, and B13 typing, using serum as an antigen source. The results obtained show a correlation of 96% (B13) and 89.1% (A2,A28) with the results obtained by conventional HLA typing. Furthermore, the results obtained were highly reproducible, since testing of 18 sera on two occasions gave concordant results with all samples tested. The variation in the content of HLA-A2 antigens in sera taken at different times from a given donor was less than 5%. A sevenfold variation was found in the serum level of HLA-A2,A28 antigens: the highest level was found in the sera from HLA-A2,A28 donors and in decreasing order in HLA-A2 homozygous, HLA-A28 homozygous, HLA-A2 heterozygous, and HLA-A28 heterozygous donors. The results of this study indicate that the DDIA is a sensitive, simple, and reproducible procedure for HLA class I typing. The DDIA offers the following advantages in comparison with the conventional lymphocytotoxic assay: it provides information not only about the expression of a given alloantigen, but also about its level; it does not require viable cells, thus facilitating retrospective studies and typing of leucopenic patients; it eliminates variability of results caused by abnormal susceptibility of target cells to complement-dependent lysis.
Antibodies, Monoclonal↗
Optimization of donor specific blood transfusion in kidney transplantation.
1. One hundred milliliters of stored whole blood DST, three times at weekly intervals is a practical, less immunizing and effective approach to enhance graft survival in recipients of a living-related donor kidney. 2. This protocol could also be used in sibling donor/recipient pairs who do not share a haplotype as well as in those who share two haplotypes to enhance graft survival. 3. The use of a short course of Cs (6 mg/kg/d for three weeks) along with DST appears to reduce the sensitization rate even lower. The dose of Cs used in this study produced no clinically significant adverse reactions, whereas Aza (1 mg/kg/d) often produces leukopenia. 4. DST produces significantly suppressed donor specific MLC responses in the early post-DST period; however, it increases the response at a later time. DST modulates immune responses in such a way that secondary responses upon grafting are more readily reversible by immunosuppressive agents.
Adult↗
HL-T, a new cell line derived from HL-60 promyelocytic leukemia cell cultures expressing terminal transferase and secreting suppressor activity.
A cell line with immature blast cell morphology was isolated from HL-60 promyelocytic leukemia cell cultures and designated HL-T. This new cell type is biphenotypic, expressing terminal transferase (TdT) together with myelomonocytoid immunologic features. TdT enzymatic activity, undetectable in HL-60, was determined to be 140 to 180 units/10(8) HL-T cells by the dGTP-assay, approximately 20% of the activity found in lymphoblastoid cell lines. HL-T predominantly synthesize the known 58-kDa TdT-protein plus a minor 54/56-kDa doublet. The 58-kDa steady state form is nonglycosylated and is phosphorylated. Precursor antigens S3.13 and MY-10, absent on HL-60, are expressed by HL-T; however, the cells are negative for HLA-Dr. Southern blot analysis by hybridization with immunoglobulin heavy chain (JH) and T cell-receptor chain gene (T beta) probes shows JH to be in the germ-line configuration in both cell lines and the T beta gene to be in germ-line in HL-60 but to be rearranged in HL-T. Truncation of the gene encoding the granulocyte-macrophage-colony-stimulating factor (GM-CSF), as found in HL-60, is not observed in HL-T. HL-T are resistant to differentiation-induction by retinoic acid and 1,25-dihydroxyvitamin D3. Cytogenetically HL-T share with HL-60 a deletion of the short arm of chromosome 9 at breakpoint p13, an aberration frequently found in patients with T cell leukemia. In addition, HL-T display t(8;9)(p11;p24) and trisomy 20. Tetraploidy is observed in 80% of HL-T metaphases with aberrations identical to those in the diploid karyotype. Like HL-60, the new line shows some surface-antigenic-T cell characteristics. Despite an antigenic pattern most consistent with that of helper-inducer T cells (T4+, D44+/-, 4B4+, 2H4-, TQ1+/-), HL-T cells and their conditioned culture medium suppress antigen, mitogen, and mixed-leukocyte-culture-mediated lymphocyte proliferation.
Cell Line↗
Altered phagocytosis by monocytes from HLA-DR2 and DR3-positive healthy adults is Fc gamma receptor specific.
Fc gamma receptor-dependent mononuclear phagocyte system (MPS) clearance of opsonized erythrocytes is prolonged in healthy adults with the class II alloantigens HLA-DR2, DR3, or DQw1, despite normal receptor-specific Fc ligand binding by monocytes in these groups. To investigate the basis for the MPS dysfunction, we determined the phagocytic capacity of blood monocytes from 66 disease-free adults and analyzed the data according to the HLA type of the subjects. The data demonstrate decreased phagocytosis of IgG-sensitized erythrocytes (EA) by monocytes from HLA-DR2, DR3, or DQw1-positive subjects compared with normals without these B cell alloantigens (2.87 +/- 0.83 erythrocytes/monocyte vs 3.87 +/- 1.05, p less than 0.004; 3.01 +/- 0.94 vs 3.87 +/- 1.05, p less than 0.02; 3.18 +/- 0.89 vs 3.87 +/- 1.05, p less than 0.02, respectively). Because HLA-DR2 and DQw1 are in linkage disequilibrium, we compared EA phagocytosis in subjects with DQw1 alone to normals without HLA-DR2, DR3, or DQw1. Among subjects positive only for DQw1, no significant decrease in phagocytosis could be seen (3.46 +/- 0.95 vs 3.87 +/- 1.05, p = NS). To determine whether these differences represented an Fc receptor-specific dysfunction or a more generalized decrease in phagocytic activity, we compared the quantitative phagocytosis of EA with that of neuraminidase-treated erythrocytes (EN), which is Fc receptor independent and beta-glucan receptor mediated. No segregation of phagocytic capacity for EN by HLA class II phenotypes could be demonstrated (DR2, 2.68 +/- 1.30 erythrocytes/monocyte; DR3, 2.95 +/- 1.30; DQw1, 2.84 +/- 1.15; others, 3.06 +/- 1.14). Our data indicate that the decrease in phagocytosis by blood monocytes from normal individuals with HLA-DR2 or DR3, the class II alloantigens associated with systemic lupus erythematosus and other autoimmune diseases, is specific for the Fc receptor-mediated process. This alteration of Fc receptor function among immunogenetically defined individuals may contribute to their predisposition to autoimmune disease. These differences may also apply to other Fc receptor-initiated cellular functions.
Adult↗
Electronic image formation in high-voltage TEM by sequential pixel acquisition.
We describe a complete hybrid imaging system for the electronic detection and manipulation of high-voltage TEM images. The system includes a recently incorporated two-dimensional beam deflector for dissecting the image into pixels by displacing it in a raster in front of an aperture leading to an electron detector. The characteristics of images thus formed by sequential pixel acquisition and displayed on a CRT are discussed and illustrated. Absorption or thickness profiles are also obtained by displaying the scanned pixel intensity in Y-modulation. Similarly, the displacement of an entire diffraction pattern allows the intensities of individual diffraction spots to be quantitated directly over a wide dynamic range. The direct splitting of the image into electronically controlled pixels can be applied to local mass measurements and to energy-loss analysis by means of a simple magnetic prism that can also provide energy filtering in lieu of a more elaborate electron-optical, image-preserving system.
Animals↗
Visualization of biological specimens by cryoHVEM.
This article describes the operation and the characteristics of cryoHVEM imaging of biological specimens using a top-entry cryostage. The procedure for inserting frozen specimens into the microscope column is also presented. Whole mounts were observed under optimal imaging conditions by combining: fixation by fast freezing for structure preservation without exposure to chemicals, observation in the hydrated (frozen) state or in the dried state without exposure to the atmosphere after the initial fixation by freezing, and ultrastructural visualization with the key imaging factors of resolution, penetration and beam-induced damage at their best by high-voltage electron microscopy.
Animals↗
Rheumatic fever-associated B cell alloantigens as identified by monoclonal antibodies.
Mice immunized with B lymphocytes obtained from patients who had had well-documented rheumatic fever in the past yielded 2 monoclonal antibodies, termed 83S19.23 and 256S10, which identified certain alloantigens present on the B cells of these patients. The frequency of the B cell marker detected by clone 83S19.23 in rheumatic fever patients was found to be 59%, 77%, and 74% in India, New Mexico, and New York, respectively. Monoclonal antibody 256S10 identified 75% of those rheumatic fever patients who were nonreactive to clone 83S19.23. Thus, the 2 antibodies identify approximately 92% of all rheumatic fever patients and suggest the presence of a diallelic genetic marker for susceptibility to rheumatic fever.
Antibodies, Monoclonal↗
Ultrastructural visualization of unfixed and unstained whole mounts by high-voltage electron microscopy at low temperatures.
A physical procedure for the visualization of cellular fine structures is described as an alternative to chemical preparative techniques. It consists of fixation by fast freezing followed by controlled etching in the cryostage of a million-volt transmission electron microscope. Whole mounts were thus observed under stable conditions with no use of chemical fixatives, solvents, or stains, with no exposure to the atmosphere, and with the improved penetration and resolution in thick specimens that characterize high-voltage electron microscopy. The preservation, contrast, and resolution exhibited by images of preparations obtained by this procedure are discussed.
Animals↗
Hepatic cirrhosis in young adults: association with adolescent onset of alcohol and parenteral heroin abuse.
Hepatic cirrhosis is infrequently diagnosed in young adults. In a hospital for addictive diseases in New York City, we found cirrhosis in 53 patients under age 35 within just 40 months. The cirrhosis was biopsy-proven in 37 patients (group I) and diagnosed clinically in 16 patients with severe liver disease (group II). Alcohol abuse was found in 51 patients (96%), and parenteral heroin abuse was seen in 52 (98%). The duration of alcohol abuse was seven or fewer years in 24 patients (45%) and 10 or fewer in 39 (74%). In 44 (83%), the substance abuse began in adolescence. Comparison of group I cirrhotic patients with 65 non-cirrhotic biopsied patients showed that cirrhosis was significantly associated with abuse of both alcohol and parenteral heroin (p less than 0.001). The distribution of 66 HLA antigens from A, B, C, and DR loci showed no differences when 42 patients were compared with 42 ethnically-matched control substance abusers. The early development of cirrhosis in these young patients may be related to multiple hepatic injuries induced by alcohol and parenteral heroin abuse and to the onset of addictive diseases during adolescence or early adult life.
Adult↗
Familial dilated cardiomyopathy.
Explore the source record for details and available documents.
Adult↗
Induction of immune alterations and successful renal transplantation with a simplified method of donor-specific blood transfusion.
We developed a new and simplified donor-specific blood transfusion (DSBT) protocol for prospective kidney transplant recipients from one-haplotype-mismatched related donors. Prospective kidney donors gave 450 ml of blood in a quad-pack unit, and the blood was stored in a blood bank. Twenty-five patients were transfused with 100 ml of the respective donor's whole blood at 1, 8, and 15 days after its storage. After DSBT, only three (12%) developed donor-specific lymphocytotoxic antibodies. Following DSBT, donor-specific mixed lymphocyte culture (MLC) was significantly suppressed, without any accelerated (secondary-type) response in early MLC. In addition, sera obtained after DSBT also suppressed donor-specific MLC significantly. Sixteen recipients subsequently received a kidney transplant from the donor, and all had functioning grafts at three months, but one lost the graft thereafter (graft survival rate: 94% at 12 months). This study indicates that (1) 100 ml of stored whole-blood DSBT three times at weekly intervals is a practical, less immunizing, and effective approach to enhance graft survival in recipients of a one-haplotype-mismatched graft; and (2) immune consequences of DSBT include induction of donor-specific cellular and humoral adaptive responses that might be conducive to successful graft outcome.
Adolescent↗
Defective mononuclear phagocyte function in systemic lupus erythematosus: dissociation of Fc receptor-ligand binding and internalization.
Fc receptor-mediated mononuclear phagocyte system (MPS) clearance is impaired in systemic lupus erythematosus (SLE) and may contribute to the pathogenesis of the immune complex disease. To investigate the basis of MPS dysfunction, we have examined concurrent in vivo and in vitro Fc receptor function in 22 patients with SLE and 23 disease-free adults. Blood monocyte Fc receptor binding was increased rather than decreased as predicted by the saturation hypothesis of MPS blockade. Rosette formation of IgG-sensitized bovine erythrocytes (EA) with monocytes demonstrated increased Fc receptor-ligand binding in SLE (percent rosettes: 40 +/- 12 vs 27 +/- 8, p less than 0.001). Scatchard analysis of the binding of radiolabeled IgG oligomers to SLE monocytes indicated a mean receptor number 30% higher than control, although this did not reach statistical significance. Despite enhanced Fc receptor-ligand (EA) binding, Fc-mediated phagocytosis of EA was decreased in SLE (1.7 +/- 0.7 erythrocytes/monocytes/hour vs 2.6 +/- 1.0, p less than 0.004). This decrease in phagocytosis by blood monocytes from SLE patients was significantly greater than that attributable to the predominance in SLE of individuals with certain HLA B cell alloantigens and intrinsically lower phagocytic rates (p less than 0.05 for all groups). This decrease therefore represents a disease-acquired characteristic. Furthermore, the phagocytic rate of the four SLE patients with marked prolongation in MPS clearance was significantly lower than that of the eight patients with near normal clearance values (p less than 0.01). Saturation of Fc receptors by immune complexes does not explain impaired immune clearance in SLE. Our results indicate that despite increased binding of the EA ligand, Fc receptor-mediated phagocytosis is markedly impaired in SLE monocytes. This impairment cannot be explained on the basis of HLA-related differences in phagocytosis among lupus patients. The defect in phagocytosis of EA is most profound in those patients with the most significantly impaired MPS clearance. Thus, the dissociation of receptor-ligand binding and receptor-mediated internalization may contribute significantly to the in vivo clearance defect in SLE.
Adult↗