A molecular genetic approach to gld "autoimmune" disease.
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Animals↗
Biomedical subjects
M F Seldin
Publications and source records attributed to M F Seldin.
Mapping of the Ly-4 (L3T4) T-cell differentiation antigen on mouse chromosome 6 by the use of RFLPs in an interspecific cross.
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Animals↗
Establishment of a molecular genetic map of distal mouse chromosome 1: further definition of a conserved linkage group syntenic with human chromosome 1q.
A linkage map of distal mouse chromosome 1 was constructed by restriction fragment length polymorphism analysis of DNAs from seven sets of recombinant inbred (RI) strains. The data obtained with seven probes on Southern hybridization combined with data from previous studies suggest the gene order Cfh, Pep-3/Ren-1,2, Ly-5, Lamb-2, At-3, Apoa-2/Ly-17,Spna-1. These results confirm and extend analyses of a large linkage group which includes genes present on a 20-30 cM span of mouse chromosome 1 and those localized to human chromosome 1q21-32. Moreover, the data indicate similar relative positions of human and mouse complement receptor-related genes REN, CD45, LAMB2, AT3, APOA2, and SPTA. These results suggest that mouse gene analyses may help in detailed mapping of human genes within such a syntenic group.
Alleles↗
Mapping of the bcl-2 oncogene on mouse chromosome 1.
Two bcl-2 alleles have been identified in inbred strains of mice by restriction fragment length polymorphism (RFLP). Analysis of a bcl-2 RFLP in a series of bilineal congenic strains (C.D2), developed as a tool for chromosomal mapping studies, revealed linkage of bcl-2 to the Idh-1/Pep-3 region of murine chromosome 1. The co-segregation of bcl-2 alleles with allelic forms of two other chromosome 1 loci, Ren-1,2 and Spna-1, in a set of back-cross progeny, positions bcl-2 7.8 cM centromeric from Ren-1,2.
Animals↗
NIH conference. Angioimmunoblastic lymphadenopathy with dysproteinemia.
Angioimmunoblastic lymphadenopathy with dysproteinemia is a disorder characterized by a sudden onset of constitutional symptoms and lymphadenopathy. Patients often have hypergammaglobulinemia, autoantibodies, rashes, thrombocytopenia, or hemolytic anemia. Diagnosis requires a lymph node biopsy that shows architectural effacement, absence of germinal centers, arborization of postcapillary venules, and a polymorphous infiltrate that includes immunoblasts. Early in the disease, activated T cells in blood and lymph nodes stimulate B cells to proliferate and produce antibody. However, late in the disease, immune suppression may result from increased suppressor function. Clonal rearrangements, which are seen in all patients with regard to either the T-cell receptor beta-chain gene or immunoglobulin genes, have been followed by malignant transformation and frank lymphoma in some patients. Thus, this disorder stands partway between benign lymphoid proliferation and clonal lymphoid transformation. The prognosis of this disorder is poor; 75% of patients die within 2 years or develop a lymphoid malignancy. The rest usually go into a sustained remission. Current treatment with corticosteroid and immunosuppressive agents is unsatisfactory, especially because of late immunosuppression and predisposition to infections.
Blood Protein Disorders↗
Clonal expansion of abnormal B cells in old NZB mice.
The spleens of old NZB mice have an abnormal population of B cells with extra chromosomes. These hyperdiploid B cells manifest increased proliferative capacity; they grow in (NZB X DBA/2)F1 spleens after intravenous injections. Molecular analysis of individual old NZB and F1 passaged spleens demonstrate that hyperdiploid cells represent a clonal or oligoclonal expansion of B cells. All spleens with at least 10% hyperdiploid cells demonstrated both heavy and kappa light chain immunoglobulin gene rearrangements by Southern blot hybridization. None of the hyperdiploid spleens from old NZB mice had lambda rearrangements and only one of five showed evidence of clonal rearrangement of the TCR-beta gene. One also had a VK10 clonal rearrangement. Elevated p53 oncogene protein was observed in NZB hyperdiploid spleen cells; however, no p53 or other oncogene rearrangements or amplifications were seen. Hyperdiploid cells were IgM-bright, IgD-dull, Ia+, dull B220, Thy-1-, and Ly-1-dull. Spleens with hyperdiploid B cells had increased percentages of Ly-1 B cells. The data suggest that hyperdiploid cells in old NZB mice represent clonal expansion of B cells and that they may represent an intermediate stage between autoimmunity and malignancy.
Aging↗
Human histone 3 F2 detects RFLPs in inbred mice, cosegregates with H4F2 and does not map to possible syntenic groups on mouse distal chromosomes 1 and distal chromosomes 3.
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Animals↗
Mouse skeletal alpha actin has limited restriction fragment length polymorphism and is not a member of the human 1q-mouse distal chromosome 1 syntatic group.
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Actins↗
Allelic variants of Ly-5 in inbred and natural populations of mice.
Allelic variants of Ly-5 in inbred commensal and other natural populations of mice were analyzed by patterns of restriction fragment length polymorphisms (RFLP) and Southern hybridization using an Ly-5 cDNA probe and by cell-surface staining with a panel of antibodies directed against polymorphic and nonpolymorphic Ly-5 determinants. New Ly-5 alleles were defined by RFLPs generated by both Eco RI and Bam HI restriction enzyme digests. The Mus musculus subspecies and other species within the genus Mus showed a strong correlation between allelic variants defined by restriction enzymes and serologic specificities. The data also suggest the conservation of the Ly-5 gene throughout the genus Mus.
Alleles↗
Effect of xid on autoimmune C3H-gld/gld mice.
The xid gene was introduced into C3H-gld/gld mice to determine its effects on the development of autoimmune disease. C3H-gld/gld.xid mice were compared with C3H-gld/gld mice for the development of lymphadenopathy, surface phenotype of lymph node (LN) cells, c-myb oncogene RNA production, serum immunoglobulin (Ig) levels, and autoantibody production. In addition, C3H-gld/gld and C3H-lpr/lpr mice were examined for serum Ig and autoantibody levels. The results showed that the xid gene had no effect on either the development of the severe lymphadenopathy characteristic of C3H-gld/gld mice or the phenotype of the Ly-2-, L3T4-, Ly-5(B220)+ T-cell subset that is expanded in the LN and spleens of these mice. Similarly, xid did not affect the high levels of c-myb oncogene RNA expression by C3H-gld/gld LN and spleen cells. By contrast, the xid gene caused a significant reduction in serum IgM but not IgA levels and almost completely ablated the generation of both IgM and IgG anti-ssDNA antibodies and anti-dsDNA antibodies. These data suggest that the xid gene can dramatically decrease the B-cell manifestations of autoimmunity in gld homozygotes without affecting their abnormal T-cell expansion. Comparisons of age-matched C3H-gld/gld and C3H-lpr/lpr mice showed that they had similarly elevated serum IgM and IgA levels and anti-ssDNA and anti-dsDNA antibody levels providing further evidence that gld and lpr produce parallel defects in C3H mice.
Animals↗
Mapping of alpha-spectrin on distal mouse chromosome 1.
DNAs from different strains of inbred mice and feral Mus spretus were found to exhibit restriction fragment length polymorphisms (RFLP) when hybridized with a probe prepared from a c-DNA clone of the mouse alpha-spectrin (Spna-1) gene. Studies of five recombinant inbred strains and (C57BL/6 X M. spretus) F1 X C57BL/6 backcross mice demonstrated that these RFLPs were allelic and that Spna-1 is closely linked to Ly-9 and Ly-17 on the distal region of chromosome 1.
Alleles↗
IL-2 modulation of murine T-cell oncogene expression.
C-myb, a cellular oncogene associated with normal thymic development, was found to be highly expressed in four interleukin 2 (IL-2)-independent T-cell lines, but not in two of three IL-2-dependent T-cell lines. The IL-2-dependent lines, HT2 and CTLL-2, were found to have low levels of c-myb mRNA in the presence of IL-2. However, short-term IL-2 depletion resulted in at least fivefold increases in c-myb message. Add-back of IL-2 after 30 hr IL-2 depletion of CTLL-2 cells resulted in return to baseline low-level c-myb mRNA. Expression of the oncogenes myc, bas, raf, and abl as well as the T-cell genes Thy-1 and CT beta did not parallel that of c-myb. These studies indicate that removal of a growth factor can result in increased levels of a specific cellular oncogene and that two nuclear protooncogenes (c-myb and c-myc) are expressed differentially during cell growth. These results may help to explain aspects of intrathymic T-cell differentiation where there is very high c-myb expression in the face of limiting amounts of growth factors such as IL-2.
Animals↗
Genetic and molecular genetic studies of murine and human lupus.
Mice and humans with systemic lupus erythematosus (SLE) have been studied with regard to cellular, genetic and molecular genetic abnormalities. B cell hyperactivity and autoantibody production are the hallmarks of this illness. In humans with SLE, there is increased stem cell, B cell precursor and B cell proliferation. The same is true of NZB mice. In lpr/lpr and gld/gld mice, marked expansion of a subpopulation of T cells allows extrathymic terminal T cell maturation and secondary B cell hyperactivity. Androgens suppress these processes and polyclonal immune activators accelerate them. Three types of genes are identified: inducing genes, accelerating genes and background genes. These give rise to abnormal expression of various cellular oncogenes, T cell receptor genes and immunoglobulin genes. The data suggest that abnormal immune regulation plays a critical role in the development of SLE, with polyclonal B cell activation being common to both mice and humans with SLE. Different genetic and cellular abnormalities underlie the ultimate syndrome, the common denominator, generalized autoimmunity, that we call SLE.
Animals↗
T cell receptor gene expression in autoimmune mice.
Autoimmunity in mice with the lpr/lpr and gld/gld genotypes is accompanied by profound lymphadenopathy characterized by the presence of a massive expansion of an unusual T cell subset. The abnormal lymph node T cells were found to express TcR beta and TcR alpha transcripts of expected sizes. There was a 10-fold increase in the 1.3-kb TcR beta transcript and a twofold increase in TcR alpha gene expression, even though Thy-1 expression was in general similar to controls. A study of T cell receptor expression during ontogeny failed to reveal any striking differences between lpr/lpr and congenic mice. There was a strong correlation between TcR beta expression and c-myb expression; however, there was no necessary association of TcR beta and c-myb expression when various T cell lines were examined. Background genes were found to influence the expression of T cell receptor genes in lpr/lpr mice. AKR-lpr/lpr lymph node cells, but not cells from other lpr/lpr mice or AKR +/+ mice, had the predominance of the 1.0-kb TcR beta transcript, which represents the nonfunctional D-J TcR beta rearrangements. Lymph nodes from MRL-lpr/lpr mice, but not C57BL/6-lpr/lpr or AKR-lpr/lpr mice, were found to express small amounts of the TcR gamma transcript. In addition, MRL-lpr/lpr but not C57BL/6-lpr/lpr mice had an age-related decrease in thymic TcR beta expression along with a decrease in thymic c-myb expression. The current study extends the characterization of T cell gene expression abnormalities in peripheral T cells of gld/gld and lpr/lpr and describes certain similarities of these cells to immature thymocytes at a molecular level. Furthermore, it illustrates the complex interactions between "background genes" and genes responsible for lymphoproliferation, which in concert lead to specific molecular and cellular abnormalities.
Animals↗
Diffuse pulmonary gallium accumulation with a normal chest radiogram in a homosexual man with Pneumocystis carinii pneumonia. A case report.
A homosexual man with A.I.D.S. (acquired immunologic deficiency syndrome) and pneumocystis infestation was found to have diffuse Ga-67 uptake in the lungs with a coincident negative chest x-ray. While Ga-67 accumulates diffusely in the lungs in a variety of conditions, the present case is the first described in a patient with A.I.D.S. in which Ga-67 was positive before roentgenographic abnormalities were demonstrated. Thus, the use of Ga-67, when A.I.D.S. is suspected, could help establish a diagnosis more promptly.
Acquired Immunodeficiency Syndrome↗
Role of Ia-positive cells in induction of secondary human immune responses to haptens in vitro.
We have described techniques for induction of primary and secondary human immune responses in vitro to lymphoid cells modified with trinitrophenyl, dinitrophenyl, and fluorescein isothiocyanate. Optimal secondary proliferative responses required the presentation of hapten on stimulator cells that shared HLA-D region determinants with the responder cell and/or the original stimulator cell. In contrast, hapten-specific cytotoxic responses assessed on modified allogeneic targets with no detected HLA homology with the responder were comparable in magnitude to those detected on modified autologous targets. Furthermore, secondary proliferative, but not cytotoxic, responses required presentation of Ia+ stimulator populations. Modified B cells, surface-immunoglobulin-negative, non T cells (null-cells), and Ia+ activated T cells all induced proliferative responses at least as effectively as equal numbers of hapten-conjugated macrophage/monocytes. Conversely, Ia(-) null cells and macrophages were entirely unable to stimulate. The data thus suggest that for proliferative responses, primed human T cells respond to modified lymphoid cells only when hapten is recognized in the context of Ia molecules.
Cytotoxicity, Immunologic↗
Recognition of hapten-modified cells in vitro by human T-lymphocytes.
Clearer definition of the recognitive structures of human T lymphocytes for antigens will be required to elucidate the molecular basis of diseases and immunological responses induced or regulated by normal or abnormal T-cell function. For this purpose we have investigated the cellular requirements for immune responses in vitro to trinitrophenyl-conjugated peripheral blood mononuclear cells. The responding cell was characterized as a T cell on the basis of rosetting with sheep erythrocytes. T-cell recognition of hapten in proliferative responses depended upon presentation of antigen in an appropriate stimulator-cell context. Neither autologous hapten-modified erythrocytes nor T cells restimulated responses of in vitro-primed lymphocytes. Moreover, hapten-conjugated non-T cells were more effective than modified unfractionated cells in restimulating proliferative responses. Both macrophages and non-T lymphocytes effectively restimulated hapten-conjugate responses.Cell-mixing experiments indicated that the failure of haptenated T cells to stimulate proliferative responses was not because of a lack of fresh macrophages; these experiments suggested instead that T cells do not express appropriate structures necessary to present haptenic determinants in an immunogenic form. Hapten-modified T cells, however, were capable of inducing primed lymphocytes to become efficient cytotoxic effector cells, indicating that T-cell recognitive units for stimulation of proliferative and cytotoxic responses are different. These data support the concept that for induction of proliferative responses, human T cells recognize conventional antigens in association with HLA-D-region-encoded Ia-like molecules.
Antibody Formation↗
Human immune responses to hapten-conjugated cells. II. The roles of autologous and allogeneic histocompatibility determinants in proliferative responses in vitro.
Proliferative responses of human lymphocytes primed in vitro to autologous TNP-cells were found to be associated with autologous D-region determinants irrespective of HLA-B locus antigens. Family studies of secondary TNP-conjugate proliferative responses demonstrated a gene dosage effect in this phenomenon. Moreover, co-culture with allogeneic cells did not affect the net TNP-conjugate proliferative responses of primed responder cells, suggesting that HLA-D region preference was due to a requirement for representation of TNP-molecules in association or combination with autologous MHC structures. Alloantigens were found to influence the sensitization of lymphocytes to autologous hapten-conjugated cells. Co-culture of allogeneic and TNP-modified autologous stimulator cells in primary cultures enhanced the secondary TNP proliferative response. Sensitization of human lymphocytes to allogeneic cells alone did not prime responses to autologous modified cells. However, priming lymphocytes to modified autologous cells potentiated responses to allogeneic cells. The data suggest a complex relationship between responses to alloantigens and modified autologous cells.
Antibody Formation↗