Studies of the effects of Y chromosome factors on the expression of autoimmune disease.
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Animals↗
Biomedical subjects
C A Laskin
Publications and source records attributed to C A Laskin.
Comparison of response to stem cell differentiation signals between normal and autoimmune mouse strains.
Normal DBA/2 and autoimmune NZB mice were studied with regard to signals eliciting differentiation and division of bone marrow stem cells. Irradiated (NZB X DBA/2)F1 mice were repopulated with various combinations of T-depleted bone marrow from NZB and DBA/2 mice. In response to the repopulation signal of irradiation, recipients of autoimmune NZB marrow initially demonstrated expansion of LY-5+ lymphoid and hemopoietic cells, particularly of the B cell lineage. The greater the proportion of NZB marrow, the higher the percentage of lymphoid cells observed 2 wk post-repopulation. B cells (ThB-positive cells) were increased in disproportionate numbers in recipients of NZB marrow, even those that had received as little as 20% NZB bone marrow cells. However, by 2 mo, the initially observed increase in lymphoid cells in recipients of NZB marrow was no longer observed. Up to 6 mo post-repopulation, cytogenetic analysis revealed that irradiated recipients were repopulated in the same proportion of DBA/2: NZB as was in the injected marrow. Endogenous colony formation assays indicated that recipients of 100% NZB, 80% NZB, and 20% NZB marrow all had greater numbers of splenic endogenous colonies than did recipients of DBA/2 marrow alone. These studies indicated that autoimmune NZB marrow repopulated irradiated mice in the proportion in which it was injected, but there was a disproportionate early increase in cells of the B lineage as well as a disproportionate increase in splenic colony formation.
Animals↗
Heterogeneity of oral tolerance defects in autoimmune mice.
Three strains of mice, BXSB, MRL-lpr/lpr, and NZB, which spontaneously develop autoimmune syndromes, all fail to become tolerant to challenge with bovine gamma-globulin (BGG) in adjuvant by prior intraperitoneal (ip) injection of BGG in tolerogenic form. In the present study, these three strains were examined for the ability of a single enteric dose of BGG or ovalbumin (OVA) to tolerize to subsequent challenge with the corresponding antigen in adjuvant. In contrast to lack of ip tolerance to BGG, BXSB mice were tolerant to gastrointestinal (GI) BGG as well as to GI OVA, suggesting that ip and GI forms of tolerance to BGG operate through distinct mechanisms in these mice. MRL-lpr/lpr mice had normal tolerance to GI OVA but not GI BGG. The presence of enteric tolerance to one antigen but not another suggests that the responsible cellular defects vary from one antigen to another. NZB mice lacked tolerance to both GI BGG and GI OVA. Splenectomy of NZB mice allowed normal tolerance to enteric BGG; spleen cells administered to splenectomized NZB mice interfered with BGG tolerance. Congenic NZB.xid mice were tolerant only to OVA. These results suggest that in NZB mice Lyb 5+ cells interfere with tolerance to enteric OVA and Lyb 5- spleen cells interfere with tolerance to enteric BGG.
Animals↗
NIH conference. Systemic lupus erythematosus: insights from animal models.
Systemic lupus erythematosus is a multisystem, antibody-mediated, autoimmune disorder that occurs spontaneously in humans and mice. Genetic factors appear to play an important predisposing role in the disorder: The presence of certain genes may produce a generalized immune abnormality, whereas others may lead to specific autoantibodies. Environmental triggers increase autoantibody production and augment the expression of illness. Bacterial and viral illnesses can provide stimulation by activating macrophages and T cells that, in turn, stimulate B cells. In the absence of normal control mechanisms, the stimulatory process is not suppressed, and excessive stem cell proliferation results in abnormal B-cell proliferation. A trigger for the disease is the signaling of the proliferating B cells to differentiate into antibody-forming cells. Most autoantibody-producing B cells can be eliminated from mice with lupus erythematosus by virtue of the presence of the gene, xid. In addition, administration of an analog of arachidonic acid is an effective treatment for murine lupus erythematosus.
Animals↗
Genetic studies in NZB mice. VI. Association of autoimmune traits in recombinant inbred lines.
Because recombinant inbred lines, which are homozygous at most loci, can have any combination of parental genes, the numbers and the association of genes responsible for traits can be suggested by examining phenotypic distribution in these lines. Such studies, reported herein, uncovered two major families of nonlinked genetic loci whose interactions underlie autoimmune abnormalities in NZB mice. One family of genes leads to antibodies to murine leukemia virus, ssDNA, and erythrocytes, as well as to defective tolerance to bovine gamma-globulin. The other group of genes leads to polyclonal B cell activation, stem cell abnormalities, endogenous murine leukemia virus expression, and NTA. These studies help explain previously observed dissociations between the traits associated with these two groups of genes. Such genetic analyses provide the basis for future molecular biologic studies of the genes and gene products that underlie autoimmune disease.
Animals↗
Comparison of stem-cell recovery in autoimmune and normal strains.
The capacity of NZB stem cells to proliferate in vivo was evaluated in two systems which required repopulation of peripheral organs. In both types of depletion systems, stem-cell repopulation after cyclophosphamide treatment or adoptive transfer repopulation in lethally irradiated hosts, it was found that NZB stem cells were hyperproliferating. The increase in proliferating cells was most pronounced in the spleens of NZB mice treated with high-dose cyclophosphamide and in lethally irradiated F1 mice reconstituted with NZB T-cell-depleted bone marrow. Thus, upon a stimulus to repopulate, NZB marrow stem cells will hyperproliferate in peripheral organs resulting in an increase in cell number. The abnormality in the marrow cells can be observed in young NZB mice when their marrow cells are in an environment which requires recovery and division.
Animals↗
NZB cells actively interfere with the establishment of tolerance to BGG in radiation chimeras.
We report experiments designed to determine if the tolerance defect in NZB mice results from i) failure of NZB cells to become tolerant, or ii) the ability of NZB cells to interfere actively with the development of tolerance. The results indicate that NZB cells are primed by the tolerogen itself and actively interfere with the expression of tolerance by DBA/2 cells, which normally can be rendered tolerant.
Animals↗
Studies of defective tolerance induction in NZB mice. Evidence for a marrow pre-T cell defect.
NZB mice manifest a defect in tolerance induction by deaggregated heterologous gamma globulins. We have used an adoptive transfer system to study the defect. Thymectomized, intact, or thymectomized recipients given thymic epithelial grafts were studied after lethal irradiation and reconstitution with NZB, DBA/2, or (NZB x DBA(F1 marrow depleted of mature T cells. NZB thymocytes were responsible for the tolerance defect of NZB mice. The information for the defect was present in the NZB marrow prethymocyte. That defect could only be expressed when there was further maturation in association with a thymus. However, the normal DBA/2 thymic epithelium served as well as the abnormal NZB thymic epithelium. These studies resolve existing conflicts as to whether the NZB marrow or thymus is responsible for the loss of tolerance in association with autoimmunity.
Animals↗
Genetic, environmental, and cellular factors in the pathogenesis of systemic lupus erythematosus.
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Androgens↗
The specificity of in vivo tolerance to haptens in NZB and normal mice after exposure to hapten-modified syngeneic spleen cells.
We have evaluated hapten-specific hyporesponsiveness induced by in vivo administration of TNP-modified syngeneic spleen cells (TNP-SC). Pretreatment of non-autoimmune mice led to hyporesponsiveness to challenge with either TNP or the closely related hapten DNP coupled to Ficoll. There was also a significant reduction of the direct PFC response after challenge with TNP-HGG. In tolerized mice challenged with TNP-HGG, the IgM portion of the serum response was similarly suppressed; however, the total serum antibody as well as the indirect PFC response was not suppressed. There was no tolerance at all when the mice were challenged with DNP-HGG. Thus, exposure to TNP-SC results in an incomplete form of hapten-specific B cell tolerance. This tolerance is selective for the IgM isotype and does not extend to the cross-reactive hapten DNP on a thymic-dependent carrier, although it does extend to a DNP on a thymic-independent carrier. Autoimmune NZB mice were defective with regard to tolerance after injection of hapten-modified syngeneic spleen cells. They did manifest a reduced direct PFC response to the challenge with TNP-Ficoll, but failed to demonstrate cross-tolerance to DNP-Ficoll challenge. Moreover, they did not have suppression of the hapten-specific IgM response after challenge with TNP on the thymic-dependent carrier. These abnormalities in tolerance induction in NZB mice to modified self may help to explain the loss of self-tolerance that occurs spontaneously and is expressed as autoimmune disease.
Animals↗
Studies of immune abnormalities in systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) in humans and in mice appears to be a syndrome with different cellular bases. In individuals, the illness is influenced by a variety of factors, including genetic, hormonal, immune, and environmental. In mice, SLE can be induced with polyclonal B-cell activators and thymectomy. Retardation of disease occurs with the gene xid on an NZB background. Tolerance studies indicate that tolerance depends upon a normal thymus. In addition, females can be nontolerant with a single immune defect, whereas males can become tolerant with only one defect; they become nontolerant with two immune defects. These studied may help to explain the prevalence of SLE in females and the protective effects of androgens. Human SLE is characterized by excessive B cell activity and impaired T cell activity, especially in active disease. A scheme by which the disease becomes activated is put forth. The details of cell-cell dialogue are becoming clearer with study of the autologous mixed lymphocyte reaction. T 4+ cells provide helper signals for T 8+ cells. Macrophages and T cells combine to regulate the AMLR. The AMLR itself gives rise to a variety of functional cells and serves as an amplification system. This system is defective in active SLE. Preliminary attempts have been made to separate human SLE into subgroups on the basis of the ratio of helper to suppressor cells (RT). A low RT is associated with renal disease, whereas a high RT characterizes patients with a multisystem illness with less important kidney involvement.
Androgens↗
Studies of defective tolerance in murine lupus.
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Animals↗
Hemochromatotic arthropathy mimicking rheumatoid arthritis. A case with subcutaneous nodules, tenosynovitis, and bursitis.
A 63-year-old man developed symmetrical polyarthritis, subcutaneous nodules at the elbows, olecranon bursitis, and recurrent tenosynovitis. He was later discovered to have idiopathic hemochromatosis. Staining of the subcutaneous nodule revealed iron deposits. These manifestations which are common to rheumatoid arthritis may be seen in hemochromatotic arthropathy.
Arthritis↗
Association of fetal heart block and massive placental infarction due to maternal autoantibodies.
Two different effects of maternal autoantibodies presented in a third-trimester pregnancy. The first was complete fetal heart block, demonstrated ultrasonographically, which correlated with the presence of anti-Ro and anti-La antibodies in the maternal serum. The second effect was decidual vasculopathy and thrombosis, a morphologic finding in the placenta that caused massive placental infarction and intrauterine death. The placental pathology correlated with the presence of anticardiolipin antibodies in the maternal serum at the time of stillbirth.
Adult↗
Twice-daily dosing of enteric-coated aspirin in patients with rheumatic diseases.
To determine the feasibility of twice daily dosing of enteric-coated aspirin (EntrophenR), a preliminary trial on 10 patients with rheumatic diseases was conducted. Three plasma salicylate levels on 2 separate occasions, 1 day apart, were determined. In 9 of the 10 patients studied at steady-state, therapeutic levels were attained (15-30 mg/dl). There were no gastrointestinal side-effects. One case developed tinnitus which resolved with a small reduction in dosage. On the basis of this short-term study, twice-daily EC-ASA appears to be effective in maintaining adequate plasma salicylate levels, and it seems to compare favourably to ASA given in multiple daily doses. On a long-term basis, it may improve patient compliance.
Adult↗