Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that the introduction of the bm12 mutation into NZB mice results in animals that spontaneously produce high titer IgG autoantibodies to dsDNA. The observation that NZB.H-2bm12 develop lupus although NZB.H-2b control mice do not, provides a unique system to study the role of Th cells in the production of antibodies to dsDNA. We have isolated, in the absence of a known stimulating autoantigen, a series of seven autoreactive T cell clones that provide help in vitro for the production of IgG anti-dsDNA antibodies by syngeneic B cells. The data on these seven cloned T cell lines was compared to two cloned T cell lines specific for keyhole limpet hemocyanin. The seven cloned T cell lines, coined clones 19D, 23G, 410F, 410H, C1, C15, and C52 all show significant help in vitro for production of IgM and IgG antibodies to ssDNA and dsDNA; antibody levels increased 7- to 30-fold compared to cultures without T cells. Clones C1, C15, and C52 were furthered studied and were shown to provide help for IgM antihistone and anti-OVA responses but provided significantly less help for IgG antibodies. In contrast, keyhole limpet hemocyanin-specific cloned T cell lines TK2 and TK5 provided help for IgM antibodies to ssDNA, dsDNA, and histone, but failed to significantly increase IgG antibodies to ssDNA, dsDNA, or histone. The cloned T cell lines were restricted to H-2bm12 and proliferated only in response to APC from NZB.H-2bm12 and B6.C-H-2bm12 but not NZB.H-2b or NZB.H-2d mice; their in vitro helper activity was inhibited by antibodies to class II. All cloned T cell lines expressed Thy-1, CD5, and TCR-alpha/beta. Three of the seven clones used TCR-V beta 4. However, the V beta expression of the four remaining autoreactive T cell clones could not be determined. All of the autoreactive cloned T cell lines produce significant IL-4 but no detectable IL-2 or IFN-gamma. We believe that HPLC-purified peptides eluted from I-Abm12 molecules from APC can potentially provide insight on the putative autoantigen.
 ...
PMID:Generation and characterization of cloned T helper cell lines for anti-DNA responses in NZB.H-2bm12 mice. 146 Feb 94

The skin is a primary site injured in lupus erythematosus (LE), but it is still controversial whether the injury is due to cells of the mononuclear infiltrate and which immunocompetent cells play the major role in the development of cutaneous LE. To better characterize the role of immunocompetent cells, we performed an immunohistochemical examination of these cells in LE-like skin lesions in MRL/Mp-lpr/lpr (MRL/lpr) mice. Skin lesions in 60 female MRL/lpr mice were monitored from onset to full development. Skin specimens from each stage were stained for epidermal Ia+ Langerhans cells (Ia(+)-LC), for Thy-1+ dendritic epidermal cells (Thy-1+DEC), and for the phenotype of the mononuclear cell infiltrates. The numbers of Ia(+)-LC and Thy-1+DEC were decreased markedly in the skin lesions at the later stage. However, the numbers of Ia(+)-LC were increased significantly in the central portion of lesions at an early stage and in the peripheral portion of lesions later. L3T4+ cells were predominant, and the L3T4/Lyt-2 ratio was high in dermal infiltrates at an early stage. With advancing stage, the L3T4/Lyt-2 ratio gradually decreased in dermal infiltrates, whereas the Thy-1.2/Lyt-2 ratio in lymph nodes was reversed. L3T4+ cells were especially predominant in dermal infiltrates under the epidermis with increased numbers of Ia(+)-LC. This immunohistochemical analysis of a mouse model of cutaneous LE revealed changes in immunocompetent cell populations with the evolution of skin lesions, and we conclude that Ia(+)-LC and Thy-1+DEC, as well as L3T4+ and Lyt-2+ cells, may play pathogenic roles in the development of skin lesions.
 ...
PMID:Characterization of cutaneous infiltrates in MRL/lpr mice monitored from onset to the full development of lupus erythematosus-like skin lesions. 167 42

We have studied human Thy-1 and T-cell receptor (TCR) antigen expression in mycosis fungoides and benign inflammatory dermatoses. The study included 24 biopsy specimens from 21 patients with mycosis fungoides (nine patch stage from eight patients, 13 plaque stage from 11 patients, and two tumor stage from two patients), six specimens from five patients with premycotic parapsoriasis (pre-mycosis fungoides), three specimens from three patients with lichen planus, 11 specimens from 11 patients with lupus erythematosus, 13 specimens from 13 patients with dermatitis, six specimens from six patients with drug eruptions, nine normal skin specimens from nine subjects, and three specimens from three patients with small plaque (benign) parapsoriasis. Immunoperoxidase studies using the avidin-biotin complex technique on serial frozen sections were performed. Primary antibodies were anti-human Thy-1, anti-alpha heterodimer of the TCR, anti-beta heterodimer of the TCR, and anti-delta heterodimer of the TCR. An extensive dendritic network of Thy-1+ cells was seen in all cases of mycosis fungoides. Epidermotropic cells were Thy-1 negative, and Thy-1 was expressed perivascularly in normal individuals and patients as previously reported. Epidermal gamma/delta cells were seen only in mycosis fungoides, where up to 60% of the epidermal lymphocytes expressed this TCR. The increased numbers of Thy-1 and gamma/delta T cells in mycosis fungoides were statistically significant when compared with normal skin or benign inflammatory dermatoses. The role of these dendritic dermal Thy-1+ cells and epidermal gamma/delta T cells in mycosis fungoides is unclear. The significant numbers of these potentially immunomodulating cells that were seen suggest that they are involved in the pathogenesis of mycosis fungoides.
 ...
PMID:Thy-1 and T-cell receptor antigen expression in mycosis fungoides and benign inflammatory dermatoses. 167 89

Induction of a graft-versus-host (GVH) reaction (GVHR) in non-irradiated (C57BL/10ScSn x DBA/2)F1 mice (BDF1) with DBA/2 lymphoid cells leads to chronic GVH disease (GVHD). One of the pathological alterations of this type of GVHD is hyperplasia of host B cells with production of lupus-like autoantibodies. This hyperstimulation of host B cells has previously been demonstrated to be induced by alloreactive donor T helper cells that were also proposed to maintain it. We provide three pieces of experimental evidence in support of this concept. First, treatment of mice with chronic GVHD by injection of monoclonal anti-Thy-1.2 antibodies, performed at week 6 after the injection of C57BL/6 lymphoid cells into (C57BL/6 x C57BL.bm12)F1 mice led to a significant decrease in the titre of anti-nuclear antibodies. Second, CD4+ donor T cells persisted in BDF1 mice with GVHD (GVHF1) for at least 10 weeks after the induction of GVHR; these T cells showed alloreactive helper activity against H-2b MHC determinants of the opposite parent in vitro. Third, T cells of GVHF1 mice, obtained 2 months after the induction of GVHR and transferred into normal secondary recipients, induced signs of chronic GVHD in DBF1 but not in DBA/2 mice. The combined results show that persisting donor T helper cells in GVHF1 mice retain their alloreactivity towards H-2 class II antigens for a long time after the induction of GVHR and they strongly suggest that these T cells are also the driving force behind the production of lupus-like autoantibodies at the late stage of chronic GVHD.
 ...
PMID:Persistence of allospecific helper T cells is required for maintaining autoantibody formation in lupus-like graft-versus-host disease. 214 86

The present study addresses the question of whether there is a difference in the frequencies of autoantibody-producing B-cell precursors in healthy compared with lupus-prone mouse strains. Spleen mononuclear cells (MNC) from 4-week-old (i.e. at the preclinical stage of lupus) mice were activated in vitro for 3 and 6 days with lipopolysaccharides (LPS) and the numbers of IgG, IgA and IgM autoantibody-producing cells were analysed by the ELISPOT assay. The results indicate a high frequency of IgM autoantibody-secreting cells after both 3 and 6 days in vitro stimulation. In spite of high frequencies of IgG-producing cells appearing late during the course of LPS stimulation, no IgG or IgA autoantibody producing cells were detected. No significant differences in the autoantibody repertoire were noted between healthy and lupus-prone mice, indicating that independent of the genetic background the immune system has the capacity to react with autoantibody production. Phenotypic analysis of LPS-induced, IgM-secreting B cells showed clearly that the majority of them were surface IgM+, CD5+ but Thy-1-.
 ...
PMID:Frequency and phenotypic feature of autoantibody-producing cell precursors in the preclinical stage of murine lupus. 226 71

The influence of dietary fat on autoimmunity in lupus-prone (NZB x NZW)F1 mice has been demonstrated. In defining further the effects of dietary lipid on the immune system of this strain, female weanling mice were placed on four diets differing in quantity and type of fat. Their immunologic response was then studied by a variety of tests at 4 and 7 mo of age. Few differences were seen among the four groups at 4 mo of age. At 7 mo of age, however, the mice receiving diets high in saturated and unsaturated fats had a reduced mitogenic response to T cell mitogens and an enhanced response to the B cell mitogen LPS. Immunoglobulin levels and delayed hypersensitivity responses did not show any consistent differences among the diet groups. At 7 mo, however, mice receiving diets high in unsaturated fat demonstrated hyperresponsiveness to injected sheep red blood cells as measured by the hemolytic plaque technique. In addition, peritoneal leukocytes from the same diet group exhibited an increased response to bromelain-treated autologous erythrocytes which was decreased after treatment with anti-Thy-1 antiserum and complement. Phagocytosis by peritoneal macrophages was significantly decreased in the animals fed high-fat diets, particular high saturated fat. Similarly, natural killer cell activity was markedly reduced in the mice with a high intake of saturated lipid, a finding which correlated with the in vitro production of interferon. These results indicate that diets high in fat influence immune responses and thus can affect the onset and severity of autoimmune disease. A low-fat diet can reduce the development of disease by maintaining normal immune responses. The data also suggest that unsaturated fat may influence T helper cell activity and therefore antibody production, whereas saturated fats may affect cellular immune responses which are dependent on membrane contact.
 ...
PMID:Dietary fat and immune function. I. Antibody responses, lymphocyte and accessory cell function in (NZB x NZW)F1 mice. 241 89

Using the patch clamp whole-cell recording technique, we studied expression of K+ channels in mAb-defined T cell subsets from diseased C3H-lpr/lpr and C3H-gld/gld mice and from healthy C3H-HeJ congenic controls. Both mutant mouse strains develop a lupus-like syndrome accompanied by hyperplasia of a functionally and phenotypically abnormal T cell subset. These defective cells, which are Thy-1.2+ CD4- CD8- B220+ F23.1+, display an abundance of type l K+ channels. Phenotypically similar lymph node T cells from normal C3H-HeJ mice, or young C3H-lpr/lpr mice before the onset of disease, do not display large numbers of type l K+ channels. CD4+ CD8- T cells (helper/inducer) from the mutant mice express a small number of type n K+ channels, and CD4- CD8+ T cells (suppressor/cytotoxic) show a low level of type l or n' K+ channels, as do their phenotypically equivalent counterparts in the normal mouse thymus. These results suggest that the abundant expression of type l K+ channels is a marker for the defective lpr and gld T cell subset and may reflect the "abnormal" proliferative status of these cells.
 ...
PMID:Abundant expression of type l K+ channels. A marker for lymphoproliferative diseases? 245 42

Monoclonal antibody to L3T4 has been used successfully to suppress autoimmunity in the New Zealand black/New Zealand white F1 (B/W) mouse model for systemic lupus erythematosus. To clarify the immunopathology of murine lupus and determine the effects of anti-L3T4 treatment on the cellular composition and histopathology of lymphoid organs, we examined the distribution of lymphocyte subsets in cryostat sections of the thymus, spleen, and lymph nodes of B/W mice. Immunohistologic specimens were obtained from female B/W mice that had received weekly intraperitoneal injections of either rat monoclonal antibody to L3T4 (2 mg/mouse/week) or phosphate buffered saline (200 microliters/mouse/week) from age 5 months until euthanasia at 8 months. B and T cell domains in each organ were identified on serial sections with monoclonal antibody directed against B220 (all B cells), Thy-1.2 (all T cells), L3T4 (helper T cells), and Ly-2 (cytotoxic/suppressor T cells). In control mice, striking cytoarchitectural abnormalities were identified in the thymuses, and the spleen and lymph nodes were hypertrophied relative to anti-L3T4 treated mice. Thymic abnormalities included amplification of medulla, formation of thymomas, and cortical atrophy. Amplified medullary regions and thymomas in B/W mice contained numerous B cells and L3T4+ T cells but few Ly-2+ T cells. The enlarged spleens and lymph nodes of control mice consisted of numerous secondary follicles with germinal centers containing an unusual subpopulation of T cells that expressed L3T4 but not Thy-1.2. In contrast, mice treated with anti-L3T4 did not develop histopathologic changes characteristic of systemic lupus erythematosus in any organ. However, treatment depleted L3T4+ cells from the spleen and lymph nodes, and it modulated the expression of L3T4 by thymocytes. These observations demonstrate that treatment with anti-L3T4 not only interferes with L3T4-dependent T cell functions, but it also prevents progressive abnormalities in lymphoid tissue in lupus-prone B/W mice. This preservation of normal lymphoid structure may contribute to the beneficial effects of anti-L3T4 on autoimmunity.
 ...
PMID:Treatment of murine lupus with monoclonal antibody to L3T4. II. Effects on immunohistopathology of thymus, spleen, and lymph node. 252 96

Murine lupus in BXSB mice is associated with B cell hyperactivity, monocyte proliferation, and impaired T cell function. However, the significance of these abnormalities, and the relationship among them, has not been clearly established. To examine the role of T cells in the pathogenesis of autoimmune disease in BXSB mice, we depleted specific T cell subsets from BXSB males by using rat IgG2b monoclonal antibodies (MAb) to either Thy-1.2 (on all T cells) or L3T4 (on "helper/inducer" T cells). A single injection of anti-Thy-1.2 (6 mg i.v.) at age 3 mo produced a sustained 40 to 50% reduction in circulating T cells for 6 mo. Treatment prevented monocytosis, reduced anti-DNA antibody concentration, and retarded renal disease, but it did not prolong life. Repeated injections of rat MAb to Thy-1.2 were precluded by the development of a host immune response to rat immunoglobulin (Ig) that can cause anaphylaxis in BXSB mice. In contrast, rat MAb to L3T4 stimulated little or no immune response to rat Ig. We therefore were able to treat BXSB mice weekly with anti-L3T4 (2 mg i.p.) from age 3 to 12 mo. Treatment reduced circulating L3T4+ cells beneath the level of detection by fluorescence analysis. It also significantly reduced monocytosis, anti-DNA antibody production, renal disease, and mortality. These findings establish that monocytosis and autoimmunity in BXSB mice are promoted by T cells. They extend our previous observation that MAb to L3T4 retard autoimmunity in NZB/NZW F1 mice. Our finding that treatment with MAb to L3T4 is effective in two strains of lupus-prone mice suggests that treatment with MAb to Leu-3/T4, the human homologue for L3T4, may be effective in people with systemic lupus erythematosus.
 ...
PMID:Administration of monoclonal anti-T cell antibodies retards murine lupus in BXSB mice. 308 36

T cells from murine lupus strains manifest complex defects in interleukin 2 (IL 2) production and receptor expression. The capacity of B cells from such mice to utilize IL 2 as a growth factor has not been previously reported and is examined herein. Anti-Thy-1.2 plus complement-treated spleen cells from 6-8-week-old autoimmune MRL-lpr/lpr mice and from age and sex-matched immunologically normal CBA/J mice were cultured with lipopolysaccharide (LPS) for 36 h and analyzed for the expression of IL 2 receptors using the monoclonal antibody 7D4. The percentage of B cells expressing IL 2 receptors was comparable in MRL-lpr/lpr and CBA/J mice. In contrast to those from CBA/J, BALB/c and (BALB/c X NZW)F1 mice, LPS-stimulated B cells from MRL-lpr/lpr and from (NZB X NZW)F1 mice were capable of proliferating in response to IL 2. Fractionation of MRL-lpr/lpr B cells using Percoll gradient density separation demonstrated that the IL 2-responsive population consisted predominantly of large cells. In addition, unfractionated B cells from MRL-lpr/lpr mice were found to be substantially more responsive to IL 2 than those from CBA/J and BALB/c mice following activation with anti-immunoglobulin plus LPS. The hyper-responsiveness to IL 2 may be a consequence of the state of activation of autoimmune B cells and is of potential importance in the pathogenesis of systemic lupus erythematosus.
 ...
PMID:Interleukin 2 is a proliferative signal for B cells from autoimmune mice. 309 46


1 2 Next >>