Gene/Protein Disease Symptom Drug Enzyme Compound
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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.
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PMID:Generation and characterization of cloned T helper cell lines for anti-DNA responses in NZB.H-2bm12 mice. 146 Feb 94

We report the Ig H and L chain V region sequences from the cDNAs encoding a monoclonal human IgG anti-cardiolipin/ssDNA autoantibody (R149) derived from a patient with active SLE. Comparison with the germ-line V-gene repertoire of this patient revealed that R149 likely arose as a consequence of an Ag-driven selection process. The Ag-binding portions of the V regions were characterized by a high number of arginine residues, a property that has been associated with anti-dsDNA autoantibodies from lupus-prone mice and patients with SLE. The VH gene encoding autoantibody R149 was a somatically mutated variant of the 51P1 gene segment, which is frequently associated with the restricted fetal B cell repertoire, malignant CD5 B cells, and natural autoantibodies. These data suggest that in SLE patients a common antigenic stimulus may evoke anti-DNA and anti-cardiolipin autoantibodies and provide further evidence that a small set of developmentally restricted VH genes can give rise to disease-associated autoantibodies through Ag-selected somatic mutations.
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PMID:A human systemic lupus erythematosus-related anti-cardiolipin/single-stranded DNA autoantibody is encoded by a somatically mutated variant of the developmentally restricted 51P1 VH gene. 151 80

The T cell-associated antigen CD5 has been shown to play an important role in the regulation of T cell activation. Monoclonal antibodies directed against CD5 upregulate helper function, and induce interleukin 2 (IL2) production by mature T cells as well as thymocytes. CD5 is also expressed on subsets of B cells associated with autoantibody production, and CD5+ B cells are present in increased numbers in patients with rheumatoid arthritis and systemic lupus erythematosis. More recently CD5 has been found to be present on human B lymphocytes following in vitro activation with phorbol myristate acetate. To date a similar functional role for CD5 has not to date been demonstrated for B cells. In this study we have shown that structurally similar CD5 molecules are present on activated B cells and T cells. In addition, CD5 on both stimulated B cells and T cells is phosphorylated, which may be important in the function of CD5 following activation. CD5 protein or mRNA was not detected on unstimulated splenic B cells depleted of any CD5+ cells. To investigate the control of CD5 expression, we examined a series of cytokines either alone or in combination for their effect on the induction of CD5. CD5 expression was specifically inhibited by IL4 but not by the other cytokines tested. This inhibition was very specific as IL4 did not inhibit the expression of other B cell activation antigens including CD25, B5, T9 and CD23 as well as the pan-B cell antigen CD20. The addition of other cytokines did not increase or reverse the inhibition of CD5 expression by IL4. This inhibition was demonstrated by immunofluorescence and flow cytometric analysis. Immunoprecipitation studies of 125I-labeled activated B cells demonstrated that there was a decrease in cell surface CD5 protein, and not simply inhibition of expression of a particular epitope. Northern blot analysis demonstrated that the expression of CD5 mRNA was markedly inhibited in the presence of IL4, whereas the induction of the protooncogene c-myb was unaffected. This suggests that IL4 inhibits CD5 protein expression on activated B cells by reducing the amount of CD5 mRNA transcription or increasing the degradation of CD5 mRNA. The role of the T cell-derived lymphokine IL4 in regulating CD5 expression may be important in the disease states characterized by increased numbers of CD5+ B cells.
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PMID:Expression and regulation of CD5 on in vitro activated human B cells. 247 77

It is possible to identify, in Epstein-Barr virus-transformed normal human cord blood B cell populations, cells present at a low frequency that produce IgG antibodies specific for dsDNA. By cloning out these B cells as immortalized monoclonal cell lines, it could be shown that the antibodies were the products of CD5 positive B cells. Two monoclonal anti-dsDNA antibodies were derived from cell lines T52 and A7 and these were further characterized as anionic (pI approximately 6.4) IgG4 kappa antibodies that bound with affinities of 7.18 x 10(9) l/mol and 3.28 x 10(9) l/mol, respectively, to dsDNA but did not bind to ssDNA. These affinities were similar to those of polyclonal IgG anti-dsDNA antibodies from lupus patients, which ranged from 1 x 10(9) -8.9 x 10(10) l/mol. Both T52 and A7 monoclonal anti-dsDNA antibodies were recognized by cord blood-derived IgM antibodies. These IgM antibodies were not rheumatoid factors but bound to the F(ab')2 of A7 and T52 while failing to recognize T50, which is an autologous IgG4 kappa monoclonal antibody without specificity for dsDNA. A cloned B cell line A24 generated from the same cord blood sample as A7 produced an IgM monoclonal antibody that bound to the heavy chains of T52 and A7, but not T50 on Western blot and inhibited the binding of these antibodies to dsDNA. A7 and T52 competitively inhibited each other in their binding to the anti-idiotype A24, and A24 inhibited the binding to dsDNA of some polyclonal IgG anti-dsDNA antibodies purified from sera of lupus patients. The level of inhibition of binding of these antibodies to dsDNA was directly proportional to the levels of expression of the idiotype recognized by A24 on these antibodies. The normal human cord blood, therefore, may contain cells that form an idiotype/anti-idiotype network in which the idiotype is expressed on IgG antibodies with specificity for dsDNA and the anti-idiotype is an IgM antibody that binds to a heavy chain idiotope in such a way as to interfere with its interaction with dsDNA. The presence of a similar idiotype on some polyclonal anti-dsDNA antibodies in lupus that are similarly inhibitable by the cord blood-derived anti-idiotype raises the possibility that this network may persist in later life and perhaps become dysfunctional in systemic lupus erythematosus.
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PMID:Normal human cord blood B cells can produce high affinity IgG antibodies to dsDNA that are recognized by cord blood-derived anti-idiotypic antibodies. 756 72

V gene sequences encoding two lupus-derived human monoclonal IgMk anti-ssDNA antibodies (2F7 and 1A6) and CD5 mRNA expression by the corresponding hybridomas were investigated. Both antibodies displayed V gene sequences nearly in germline configuration compared with their putative germline counterparts. It appeared that 2F7 used hv3019b9/HUD-3/JH6 and 12La/Jk2, while 1A6 utilized HHG19/D31-HUD-3/JH2 and Humkv328h5/Jk1. Assessment of R/S mutation ratios suggested that 2F7 and 1A6 have not undergone the antigen-driven somatic mutation. The HCDR3 featuring arginine appeared to be important in determining the anti-ssDNA specificity. CD5 mRNA was negative in both hybridomas. Since 2F7 was previously shown to be monospecific and of high affinity, these results provide the molecular basis of such unique immunochemical characteristics of the IgM anti-ssDNA antibody. Germline V genes and N sequences may be selected to confer such anti-ssDNA specificity during V gene rearrangement, which might involve CD5-negative B cells.
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PMID:V gene sequences of human anti-ssDNA antibodies secreted by lupus-derived CD5-negative B cell hybridomas. 862 57

Polyclonal B cell activation has been thought to play the critical role in production of autoantibodies, and possible activation of autoreactive T cells in murine lupus, especially abnormal expansion of CD5+ B cells, is one of the characteristic findings in these mice. The aim of this study was to investigate further the characteristics and function of CD5+ and CD5- B cells. Both CD5+ and CD5- B cells were isolated for in vitro autoantibody production, cytokine expression and in vivo anti-DNA antibody production with reconstitution of severe combined immunodeficient (SCID) mice. The data showed: (i) both CD5+ and CD5- B cells produced a high level of anti-DNA antibody after stimulation with lipopolysaccharide (LPS) plus IL-5; (ii) both peritoneal CD5+ and CD5- B cells expressed a high level of IL-10 mRNA after stimulation with LPS, while in contrast CD5- B cells of non-autoimmune BALB/c mice did not express IL-10 mRNA after stimulation; (iii) SCID mice reconstituted with either CD5+ or CD5- B cells all produced significant levels of anti-DNA antibodies in vivo and manifested with proteinuria. These data suggest both CD5+ and CD5- B cells play important roles in polyclonal B cell activation and subsequent autoantibody production. Generalized polyclonal B cell activation, instead of expanding a certain subpopulation of B cells, contributed to the pathogenesis of autoimmunity in murine lupus.
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PMID:In vitro and in vivo functional analysis of CD5+ and CD5- B cells of autoimmune NZB x NZW F1 mice. 891 70

Recent evidence indicates that B cell receptor signaling plays a role in the generation of the B-1 cell lineage that expresses the CD5 marker, and the CD95-mediated death plays an essential role in maintaining B cell tolerance. We therefore probed CD5 and CD95 expression on B cells from systemic lupus erythematosos (SLE) patients and control subjects. Firstly, in agreement with previous studies, we found that CD5 expression (11%) was relatively constant among control individuals. We also noted that the activation of B cells up-regulates this marker. Unexpectedly, we found that the B-1 cell subset is under-represented (3.9+/-0.3%) in SLE patients in an inactive stage of the disease. Together with related studies, these findings suggest that there is a correlation between CD5 expression and disease activity. Secondly, we found that CD95(+) B cells can be divided into two subsets expressing a high- (CD95(high)) and a low-density (CD95(low)) of CD95. There was no difference in the proportion of total CD95(+) B cells (23.5+/-2.8) in the two groups, but SLE patients in an inactive phase of the disease characteristically expressed a relatively high proportion (50%) of CD95(high) B cells. This finding would mean that a large fraction of B lymphocytes are sensitive to apoptosis, implying that autoantibody-producing B cells are derived from CD95(low) B cells and are relatively resistant to apoptosis.
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PMID:High-density expression of CD95 on B cells and underrepresentation of the B-1 cell subset in human lupus. 980 28

Recent studies indicate that normal B cells can be primed to differentiate into two distinct cytokine-secreting effector subsets, Be1 and Be2. The aim of this study was to analyse, for the first time, Be1 and Be2 cells at the single cell level in SLE patients using the recently developed technique of flow cytometry for intracellular cytokines. Peripheral blood mononuclear cells (PBMC) from SLE patients and age- and sex-matched normal controls were cultured for 24 h in the presence or absence of phorbal myristate acetate and ionomycin (PMA/I) or lipopolysaccharide (LPS). The production of type I (IFN-gamma, IL-2) and type 2 (IL-4, IL-5, IL-6, IL-10, IL-13) cytokines by B cells (and IL-10 production by fractionated CD5+ and CD5- B cells) was investigated using an intracellular cytokine staining technique and flow cytometry. In the absence of PMA/I stimulation, the percentage of B cells from SLE patients was significantly lower than those of normal subjects and significantly more SLE B cells spontaneously produced IL-10 than controls. Moreover, CD5+ B cells from SLE patients were enriched for cells with signs of previous in vivo activation and for high levels of IL-10 production. A significant positive correlation was observed between the percentage of IL-10- and IL-6-producing PMA/I-stimulated B cells in SLE patients, but not in controls. There were no significant differences in the production of other cytokines by B cells of SLE patients and normal subjects. In conclusion, a general alteration of type 1 and type 2 cytokine production by B cells is not observed in SLE patients. The role of B cell cytokines in the pathogenesis of SLE appears to be exerted by elevated secretion of in vivo IL-10, which may play an important role in the immune dysregulation observed in SLE patients. Moreover, the cross regulation of IL-10 and IL-6 is disrupted in SLE patients.
Lupus 2003
PMID:Assessment of Be1 and Be2 cells in systemic lupus erythematosus indicates elevated interleukin-10 producing CD5+ B cells. 1276 98

The dietary supplement and adrenergic receptor agonist ephedrine has been a controversial topic as its safety has been questioned. Beta-adrenergic receptor (beta-AR) activation causes immunomodulation, which may contribute to promotion of autoimmune pathology. This report investigated the ability of ephedrine to exacerbate processes associated with autoimmune disease in a lupus-prone mouse model. To mimic human supplementation, ephedrine was administered to NZM391 (lupus-prone) and BALB/c (nonlupus prone) mice orally twice a day for three months at a dose of 50 and 100 microg/day. Some ephedrine-treated NZM391 mice also were preadministered the beta-AR antagonist propranolol to investigate beta-AR involvement. Mice were bled monthly, and sera were assayed for a variety of lupus manifestations and immunological measurements. In NZM391 males and females, both doses of ephedrine significantly increased lupus manifestations, including IgG production and organ-directed autoantibody titers, and significantly lowered the ratio of IgG2a/IgG1 compared to controls. Ephedrine significantly decreased female lifespan and significantly increased circulating populations of plasma cells (CD38(hi) CD19(lo) cytoplasmic IgG+) and CD40+ B1a cells, while preventing an age-related decrease in the B1a cell population expressing a high level of CD5. While ephedrine induced gender-specific immunomodulation in BALB/c mice, increases in the lupus manifestations of anti-dsDNA titers and serum urea nitrogen were not detected. Preadministration of propranolol decreased lupus manifestations and serum levels of IgG and IgE in ephedrine-treated mice, but did not block the shift towards IgG1 production. These findings indicate that ephedrine via beta-AR can exacerbate lupus symptoms in NZM391 mice and that blockade of the beta-ARs on B cells, and not T cells, apparently was of greater importance as the inhibition of lupus symptoms corresponded to an inhibition of immunoglobulin levels, not a change of Th1/Th2 balance.
Lupus 2005
PMID:The dietary supplement ephedrine induces beta-adrenergic mediated exacerbation of systemic lupus erythematosus in NZM391 mice. 1586 16

Splenic lymphoma with villous lymphocytes (SLVL) is a rare lymphoproliferative disorder characterized by the presence of typical lymphoid cells with villous projections and monoclonal immunoglobulin (M-Ig) in about 30% of patients. The simultaneous presence of more than one M-Ig in SLVL has not been reported. We present two patients with SLVL, each with three serum M components associated with the presence of rheumatoid factor (RF) and antiphospholipid antibodies (APLA) together with fatal thromboembolic events. Both patients presented with splenomegaly and typical bone marrow cytology with 30-50% infiltration of lymphoid cells that had the characteristics of villous lymphocytes. Immunohistochemistry of bone marrow histology showed CD20++, CD43-/+, CD5-, IgM+, lambda+ and kappa-. In serum, two M-IgM lambda components were combined with M-IgG lambda in case 1 and with M-IgA lambda in case 2. In both cases, M-IgM displayed RF as well as lupus anticoagulant activity and free monoclonal lambda (lambda) light chains were present. In addition to M-IgM, in case 1 M-IgG also behaved like an APLA. One patient was splenectomized. Both patients suffered thromboembolic complications and died 3 and 8 months after presentation with signs of massive pulmonary thromboembolism.
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PMID:Multiple M components in two patients with splenic lymphoma with villous lymphocytes. 1600 26


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