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author:("abou, nabic I")
1.  Estradiol Differentially Regulates Calreticulin: A Potential Link with Abnormal T Cell Function in Systemic Lupus Erythematosus? 
Lupus  2013;22(6):583-596.
Systemic lupus erythematosus (SLE) is an autoimmune disease that affects women nine times more often than men. The present study investigates estradiol-dependent control of the calcium buffering protein, calreticulin, to gain further insight into the molecular basis of abnormal T cell signaling in SLE T cells.
T cells were purified from blood samples obtained from healthy females and SLE patients. Calreticulin expression was quantified by real time polymerase chain amplification. Calreticulin and estrogen receptor-α were co-precipitated and analyzed by Western blotting to determine if the proteins associate in T cells.
Calreticulin expression increased (p= 0.034)in activated control T cells, while estradiol decreased (p = 0.044) calreticulin in resting T cells. Calreticulin expression decreased in activated SLE T cell samples and increased in approximately 50% of resting T cell samples. Plasma estradiol was similar (p > 0.05) among SLE patients and control volunteers. Estrogen receptor-αand calreticulin co-precipitated from nuclear and cytoplasmic T cell compartments.
The results indicate that estradiol tightly regulates calreticulin expression in normal human T cells and the dynamics are different between activated and resting T cells. The absence of this tight regulation in SLE T cells could contribute to abnormal T cell function.
PMCID: PMC4072130  PMID: 23535532
SLE; human T cells; estradiol; calreticulin; estrogen receptor-α
2.  1 Estradiol Targets T Cell Signaling Pathways in Human Systemic Lupus 
Clinical immunology (Orlando, Fla.)  2009;133(3):428-436.
The major risk factor for developing systemic lupus erythematosus (SLE) is being female. The present study utilized gene profiles of activated T cells from females with SLE and healthy controls to identify signaling pathways uniquely regulated by estradiol that could contribute to SLE pathogenesis. Selected downstream pathway genes (+/− estradiol) were measured by real time polymerase chain amplification. Estradiol uniquely upregulated six pathways in SLE T cells that control T cell function including interferon-α signaling. Measurement of interferon-α pathway target gene expression revealed significant differences (p = 0.043) in DRIP150 (+/− estradiol) in SLE T cell samples while IFIT1 expression was bimodal and correlated moderately (r = 0.55) with disease activity. The results indicate that estradiol alters signaling pathways in activated SLE T cells that control T cell function. Differential expression of transcriptional coactivators could influence estrogen-dependent gene regulation in T cell signaling and contribute to SLE onset and disease pathogenesis.
PMCID: PMC2783703  PMID: 19793680
SLE; estradiol; interferon-α; T cell signaling; microarray
3.  Network Theory in Autoimmunity 
Journal of Clinical Investigation  1981;67(5):1297-1304.
Regulation of serum anti-DNA antibody in systemic lupus erythematosus (SLE) by an antiidiotypic antibody was evaluated. Various sera from SLE patients in active and inactive states of their disease, as well as sera from normal individuals, were first completely depleted of anti-DNA and of DNA by affinity chromatography. The suppressive capacity of equimolar concentrations of the various depleted sera (blocking sera) on target lupus sera were determined. The target sera were from lupus patients with known DNA-binding capacity. Blocking sera from inactive SLE suppressed the binding of autologous anti-DNA antibody to [3H]DNA (n = 19,P < 0.01). Blocking sera from active SLE (n = 19), as well as human serum albumin, did not suppress. Sera from normal donors who had no contact with lupus patients or with lupus sera did not suppress (n = 14, P > 0.5), whereas those from normal donors who had contact with lupus patients or sera did suppress the binding (n = 5,P < 0.02). The anti-anti-DNA antibody suppressive activity in the inactive lupus serum was shown to be localized within the F(ab′)2 portion of immunoglobulin (Ig)G and could not be removed upon adsorption by normal human gammaglobulin. Furthermore, immune complexes could be detected by a Clq binding assay when the inactive lupus blocking sera were incubated with the anti-DNA antibody containing target sera. The specificity of the suppressive serum factor was shown by its inability to block the binding of tetanus toxoid to antitetanus antibody and its ability to block the binding of DNA to F(ab′)2 fragments of active lupus IgG.
Regulation of serum anti-DNA antibody levels by anti-antibodies could induce and maintain disease remission in lupus patients and prevent disease expression in normals.
PMCID: PMC370696  PMID: 6971876
4.  Suppressor-Cell Antibody in Systemic Lupus Erythematosus 
Journal of Clinical Investigation  1979;63(3):536-539.
Circulating antibodies that could be responsible for the suppressor thymus-derived (T)-cell dysfunction in active systemic lupus erythematosus (SLE) were investigated. Sera from 14 active and inactive SLE patients were compared with a pool of 22 normal sera. All sera were adsorbed with a pool of normal platelets to exclude antihistocompatibility leukocyte antigen antibodies; with AB erythrocytes to exclude isohemagglutinins; and with a pool of normal bone marrow-derived (B) lymphocytes, monocytes, and neutrophils to deplete anti-B-cell antibodies, Fc-receptor antibodies, and antibodies directed against neutrophils or monocytes. Sera from active SLE patients were capable of inhibiting the activation of normal, blood lymphocytes by concanavalin A to become suppressor cells. The latter were assayed by coculturing the concanavalin A-activated cells with autologous lymphocytes, which were then activated with either phytohemagglutinin for proliferative response or with pokeweed mitogen for B-cell immunoglobulin (Ig) synthesis and secretion. Specific incorporation of cultures with phytohemagglutinin showed a value of 67±13 (mean±SD) for suppressor cells treated with adsorbed, active SLE sera. This value was significantly different (P < 0.001) from that of cells treated with the inactive SLE sera or with the pool of normal sera. Similar findings were seen with respect to the B-cell target parameters. Cytoplasmic Ig and IgG in supernates of cultures with pokeweed mitogen showed values of 17±5% and 717±134 ng/culture, respectively, for suppressor cells treated with the adsorbed, active SLE sera. This was significantly different from those treated with the inactive SLE sera or with the pool of normal sera. The antisuppressor-cell factor was shown to be IgG, complement independent, not cytotoxic, active at 37°C and at room temperature, but not at 4°C, and adsorbable with T cells.
Suppressor T-cell antibody in sera of active SLE patients could be responsible for the observed suppressor T-cell dysfunction seen in active SLE. The mechanisms responsible for the induction of the antisuppressor-cell antibody are unknown.
PMCID: PMC371984  PMID: 311787
5.  Suppressor-Cell Dysfunction in Systemic Lupus Erythematosus 
Journal of Clinical Investigation  1978;62(4):789-796.
To characterize the cell(s) responsible for the suppressor-cell dysfunction in active systemic lupus erythematosus (SLE), we fractionated blood mononuclear cells into thymus-derived (T), bone marrow-derived (B), and monocyte-depleted populations. Various cell populations from active SLE, inactive SLE, or normals, were activated with Concanavalin A, washed, and then co-cultured with active SLE cells. Soluble immune response suppressor (SIRS) from culture supernates of the activated cells was also used for the possible correction of the suppressor-cell dysfunction. Suppression was tested by enumerating DNA-binding cells by radioautography and by quantitating anti-DNA antibody in culture supernates by radioimmunoassay; and immunoglobulin was tested in cells and supernates by the immunofluorescence and the immunofluor techniques, respectively. Except for the numbers of DNA-binding cells, which were not suppressed, all the other three parameters in co-cultures with cells from active SLE patients were suppressed by Concanavalin A-activated cells (P < 0.001), or by SIRS (P < 0.05) from normals or inactive SLE patients. Concanavalin A-activated autologous or allogeneic active SLE cells and nonactivated cells from active or inactive SLE failed to suppress the various B-cell functions. Nonactivated normal cells suppressed levels of anti-DNA and immunoglobulin in supernates (P < 0.05).
In characterizing the cells responsible for the suppressor dysfunction, it was clear from the results that T cells responsive to Concanavalin A activation are deficient in active SLE and fail to generate SIRS. On the other hand, monocytes from active SLE patients are responsive to signals from the activated T cells of normals or inactive SLE donors. Because SIRS suppresses active SLE cells in vitro, it might be considered therapeutically for the in vivo modulation of SLE.
PMCID: PMC371830  PMID: 308952
6.  Comparative Study of Bone Marrow and Blood B Cells in Infantile and Acquired Agammaglobulinemia 
Journal of Clinical Investigation  1973;52(9):2218-2224.
The status of immunoglobulin (Ig) receptors of the bone marrow dependent (B) cells present in either the bone marrow (BM) or peripheral blood (PB) of three patients with infantile agammaglobulinemia (I-AGG), or seven patients with acquired agammaglobulinemia (A-AGG) is compared with those of 12 controls. Quantitative and qualitative changes of the different classes of Ig receptors on B cells were evaluated by their capacity to bind [125I]anti-Ig, to be stained with fluorescinated anti-Ig and their in vitro proliferative capacity upon incubation with the anti-Ig. Patients with I-AGG lacked B cells in both the BM and PB. Whereas BM cells of patients with A-AGG carried receptors similar to control cells, their blood B cells had fewer IgM, IgG, and IgA cells which failed to proliferate in vitro in the presence of the anti-Ig. An anti-IgM of the IgG class was detected in the sera of patients with A-AGG but not in sera of I-AGG. The isolated anti-IgM agglutinated human red cells coated with IgM. The anti-IgM partially blocked the binding of fluorescinated or radiolabeled anti-IgM to IgM peripheral blood lymphocytes of normal controls. The eluted anti-IgM in presence of complement was partially cytotoxic to normal cells. It is concluded that I-AGG-B cell defect is due to failure of B cell development in the bone marrow compartment whereas the peripheral exclusion of IgM cells by an anti-IgM with the subsequent failure of differentiation of both IgG and IgA cells could be an important mechanism in A-AGG-B cell defect.
PMCID: PMC333023  PMID: 4580388
By appropriate irradiation and cell transfer experiments, a direct correlation was observed between the presence of viable and immunologically active antigen-reactive cells and the capacity of the rabbits to respond following immunization. Rabbits given 800 R total body irradiation were unable to elicit a humoral immune response nor did they possess significant numbers of antigen-reactive cells. The ability to respond with humoral antibody formation did not reappear until antigen-reactive cells could be detected. These results strongly indicate that the presence of competent antigen-reactive cells are necessary for the successful induction of the humoral immune response in the rabbit.
PMCID: PMC2138722  PMID: 5343438
Rabbits were made immunologically tolerant to either human serum albumin or bovine gamma globulin by the neonatal administration of antigen. At 10 wk of age, they were challenged with the tolerogenic antigen and found to be non-responsive. However, these tolerant rabbits could respond with humoral antibody formation directed toward the tolerogenic antigen if they were treated with normal, allogeneic bone marrow or bone marrow obtained from a rabbit made tolerant toward a different antigen. They were incapable of responding if they were given bone marrow obtained from a rabbit previously made tolerant to the tolerogenic antigen. Irradiated rabbits were unable to respond if treated with tolerant bone marrow, but could respond well if given normal bone marrow. Since it has previously been demonstrated that the antibody-forming cell, in an irradiated recipient of allogeneic bone marrow, is of recipient and not donor origin, the data presented strongly indicate that the unresponsive cell in the immunologically tolerant rabbit is the antigen-reactive cell.
PMCID: PMC2138669  PMID: 4183777
The antigen-reactive cells in normal rabbit bone marrow could be isolated from a suspension of marrow cells by passage of the cells through an antigen-sensitized glass bead column. The cells which passed through the column were deficient in antigen-reactive cells directed to the antigen used to sensitize the glass beads, whereas the cells eluted from the column could transfer antibody-forming capacity to irradiated recipients only with respect to the specific sensitizing antigen. Separation of the bone marrow antigen-reactive cells could not be achieved by passage of the cells through nonsensitized glass bead columns or in the presence of excess free antigen in the column. Cells which were retained by, and later eluted from, the antigen-sensitized glass bead columns were mostly small mononuclear cells, whereas cells which passed through the columns were morphologically similar to the original unfractionated bone marrow cell suspension. The data indicate the presence of an antibody or antibody-like structure, with defined immunological specificity, on the surface of the normal bone marrow antigen-reactive cell.
PMCID: PMC2138668  PMID: 4893095
Irradiated rabbits given allogeneic bone marrow cells from normal adult donors responded to an injection of sheep red blood cells by forming circulating antibodies. Their spleen cells were also capable of forming many plaques using the hemolysis in gel technique, and were also capable of undergoing blastogenesis and mitosis and of incorporating tritiated thymidine upon exposure to the specific antigen in vitro. However, irradiated rabbits injected with allogeneic bone marrow obtained from rabbits injected with sheep red blood cells 24 hr prior to sacrifice (primed donors) were incapable of mounting an immune response after stimulation with sheep red cells. This loss of reactivity by the bone marrow from primed donors is specific for the antigen injected, since the immune response of the irradiated recipients to a non-cross-reacting antigen, the horse red blood cell, is unimpaired. Treatment of the bone marrow donors with high-titered specific antiserum to sheep red cells for 24 hr prior to sacrifice did not result in any diminished ability of their bone marrow cells to transfer antibody-forming capacity to sheep red blood cells. The significance of these results, with respect to the origin of the antigen-reactive and antibody-forming cells in the rabbit, is discussed.
PMCID: PMC2138626  PMID: 5766947
11.  Comparative Study of the In Vitro Proliferative Responses of Blood and Synovial Fluid Leukocytes of Rheumatoid Arthritis Patients 
Journal of Clinical Investigation  1973;52(7):1627-1631.
Lymphocyte-rich suspensions from blood and synovial fluid (SF) of 20 patients with rheumatoid arthritis (RA) and from blood of 12 normal subjects, were cultured with heat-aggregated, aggregate-free, and native human gamma globulin (HGG), with autologous IgG separated from RA-SF by anion-exchange chromatography and with phytohemagglutinin (PHA). No significant differences were noted between the in vitro proliferative responses of blood lymphocytes of RA and normal controls to any of these preparations. Significant differences were noted between blood and SF lymphocytes of RA patients with respect to their responses to the aggregate-free HGG and to PHA. Incubation of RA-SF cells but not RA-blood cells with aggregate-free HGG before their culture with the aggregated HGG markedly suppressed the in vitro proliferative response to the latter. The observed differences between blood and SF lymphocytes and the suppression of blastogenic response of SF cells by exposure to the aggregate-free preparation raise the possibility of modulating the immune and/or the inflammatory responses in RA.
PMCID: PMC302435  PMID: 4124157

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