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PubMed1988

Enzyme-linked immunosorbent assay for detection of retroviral gp70 and gp70-anti-gp70 immune complexes in sera from SLE mice.

Since a retroviral envelope glycoprotein, gp70, present in sera is prominently involved in the pathogenesis of murine systemic lupus erythematosus (SLE), the detection of gp70-anti-gp70 immune complexes (gp70 IC) is particularly useful for the study of murine SLE. To facilitate the detection of gp70 and gp70 IC, we have developed a simple and sensitive enzyme-linked immunosorbent assay (ELISA). Using an affinity column coupled with whole mouse serum proteins containing serum gp70 or with Rauscher murine leukaemia virus (MuLV), antibodies specific to serum gp70 or to Rauscher MuLV gp70 were purified from hyperimmune goat anti-Rauscher MuLV gp70 antisera. Only affinity-purified anti-serum gp70 fraction, but not anti-Rauscher MuLV gp70 fraction, was able to detect serum gp70 efficiently in the ELISA, because only a minor fraction of goat anti-Rauscher MuLV gp70 antibodies is cross-reacting with serum gp70. This procedure could be applied to other antigen-antibody systems, in which only antibodies to heterologous cross-reacting antigens are available, to detect free and antibody-complexed antigens in pathological sera.

Animals↗
PubMed1988

An idiotope-specific autoantibody in SLE.

The public idiotype Id-16/6 and the public idiotope Id-LLa were originally defined on the same human monoclonal anti-DNA antibody, but they are also known to occur separately on other anti-DNA antibodies. We sought the presence of these immunoglobulin variable region markers in purified immunoglobulins from the serum of nine patients with systemic lupus erythematosus (SLE) and 33 healthy donors. Sera from five patients were positive for Id-16/6, and five were positive for Id-LLa. The immunoglobulin preparations were passed over a Sepharose-Id-16/6 column in order to recover auto-anti-idiotypes. An eluate of that column was obtained from the immunoglobulin preparation of one patient whose serum was Id-16/6+ and Id-LLa-. This eluate was shown by competition assay to bind to IdLLa. This is the first demonstration of spontaneously arising human auto-anti-idiotypes against a specific idiotypic system in SLE. The results suggest that antibodies against the Id-LLa idiotope may play a role in immunoregulation.

Antibody Specificity↗
PubMed1978

The reaction of SLE antibodies with native, single stranded RNA: radioassay and binding specificities.

Escherichia coli 3H-tRNA and MS2 phage 125I-RNA were prepared and used in a sensitive nitrocellulose filter assay. Antibodies that bound these RNA ligands occurred in the sera of several patients with SLE, but not in sera of patients with other connective tissue diseases. The antibody populations that bound polyribonucleotides (largely IgG) were distinct from antibody populations that bound polydeoxyribonucleotides. Competition experiments showed that the anti-RNA antibodies preferentially bound native ssRNA as compared with synthetic single and double stranded polyribonucleotides. There was increasing affinity with increasing m.w. of the ssRNA. The anti-tRNA population was of restricted heterogeneity (Sips index 0.83) and bound tRNA with an average association constant (Ko) of 9 x 10(6) l/mole at 4 degrees C. The anti-MS2 RNA population was much more heterogeneous (Sips index 0.67) and bound MS2 RNA with a Ko of about 3 x 10(9) l/mole at 4 degrees C. Whereas NZB/NZW mice spontaneously produce RNA reactive antibodies with conformation specificity for native tRNA, human SLE anti-RNA antibodies appear to have very little of this type of conformation specificity.

Antibody Specificity↗
PubMed1987

A common idiotype expressed on a murine anti-Sm monoclonal antibody and antibodies in SLE sera.

A rabbit anti-idiotypic antiserum made against a murine monoclonal anti-Sm autoantibody (Y2) was used in a solid-phase radioimmunoassay to investigate idiotypic cross-reactivity among anti-Sm antibodies present in sera from patients with systemic lupus erythematosus. Sera from 25 of 51 SLE patients (49%) containing anti-Sm antibodies were positive for this Y2 idiotype compared to only one of 22 normal human sera. Nine of 28 SLE patients (32%) whose sera were anti-Sm negative were also positive for the Y2 idiotype in low titre. Binding was not due to rheumatoid factor-like activity but was specific for the Y2 determinant and could be eliminated by absorption with Y2 monoclonal antibodies. The anti-idiotypic antibody blocked the ability of 12 of 25 anti-Sm positive lupus sera to bind Sm. Conversely, Sm antigen inhibited the binding of anti-idiotypic antibody in nine of 12 lupus sera.

Animals↗
PubMed1986

Extractable nuclear antigen (ENA) autoantibodies in SLE: an immunogenetic relationship with HLA, C4 and Bf alleles.

Sera from 36 subjects with systemic lupus erythematosus (SLE) were examined for extractable nuclear antigen (ENA) autoantibodies by immunoassay with the ribonucleoprotein (RNP) subset being determined by immunodiffusion. The prevalence of the genetic markers of HLA, the fourth complement component (C4) and properdin factor (Bf), which are all coded for within the major histocompatibility complex on chromosome 6 were analysed in relation to various parameters of these autoantibodies. The following associations were observed: The lowest ENA antibody titres of the RNP negative group were associated with HLA A9 (P less than 0.05), while the lowest RNA-ase sensitive ENA (RSE) subset antibody levels were associated with HLA Dr 1 (P less than 0.05). For the complement markers, C4 AQo was associated with the lowest affinity ENA antibodies (P less than 0.05), while the BF F allele and Fs phenotype had lower RSE antibody levels than did the S allele (P less than 0.05) and the SS phenotype (P less than 0.05) respectively. This study demonstrated diverse association between various MHC markers and ENA antibody parameters, indicating that there are distinctive immunogenetic influences over ENA autoantibodies in SLE.

Adolescent↗
PubMed1986

Mononuclear phagocyte system in SLE. II. A kinetic model of immune complex handling in systemic lupus erythematosus.

Using the principles of reaction kinetics, we constructed a model for the handling of immune complexes and the pathogenesis of SLE immune complex disease. The model incorporates rate constants for complement- and Fc-mediated clearance, parameters for autoantibody, complement and immune complex levels, and scores for clinical disease activity. The model assumes that complement fixation by immune complexes is a prerequisite for complement-mediated clearance and that disease activity results from immune complex deposition. To test the relationships derived, data from 32 lupus patients were analyzed and the predictions were compared with actual findings. The model predicts a low correlation coefficient between disease activity and immune complex levels (found, r = 0.25, p greater than 0.1). The model also predicts a poor correlation between disease activity and impaired Fc-mediated clearance in patients with normal complement levels (found, r = 0.10, p greater than 0.1), but a high correlation coefficient between disease activity and impaired Fc-mediated clearance in patients with hypocomplementemia (found, r = 0.61, p less than 0.001). In patients with normal complement levels, the model predicts a good correlation between anti-DNA antibody and immune complex levels (found, r = 0.71, p less than 0.001), whereas hypocomplementemic patients should have a good correlation between anti-DNA to CH50 ratios and immune complex levels (found, r = 0.73, p less than 0.001). The model predicts that disease activity should correlate better with the product of the anti-DNA to CH50 ratio and the rate constant for Fc-mediated clearance than with any single parameter (found, r = 0.85, p less than 0.0001). These significant correlations, which were predicted by the model, suggest that complement-mediated mechanisms are the first line of host defense against immune complex-induced injury, that the efficiency of complement opsonization plays a central role, and that both abnormal complement- and Fc-receptor function leads to active renal disease in SLE.

Antibodies, Antinuclear↗
PubMed1987

Spontaneous production of B cell growth factors by SLE lymphocytes.

Systemic lupus erythematosus blood lymphocytes produce B cell growth factors (BCGF) spontaneously to an extent comparable with pokeweed mitogen-stimulated lymphocytes from normal donors. BCGF production by SLE lymphocytes is not increased by PWM and these cells are refractory to exogenous BCGF. Production requires B cells and irradiated T cells but not accessory cells. The properties of spontaneously synthesized BCGF differ in some respects from those induced by PWM. These findings suggest that the abnormal B cell proliferation characteristic of SLE may result, at least in part, from autostimulatory growth factors.

Growth Substances↗
PubMed1986

Role of the Sm antigen in the generation of anti-Sm autoantibodies in the SLE-prone MRL mouse.

MRL/Mp-+/+ (+/+) and MRL/Mp-lpr/lpr (lpr) mice spontaneously produce the SLE-specific anti-nuclear antibody, anti-Sm. Previous work on the clonality and specificity of the anti-Sm response has suggested that the Sm antigen itself induces this autoantibody. In the present work, we have directly investigated the immunogenicity of Sm. In short-term cultures, Sm antigen was shown to be important for the de novo generation of anti-Sm PFC in vitro. The addition of purified Sm to cultures of spleen cells from anti-Sm-positive lpr mice augmented the number of anti-Sm PFC on day 4. Also, the addition of Fab anti-Sm to such cultures inhibited the generation of anti-Sm PFC, probably by blocking determinants on endogenous Sm. The ability of the autoantigen to initiate anti-Sm generation in vivo was investigated by hyperimmunizing +/+ mice with Sm from rabbit or mouse sources. Such mice specifically produced antibodies that recognized both rabbit and mouse Sm as determined by ELISA. The IgG subclass distribution of these induced antibodies was similar to that of spontaneous anti-Sm antibodies found in older mice of the same strain. Our data indicate that the Sm antigen can both initiate and augment production of the anti-Sm autoantibody. These findings provide additional evidence that the spontaneous anti-Sm response in SLE is antigen driven.

Animals↗
PubMed1986

Kaposi's sarcoma in a patient with SLE.

A 31-year-old woman with systemic lupus erythematosus (SLE) taking chronic corticosteroid therapy developed Kaposi's sarcoma. Three weeks after a single intravenous dose of cyclophosphamide for central nervous system vasculitis she died. Autopsy revealed disseminated Kaposi's sarcoma involving the skin and lung, as well as other visceral organs. This is the first case of widespread Kaposi's sarcoma developing in a patient with SLE.

Adrenal Cortex Hormones↗
PubMed1985

Monoclonal anti-DNA antibodies: an approach to studying SLE nephritis.

Several data suggest that the glomerular deposits of DNA and anti-DNA antibodies observed in SLE result from complex formation in situ. The aim of this study was to investigate this hypothesis in normal C57BL/6 mice by using monoclonal anti-DNA antibodies (mAb). Renal localization of intravenously introduced ds DNA was demonstrated in mice injected intraperitoneally with LPS 48 h before. Then, a single IgG2b or a mixture of IgG2a and IgG2b anti-ds DNA mAb were given with the aim of forming DNA: anti-DNA complexes at the glomerular level. No immunoglobulin deposits were observed regardless of the antibody dose used. The mAb used may possess some of the qualitative properties suspected to be nephritogenic. Thus, the limiting factors in the induction of a passive nephritis could be either the absence of glomerular DNA deposits or the inability by using a single antigen-antibody system, to recreate the pathophysiological conditions seen in SLE, where a high number of antigen-antibody systems is implicated in the genesis, of glomerular lesions.

Animals↗
PubMed1985

The in vitro production of anti-DNA antibody by cultured peripheral blood or tonsillar lymphoid cells from normal donors and SLE patients.

Anti-DNA antibody responses by cultured circulating lymphocytes from SLE patients and by the tonsillar lymphoid cells of normal donors were detected and enumerated by a sensitive specific ELISA of culture supernatants, or by a hemolytic anti-DNA PFC assay. Although spontaneous IgM and IgG anti-DNA and anti-ssDNA responses were characteristic of SLE lymphocytes and spontaneous IgM anti-ssDNA responses were characteristic of tonsillar lymphocytes, the circulating lymphocytes of normal controls never produced anti-DNA antibodies spontaneously, and rarely after PWM stimulation. The anti-DNA antibody PFC response of tonsil lymphocytes correlated directly with the total number of immunoglobulin-producing cells measured by a reverse hemolytic PFC assay. Mixing experiments in which we employed cultures of comparable numbers of separately enriched autologous circulating and tonsillar B and T cells revealed that tonsillar tissue contained an enriched population of anti-DNA antibody precursor B cells and/or helper T cells.

Adolescent↗
PubMedDate not supplied

Chronic active hepatitis in a patient presenting with clinical and serological evidence of SLE.

A patient with clinical and serological manifestations of systemic lupus erythematosus (SLE) without renal or neurological manifestations was managed conservatively for 4 1/2 years. At this time she developed ascites and abnormal liver function tests, and was found to have severe chronic active hepatitis (CAH) with cirrhosis and portal hypertension. No clinical or biochemical evidence of liver disease was documented over the first 3 1/2 years of her illness, though no tests were performed in the 12 months before diagnosis. This case emphasizes the value of monitoring liver function tests over extended periods in such patients, since appropriate immunosuppressive therapy may benefit CAH, and as in this case, systemic manifestations of CAH may simulate SLE and precede clinical liver disease.

Adult↗
PubMed1983

Analysis of vascular lesions in murine SLE. I. Association with serologic abnormalities.

In murine SLE, two different vascular lesions can develop. A necrotizing polyarteritis (NPA), exclusively found in MRL/I mice, is characterized by a dense infiltration of PMN and fibrinoid necrosis of the arterial wall. The second, a degenerative vascular lesion, occurs in a low incidence in all SLE mice, except the (NZW X BXSB)F1 (WBF1) male, in which its incidence is 100%. This lesion shows subendothelial deposits of immunoglobulins with minimal or no inflammatory or proliferative reaction. This degenerative vascular disease (DVD) is predominantly localized in the coronary arteries and is highly correlated with myocardial infarction. Serologic analysis revealed that NPA in MRL/I mice was associated with relatively late development of high levels of autoantibodies and circulating immune complexes; DVD in WBF1 mice was associated with an early onset of autoantibody production of a low magnitude that gave rise to a persistent low level of circulating immune complexes. Characterization of circulating immune complexes in MRL/I mice showed these complexes were mainly of intermediate size (7S-19S) and contained predominantly anti-DNA antibodies. In WBF1 mice, complexes were barely detectable and contained mostly anti-gp70 antibodies. Elution of kidneys showed that the major antibody deposited in MRL/I mice has an anti-DNA specificity, whereas in WBF1 animals, the major antibody was anti-gp70. Furthermore, a 10 times greater amount of immunoglobulins could be eluted from WBF1 hearts with DVD than from MRL/I and BXSB hearts. Additionally, we found that the lack of an inflammatory reaction in DVD was not because of a preferential deposition of noncomplement-fixing IgG1 antibodies nor could it be related to a defective inflammatory response, because WBF1 mice had an undiminished reverse passive Arthus reaction throughout their lives. It is concluded that NPA develops secondary to high levels of autoantibodies with a concomitant rise in immune complexes, whereas DVD is associated with sustained low levels of circulating immune complexes.

Animals↗
PubMed1980

Use of the ELISA to screen for anti-thymocyte and anti-beta 2-microglobulin antibodies in leprosy and SLE.

A report is given of the use of the enzyme-linked immunosorbent assay to measure antibody to preparations of human thymocyte membranes (HTMA) and to beta 2-microglobulin. The assay described is simple and rapid, and requires only small quantities of an easily stored membrane preparation. The advantages of this technique over conventional methods involving cytotoxicity are discussed. Raised levels of IgM antibody to beta 2-microglobulin were detected in sera from SLE patients. Raised levels of IgG and IgM antibody to HTMA were found in sera from most active lepromatous cases. Two of eight sera from SLE patients showed raised IgG anti-HMTA, but not raised IgM. An attempt was made to study the subclass of the IgG antibodies found, but when checked against purified human IgG myeloma proteins, the available anti-subclass sera were found to lack the necessary degree of specificity in this assay.

Antigens, Surface↗
PubMed1982

Functional analysis of the defective T cell regulation of the antigen-specific PFC response in SLE patients: differentiation of suppressor precursor cells to suppressor effector cells.

The investigation described here is concerned with the T cell regulation of the antigen-specific antibody response which has been studied in patients suffering from systemic lupus erythematosus (SLE). Apart from the fact that T helper cell activity was found to be less efficient, it appeared that the peripheral blood leucocytes (PBL) of patients in an active stage of the disease did not contain the suppressor precursor cells, which functions as the target cell for the inductive signal of T mu+ suppressor inducer cells. The absence of the suppressor precursor cells in SLE patients coincided with the absence of T gamma+ suppressor effector cells. Characterization of the (post-thymic) precursor cells (derived from normal donors) with the aid of monoclonal antibodies of the OKT series and several other markers pointed out that this population contains OKT4+ as well as OKT8+ cells. Further experiments demonstrated that the cells are capable of rosetting with autologous erythrocytes, and do not bear Fc receptors for IgM or IgG. Considering the various findings as a whole the conclusion is warranted that the post-thymic suppressor precursor T cell can differentiate into a suppressor effector cell only after interaction with T suppressor inducer cells.

Antibodies, Monoclonal↗
PubMed1984

Cellular DNA content of T helper, T suppressor and B lymphocytes in SLE.

The ratio of in vivo activated T helper, T suppressor and B cells in the blood of patients with SLE has been studied through simultaneous subset specific immunofluorescence labelling and the analysis of cellular DNA content with the help of flow fluorimetry. In the active stage of the disease an increase was observed in the proportion of proliferating cells either among the T helper cells or the B cells. Occasionally, however, the rate of proliferation in both subsets grew at the same time. Cases with a high number of activated B cells have proved to be more serious. The percentage of the T suppressor cells in the S-G2-M phase of the cell cycle increased moderately in both the active and the inactive stages of the disease. Our results are also discussed in relation to the pathogenetic mechanism of SLE.

B-Lymphocytes↗
PubMedDate not supplied

Saturable, high-avidity monocyte receptors for monomeric IgG and Fc fragments increase in SLE and lyme disease.

We have devised an assay for quantifying high-avidity Fc receptors for monomeric IgG on peripheral blood monocytes. In the development of a radiolabelled ligand for the assay, we found that Fc fragments offer several advantages over 7S-IgG. Compared to the latter ligand, the fragments interacted more cleanly with a single high-avidity binding site, appeared to have easier access to this site, and, since they showed no binding to Millipore filters, their use made possible a wash procedure that was convenient and rapid, thus minimizing loss of specifically bound ligand. Application of the assay to a study of ten normal controls, five patients with SLE, and three patients with Lyme disease demonstrated that normal monocytes bear approximately 10,000 high-avidity binding sites per cell. In contrast, patient monocytes bore significantly more Fc receptors; on average their cells had about 40,000 such sites per cell (P = 0.01) and sometimes as many as 100,000 sites per cell. Both normal and patient monocytes bound IgG or Fc fragments with an apparent association constant (KA) of approximately 10(8) M-1. The majority of patients with active SLE and Lyme disease had serum C1q-binding material compatible with the presence of circulating immune complexes. This study shows that these putative circulating immune complexes do not necessarily lead to a reduction in the number of Fc receptors on peripheral blood monocytes. Rather, the data suggest that in the course of immune mediated diseases, either monocytes are activated in vivo to express greater numbers of Fc receptors, or a subset of monocytes bearing more Fc receptors is expanded.

Antibody Affinity↗