[Autoantibodies: part of the normal preimmune repertoire].
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Autoantibodies↗
Biomedical subjects
Y Naparstek
Publications and source records attributed to Y Naparstek.
A single germline VH gene segment of normal A/J mice encodes autoantibodies characteristic of systemic lupus erythematosus.
These experiments tested the hypothesis that unmutated germline genes from normal mice can encode autoantibodies. We found that the unmutated VHIdCR gene segment, which encodes a large proportion of antiarsonate antibodies in A/J mice, also encodes antibodies with the ability to bind to DNA and cytoskeletal proteins. After Ars immunization, at a time when the VHIdCR gene segment mutates and antibody affinity for the hapten increases, reactivity with the autoantigens was lost. Six antibodies obtained after immunization with Ars bound both the Ars and DNA. Results of competitive inhibition assays suggested that the same variable region site in the antibodies bound to both Ars and DNA. The properties of the individual germline-encoded antibodies, which include reactivity to both DNA and cytoskeletal proteins, suggest that autoantibodies characteristic of SLE might be a subset of antibodies encoded by unmutated germline V genes.
Animals↗
Plasma calcium and phosphate levels in an adult noninsulin-dependent diabetic population.
Duplicate or triplicate measurements of fasting plasma glucose, calcium (Ca), phosphate (Pi), and glycosylated hemoglobins were performed on a group of non-insulin dependent diabetic patients and controls at 3-6 month intervals. In the diabetic group (48 males and 44 females), 18 were on diet only, 21 on diet and oral hypoglycemic treatment, and 51 on diet and insulin. These were a total of 217 measurements for each parameter. Results were compared to 416 measurements obtained from sex and age-matched controls. Plasma Ca levels were higher in the diabetic group (2.48 +/- 0.004 vs 2.38 +/- 0.006 mmol/liter) P less than 0.001; plasma Pi levels were similar to those of controls. The difference in plasma Ca was not influenced by age, sex, or mode of treatment. No correlation was found in the three treatment groups between plasma Ca and duration of diabetes nor with patients' weights. The results are consistent with the view that an alteration in calcium homeostasis accompanies the diabetic state.
Adult↗
In vitro production of an anti-DNA idiotype by lymphocytes of normal subjects and patients with systemic lupus erythematosus.
We investigated whether normal B cells can synthesize antibodies with an idiotypic marker that occurs with high frequency in anti-DNA antibodies of patients with systemic lupus erythematosus (SLE). This idiotype, Id16/6, has been found in the serum of patients with active SLE and in monoclonal anti-DNA antibodies derived from unrelated patients with the disease. We found that cultured lymphocytes of all normal subjects tested produced Id16/6 when stimulated by pokeweed mitogen (PWM). By contrast, lymphocytes from SLE patients produced Id16/6 even without mitogenic stimulation, whether or not they were obtained from patients in remission or relapse. Relapsed patients' lymphocytes spontaneously produced the highest levels of Id16/6 which was found in IgG and IgA, in addition to IgM. The majority of Id16/6 produced by PWM-stimulated lymphocytes from either normal subjects or patients in remission did not bind to nucleic acid. In relapse, however, the nucleic acid-binding proportion of Id16/6 rose substantially, indicating that the spontaneously activated B cells in active SLE differ from the subset of B cells that produce Id16/6 upon PWM stimulation. The findings suggest that the lupus Id16/6 family is conserved in normal individuals and it consists of two populations of antibodies with different antigenic specificities. The major set is not directed against nucleic acid antigens; its antigenic specificity is unknown and it dominates the Id16/6 family that appears after PWM stimulation. The other, minor set binds to nucleic acids and becomes prominent in clinically active lupus. These two sets of idiotypically related antibodies may be connected by an immunoregulatory network.
Adult↗
Effects of interferon-alpha on the expression of a lupus idiotype in normal humans.
Interferon (IFN) has extensive immunoregulatory effects but its role in systemic lupus erythematosus (SLE) remains obscure. The observations that a high proportion of patients with active SLE have increased IFN levels in their sera, and that IFN injected to lupus-prone mice aggrevates their disease, led us to examine the effects of IFN on the production of 16/6--a high frequency idiotype of monoclonal anti-DNA antibodies produced by human-human hybridomas derived from SLE patients. Peripheral blood mononuclear cells (PBMC) of healthy donors or of patients with SLE were incubated with IFN and pokeweed mitogen (PWM). Seven-day supernatants were assayed for total IgM, for IgM with 16/6 idiotype, and for IgM anti-DNA activity. PWM-stimulated PBMC of all healthy donors examined produced the 16/6 idiotype (mean 2.5 ng/ml). A significant increase of 16/6 in normals (above the level with PWM alone) was noted with 10-100 u/ml of IFN-alpha but not with 500 u/ml. In 3/10 normals the addition of IFN-alpha resulted in detectable anti-DNA activity. The IFN-induced increase in 16/6 idiotype was significantly more than the increase in IgM (335% vs 47% above baseline, with 10 u/ml of IFN). These effects of IFN could not be demonstrated in the absence of PWM nor in T-cell-depleted preparations. Recombinant IFN-gamma had no augmenting effect on 16/6 production. Three SLE patients in remission had elevated levels of 16/6 in their PBMC supernatant (15-200 ng/ml) which could not be further augmented by IFN. Thus, we have demonstrated the potential of PWM-stimulated normal lymphocytes to generate a "lupus" idiotype and shown that production of this idiotype requires T cells and is preferentially enhanced by IFN-alpha. Further studies of the effects of IFN on the expression of anti-DNA antibodies may clarify a postulated role of IFN in autoimmune diseases.
Adult↗
Immunogenetics of rheumatoid arthritis in Israel.
In an attempt to study the variation of associations between HLA and rheumatoid disease a population of 44 Ashkenazi and 29 non-Ashkenazi patients with Rheumatoid Arthritis were tested for HLA-A, B, C and DR antigens and compared with the relevant control groups. In contrast to the results obtained in Middle European or North American Caucasians, Rheumatoid Arthritis in Israel is not associated with B15 and Cw3, indicating that it is very unlikely that B- and C-locus antigens are involved in coding for disease susceptibility for RA. The allele DR4 which is found associated with RA in almost all populations tested so far was in the total patient group (47.9%) slightly but not significantly more frequent than in the control group (38.3%). This difference was entirely due to a nonsignificant increase in the frequency of DR4 in the Ashkenazi patients (54.5%) compared to controls (40%), while the frequency of DR4 in non-Ashkenazi patients and controls was virtually identical (38.0% vs 36.7%). Another surprising finding was that the frequency of HLA-DR1, which has been reported to be increased in different populations of patients with RA was found to be completely normal in the present study on Israeli patients. The alleles of the Bf and the GLO system did not show any significant difference between patients and controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Antibodies, Antinuclear↗
Immunogenetics of juvenile chronic arthritis in Israel.
Typing for HLA-A,B,C and DR antigens was performed in 61 Israeli patients with juvenile chronic arthritis (JCA) and in 120 unrelated controls. No significant associations were apparent in the overall patient group. DR5 was significantly increased in the non-Ashkenazi patients with pauciarticular onset of disease. The only three DRw8 positive patients in the study had pauciarticular onset. DR5 and DRw8 were found in 9 of 10 patients with age of onset less than 3 years. Increased frequencies of Bw50 and Cw6 were observed in patients with systemic onset. Typing for properdin factor (Bf) and glyoxylase (GLO) was carried out in 45 and 50 of the patients, respectively. No associations with alleles of the complement Bf system or the HLA linked GLO system were evident. The confirmation in the ethnically distinct Israeli population of the previously described association of DR5 with pauciarticular JCA suggests that this gene may be closely related to the disease susceptibility gene.
Adolescent↗
Immunochemical similarities between monoclonal antibacterial Waldenstrom's macroglobulins and monoclonal anti-DNA lupus autoantibodies.
Six monoclonal IgM from patients with Waldenstrom's macroglobulinemia that react with Klebsiella polysaccharides were tested for their ability to bind to nucleic acid antigens. One of the macroglobulins bound to the polynucleotide poly(G), and one bound to poly(G), poly(I), and single-stranded DNA. The reaction with the polynucleotides was specifically inhibited by the Klebsiella polysaccharide K30. A monoclonal lupus anti-DNA antibody (16/6) was found to react weakly with the Klebsiella polysaccharides K30 and K21. Five of the Waldenstrom macroglobulins shared an idiotypic determinant with the 16/6 anti-DNA antibody. The reaction between the macroglobulins and the antiidiotype serum was specifically inhibited by Klebsiella polysaccharides, an indication that the idiotypic marker was in the antigen-binding site of the macroglobulins. These results indicate the existence of widely dispersed conserved variable region genes that encode idiotypically related immunoglobulins with the capacity to bind to both bacterial polysaccharides and nucleic acids. Such genes can be expressed by patients with either Waldenstrom's macroglobulinemia or systemic lupus erythematosus.
Antibodies, Bacterial↗
Short course of synacthen therapy as an adjunct in the management of rheumatoid arthritis.
The effect of synthetic adrenocorticotrophic hormone (Synacthen), in conjunction with hydroxychloroquine, aurothioglucose, or penicillamine, was evaluated retrospectively in 21 patients with rheumatoid arthritis (RA). One mg of depo Synacthen was administered at increasing intervals of 4 to 14 days for a total period of 3 to 7 months. Fourteen patients with RA on either hydroxychloroquine or aurothioglucose and not on Synacthen, served as controls. Patients in the Synacthen group were, on the whole, sicker, as indicated by a lower functional capacity, higher mean erythrocyte sedimentation rate, and systemic and articular indices. Physicians' estimate of the patients condition after 1 - 2 months of therapy showed no improvement or deterioration in 10 out of 13 cases in the control group. Likewise, the erythrocyte sedimentation rate decreased significantly more and seronegativity was achieved in more of the Synacthen-treated cases. Six to 8 months after the beginning of therapy (1 to 4 months after cessation of Synacthen) clinical improvement was comparable in both groups, although seroconversion was more common in patients who had received Synacthen (7 out of 10 as compared to 1 out of 7 respectively). It is suggested that Synacthen may be used safely in the early phase of selected RA patients, until the effect of second-line drugs is achieved.
Adrenocorticotropic Hormone↗
Homology of the NH2-terminal amino acid sequences of the heavy and light chains of human monoclonal lupus autoantibodies containing the dominant 16/6 idiotype.
The NH2-terminal amino acid sequences have been determined by automated Edman degradation for the heavy and light chains of five monoclonal IgM anti-DNA autoantibodies that were produced by human-human hybridomas derived from lymphocytes of two patients with systemic lupus erythematosus. Four of the antibodies were closely related to the idiotype system 16/6, whereas the fifth antibody was unrelated idiotypically. The light chains of the 16/6 idiotype-positive autoantibodies (HF2-1/13b, HF2-1/17, HF2-18/2, and HF3-16/6) had identical amino acid sequences from residues 1 to 40. Their framework structures were characteristic of VKI light chains. The light chain of the 16/6 idiotype-negative autoantibody HF6-21/28 was characteristic of the VKII subgroup. The heavy chains of the 16/6 idiotype-positive autoantibodies had nearly identical amino acid sequences from residues 1 to 40. The framework structures were characteristic of the VHIII subgroup. In contrast, the GM4672 fusion partner of the hybridoma produced small quantities of an IgG with a VHI heavy chain and a VKI light chain. The heavy chains of the lupus autoantibodies and the light chains of those autoantibodies that were idiotypically related to the 16/6 system had marked sequence homology with WEA, a Waldenstrom IgM that binds to Klebsiella polysaccharides and expresses the 16/6 idiotype. These results indicate a striking homology in the amino termini of the heavy and light chains of the lupus autoantibodies studied and suggest that the V regions of the heavy and light chains of the 16/6 idiotype-positive DNA-binding lupus auto-antibodies are each encoded by a single germ line gene.
Amino Acid Sequence↗
Detection of cross reactive anti-DNA antibody idiotypes on tissue-bound immunoglobulins from skin biopsies of lupus patients.
Cross-reactive anti-DNA antibody idiotypes have been identified on tissue-bound immunoglobulins from skin biopsies of patients with systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE). Four polyclonal and two monoclonal anti-idiotypic reagents were used to screen biopsies from 24 patients with SLE, 23 patients with DLE, and 15 other patients with IgM-positive skin biopsies. Up to 46% of the SLE patients and 30% of the DLE patients were found to share idiotypes present on immunoglobulins deposited at the dermal-epidermal junction. Inhibition studies in four patients indicated that the idiotypes were on anti-DNA antibodies. In contrast, none of the anti-idiotypic antibodies bound to any of the control biopsies. These findings imply that some tissue-bound autoantibodies are derived from related families of high-frequency germ-line genes that are expressed in both SLE and DLE.
Antibodies, Antinuclear↗
Shared idiotypes are expressed on mouse and human anti-DNA autoantibodies.
The expression of common idiotypes on human and mouse anti-DNA monoclonal autoantibodies made by hybridomas was examined by their competitive binding to anti-idiotype antibodies. Some murine autoantibodies inhibited the binding of a human anti-DNA autoantibody 16/6 to monoclonal or polyclonal anti-idiotypic antibodies. Another human antibody (134) was not inhibited in its binding to homologous anti-idiotypic antibodies. The expression of the human 16/6 idiotype on mouse antibodies was restricted to those that had a specificity similar to the 16/6 antibody itself, their major properties being that they reacted more strongly with single stranded DNA (ssDNA) than double stranded DNA (dsDNA). One mouse antibody expressing the 16/6 idiotype also bound weakly to RNA. The results imply structural similarities between the binding sites of the antibodies in the two species, and are consistent with evolutionary conservation of V genes coding for primitive ancestral antibodies that react with DNA and become diversified through somatic mutation.
Animals↗
Familial hereditary thrombocytopenia and HLA.
Three generations of a Jewish family with hereditary thrombocytopenia (HT) are described. The disease was manifested clinically by mild bleeding tendency since infancy. Circumcision, however, did not result in excessive bleeding. HLA study in this family indicated that the HT locus is not linked to HLA.
Adult↗
Focal glomerulonephritis in the course of hydralazine-induced lupus syndrome.
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Biopsy↗
T lymphocyte lines induce autoimmune encephalomyelitis, delayed hypersensitivity and bystander encephalitis or arthritis.
Lines of rat T lymphocytes responsive to the basic protein of myelin (BP) or to the purified protein derivative of Mycobacterium tuberculosis (PPD) were inoculated i.v. into recipient rats. As reported previously, the anti-BP line cells, but not the anti-PPD line cells spontaneously accumulated in the central nervous system and caused encephalomyelitis. However, the anti-PPD line cells could be induced to enter the brain and cause bystander encephalitis by intracerebral inoculation of PPD. Anti-PPD or anti-BP line cells could mediate delayed-type hypersensitivity skin reactions or bystander arthritis elicited by specific antigen. The lines did not cause specific cytolysis in vitro. Susceptibility to delayed-type hypersensitivity or bystander disease was long lasting in rats inoculated with anti-PPD line cells, while rats inoculated with anti-BP line cells were susceptible for only a few days. Thus, lines of T lymphocytes can mediate a variety of pathological reactions directed by the presence of specific antigen, self or foreign.
Animals↗
Case report: spurious hypokalemia in myeloproliferative disorders.
Four patients with myeloproliferative disorders and hypokalemia due to an artifactual in vitro phenomenon are described. Hypokalemia was due to an increased potassium uptake by the abnormal white blood cells. Spurious hypokalemia may explain in part the electrolyte disturbances found in many leukemic patients.
Adult↗
Disseminated mycobacterial disease caused by Mycobacterium szulgai.
Disseminated mycobacterial disease due to Mycobacterium szulgai occurred in a previously healthy young man. The clinical picture included fever, mediastinal and generalized lymphadenopathy, hemoptysis, and skin lesions but was dominated by progressive multifocal osteomyelitis. Immunological studies revealed a decrease in T-lymphocyte reaction to mitogens, but this was tested late in the course of the disease and may have been secondary. In spite of repeated surgical drainage and treatment with multiple antituberculous drugs for a period of two years, new lesions continue to appear mainly in the bones. Mycobacterium szulgai was isolated from 28 bone specimens, as well as from skin lesions and sputum. To the best of our knowledge, this is the first report of disseminated disease due to this organism.
Adolescent↗
[Nervous system lupus erythematosus].
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Central Nervous System Diseases↗