Pathogenic anti-DNA antibodies in SLE: idiotypic families and genetic origins

We have adopted an idiotypic approach to study the double stranded DNA (dsDNA) binding antibodies of systemic lupus erythematosus (SLE). Three anti-idiotypic reagents, 8.12, 3I, and F4, identify cross reactive idiotypes that are each expressed on anti-dsDNA antibodies in the sera of many patients with SLE. These idiotypic antibodies are implicated in the pathogenesis of SLE as they are present in immune complex deposits in the kidneys of patients with SLE glomerulonephritis. The autoantibody associated idiotypes are also expressed on antibodies that do not bind DNA. We are investigating the origin of the pathogenic anti-dsDNA antibodies of SLE by comparing the autoantibodies, the antibodies to foreign antigens, and the myeloma proteins that express each SLE associated idiotype. In conjunction with serological analysis of these idiotypic systems, molecular genetic studies indicate that both the 8.12 and the 3I autoantibody associated idiotypes may be germline encoded, while the F4 idiotype is generated by somatic mutation. The data further suggest that the antigenic specificity of the pathogenic anti-DNA antibodies of SLE is acquired through somatic mutation of germline immunoglobulin genes. By studying the regulation of genes capable of encoding pathogenic autoantibodies, in both SLE patients and non-autoimmune individuals, we may be able to elucidate the pathogenesis of autoimmune disease and begin to design more effective therapeutic interventions.     

Lupus anti-DNA antibodies bearing the 8.12 idiotype appear to be somatically mutated

Anti-DNA antibodies in systemic lupus erythematosus (SLE) sera were analyzed using an antiidiotype designated 8.12 which recognizes a determinant on lambda light chains highly expressed in SLE sera. Eight of ten normal individuals had peripheral blood lymphocytes which produced high-titered 8.12-positive antibodies, following transformation with Epstein Barr virus, implying that the 8.12-reactive sequence originates in the germline gene (GLG). Of 58 SLE sera, 32 contained elevated titers of 8.12-reactive antibodies. Twenty-three of these sera had 8.12-reactive anti-DNA antibodies, suggesting a strong correlation between 8.12 idiotype and DNA binding. Moreover, 20 of 26 8.12-reactive IgG antibodies and only 4 of 10 8.12-reactive IgM antibodies bound DNA (P<0.05). These observations strengthen our previous findings in myeloma sera that DNA binding is associated with IgG isotype in the 8.12 idiotype system and suggest that the acquisition of anti-DNA reactivity in antibodies bearing the GLG idiotype 8.12 is achieved by somatic mutation, a feature of an antigen-driven response.     

Antinuclear Autoantibodies in Flaky Skin ( fsn ) Mutant Mice

Mice homozygous for the flaky skin ( fsn ) single gene mutation have a severe hyperproliferative disease resulting complex phenotype, which includes widespread inflammation and autoimmunity. Flaky skin mice have several serological and pathological features that share similarities with the human systemic autoimmune disease systemic lupus erythematosus (SLE). Analyses of the antinuclear and anti-dsDNA autoantibodies in fsn / fsn mice indicate that they are low titer IgG antibodies. These low titer anti-dsDNA autoantibodies can ultimately form immune complex deposition in the glomeruli associated kidney damage. IgE antibodies were identified in the immune complex deposition, however their role in the pathology is not determined. It is hypothesized that the mechanism of autoantibody production and autoimmune disease pathogenesis in mice homozygous for the fsn mutation is initiated by non-specific polyclonal activation of B-lymphocytes resulting in the synthesis of low affinity autoantibodies.     

Idiotypic heterogeneity of VKIII autoantibodies to red blood cell antigens.

VKIII light (L) chains are commonly expressed by human autoantibodies with diverse binding specificities, including red blood cell antigens. To better understand the physiologic and pathologic expression of these L chain variable region genes, we have created a panel of murine monoclonal anti-idiotypic antibodies by immunization with a human lymphoblastoid B cell line that secretes an IgM VKIII autoantibody specific for the I red blood cell carbohydrate determinant. The binding specificities of these nine murine monoclonal antibodies, termed IV.1-IV.9, were evaluated against a large panel of monoclonal Ig proteins and compared to two previously well-characterized monoclonal anti-idiotypes, 6B6.6 and 17.109; these two anti-idiotypes have been shown to primarily identify VKIII rheumatoid factors derived from the kv328 (VKIIIa) and kv325 (VKIIIb) genes, respectively. In contrast, our anti-idiotypic antibodies identified (public) cross-reactive idiotypes present on many VKIII proteins that included both anti-erythrocyte and rheumatoid factor autoantibodies. Certain anti-idiotypic antibodies (IV.2 and IV.6) were restricted to VKIIIa L chains but differed from the 6B6.6 anti-idiotype by binding to a larger subset of VKIIIa proteins representing the products of at least two VKIIIa genes. One antibody of our panel (IV.5) recognized a private idiotope expressed only by the immunizing antibody. Using the panel of anti-idiotypic antibodies to evaluate erythrocyte autoantibodies with different serologic specificities, we found striking heterogeneity of L chain idiotype expression, even among known VKIII anti-i/I autoantibodies. These findings differ from the recently described structural and idiotypic conservation associated with the H chain of anti-i/I autoantibodies. From correlations of idiotypic reactivity with L chains of known sequence, it is postulated that the observed heterogeneity of L chain idiotype expression is due to differences in the genetic origin and/or somatic diversification of L chain variable region genes. Furthermore, subtle variability of L chain structure may contribute in part to the differences in fine binding specificity among anti-I and anti-i autoantibodies.     

Antinuclear autoantibodies in flaky skin (fsn) mutant mice

Mice homozygous.for the flaky skin (fsn) single gene mutation have a severe hyperproliferative disease resulting complex phenotype, which includes widespread inflammation and autoimmunity. Flaky skin mice have several serological and pathological features that share similarities with the human systemic autoimmune disease systemic lupus erythematosus (SLE). Analyses of the antinuclear and anti-dsDNA autoantibodies in fsn/fsn mice indicate that they are low titer IgG antibodies. These low titer anti-dsDNA autoantibodies can ultimately form immune complex deposition in the glomeruli associated kidney damage. IgE antibodies were identified in the immune complex deposition, however their role in the pathology is not determined. It is hypothesized that the mechanism of autoantibody production and autoimmune disease pathogenesis in mice homozygous for the fsn mutation is initiated by non-specific polyclonal activation of B-lymphocytes resulting in the synthesis of low affinity autoantibodies.     

Parallelism of serum anti-F(ab')2 and anti-cationic IgG reactivities in patients with systemic lupus erythematosus

Cationic anti-DNA antibodies may be related to glomerular injury in murine lupus nephritis or in patients with systemic lupus erythematosus (SLE). Therefore, anti-cationic antibodies in SLE could include antibodies with regulatory function on such pathogenic cationic molecules. Since anti-F(ab')2 antibodies may be involved in the idiotype control of anti-DNA antibodies in some patients with inactive SLE, the present study was aimed to determine if SLE patients with significant serum levels of anti-F(ab')2 produce antibodies reacting with cationic IgG molecules. Three SLE sera with high titers of anti-F(ab')2 antibodies were individually adsorbed by sequential affinity chromatography on three Sepharose columns coupling normal IgG from Cohn Fraction II, pooled cationic IgG myeloma paraproteins displaying idiotypic anti-DNA markers (F4 and 8.12), and F(ab')2 fragment from allogeneic IgG, respectively. Eluates obtained from cationic IgG adsorption showed predominant anti-F(ab')2 reactivity. A similar profile was also detected in a serum from a normal control donor with high levels of anti-F(ab')2. Biotinylation of anti-cationic eluates showed that such antibodies were significantly more reactive with cationic than anionic or neutral IgG, confirming their apparent affinity for positively charged antigens on IgG molecules. Since anti-cationic absorptions were able to remove the anti-F(ab')2 activities in the SLE sera studied, it is possible that anti-cationic antibodies could function as immunoregulatory antibodies in the idiotypic control of some SLE autoreactive phenomena, including glomerular anti-DNA deposition.     

Pathogenic anti-DNA idiotype-reactive IgG in intravenous immunoglobulin preparations.

This study was addressed to explore the reactivity of natural anti-idiotypes from commercial lots of immunoglobulins to several idiotypes (Ids), usually expressed by anti-DNA molecules in lupus nephritis. Eleven intravenous immunoglobulin (IVIG) preparations and nine (three polyvalent and six hyper-immune) intramuscular IgG were investigated for specific content of anti-DNA, anti-F(ab')2 and antibodies reacting with several anti-DNA IgG Ids. Two samples (nos 6 and 11) showed high reactivity with allogeneic F(ab')2 and with F(ab')2 of myeloma proteins bearing the anti-DNA Id 3I+ and the 8.12+. Since both 3I and 8.12 Id markers are known to characterize pathogenic anti-DNA IgG in systemic lupus erythematosus (SLE), anti-Id antibodies to these markers were obtained by absorbing the IVIG samples nos 6 and 11 to Sepharose columns coupled with pooled F(ab')2 fragments of 3I(+)-F4(+)-8.12(+)-myeloma proteins. Inhibition experiments showed that anti-8.12 Id-eluted IgG induced a selective suppression of the DNA-reactive antibodies derived from patients with active lupus nephritis to their substrate, suggesting the involvement of 8.12+ molecules in the SLE glomerular damage. Since 8.12+ anti-DNA are nephritogenic antibodies, the occurrence of anti-8.12+ Id in commercial IVIG may be of potential therapeutic relevance in modulating the pathogenic SLE Id network. Previous variable results of IVIG treatment in SLE, such as resolution of proteinuria or worsening nephritis, could be related to variable enrichment of different lots of IVIG in suppressive anti-pathogenic Id antibodies.     

Expression of an interspecies idiotype in sera of SLE patients and their first-degree relatives.

Sera from 29 SLE patients and 81 first-degree healthy family members were tested for quantitative expression of a cross-reactive idiotype present on a murine monoclonal anti-Sm autoantibody (Y2). Forty-one percent of SLE patients and 27% of all relatives showed increased serum levels of the Y2 idiotype compared to 6% in a normal, unrelated control group. In addition, female relatives of SLE patients showed slightly increased levels of anti-Sm antibodies compared to male relatives (15% vs 3%). In one of the 28 families and three unrelated SLE patients studied, there was a significant correlation between the Y2 idiotype expression and expression of another idiotype present on anti-DNA antibodies (1341d). Affinity column absorption studies showed that these two idiotypes were present on different antibody molecules. This study demonstrates: (1) a genetic predisposition for an anti-Sm antibody idiotype expression in humans; and (2) that two different idiotypes may be under parallel or coordinate regulation.     

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.     

Immunization with peptides derived from the idiotypic region of lupus-associated autoantibodies delays the development of lupus nephritis in the (SWR x NZB)F1 murine model

Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease affecting 40-50/100,000 Americans. Although most of the research on pathogenic antibodies focuses on antigenic specificity, there is increasing evidence that specific immunoglobulin idiotypes may mediate lupus nephritis independent of autoantigen specificity. In previous work, our laboratory characterized a set of nephritogenic monoclonal antibodies with substantial idiotypic cross-reactivity, produced by the spontaneous SLE model (SWR x NZB)F(1) (SNF(1)), termed Id(LN)F(1). Peptides derived from one of these antibodies, Id540, was previously shown to stimulate pathogenic T-cells from prenephritic SNF(1) mice, similar to what has been seen for pathogenic A6.1 antibody produced by the (NZB x NZW)F(1) model. In this study, we immunized pre-nephritic SNF(1) mice with p62-73, a peptide derived from the variable region of Id540 and, in separate experiments, with p58-69, a peptide derived from the variable region of A6.1. In both cases, immunization resulted in increased survival and delayed nephritis; however, while both peptides affected levels of anti-DNA antibodies, immunization with p62-73 only affected levels of Id(LN)F(1) antibodies. These findings confirm the roles of pathogenic idiotypes in the pathogenesis of lupus nephritis and suggest that therapies that target specific idiotypes might be a potential tool in the management of SLE.     

A common anti-DNA idiotype and other autoantibodies in sera of offspring of mothers with systemic lupus erythematosus.

Since the immune response in fetuses of mothers with systemic lupus erythematosus (SLE) is unknown, we investigated sera from six mothers and their paired offspring by enzyme-linked immunosorbent assay (ELISA) for the presence of a common anti-DNA idiotype (16/6 Id) and, as control, for the presence of an unrelated public idiotype of antibody to hepatitis B surface antigen (HBsAg). In addition, maternal as well as fetal sera were evaluated for the presence of antibodies to ssDNA, dsDNA, poly(I), poly (dT), RNA, cardiolipin, total histones and the presence of lupus anticoagulant. Clinically active SLE mothers showed in general increased IgG and, to a lesser extent, IgM autoantibody activity. Circulating lupus anticoagulant was detectable in clinically active mothers only. All offspring of clinically active SLE mothers showed increased IgG autoantibodies to a variety of antigens, while IgM antibodies were detected in only one fetus. In contrast, fetuses of clinically inactive mothers showed only minor IgG activity. Common anti-DNA-idiotype (16/6 Id) activity also correlated with disease activity in both maternal and fetal compartments. One clinically active mother was 16/6-negative; her offspring was, however, positive, indicating de novo production of the idiotype by the fetus. In contrast, a control anti-HBsAg idiotype was not detected in either maternal or fetal sera. It therefore appears that offspring of clinically active SLE mothers serologically reflect maternal disease activity. Furthermore, autoantibodies and common idiotype of autoantibodies can be found within the fetal compartment even in the absence of such antibodies in the maternal serum. Discrepancies between mothers and offspring in IgM-autoantibody levels and the presence of new idiotypes in fetuses are indicative of fetal de novo autoantibody production.     

Idiotypic spreading promotes the production of pathogenic autoantibodies

We propose that a major immunoregulatory abnormality in murine and human autoantibody-mediated disease is idiotypic spreading. By this mechanism, B cells with the genetic information to produce immunoglobulin (Ig) bearing certain public idiotypes (Ids) are selectively upregulated, probably by Id-recognizing helper T cells. The model in which we are testing the hypothesis is systemic lupus erythematosus (SLE) in humans and NZB/NZW F1 (BW) female mice. Recent experiments have shown that the number of public Ids expressed on the Ig of nephritic BW mice is quite restricted. IdX is the dominant Id on serum Ig; IdGN1 and IdGN2 are also common. All three Ids were initially derived from spontaneous antibodies to DNA. Together the three are present on 85% of the total Ig repertoire. Such restriction suggests idiotypic spreading. In glomerular Ig deposits from nephritic BW mice, IdGN1 and IdGN2 are found on 45% of the total Ig: IdX is present in minute amounts. Furthermore, suppression of IdGNs by administration of anti-IdGN1 to BW mice resulted in significant delay in the onset of nephritis, but the IdGNs escaped from control and eventually caused a fatal nephritis. Finally, studies of glomerular Ig deposits in renal biopsies of patients with SLE have shown that IdGN2 dominates such Ig, being present in 76% of renal biopsies from SLE patients and in 6% from patients with non-lupus immune nephritis. Therefore, we have concluded that IdGN1 and IdGN2 are markers of nephritogenic subsets of autoantibodies and are probably the products of idiotypic spreading most likely to cause disease. Finally, after a review of recent experiments suggesting the dominance of autoreactive, Mossman Type 2 T helper cells in nephritic BW mice, it is hypothesized that autoreactive, IdGN-recognizing helper T cells may be central to the sustained upregulation of pathogenic autoantibodies in murine and human SLE.     

SLE患者血清抗F(ab′)_2片段抗体的测定及其临床意义

用酶解法制备正常人 IgG-F(ab')_2片段及 SLE 患者血清抗 ds-DNA-F(ab')_2片段,ELISA 法检测同一组(46例)SLE 患者血清中抗 F(ab')_2片段抗体,两者检测结果呈高度相关性.同时发现,缓解期 SLE 患者血清中抗 F(ab')_2片段抗体水平明显高于活动期 SLE 患者,而抗 ds-DNA 抗体水平与之相反.提示,正常人 IgG-F(ab')_2片段与 SLE 患者血清抗 ds-DNA-F(ab')_2片段可能有共同的结构表位,其抗 F(ab')_2片段抗体测定可作为临床观察 SLE 活动性的一个指标.     

An analysis of autoimmunity through studies of DNA antibody idiotypes

The existence of idiotypic networks, first postulated over 12 years ago, is now widely recognised. Idiotypic analyses of autoantibodies have been reported among both hybridoma-derived and naturally occurring immunoglobulins. In this review the many studies of idiotypes detected on anti-DNA antibodies, notably one designated 16/6, are analysed to see what clues they offer to our understanding of autoimmunity. The links between infection and autoimmunity are emphasised by this analysis. It is also obvious that idiotypes first identified an autoantibodies are not confined to these immunoglobulins. Thus, the 16/6 idiotype originally described on a hybridoma-derived monoclonal anti-DNA antibody has also been identified on naturally occurring antibodies binding the Klebsiella polysaccharide K30.     

Anti-alpha-actinin antibodies: a new marker of lupus nephritis

The exact role of anti-ds (double stranded) DNA antibodies in the pathogenesis of kidney injury in lupus nephritis remains a focus of continuing investigation. One theory explaining the pathogenicity of anti-dsDNA antibodies in lupus nephritis is direct cross-reactivity with renal antigens. Several years ago, alpha-actinin was identified as a major cross-reactive target for pathogenic anti-dsDNA antibodies in murine SLE. Indeed, binding of a nephritogenic murine anti-dsDNA antibody was stronger to the alpha-actinin derived from a lupus prone mouse mesangial cell line as compared to alpha-actinin in a non-autoimmune mouse mesangial cell line. Furthermore, we recently showed that immunization of non-autoimmune mice with alpha-actinin induces anti-chromatin antibodies, glomerular IgG deposition and proteinuria. In humans, anti-alpha-actinin autoantibodies (Ab) were associated with anti-dsDNA Ab in SLE. In those patients, anti-alpha-actinin rather than anti-dsDNA Ab were significantly associated with glomerulonephritis and disease activity. The anti-alpha-actinin reactivity was associated with high avidity anti-dsDNA Ab. Moreover, the anti-alpha-actinin response was related to the actin-binding site of alpha-actinin. Taken together, these studies indicate that detection of anti-alpha-actinin Ab, in association with anti-dsDNA Ab, may constitute a new marker in lupus nephritis.     

The origin of autoantibodies

Autoimmune diseases are characterized by the appearance of autoantibodies (autoAb) which may participate in their pathogenesis, but autoAb have also been found in normals with a variety of other conditions. The production of hybridomas from lymphocytes of unimmunized normal mice and healthy humans and analysis of the monoclonal autoAb (m-autoAb) obtained, showed that many had polyspecific autoAb reactivity, binding to many seemingly unrelated self-antigens, or to several organs. Most m-autoAb were of the IgM class and shared a common cross-reactive idiotype (CRI). Low levels of Ab with similar binding pattern and idiotype are continuously represented in the serum of mice and humans who have no evidence of autoimmune or other disease. Very similar Ab appear in autoimmune diseases. Studies of m-autoAb derived from lupus-prone mice and from patients with systemic lupus erythematosus (SLE) and other autoimmune diseases also revealed polyspecific binding, IgM isotype and CRI. Moreover, these CRI, which were almost identical with the idiotypes of natural autoAb in normals, may identify a group of pathogenic Ab in the lupus mice and SLE patients. Since the data clearly suggest that lymphocytes that make autoAb are common and are part of the normal B cell repertoire coded by widely dispersed germline genes, there remain the basic problems of the function of these autoAb in health, as well as the question of their regulation and activation in vivo. Several postulated functions and immunoregulatory mechanisms are discussed and the possible role of certain factors, especially viruses, in enhancing autoAb production and autoimmunity, is assessed.     

Soluble human CD83 ameliorates lupus in NZB/W F1 mice

In the present study we explored the immunomodulatory potential of prokaryotically expressed soluble CD83 in the treatment of murine lupus using the NZB/W F1 mouse model. Therefore female NZB/W F1 lupus mice were treated either with sCD83 or PBS for 4 weeks. sCD83 treated mice showed a significantly delayed onset of anti-dsDNA autoantibody production when compared with the control group. Importantly, during the treatment period with sCD83 none of the mice showed elevated levels of anti-dsDNA autoantibodies. In addition, NZB/W F1 mice which received sCD83 displayed lower concentrations of anti-histone IgG autoantibodies. Furthermore, there was no difference in total IgG antibodies, indicating a modulatory role for sCD83 in the production of self-reactive antibodies without decreasing total IgG. These results indicate that administration of sCD83 has profound immune-modulatory effects on the induction of autoantibodies in NZB/W F1 lupus mice and may thus be a promising approach to interfere with autoimmunity in SLE and other autoantibody-driven diseases.     

The homogeneous multiplexed system--a new method for autoantibody profile in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a multi-systemic autoimmune disease leading to immunological aberrations and excessive multiple autoantibody production. The aim of this study was to investigate the prevalence of multiple autoantibodies in SLE patients utilizing the multiplex system method. We analyzed the presence of elevated titers of anti-Ro, anti-La, anti-RNP, anti-Sm, anti-Jo1, anti-centromere, anti-Scl-70, anti-histone, and anti-dsDNA antibodies in 199 serum samples (113 SLE patients, 86 healthy donors). We compared the type, level and number of autoantibodies and the correlation between the autoantibody profile and disease severity utilizing the SLEDAI score. Elevated titers of at least one autoantibody were detected in 48% of 42 SLE patients. Elevated titers of anti-Ro antibodies were most commonly detected. The distribution of specific autoantibodies was: anti-Ro- 23.8%, anti-dsDNA- 19%, antihistone- 19%, anti-RNP- 14.2%, anti-La antibodies- 11.9%, anti-Sm- 7.1%, anti-Scl 70-4.7%, and anti-centromere- 2.4%. Utilizing ROC analysis, the sensitivity and specificity of anti-DNA antibodies at a cutoff value of 34 IU/ml were 87.1% and 79.4% respectively. Elevated titers of anti-Jo1 antibody were not detected. There was a correlation with the titer of anti-Ro antibodies and disease activity by the SLEDAI score. Seven patients harbored one autoantibody only, 15 patients harbored 2-3 autoantibodies, 3 patients harbored 4-5 autoantibodies, and one patient harbored 6 autoantibodies. A correlation between the number of autoantibodies per patient and disease severity was found. One patient with a multitude of autoantibodies had severe lupus and a myriad of clinical manifestations. In conclusion, the multiplex system is specific and sensitive, provides an autoantibody profile in a single test, and may be useful as a diagnostic test for SLE. Elevated anti-Ro antibodies are associated with severe disease. An autoantibody load may be indicative of more severe disease.     

Demonstration of idiotypes expressed on basophil-bound IgE antibodies by using anti-idiotype-induced histamine release in grass pollen-allergic patients.

This study was designed to analyse further the idiotypic cross-reactivity between anti-Lol p I murine monoclonal antibodies of IgG isotype and basophil-bound human IgE antibodies from grass pollen-sensitive patients. It was also designed to determine the expression frequency of the idiotypes present on cell-bound IgE. Rabbit anti-idiotypic antisera were produced against idiotypes of three anti-Lol p I monoclonal antibodies (290A-167, 539A-6 and 348A-6) of different specificities. Basophils from 19 patients reacting to Lol p I allergen, as shown by positive skin test reactions and by the presence of serum-specific IgE antibodies (measured by RAST), were challenged with these rabbit anti-idiotypic antibodies and the histamine released was measured. Our data indicate that IgE-borne idiotypes were expressed as follows: (i) co-expression of the three idiotypes in 15% of patients; (ii) co-expression of two idiotypes in 21% of patients; and (iii) expression of a unique idiotype (290A-167) in 42% of patients. Among the three idiotypes, 290A-167 was shown to be a public idiotype since it was expressed in 80% of patients. Fab fragments of anti-idiotypic antibodies could inhibit anti-idiotype-induced histamine release, but optimal conditions varied from one patient to another.     

Anti-idiotypic induced suppression of Sjögren''s syndrome associated anti-La autoantibody secretion in vitro.

Peripheral blood mononuclear cells from patients with Sjögren''s Syndrome spontaneously secrete autoantibodies to the La antigen when cultured in vitro. This paper reports that specific IgG autoantibody production in vitro is suppressed by pre-treatment of CD8+ enriched T cells with rabbit polyclonal antibodies to idiotypes borne by circulating autologous anti-La antibodies. Treatment of this T cell subpopulation with anti-idiotypes specific for circulating anti-La antibodies from other patients or for anti-DNA antibodies was without effect on anti-La antibody production. Similarly anti-La anti-idiotypes had no effect on the production of autoantibodies to other ribonucleoprotein antigens such as nRNP/Sm. These data show that CD8+ T cells are the main targets for anti-idiotypic control in vitro. We suggest that the relative deficit of these cells, plus a surfeit of CD4+ T cells at the site of the pathological lesion within the salivary gland permits localized production of autoantibodies. Thus, dysregulation of the idiotypic network could contribute to the pathogenesis of Sjögren''s Syndrome.