Publisher Summary This chapter reviews the histopathologic, serologic, lymphocytic, virological, hormonal, and genetic characteristics of murine models of systemic lupus erythematosus (SLE). The pathogenetic mechanisms underlying murine SLE are highly complex, apparently well-programmed genetically, but still diverse and their bases not as yet well defined. Significant serologic and cellular experimental data support the statement that the final immunopathologic perturbation in murine (and human) SLE is a B lymphocyte hyperactivity with corresponding enhancement of serum antibodies and autoantibodies, particularly IgG, and consequent formation of pathogenic antigen–antibody ICs. On the basis of the available data, it appears that this B cell hyperactivity is polyclonal but not necessarily panclonal in nature, because not only antibodies against a wide array of autoantigens but also antibodies against incidental antigens, such as haptens, can be detected. The presence of autoantibodies and of their idiotypes in some recombinant lupus x normal murine lines expressing the normal partner's V genes, normal mice in which an exogenous or endogenous (Ipr gene) immunostimulator has been introduced, and unmanipulated normal mice indicate that lupus mice are not unique in their structural genetic Ig elements, whose presence determines the development of their autoimmune disease. The cause of B cell hyperactivity in lupus has not yet been fully elucidated. Autonomous B cell maturation does not appear likely, because B cell proliferation and differentiation in lupus mice was found to be dependent on the same number of accessory signals as in normal mice.

Murine models of systemic lupus erythematosus.

Purpose:To determine the prevalence of lupus anticoagulant and anticardiolipin in systemic lupus erythematosus (SLE) and in non-SLE disorders, and to evaluate the clinical significance of ...

Antiphospholipid Antibodies: Anticardiolipin and the Lupus Anticoagulant in Systemic Lupus Erythematosus (SLE) and in Non-SLE Disorders

PURPOSE To determine the prevalence of lupus anticoagulant and anticardiolipin in systemic lupus erythematosus (SLE) and in non-SLE disorders, and to evaluate the clinical significance of these autoantibodies as they relate to thromboembolic events, neuropsychiatric disorders, thrombocytopenia, and fetal loss. DATA IDENTIFICATION A computer-assisted search of the literature (MEDLINE, 1966 to 1989) and review of the bibliographies of all identified articles. STUDY SELECTION Series of ten or more subjects were included if the assays used for detecting lupus anticoagulant or anticardiolipin met the specified minimal criteria for validity. DATA EXTRACTION Series were categorized according to antibody type and underlying disease. A systematic appraisal of patient selection methods, study design, and assay methods was done. RESULTS OF DATA ANALYSIS An analysis of 29 published series (comprising over 1000 patients with SLE) yielded an average frequency of 34% for the lupus anticoagulant and 44% for anticardiolipin. Antiphospholipid antibodies are also prevalent in patients with various non-SLE disorders. In patients with SLE, a statistically significant association exists between the presence of either antibody and a history of thrombosis, neurologic disorders, or thrombocytopenia. The available data suggest, but do not firmly support, an association between antiphospholipid antibodies and history of fetal loss in women with SLE. Contrary to prevailing opinion, none of these associations have been shown conclusively in patients with non-SLE disorders. CONCLUSIONS The results of predominantly retrospective series suggest that for certain persons (patients with SLE or closely related disorders) antiphospholipid antibodies may be important risk factors for thrombosis, neurologic disease, thrombocytopenia, and fetal loss. Standardized tests for lupus anticoagulant and anticardiolipin, as well as long-term, prospective clinical studies, are needed to determine the prognostic value of antiphospholipid antibodies.

Antiphospholipid Antibodies: Anticardiolipin and the Lupus Anticoagulant in Systemic Lupus Erythematosus (SLE) and in Non-SLE Disorders: Prevalence and Clinical Significance

The proximate cause of autoantibodies characteristic of systemic autoimmune diseases has been controversial. One hypothesis is that autoantibodies are the result of polyclonal nonspecific B cell activation. Alternatively, autoantibodies could be the result of antigen-driven B cell activation, as observed in secondary immune responses. We have approached this question by studying monoclonal anti-DNA autoantibodies derived from unmanipulated spleen cells of the autoimmune MRL/lpr mouse strain. This analysis shows that anti-DNAs, like rheumatoid factors (19), are the result of specific antigen-driven stimulation. In addition, correlation of sequences with fine specificity shows that: (a) somatic mutations can cause specificity for dsDNA and that such mutations are selected for; (b) arginine residues play an important role in determining specificity; and (c) anti-idiotypes that recognize the majority of anti-DNA are probably not specific for any one family of V regions.

https://rupress.org/jem/article-pdf/171/1/265/1099981/265.pdf

Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation.

To evaluate the predictive power of changes in levels of antibodies to double-stranded DNA (anti-dsDNA) as a predictor of disease exacerbations in systemic lupus erythematosus (SLE), we performed a prospective study on 72 unselected patients with SLE (mean duration of study 18.5 months, range 6-35 months). Patients were seen at least once every 3 months, and disease activity was scored according to a specific protocol. Plasma samples were obtained at least once every month and were assessed for anti-dsDNA antibody (by the Crithidia luciliae assay, an enzyme-linked immunosorbent assay [ELISA], and the Farr assay) and for complement components C3 and C4. Twenty-seven of 33 disease exacerbations observed during the study period were accompanied by a positive test result for anti-dsDNA antibody (27 by the Farr assay, 19 by the C luciliae assay, and 23 by the ELISA). Twenty-four of these exacerbations were preceded by a significant increase in anti-dsDNA antibody levels (23 by the Farr assay, 12 by the C luciliae assay, and 17 by the ELISA). The first observance of a significant increase in anti-dsDNA antibody levels preceded the exacerbation by 8-10 weeks. Significant increases in anti-dsDNA antibody levels not followed by an exacerbation were observed in 5 cases by the Farr assay, in 7 cases by the C luciliae assay, and in 3 cases by the ELISA; however, in 3 cases, 2 cases, and 1 case, respectively, these increases were followed by an increase in disease activity that did not fulfill the criteria for an exacerbation. Serial measurement of anti-dsDNA antibody levels was more sensitive for predicting exacerbations than was measurement of C3 and/or C4 levels (P less than 0.03). Serial assessment of anti-dsDNA antibody levels, especially by the Farr assay, is a sensitive and reasonably specific method for predicting disease exacerbations in SLE.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780330505

Measurement of increases in anti-double-stranded DNA antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus. A long-term, prospective study.

Idiotypic cross-reactions were evaluated in 60 polynucleotide-binding monoclonal lupus autoantibodies produced by human-human hybridomas that were derived from seven unrelated patients with SLE. Three antiidiotype reagents were prepared by immunization of rabbits or a mouse with monoclonal autoantibodies from two patients. Binding of the three reagents to their corresponding idiotypes was inhibited by one or more polynucleotides, an indication that the antiidiotypes reacted with the variable regions of the autoantibodies. Each antiidiotype appeared to detect a different idiotypic determinant. Of the 60 monoclonal autoantibodies tested, 40 reacted in one or more competitive immunoassays; 15 reacted with one antiidiotype, 10 reacted with two antiidiotypes and 15 reacted with three antiidiotypes. A monoclonal antiidiotype reagent cross-reacted with autoantibodies from six of the seven patients. The idiotypic cross-reactions of immunoglobulins from unrelated patients suggest that the autoantibodies are derived from related families of germ line genes that are expressed by patients with SLE.

https://rupress.org/jem/article-pdf/158/3/718/1093850/718.pdf

Idiotypic cross-reactions of monoclonal human lupus autoantibodies.

Binding of cytoskeletal proteins by monoclonal anti-DNA lupus autoantibodies☆

Analysis of the binding of serum from 56 systemic lupus erythematosus patients to native DNA (nDNA), denatured DNA (dDNA), poly I, poly(dT), RNA, and cardiolipin revealed multiple antigen binding in many of the sera. Raised levels of antibodies (IgG and/or IgM) to denatured DNA were found in the highest percentage (68%) of patients. A small subset of patients with multiple raised IgM antibodies, renal disease, and vasculitic skin rash was identified. No correlation between multiple serologic activity and clinical disease was found.

Multiple serologic reactions and their relationship to clinical activity in systemic lupus erythematosus.

1. A Short History of Autoimmune Diseases 2. Autoimmune Diseases - Clinical Features and Animal Models 3. Natural Autoimmunity (i) Natural autoantibodies (ii) Autoantibodies in healthy populations 4. Analysis of the Components of the Immune System Involved in Autoimmunity (i) Immune complexes and antibody mediated damage (ii) Idiotype network (iii) Glycosylation studies: Analysis of abnormalities in the oligosaccharides attached to IgG (iv) T Suppressor cells (v) Natural killer cells 5. The genetic components of autoimmunity (i) Family studies (ii) Autoimmune disease and the major histocompatability complex (MHC/HLA) (iii) The Gm allotype system and autoimmune diseases (iv) Complement deficiency and autoimmunity (v) Immunodeficiency states and autoimmune conditions (vi) IgA deficiency and autoimmunity 6. Hormonal Components and Autoimmune Diseases (i) Sex steroids (ii) Autoimmunity and pregnancy (iii) Thymic hormones and autoimmunity (iv) The effect of corticosteroids on the immune system (v) Vitamin D, the immune system and autoimmunity (vi) Cytokines and autoimmunity 7. Environmental Factors and Autoimmunity (i) Drugs and autoimmunity (ii) Infection and autoimmunity (iii) Mycobacteria and autoimmunity (iv) HIV Infection and autoimmunity (v) Nutrition and autoimmunity (vi) Ultraviolet light and autoimmunity (vii) Toxins and chemicals (viii) Stress and autoimmunity 8. Ageing and autoimmunity 9. Cancer and autoimmunity (i) Malignancy in autoimmune conditions (ii) Autoimmune syndromes in cancer (iii) Autoantibodies in malignant diseases 10. Graft versus Host Disease and Autoimmunity 11. Treatment of the Autoimmune Diseases 12. Concluding Remarks: The Mosaic of Autoimmunity

David A. Isenberg

Papers

Idiotypic cross-reactions of monoclonal human lupus autoantibodies.

Binding of cytoskeletal proteins by monoclonal anti-DNA lupus autoantibodies☆

Multiple serologic reactions and their relationship to clinical activity in systemic lupus erythematosus.

The mosaic of autoimmunity : (the factors associated with autoimmune disease )

Common lupus anti-DNA antibody idiotypes in chronic liver diseases