Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease, which is autoimmune in origin and is characterized by the presence of autoantibodies directed against nuclear antigens. It is a multi-system disease, and patients can present in vastly different ways. Prevalence varies with ethnicity, but is estimated to be about 1 per 1000 overall with a female to male ratio of 10:1. The clinical heterogeneity of this disease mirrors its complex aetiopathogenesis, which highlights the importance of genetic factors and individual susceptibility to environmental factors. SLE can affect every organ in the body. The most common manifestations include rash, arthritis and fatigue. At the more severe end of the spectrum, SLE can cause nephritis, neurological problems, anaemia and thrombocytopaenia. Over 90% of patients with SLE have positive anti-nuclear antibodies (ANA). Significant titres are accepted to be of 1:80 or greater. SLE is a relapsing and remitting disease, and treatment aims are threefold: managing acute periods of potentially life-threatening ill health, minimizing the risk of flares during periods of relative stability, and controlling the less life-threatening, but often incapacitating day to day symptoms. Hydroxychloroquine and non-steroidal anti-inflammatory drugs are used for milder disease; corticosteroids and immunosuppressive therapies are generally reserved for major organ involvement; anti-CD20 monoclonal antibody is now used in patients with severe disease who has not responded to conventional treatments. Despite enormous improvements in prognosis since the introduction of corticosteroids and immunosuppressive drugs, SLE continues to have a significant impact on the mortality and morbidity of those affected.

/pdf/systemic-lupus-erythematosus-34b38trluu.pdf

Systemic lupus erythematosus

Rheumatoid arthritis. Pathophysiology and implications for therapy.

Tumor necrosis factor antagonist mechanisms of action: A comprehensive review

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.

Rheumatoid arthritis (RA) is a widely prevalent (1-3%) chronic systemic disease thought to have an autoimmune component; both humoral and cellular mechanisms have been implicated. Primary osteoarthritis (OA) is considered to be distinct from rheumatoid arthritis, and here damage is thought to be secondary to cartilage degeneration. In rheumatoid arthritis, immune complexes are present that consist exclusively of immunoglobulin, implying that this is both the 'antibody' (rheumatoid factor [RF]) and the 'antigen' (most commonly IgG). Autoantigenic reactivity has been localized to the constant-region (C gamma 2) domains of IgG. There is no evidence for a polypeptide determinant but carbohydrate changes have been reported. We have therefore conducted a study, simultaneously in Oxford and Tokyo, to compare in detail the N-glycosylation pattern of serum IgG (Fig. 1) isolated from normal individuals and from patients with either primary osteoarthritis or rheumatoid arthritis. The results, which required an evaluation of the primary sequences of approximately 1,400 oligosaccharides from 46 IgG samples, indicate that: (1) IgG isolated from normal individuals, patients with RA and patients with OA contains different distributions of asparagine-linked bi-antennary complex-type oligosaccharide structures, (2) in neither disease is the IgG associated with novel oligosaccharide structures, but the observed differences are due to changes in the relative extent of galactosylation compared with normal individuals. This change results in a 'shift' in the population of IgG molecules towards those carrying complex oligosaccharides, one or both of whose arms terminate in N-acetylglucosamine. These two arthritides may therefore be glycosylation diseases, reflecting changes in the intracellular processing, or post-secretory degradation of N-linked oligosaccharides.

/pdf/association-of-rheumatoid-arthritis-and-primary-af3mchbweb.pdf

Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG.

The clearance kinetics of passively administered soluble human serum albumin (HSA)antiHSA complexes were studied in mice at varied doses. Complexes with a molecular composition exceeding Ag2Ab2 (τ 11S complexes) were preferentially cleared by the hepatic reticuloendothelial system. As the dose of administered complexes was increased to levels known to induce glomerulonephritis, however, saturation of the reticuloendothelial system occurred. Three lines of evidence supported this conclusion: 1) The proportion of injected complexes cleared with the fastest half-life became less as the dose was increased. 2) Saturation was demonstrated in the first-order reaction that describes the clearance of τ 11 S complexes (τ Ag2Ab2). 3) The specific hepatic uptake of complexes approached a maximum as the dose was increased. Due to saturation of the reticuloendothelial system, the τ 11 S complexes persisted in the circulation and thereby the likelihood of their non-hepatic tissue deposition was enhanced. The possible contribution of saturation of the reticuloendothelial system to the pathogenesis of glomerulonephritis in experimental serum sickness is discussed.

Saturation of the Reticuloendothelial System with Soluble Immune Complexes

Solid phase immunoadsorbents were prepared by coupling antigens to agarose. With this technique specific antibodies were easily isolated in large amounts. The gammaG-globulin class of antibodies isolated in this manner were not denatured as judged by their normal biological half-life in rabbits. Soluble immune complexes at fivefold antigen excess were prepared from isolated specific antibodies and HSA, human lambda-chains, human lambdaG-globulins, and a Waldenstrom's macroglobulin as antigens. In all these preparations a characteristic immune complex was encountered that represented the smallest stable antigen-antibody union. In the HSA-anti-HSA system they were found to be AgAb(2) complexes, and Ag(2)Ab complexes in the gammaG-anti-gammaG system. These stable complexes fixed complement ineffectively. Also, a spectrum of larger complexes was present in each system, and these complexes fixed complement effectively. With intact antibodies the disappearance curves of immune complexes from the circulation were composed of three exponential components. The immune complexes larger than AgAb(2) were quickly removed from the circulation with half-lives of 0.09-0.37 hr. Their clearance was not dependent on complement components, in that depletion of complement by cobra venom factor and aggregated gammaG-globulin did not alter the pattern of their removal from the circulation. However, when the interchain disulfide bonds of antibodies were reduced and alkylated, the removal of the lambda-anti-lambda, HSA-anti-HSA, and gammaG-anti-gammaG complexes was altered. In these experiments the disappearance curves were composed of two exponential components and the rapid removal of the greater than AgAb(2) complexes did not occur. The immune complexes prepared from reduced and alkylated antibodies fixed complement ineffectively. The presented data indicate that the rapid removal of circulating immune complexes, containing gammaG-globulin molecules as antibodies, depends primarily on the number of antibodies involved. Furthermore, complement fixation is not involved in the rapid removal of such complexes. Nevertheless, the rapid removal of immune complexes and their ability to fix complement have similarities for optimal function in that both processes require intact interchain disulfide bonds of antibodies and complexes that exceed the AgAb(2) combination.

/pdf/studies-on-antigen-antibody-complexes-i-elimination-of-388k5defnt.pdf

Studies on antigen-antibody complexes. I. Elimination of soluble complexes from rabbit circulation.

OBJECTIVE: To determine the specific antibodies present in glomerular immune deposits in patients with systemic lupus erythematosus (SLE). METHODS: Kidney tissue was obtained at autopsy and stored frozen until used. Glomeruli were isolated from the renal cortex, sonicated, and the glomerular basement membrane fragments were extracted with a pH 2.5 buffer or 6 M guanidine hydrochloride. The latter method provided a higher yield and was used in most of the 23 specimens studied. The extracted IgG was quantified by a capture assay using an ELISA with chemiluminescence. IgG antibodies to 14 different antigens were quantified by the same type of assay. The enrichment of antibodies in the extracts was determined in comparison to the initial supernatant of glomeruli that served as a serum surrogate. RESULTS: Antibodies to dsDNA, the collagen-like region of C1q, Sm, SSA, SSB, and chromatin were enriched in glomerular extracts, mainly from patients with proliferative lupus glomerulonephritis. The IgG binding to histones resulted from the presence of immune or non-immune aggregates of IgG. In some specimens all 6 of the above-listed antibodies were enriched. In one specimen antibodies to myeloperoxidase were enriched. Antibodies to cathepsin G, lactoferrin, and beta2-glycoprotein I were not detected. Antibodies to Epstein-Barr viral capsid antigen and nuclear antigen 1 and antibodies to tetanus toxoid were detected in the serum surrogate, but were not enriched in extracts of glomerular basement membrane fragments. CONCLUSION: Autoantibodies with multiple different specificities form the immune deposits in glomeruli of patients with SLE, including antibodies to dsDNA, Sm, SSA, SSB, the collagen-like region of C1q, and chromatin.

https://www.jrheum.org/content/jrheum/30/7/1495.full.pdf

Multiple autoantibodies form the glomerular immune deposits in patients with systemic lupus erythematosus.

The ability of human VH3 immunoglobulins (Ig) to bind to staphylococcal protein A (SPA) via their Fab region is analogous to the binding of bacterial superantigens to T cell receptors. The present report establishes the structural basis for the interaction of SPA and VH3 Ig. We have studied a panel of 27 human monoclonal IgM that were derived from fetal B lymphocytes. As such, these IgM were expected to be encoded by unmutated germline genes. Binding to SPA in ELISA occurred with 15 of 15 VH3 IgM, but none of 12 IgM from the VH1, VH4, VH5, or VH6 families. The VH sequences of the 27 IgM were derived from 20 distinct VH elements, including 11 from the VH3 family. Use of D, JH, and CL genes was similar among VH3 and non-VH3 IgM. A comparison of the corresponding VH protein sequences, and those of previously studied IgM, identified a probable site for SPA binding that includes VH3 residues in framework region 3 (FR3), and perhaps FR1 and 3' complementary determining region 2. The results thus demonstrate that among human IgM, specificity for SPA is encoded by at least 11 different VH3 germline genes. Furthermore, like the T cell superantigens, SPA likely binds to residues in the VH framework region, outside the classical antigen-binding site of the hypervariable loops.

/pdf/the-structural-basis-of-germline-encoded-vh3-immunoglobulin-4wtta1c49r.pdf

The structural basis of germline-encoded VH3 immunoglobulin binding to staphylococcal protein A.

It is concluded that the relative adherence of soluble immune complexes to macrophages is influenced both by the number of receptor sites for IgG per cell, and by their average association constant.

Mart Mannik

Papers

Saturation of the Reticuloendothelial System with Soluble Immune Complexes

Studies on antigen-antibody complexes. I. Elimination of soluble complexes from rabbit circulation.

Multiple autoantibodies form the glomerular immune deposits in patients with systemic lupus erythematosus.

The structural basis of germline-encoded VH3 immunoglobulin binding to staphylococcal protein A.

The macrophage receptor for IgG: number and affinity of binding sites.