Background Although much is known about the natural history of systemic lupus erythematosus (SLE), the development of SLE autoantibodies before the diagnosis of the disease has not been extensively explored. We investigated the onset and progression of autoantibody development before the clinical diagnosis. Methods The Department of Defense Serum Repository contains approximately 30 million specimens prospectively collected from more than 5 million U.S. Armed Forces personnel. We evaluated serum samples obtained from 130 persons before they received a diagnosis of SLE, along with samples from matched controls. Results In 115 of the 130 patients with SLE (88 percent), at least one SLE autoantibody tested was present before the diagnosis (up to 9.4 years earlier; mean, 3.3 years). Antinuclear antibodies were present in 78 percent (at a dilution of 1:120 or more), anti–double-stranded DNA antibodies in 55 percent, anti-Ro antibodies in 47 percent, anti-La antibodies in 34 percent, anti-Sm antibodies in 32 pe...

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Development of autoantibodies before the clinical onset of systemic lupus erythematosus.

Interleukin-6, an inflammatory cytokine, is characterized by pleiotropy and redundancy of action Apart from its hematologic, immune, and hepatic effects, it has many endocrine and metabolic actions Specifically, it is a potent stimulator of the hypothalamic-pituitary-adrenal axis and is under the tonic negative control of glucocorticoids It acutely stimulates the secretion of growth hormone, inhibits thyroid-stimulating hormone secretion, and decreases serum lipid concentrations Furthermore, it is secreted during stress and is positively controlled by catecholamines Administration of interleukin-6 results in fever, anorexia, and fatigue Elevated levels of circulating interleukin-6 have been seen in the steroid withdrawal syndrome and in the severe inflammatory, infectious, and traumatic states potentially associated with the inappropriate secretion of vasopressin Levels of circulating interleukin-6 are also elevated in several inflammatory diseases, such as rheumatoid arthritis Interleukin-6 is negatively controlled by estrogens and androgens, and it plays a central role in the pathogenesis of the osteoporosis seen in conditions characterized by increased bone resorption, such as sex-steroid deficiency and hyperparathyroidism Overproduction of interleukin-6 may contribute to illness during aging and chronic stress Finally, administration of recombinant human interleukin-6 may serve as a stimulation test for the integrity of the hypothalamic-pituitary-adrenal axis

The Pathophysiologic Roles of Interleukin-6 in Human Disease

Systemic vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) is the most frequent cause of rapidly progressive glomerulonephritis. Renal failure at presentation carries an increased risk for ESRD and death despite immunosuppressive therapy. This study investigated whether the addition of plasma exchange was more effective than intravenous methylprednisolone in the achievement of renal recovery in those who presented with a serum creatinine >500 micromol/L (5.8 mg/dl). A total of 137 patients with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine >500 micromol/L (5.8 mg/dl) were randomly assigned to receive seven plasma exchanges (n = 70) or 3000 mg of intravenous methylprednisolone (n = 67). Both groups received oral cyclophosphamide and oral prednisolone. The primary end point was dialysis independence at 3 mo. Secondary end points included renal and patient survival at 1 yr and severe adverse event rates. At 3 mo, 33 (49%) of 67 after intravenous methylprednisolone compared with 48 (69%) or 70 after plasma exchange were alive and independent of dialysis (95% confidence interval for the difference 18 to 35%; P = 0.02). As compared with intravenous methylprednisolone, plasma exchange was associated with a reduction in risk for progression to ESRD of 24% (95% confidence interval 6.1 to 41%), from 43 to 19%, at 12 mo. Patient survival and severe adverse event rates at 1 yr were 51 (76%) of 67 and 32 of 67 (48%) in the intravenous methylprednisolone group and 51 (73%) of 70 and 35 of (50%) 70 in the plasma exchange group, respectively. Plasma exchange increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone. Patient survival and severe adverse event rates were similar in both groups.

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Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis

Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome. A prospective study in 342 patients.

Neutrophils play important roles in host defense against all classes of infectious agents but, para- doxically, they are also involved in the pathology of van- ous inflammatory conditions. Their microbicidal armory consists of oxidative and nonoxidative processes that are activated simultaneously upon phagocytosis. Although destruction of infectious agents occurs intracellulanly, release of cytotoxic molecules into the extracellulan milieu can damage body tissues. Neutrophils are heterogeneous. Subpopulations exist in various stages from dormant to primed to fully activated. The activities of neutrophils are regulated locally in microenvironments and systemi- cally by a plethora of mediators including cytokines, "classical" neuroendocrine hormones, and bioactive lipids. The net response depends on a complex balance of stimulatory and inhibitory pathways that are regulated by these mediators. Although some effector and regula- tory pathways are vital, considerable redundancy is also evident. Identification of the essential mediators and the unraveling of any interactions may be the keys to under- standing the neutrophil paradox and developing then- apeutic strategies that optimize microbial killing and minimize host tissue damage. Finally, reports that neu- trophils can act as drug delivery vectors and that their function is influenced by stress and other lifestyle factors suggest that new homeostatic functions for these cells, outside their traditional roles in host defense and inflam- mation, remain to be identified: some are speculated on here.J. Leukoc. Biol. 56: 672-686; 1994.

Neutrophils, host defense, and inflammation: a double-edged sword.

Antineutrophil cytoplasmic antibodies: A still-growing class of autoantibodies in inflammatory disorders

Antiproteinase 3- and antimyeloperoxidase-associated vasculitis

To develop an animal model for antimyeloperoxidase (MPO)-associated necrotizing crescentic glomerulonephritis (NCGN), we immunized Brown Norway rats with MPO and localized a neutrophil lysosomal enzyme extract, primarily consisting of MPO and elastinolytic enzymes, plus H2O2, the substrate of MPO, to the glomerular basement membrane (GBM). Upon immunization rats developed antibodies and positive skin tests to MPO. After unilateral perfusion of the left kidney with the lysosomal enzyme extract and H2O2, MPO and immunoglobulin (Ig)G localized transiently along the GMB. At the time of maximal inflammation, at 4 and 10 d after perfusion, MPO, IgG, and C3 could not be detected anymore. MPO-immunized rats perfused with the lysosomal enzyme extract and H2O2, in contrast to control-immunized and/or control-perfused rats, developed a proliferative GN characterized by intra- and extracapillary cell proliferation, ruptured Bowman's capsule, periglomerular granulomatous inflammation, and formation of giant cells. Monocytes, polymorphonuclear leukocytes (PMN), and to a far lesser extent T cells were found in the glomeruli. Interstitial infiltrates consisted of monocytes, PMN, and T cells. Granulomatous vasculitis of small vessels was found at 10 d after perfusion. The proliferative NCGN in this rat model closely resembles human anti-MPO-associated pauci-immune NCGN, and enables the study of the pathophysiology of anti-MPO-associated NCGN.

https://rupress.org/jem/article-pdf/177/4/905/1103645/905.pdf

Antimyeloperoxidase-associated proliferative glomerulonephritis: an animal model.

To investigate the possible role of IL-6 in the activation of the autoimmune process in systemic lupus erythematosus (SLE), we serially measured concentrations of IL-6, IgG, and anti-dsDNA antibodies before and during exacerbations in patients with SLE. In addition, we serially related the IL-6 response to the generation of the acute phase reactant C-reactive protein (CRP). Sixteen consecutive patients who developed an exacerbation were analysed in this study. Blood samples were drawn in EDTA monthly. At the time of maximal disease activity during exacerbation, IL-6 plasma concentrations were increased (greater than or equal to 6 pg/ml) in 12 out of the 16 cases. Concentrations of IL-6 correlated with the concentrations of CRP (P less than 0.01) and the score of the disease activity index (P less than 0.05). No correlation was found between IL-6 concentrations and concentrations of anti-dsDNA or IgG. The course of changes in IL-6 concentrations before the exacerbation was variable. Five out of the 16 exacerbations studied were characterized by a prominent rise of IL-6 at the time of maximum disease activity. In this subgroup serositis as well as elevated concentrations of CRP were observed more frequently (P less than 0.02). Seven exacerbations were not accompanied or preceded by changes in IL-6 concentrations and showed generally low IL-6 concentrations. In this latter subgroup cerebral involvement was seen more frequently (P less than 0.02). Our data do not suggest a pathogenic role for IL-6 in the generation of IgG and/or anti-dsDNA antibodies before exacerbations. Rises of IL-6 concentrations before exacerbations in SLE seem only to occur in a subgroup of patients with SLE characterized by the presence of serositis and elevated concentrations of CRP during exacerbation.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2249.1992.tb05840.x

Plasma concentration of IL-6 in systemic lupus erythematosus; an indicator of disease activity ?

Background Smoking influences numbers and function of peripheral blood lymphocytes (PBL) by a process that is badly understood. We conducted this study to evaluate whether the immune impairment of smoking might be related to changes in the expression or functionality of Fas, a cell surface molecule that plays a central role in immune homeostasis and cytotoxic activity. Methods PBL from 10 smoking and 10 nonsmoking healthy volunteers were isolated. Flow cytometry was performed to measure the state of activation, Fas expression and apoptosis of PBL. Functionality of Fas was rested by assessing apoptosis after incubation of isolated lymphocytes with agonistic anti-Fas antibodies in four smoking and four nonsmoking individuals. Results Smoking was associated with an increase in the percentage of Fas-expressing CD4(+) T and B lymphocytes. A decrease in the percentage of activated (CD38(+)) B cells was observed. In vitro Fas-induced apoptosis did not appear different between smokers and nonsmokers. No differences in the percentages of circulating apoptotic lymphocytes could be demonstrated between smoking and nonsmoking individuals. Conclusion Smoking is associated with increased Fas expression on PBL in general, and on B cells in particular. This might render these cells more susceptible for apoptosis. As Fas is functionally intact this may also explain the reduced percentage of activated (CD38(+)) B cells found in smoking individuals. The latter may contribute to the reduced humoral immune response observed in smokers.

Cgm Kallenberg

Papers

Antineutrophil cytoplasmic antibodies: A still-growing class of autoantibodies in inflammatory disorders

Antiproteinase 3- and antimyeloperoxidase-associated vasculitis

Antimyeloperoxidase-associated proliferative glomerulonephritis: an animal model.

Plasma concentration of IL-6 in systemic lupus erythematosus; an indicator of disease activity ?

Effects of smoking on activation markers, Fas expression and apoptosis of peripheral blood lymphocytes