A Protective Role for Innate Immunity in Autoimmune Disease

Carroll, Michael

doi:10.1006/clim.1999.4813

Cited by 26 publications

(18 citation statements)

References 65 publications

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“…Deficiency of C1q accelerated disease in MRL/Mp ϩ/ϩ mice (55), whereas deficiencies of C4 or CR1/ CR2 resulted in enhanced autoimmune disease, including lupus nephritis, in C57BL/6.lpr/lpr mice (56 -58). Although almost certainly an oversimplification, these data have been interpreted to indicate that classical pathway activation on apoptotic debris, rich in nuclear components, is necessary for their appropriate clearance and maintenance of tolerance, as signaled through the B lymphocyte CR1/CR2 (59,60).…”

Section: Discussionmentioning

confidence: 99%

Administration of a Soluble Recombinant Complement C3 Inhibitor Protects Against Renal Disease in MRL/lpr Mice

Bao

Haas²,

Kraus³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Complement receptor 1-related gene/protein y (Crry) in rodents is a potent membrane complement regulator that inhibits complement C3 activation by both classical and alternative pathways. To clarify the role of complement in lupus nephritis, MRL/lpr mice were given Crry as a recombinant protein (Crry-Ig) from 12 to 24 wk of age. Control groups were given saline or normal mouse IgG. Sera and urine were collected biweekly. Only 1 of 20 (5%) Crry-Ig-treated mice developed renal failure (BUN Ͼ 50 mg/dl) compared with 18 of 38 (47.4%) mice in control groups (P ϭ 0.001). BUN levels at 24 wk were reduced from 68.8 Ϯ 9.7 mg/dl in control groups to 38.5 Ϯ 3.9 mg/dl in the Crry-Ig-treated group (P Ͻ 0.01). Urinary albumin excretion at 24 wk was also significantly reduced from 5.3 Ϯ 1.4 mg/mg creatinine in the control groups to 0.5 Ϯ 0.2 mg/mg creatinine in the Crry-Ig-treated group (P Ͻ 0.05). Of the histologic data at 24 wk, there was a significant reduction in scores for glomerulosclerosis and C3d, IgG, IgG3, and IgA staining intensity in glomeruli in complement-inhibited animals. Crry-Ig-treated animals were also protected from vasculitic lesions. Although there was no effect on relevant autoimmune manifestations such as anti-double stranded DNA titers or cryoglobulin IgG3 levels, circulating immune complex levels were markedly higher in complement-inhibited animals. Thus, inhibition of complement activation with Crry-Ig significantly reduces renal disease in MRL/lpr lupus mice. The data support the strategy of using recombinant complement C3 inhibitors to treat human lupus nephritis.

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Section: Discussionmentioning

confidence: 99%

Administration of a Soluble Recombinant Complement C3 Inhibitor Protects Against Renal Disease in MRL/lpr Mice

Bao

Haas²,

Kraus³

et al. 2003

Journal of the American Society of Nephrology

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“…There were no differences between MRL/lpr animals with and without the Crry transgene at 18, 21, and 24 wk of age (Table II). Thus, complement inhibition with sCrry does not appear to affect the underlying autoimmunity in MRL/lpr mice, as can occur with complete complement protein deficiencies of early classical pathway components (31,32).…”

Section: Complement Inhibition With Scrry Does Not Affect Underlying mentioning

confidence: 94%

Transgenic Expression of a Soluble Complement Inhibitor Protects Against Renal Disease and Promotes Survival in MRL/lprMice

Bao

Haas

Boackle

et al. 2002

The Journal of Immunology

105

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To investigate the role of complement in lupus nephritis, we used MRL/lpr mice and a transgene overexpressing a soluble complement regulator, soluble CR1-related gene/protein y (sCrry), both systemically and in kidney. Production of sCrry in sera led to significant complement inhibition in Crry-transgenic mice relative to littermate transgene negative controls. This complement inhibition with sCrry conferred a survival advantage to MRL/lpr mice. In a total of 154 animals, 42.5% transgene-negative animals had impaired renal function (blood urea nitrogen > 50 mg/dl) compared with 16.4% mice with the sCrry-producing transgene (p < 0.001). In those animals that died spontaneously, MRL/lpr mice with the sCrry-producing transgene did not die of renal failure, while those without the transgene did (blood urea nitrogen values of 46.6 ± 9 and 122 ± 29 mg/dl in transgene-positive and transgene-negative animals, respectively; p < 0.001). Albuminuria was reduced in those transgenic animals in which sCrry expression was maximally stimulated (urinary albumin/creatinine = 12.4 ± 4.3 and 36.9 ± 7.7 in transgene-positive and transgene-negative animals, respectively; p < 0.001). As expected in the setting of chronic complement inhibition, there was less C3 deposition in glomeruli of sCrry-producing transgenic mice compared with transgene-negative animals. In contrast, there was no effect on glomerular IgG deposition, levels of anti-dsDNA Ab and rheumatoid factor, or spleen weights between the two groups. Thus, long-term complement inhibition reduces renal disease in MRL/lpr mice, which translates into improved survival. MRL/lpr mice in which complement is inhibited still have spontaneous mortality, yet this is not from renal disease.

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“…Complement participates in autoimmune-mediated tissue damage (4). To avoid excessive damage to host cells and tissues, activation of the complement cascade is tightly regulated (5) through a set of membrane and plasma inhibitors.…”

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confidence: 99%

Synergy between Two Active Sites of Human Complement Receptor Type 1 (CD35) in Complement Regulation: Implications for the Structure of the Classical Pathway C3 Convertase and Generation of More Potent Inhibitors

Krych-Goldberg

Hauhart

Porzukowiak

et al. 2005

The Journal of Immunology

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The extracellular domain of the complement receptor type 1 (CR1; CD35) consists entirely of 30 complement control protein repeats (CCPs). CR1 has two distinct functional sites, site 1 (CCPs 1–3) and two copies of site 2 (CCPs 8–10 and CCPs 15–17). In this report we further define the structural requirements for decay-accelerating activity (DAA) for the classical pathway (CP) C3 and C5 convertases and, using these results, generate more potent decay accelerators. Previously, we demonstrated that both sites 1 and 2, tandemly arranged, are required for efficient DAA for C5 convertases. We show that site 1 dissociates the CP C5 convertase, whereas the role of site 2 is to bind the C3b subunit. The intervening CCPs between two functional sites are required for optimal DAA, suggesting that a spatial orientation of the two sites is important. DAA for the CP C3 convertase is increased synergistically if two copies of site 1, particularly those carrying DAA-increasing mutations, are contained within one protein. DAA in such constructs may exceed that of long homologous repeat A (CCPs 1–7) by up to 58-fold. To explain this synergy, we propose a dimeric structure for the CP C3 convertase on cell surfaces. We also extended our previous studies of the amino acid requirements for DAA of site 1 and found that the CCP 1/CCP 2 junction is critical and that Phe82 may contact the C3 convertases. These observations increase our understanding of the mechanism of DAA. In addition, a more potent decay-accelerating form of CR1 was generated.

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A Protective Role for Innate Immunity in Autoimmune Disease

Cited by 26 publications

References 65 publications

Administration of a Soluble Recombinant Complement C3 Inhibitor Protects Against Renal Disease in MRL/lpr Mice

Administration of a Soluble Recombinant Complement C3 Inhibitor Protects Against Renal Disease in MRL/lpr Mice

Transgenic Expression of a Soluble Complement Inhibitor Protects Against Renal Disease and Promotes Survival in MRL/lprMice

Synergy between Two Active Sites of Human Complement Receptor Type 1 (CD35) in Complement Regulation: Implications for the Structure of the Classical Pathway C3 Convertase and Generation of More Potent Inhibitors

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