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Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2.

Chen Z, Koralov SB, Kelsoe G - J. Exp. Med. (2000)

Bottom Line: The complement system enhances antibody responses to T-dependent antigens, but paradoxically, deficiencies in C1 and C4 are strongly linked to autoantibody production in humans.Moreover, deficiencies in C4 or complement receptors 1 and 2 (CR1/CR2) lead to reduced selection against autoreactive B cells and impaired humoral responses.This systemic lupus erythematosus-like autoimmunity is highly penetrant; by 10 mo of age, all C4(-)(/)- females and most males produced ANA.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.

ABSTRACT
The complement system enhances antibody responses to T-dependent antigens, but paradoxically, deficiencies in C1 and C4 are strongly linked to autoantibody production in humans. In mice, disruption of the C1qa gene also results in spontaneous autoimmunity. Moreover, deficiencies in C4 or complement receptors 1 and 2 (CR1/CR2) lead to reduced selection against autoreactive B cells and impaired humoral responses. These observations suggest that C1 and C4 act through CR1/CR2 to enhance humoral immunity and somehow suppress autoimmunity. Here we report high titers of spontaneous antinuclear antibody (ANA) in C4(-/)- mice. This systemic lupus erythematosus-like autoimmunity is highly penetrant; by 10 mo of age, all C4(-)(/)- females and most males produced ANA. In contrast, titers and frequencies of ANA in Cr2(-)(/)- mice, which are deficient in CR1 and CR2, never rose significantly above those in normal controls. Glomerular deposition of immune complexes (ICs), glomerulonephritis, and splenomegaly were observed in C4(-)(/)- but not Cr2(-)(/)- mice. C4(-)(/)-, but not Cr2(-)(/)-, mice accumulate activated T and B cells. Clearance of circulating ICs is impaired in preautoimmune C4(-)(/)-, but not Cr2(-)(/)-, mice. C4 deficiency causes spontaneous, lupus-like autoimmunity through a mechanism that is independent of CR1/CR2.

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Impaired clearance of ICs in C4−/− mice. Cohorts of B6/129.Ighb (♦), Cr2−/− (▪), C4+/− (○), and C4−/− (•) mice were each injected with 100 RU of ICs through tail veins and bled from orbital sinus at 2, 10, 30, 50, or 70 min after IC injection. IC levels in plasma were assessed by ELISA. Data in the figure were determined with a goat anti–mouse IgG2b detector antibody; inset data were determined with goat anti–mouse Igλ. Upper curves represent the kinetics of IC clearance in C4−/− mice, and lower curves are average clearance rates by B6/129.Ighb, C4+/−, and Cr2−/− mice; these values do not differ significantly from each other (P > 0.05; Student's t test). Individual clearance curves for B6/129.Ighb, C4+/−, and Cr2−/− mice are not shown, but IC RU (mean ± SEM) values for each group are presented; each point represents two to six mice. At the time points of 10, 30, 50, and 70 min, IC levels in C4−/− animals differ significantly from B6.Ighb mice (P < 0.05, Student's t test).
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Figure 6: Impaired clearance of ICs in C4−/− mice. Cohorts of B6/129.Ighb (♦), Cr2−/− (▪), C4+/− (○), and C4−/− (•) mice were each injected with 100 RU of ICs through tail veins and bled from orbital sinus at 2, 10, 30, 50, or 70 min after IC injection. IC levels in plasma were assessed by ELISA. Data in the figure were determined with a goat anti–mouse IgG2b detector antibody; inset data were determined with goat anti–mouse Igλ. Upper curves represent the kinetics of IC clearance in C4−/− mice, and lower curves are average clearance rates by B6/129.Ighb, C4+/−, and Cr2−/− mice; these values do not differ significantly from each other (P > 0.05; Student's t test). Individual clearance curves for B6/129.Ighb, C4+/−, and Cr2−/− mice are not shown, but IC RU (mean ± SEM) values for each group are presented; each point represents two to six mice. At the time points of 10, 30, 50, and 70 min, IC levels in C4−/− animals differ significantly from B6.Ighb mice (P < 0.05, Student's t test).

Mentions: Complement is implicated in the clearance of ICs 8. Walport et al. 8 have proposed that autoimmunity in complement-deficient patients might result from failure to clear immunogenic ICs. Thus, we tested the role of C4 in the clearance of soluble ICs in vivo at an age (2 mo) when C4−/− mice show no apparent signs of autoimmunity. Cohorts (n = 2–6) of 2-mo-old C4−/−, C4+/−, Cr2−/−, and B6/129.Ighb mice were injected intravenously with 100 RU of soluble ICs. Levels of IC in plasma (∼30 RU/ml) were comparable in all groups at 2 min after injection (Fig. 6). From 2 to 10 min, IC concentrations in plasma decreased about threefold in C4+/−, Cr2−/−, and wild-type mice; plasma IC levels in C4−/− mice, however, remained almost constant during this period. After 10 min, clearance rates were identical in all groups, including C4−/−. The initial delay in IC clearance by C4−/− mice resulted in a persistent, two- to threefold increase in circulating IC levels over that of Cr2−/− mice and B6/129.Ighb controls. Higher levels of ICs in C4−/− mice remained for as long as 70 min after IC administration (Fig. 6). Rapid clearance of ICs in Cr2−/− mice suggests that CR1/CR2 plays a minor role in eliminating this type of IC from the blood circulation.


Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2.

Chen Z, Koralov SB, Kelsoe G - J. Exp. Med. (2000)

Impaired clearance of ICs in C4−/− mice. Cohorts of B6/129.Ighb (♦), Cr2−/− (▪), C4+/− (○), and C4−/− (•) mice were each injected with 100 RU of ICs through tail veins and bled from orbital sinus at 2, 10, 30, 50, or 70 min after IC injection. IC levels in plasma were assessed by ELISA. Data in the figure were determined with a goat anti–mouse IgG2b detector antibody; inset data were determined with goat anti–mouse Igλ. Upper curves represent the kinetics of IC clearance in C4−/− mice, and lower curves are average clearance rates by B6/129.Ighb, C4+/−, and Cr2−/− mice; these values do not differ significantly from each other (P > 0.05; Student's t test). Individual clearance curves for B6/129.Ighb, C4+/−, and Cr2−/− mice are not shown, but IC RU (mean ± SEM) values for each group are presented; each point represents two to six mice. At the time points of 10, 30, 50, and 70 min, IC levels in C4−/− animals differ significantly from B6.Ighb mice (P < 0.05, Student's t test).
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Figure 6: Impaired clearance of ICs in C4−/− mice. Cohorts of B6/129.Ighb (♦), Cr2−/− (▪), C4+/− (○), and C4−/− (•) mice were each injected with 100 RU of ICs through tail veins and bled from orbital sinus at 2, 10, 30, 50, or 70 min after IC injection. IC levels in plasma were assessed by ELISA. Data in the figure were determined with a goat anti–mouse IgG2b detector antibody; inset data were determined with goat anti–mouse Igλ. Upper curves represent the kinetics of IC clearance in C4−/− mice, and lower curves are average clearance rates by B6/129.Ighb, C4+/−, and Cr2−/− mice; these values do not differ significantly from each other (P > 0.05; Student's t test). Individual clearance curves for B6/129.Ighb, C4+/−, and Cr2−/− mice are not shown, but IC RU (mean ± SEM) values for each group are presented; each point represents two to six mice. At the time points of 10, 30, 50, and 70 min, IC levels in C4−/− animals differ significantly from B6.Ighb mice (P < 0.05, Student's t test).
Mentions: Complement is implicated in the clearance of ICs 8. Walport et al. 8 have proposed that autoimmunity in complement-deficient patients might result from failure to clear immunogenic ICs. Thus, we tested the role of C4 in the clearance of soluble ICs in vivo at an age (2 mo) when C4−/− mice show no apparent signs of autoimmunity. Cohorts (n = 2–6) of 2-mo-old C4−/−, C4+/−, Cr2−/−, and B6/129.Ighb mice were injected intravenously with 100 RU of soluble ICs. Levels of IC in plasma (∼30 RU/ml) were comparable in all groups at 2 min after injection (Fig. 6). From 2 to 10 min, IC concentrations in plasma decreased about threefold in C4+/−, Cr2−/−, and wild-type mice; plasma IC levels in C4−/− mice, however, remained almost constant during this period. After 10 min, clearance rates were identical in all groups, including C4−/−. The initial delay in IC clearance by C4−/− mice resulted in a persistent, two- to threefold increase in circulating IC levels over that of Cr2−/− mice and B6/129.Ighb controls. Higher levels of ICs in C4−/− mice remained for as long as 70 min after IC administration (Fig. 6). Rapid clearance of ICs in Cr2−/− mice suggests that CR1/CR2 plays a minor role in eliminating this type of IC from the blood circulation.

Bottom Line: The complement system enhances antibody responses to T-dependent antigens, but paradoxically, deficiencies in C1 and C4 are strongly linked to autoantibody production in humans.Moreover, deficiencies in C4 or complement receptors 1 and 2 (CR1/CR2) lead to reduced selection against autoreactive B cells and impaired humoral responses.This systemic lupus erythematosus-like autoimmunity is highly penetrant; by 10 mo of age, all C4(-)(/)- females and most males produced ANA.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.

ABSTRACT
The complement system enhances antibody responses to T-dependent antigens, but paradoxically, deficiencies in C1 and C4 are strongly linked to autoantibody production in humans. In mice, disruption of the C1qa gene also results in spontaneous autoimmunity. Moreover, deficiencies in C4 or complement receptors 1 and 2 (CR1/CR2) lead to reduced selection against autoreactive B cells and impaired humoral responses. These observations suggest that C1 and C4 act through CR1/CR2 to enhance humoral immunity and somehow suppress autoimmunity. Here we report high titers of spontaneous antinuclear antibody (ANA) in C4(-/)- mice. This systemic lupus erythematosus-like autoimmunity is highly penetrant; by 10 mo of age, all C4(-)(/)- females and most males produced ANA. In contrast, titers and frequencies of ANA in Cr2(-)(/)- mice, which are deficient in CR1 and CR2, never rose significantly above those in normal controls. Glomerular deposition of immune complexes (ICs), glomerulonephritis, and splenomegaly were observed in C4(-)(/)- but not Cr2(-)(/)- mice. C4(-)(/)-, but not Cr2(-)(/)-, mice accumulate activated T and B cells. Clearance of circulating ICs is impaired in preautoimmune C4(-)(/)-, but not Cr2(-)(/)-, mice. C4 deficiency causes spontaneous, lupus-like autoimmunity through a mechanism that is independent of CR1/CR2.

Show MeSH
Related in: MedlinePlus