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Germline deletion of β2 microglobulin or CD1d reduces anti-phospholipid antibody, but increases autoantibodies against non-phospholipid antigens in the NZB/W F1 model of lupus.

Singh RR, Yang JQ, Kim PJ, Halder RC - Arthritis Res. Ther. (2013)

Bottom Line: Since CD1d is known to bind and present phospholipid antigens to T cells, we asked if the deficiency of β2m or CD1d will impact the development of anti-phospholipid antibodies as compared to other aspects of lupus autoimmunity.Whereas β2m° BWF1 mice had reduced serum IgG, they had increased mortality, nephritis, serum IgG anti-DNA antibody and RF as compared to heterozygous and wild-type littermates.Such CD1d dependence of anti-CL antibody production is not mediated by CD1d/glycolipid-reactive iNKT cells, as these cells reduced the production of RF and anti-DNA antibodies but had no effect on anti-CL antibodies.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: β2-microglobulin (β2m) is required for the surface expression of MHC class I and class I-like proteins such as CD1d, Qa1 and neonatal Fc receptor (FcRn), all of which may impact the development of autoimmunity. Since CD1d is known to bind and present phospholipid antigens to T cells, we asked if the deficiency of β2m or CD1d will impact the development of anti-phospholipid antibodies as compared to other aspects of lupus autoimmunity.

Methods: We introgressed the β2m- genotype onto the NZB and NZW backgrounds for 12 to 14 generations to generate genetically lupus-susceptible (NZB/NZW)F1 (BWF1) mice that are β2m-deficient (β2m°). Circulating immunoglobulins (Ig), rheumatoid factor (RF), anti-DNA and anti-cardiolipin (anti-CL) antibodies, and renal disease were analyzed in these and CD1d-deficient (CD1d°) BWF1 mice that we had previously generated.

Results: Whereas β2m° BWF1 mice had reduced serum IgG, they had increased mortality, nephritis, serum IgG anti-DNA antibody and RF as compared to heterozygous and wild-type littermates. These effects were recapitulated in CD1d° BWF1 mice, except that they also had increased serum IgG as compared to control littermates. Intriguingly, both β2m° and CD1d° mice had lower serum anti-CL antibody levels than in control littermates. Such CD1d dependence of anti-CL antibody production is not mediated by CD1d/glycolipid-reactive iNKT cells, as these cells reduced the production of RF and anti-DNA antibodies but had no effect on anti-CL antibodies.

Conclusions: We report a novel dichotomous role of β2m and CD1d, whereby these molecules differently regulate autoimmunity against phospholipid versus non-phospholipid autoantigens.

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Serum anti-dsDNA autoantibodies and rheumatoid factor (RF) are increased in β2 microglobulin-deficient (β2m°) BWF1 mice. β2m+/+ (n = 18 female and 12 male, closed circles), β2m+/- (n = 30 female and 28 male, triangles), and β2m-/- (n = 11 female and 10 male, open circles) mice were bled and serum samples tested for IgG anti-dsDNA antibody and RF. (a) Results are expressed as the percent of mice with autoantibodies, using a cutoff level of the mean + 4 SD optical density (OD) value in sera from six normal age-matched BALB/c mice. Results pooled from male and female mice are shown (*P <0.05, **P <0.01; Fisher's exact test). (b) Results of autoantibodies are shown as the mean ± standard error of log U/ml in male and female mice separately (*P <0.01 to 0.05, **P <0.001, Student's t-test).
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Figure 3: Serum anti-dsDNA autoantibodies and rheumatoid factor (RF) are increased in β2 microglobulin-deficient (β2m°) BWF1 mice. β2m+/+ (n = 18 female and 12 male, closed circles), β2m+/- (n = 30 female and 28 male, triangles), and β2m-/- (n = 11 female and 10 male, open circles) mice were bled and serum samples tested for IgG anti-dsDNA antibody and RF. (a) Results are expressed as the percent of mice with autoantibodies, using a cutoff level of the mean + 4 SD optical density (OD) value in sera from six normal age-matched BALB/c mice. Results pooled from male and female mice are shown (*P <0.05, **P <0.01; Fisher's exact test). (b) Results of autoantibodies are shown as the mean ± standard error of log U/ml in male and female mice separately (*P <0.01 to 0.05, **P <0.001, Student's t-test).

Mentions: Exacerbation of lupus, despite reduced IgG levels, in β2m° mice raised a possibility that they develop disease via a mechanism that is not dependent on IgG autoantibodies. However, the frequency of positivity and serum levels of IgG anti-dsDNA antibody were higher in β2m° mice than in control mice (Figure 3a, b). Male BWF1 mice, which normally do not develop autoantibodies in early life, had a marked increase in the prevalence of anti-dsDNA antibody (0% in β2m+/+ vs 31% in β2m° mice at 4 months of age; P = 0.01; Fisher's exact test (data not shown)). Thus, anti-DNA B cells must be profoundly activated in β2m° mice from early life.


Germline deletion of β2 microglobulin or CD1d reduces anti-phospholipid antibody, but increases autoantibodies against non-phospholipid antigens in the NZB/W F1 model of lupus.

Singh RR, Yang JQ, Kim PJ, Halder RC - Arthritis Res. Ther. (2013)

Serum anti-dsDNA autoantibodies and rheumatoid factor (RF) are increased in β2 microglobulin-deficient (β2m°) BWF1 mice. β2m+/+ (n = 18 female and 12 male, closed circles), β2m+/- (n = 30 female and 28 male, triangles), and β2m-/- (n = 11 female and 10 male, open circles) mice were bled and serum samples tested for IgG anti-dsDNA antibody and RF. (a) Results are expressed as the percent of mice with autoantibodies, using a cutoff level of the mean + 4 SD optical density (OD) value in sera from six normal age-matched BALB/c mice. Results pooled from male and female mice are shown (*P <0.05, **P <0.01; Fisher's exact test). (b) Results of autoantibodies are shown as the mean ± standard error of log U/ml in male and female mice separately (*P <0.01 to 0.05, **P <0.001, Student's t-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 3: Serum anti-dsDNA autoantibodies and rheumatoid factor (RF) are increased in β2 microglobulin-deficient (β2m°) BWF1 mice. β2m+/+ (n = 18 female and 12 male, closed circles), β2m+/- (n = 30 female and 28 male, triangles), and β2m-/- (n = 11 female and 10 male, open circles) mice were bled and serum samples tested for IgG anti-dsDNA antibody and RF. (a) Results are expressed as the percent of mice with autoantibodies, using a cutoff level of the mean + 4 SD optical density (OD) value in sera from six normal age-matched BALB/c mice. Results pooled from male and female mice are shown (*P <0.05, **P <0.01; Fisher's exact test). (b) Results of autoantibodies are shown as the mean ± standard error of log U/ml in male and female mice separately (*P <0.01 to 0.05, **P <0.001, Student's t-test).
Mentions: Exacerbation of lupus, despite reduced IgG levels, in β2m° mice raised a possibility that they develop disease via a mechanism that is not dependent on IgG autoantibodies. However, the frequency of positivity and serum levels of IgG anti-dsDNA antibody were higher in β2m° mice than in control mice (Figure 3a, b). Male BWF1 mice, which normally do not develop autoantibodies in early life, had a marked increase in the prevalence of anti-dsDNA antibody (0% in β2m+/+ vs 31% in β2m° mice at 4 months of age; P = 0.01; Fisher's exact test (data not shown)). Thus, anti-DNA B cells must be profoundly activated in β2m° mice from early life.

Bottom Line: Since CD1d is known to bind and present phospholipid antigens to T cells, we asked if the deficiency of β2m or CD1d will impact the development of anti-phospholipid antibodies as compared to other aspects of lupus autoimmunity.Whereas β2m° BWF1 mice had reduced serum IgG, they had increased mortality, nephritis, serum IgG anti-DNA antibody and RF as compared to heterozygous and wild-type littermates.Such CD1d dependence of anti-CL antibody production is not mediated by CD1d/glycolipid-reactive iNKT cells, as these cells reduced the production of RF and anti-DNA antibodies but had no effect on anti-CL antibodies.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: β2-microglobulin (β2m) is required for the surface expression of MHC class I and class I-like proteins such as CD1d, Qa1 and neonatal Fc receptor (FcRn), all of which may impact the development of autoimmunity. Since CD1d is known to bind and present phospholipid antigens to T cells, we asked if the deficiency of β2m or CD1d will impact the development of anti-phospholipid antibodies as compared to other aspects of lupus autoimmunity.

Methods: We introgressed the β2m- genotype onto the NZB and NZW backgrounds for 12 to 14 generations to generate genetically lupus-susceptible (NZB/NZW)F1 (BWF1) mice that are β2m-deficient (β2m°). Circulating immunoglobulins (Ig), rheumatoid factor (RF), anti-DNA and anti-cardiolipin (anti-CL) antibodies, and renal disease were analyzed in these and CD1d-deficient (CD1d°) BWF1 mice that we had previously generated.

Results: Whereas β2m° BWF1 mice had reduced serum IgG, they had increased mortality, nephritis, serum IgG anti-DNA antibody and RF as compared to heterozygous and wild-type littermates. These effects were recapitulated in CD1d° BWF1 mice, except that they also had increased serum IgG as compared to control littermates. Intriguingly, both β2m° and CD1d° mice had lower serum anti-CL antibody levels than in control littermates. Such CD1d dependence of anti-CL antibody production is not mediated by CD1d/glycolipid-reactive iNKT cells, as these cells reduced the production of RF and anti-DNA antibodies but had no effect on anti-CL antibodies.

Conclusions: We report a novel dichotomous role of β2m and CD1d, whereby these molecules differently regulate autoimmunity against phospholipid versus non-phospholipid autoantigens.

Show MeSH
Related in: MedlinePlus