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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 immunoglobulin (Ig) levels in β2 microgloblin-deficient (β2m°) BWF1 mice: reduced polyclonal total IgG, but not IgM. β2m+/+ (n = 18 to 22 female and 12 male, closed circles), β2m+/- (n = 30 to 35 female and 28 to 35 male, triangles) and β2m° (n = 11 to 16 female and 10 to 16 male, open circles) mice were bled and sera tested for total IgG, IgG2a and IgM. Results are expressed as the mean ± standard error. (a, b) Serum levels of total IgG and IgG2a isotype were lower in β2m° mice than in control animals (*P <0.05, **P <0.01 to <0.001; Student's t-test). (c) Serum levels of total IgM were higher in β2m° than in β2m+/+ mice (*P <0.05, Student's t-test).
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Figure 2: Serum immunoglobulin (Ig) levels in β2 microgloblin-deficient (β2m°) BWF1 mice: reduced polyclonal total IgG, but not IgM. β2m+/+ (n = 18 to 22 female and 12 male, closed circles), β2m+/- (n = 30 to 35 female and 28 to 35 male, triangles) and β2m° (n = 11 to 16 female and 10 to 16 male, open circles) mice were bled and sera tested for total IgG, IgG2a and IgM. Results are expressed as the mean ± standard error. (a, b) Serum levels of total IgG and IgG2a isotype were lower in β2m° mice than in control animals (*P <0.05, **P <0.01 to <0.001; Student's t-test). (c) Serum levels of total IgM were higher in β2m° than in β2m+/+ mice (*P <0.05, Student's t-test).

Mentions: Hypergammaglobulinemia is a feature of lupus. Thus, we expected to find increased IgG in β2m° BWF1 mice that experienced severe disease (Figure 1). However, β2m° BWF1 mice had reduced serum levels of total IgG and IgG2a as compared to β2m+/- and β2m+/+ littermates (Figure 2a, b). Serum levels of total IgM (Figure 2c), however, were unaffected in β2m° mice. Thus, β2m° BWF1 mice experience disease exacerbation at an age when they have low levels of total IgG and the IgG isotype of most pathogenic autoantibodies, IgG2a [32].


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 immunoglobulin (Ig) levels in β2 microgloblin-deficient (β2m°) BWF1 mice: reduced polyclonal total IgG, but not IgM. β2m+/+ (n = 18 to 22 female and 12 male, closed circles), β2m+/- (n = 30 to 35 female and 28 to 35 male, triangles) and β2m° (n = 11 to 16 female and 10 to 16 male, open circles) mice were bled and sera tested for total IgG, IgG2a and IgM. Results are expressed as the mean ± standard error. (a, b) Serum levels of total IgG and IgG2a isotype were lower in β2m° mice than in control animals (*P <0.05, **P <0.01 to <0.001; Student's t-test). (c) Serum levels of total IgM were higher in β2m° than in β2m+/+ mice (*P <0.05, Student's t-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672782&req=5

Figure 2: Serum immunoglobulin (Ig) levels in β2 microgloblin-deficient (β2m°) BWF1 mice: reduced polyclonal total IgG, but not IgM. β2m+/+ (n = 18 to 22 female and 12 male, closed circles), β2m+/- (n = 30 to 35 female and 28 to 35 male, triangles) and β2m° (n = 11 to 16 female and 10 to 16 male, open circles) mice were bled and sera tested for total IgG, IgG2a and IgM. Results are expressed as the mean ± standard error. (a, b) Serum levels of total IgG and IgG2a isotype were lower in β2m° mice than in control animals (*P <0.05, **P <0.01 to <0.001; Student's t-test). (c) Serum levels of total IgM were higher in β2m° than in β2m+/+ mice (*P <0.05, Student's t-test).
Mentions: Hypergammaglobulinemia is a feature of lupus. Thus, we expected to find increased IgG in β2m° BWF1 mice that experienced severe disease (Figure 1). However, β2m° BWF1 mice had reduced serum levels of total IgG and IgG2a as compared to β2m+/- and β2m+/+ littermates (Figure 2a, b). Serum levels of total IgM (Figure 2c), however, were unaffected in β2m° mice. Thus, β2m° BWF1 mice experience disease exacerbation at an age when they have low levels of total IgG and the IgG isotype of most pathogenic autoantibodies, IgG2a [32].

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