Abstract
Introductionβ2-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.MethodsWe introgressed the β2m-null 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.ResultsWhereas 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.ConclusionsWe report a novel dichotomous role of β2m and CD1d, whereby these molecules differently regulate autoimmunity against phospholipid versus non-phospholipid autoantigens.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by uncontrolled production of autoantibodies against a variety of antigens such as nucleic acids and phospholipids, hypergammaglobulinemia and multi-organ inflammation [1]
We found that while immunoglobulin G (IgG) anti-DNA antibody levels were reduced in the presence of aGalCer, IgG anti-CL antibody levels were unaffected (Figure 6a)
We have recently reported that CD1d-restricted iNKT cells that respond to glycolipid aGalCer suppress the production of anti-DNA antibody and rheumatoid factor (RF) [31,48]
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by uncontrolled production of autoantibodies against a variety of antigens such as nucleic acids and phospholipids, hypergammaglobulinemia and multi-organ inflammation [1]. B2m° MRL-lpr/lpr mice exhibit decreases in anti-DNA antibody production, hypergammaglobulinemia and lupus nephritis [14,15,16]. These protective effects of b2m deficiency have been linked with the absence of FcRn [15], which is known to inhibit immunoglobulin G (IgG) catabolism [17,18]. Lupus dermatitis is aggravated in b2m° MRLlpr/lpr mice [16] Mechanisms underlying such disparate effects of b2m-deficiency on autoimmune disease remain to be determined. Since b2m promotes the activation of CD8+ and NKT cells via its association with MHC class I and CD1d, respectively, b2m deficiency may aggravate aspects of autoimmunity that are normally controlled by such potentially regulatory T-cells [5,6,7]
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