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

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.

iNKT Cells in Lupus Development

“…Deficiency of CD1 in BWF1 mice further worsened the glomerulonephritis as compared to wild-type mice [8]. Similar findings are evident in β2-microglobulin knockout BWF1 mice, where iNKT cells are also deficient as CD1 knockout mice [9]. Interestingly, activation of iNKT cells with α-GalCer in BWF1 mice at an early age by short term ameliorated the glomerulonephritis [10].…”

Treatment with anti‐neonatal Fc receptor (FcRn) antibody ameliorates experimental epidermolysis bullosa acquisita in mice

“…However, genetic deficiency of either the FcRn α chain or β2 microglobulin has also been reported to enhance the production of certain autoantibodies in the mouse (Singh, Yang, Kim, & Halder, ) and to lead to spontaneous arthritis development (Kingsbury et al, ). Furthermore, application of FcRn‐targeted treatments in long‐term therapeutic settings had not been performed so far, although no adverse events were detected in a non‐human primate study where animals were administered for long periods of time with high doses of an anti‐FcRn monoclonal antibody (Smith et al, ).…”

Dysregulated CD25 and Cytokine Expression by γδ T Cells of Systemic Sclerosis Patients Stimulated With Cardiolipin and Zoledronate

“…In support of this, 10–20% of SSc patients have antibodies to cardiolipin (CL), a mitochondrial autolipid that is also present in microorganisms (11). Moreover, the T cell response to CL in a murine model of autoimmunity was independent of classical lipid responsive αβ TCR + invariant natural killer T (iNKT) cells, suggesting that lipid reactive γδ T cells, rather than iNKT cells, may play a more critical role in disease-related autoimmune responses to CL (12). However, there is no available evidence to indicate that human γδ T cells in SSc recognize and respond to CL.…”