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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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Distinct roles of different β2 microglobulin (β2m)-associated glycoproteins in the regulation of humoral autoimmunity. The findings in this report and previous studies suggest that β2m may affect lupus-like autoimmunity via at least six possible mechanisms: 1) neonatal Fc receptor (FcRn) effects on immunoglobulin G (IgG) catabolism [17,18] (Figure 2); 2) Qa-1-restricted CD8+ regulatory or suppressor T-cells that can suppress autoimmunity [39]; 3) major histocompatability complex (MHC) class I-restricted CD8+ Ti cells (inhibitory T-cells) that suppress autoantibody production via production of transforming growth factor β [5,28]; 4) MHC class I-restricted CD8+ cytotoxic T lymphocytes (CTL) that can ablate autoreactive B-cells [6]; 5) protective role of CD1d-restricted glycolipid (GL)-reactive invariant natural killer T (iNKT)-cells in autoimmunity [8,24,31,42,44] (Figures 4 and 6a); and 6) the ability of CD1d to bind phospholipid (PL) antigens to induce anti-phospholipid autoimmunity (Figure 5). RF, rheumatoid factor; APC, antigen presenting cell.
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Figure 7: Distinct roles of different β2 microglobulin (β2m)-associated glycoproteins in the regulation of humoral autoimmunity. The findings in this report and previous studies suggest that β2m may affect lupus-like autoimmunity via at least six possible mechanisms: 1) neonatal Fc receptor (FcRn) effects on immunoglobulin G (IgG) catabolism [17,18] (Figure 2); 2) Qa-1-restricted CD8+ regulatory or suppressor T-cells that can suppress autoimmunity [39]; 3) major histocompatability complex (MHC) class I-restricted CD8+ Ti cells (inhibitory T-cells) that suppress autoantibody production via production of transforming growth factor β [5,28]; 4) MHC class I-restricted CD8+ cytotoxic T lymphocytes (CTL) that can ablate autoreactive B-cells [6]; 5) protective role of CD1d-restricted glycolipid (GL)-reactive invariant natural killer T (iNKT)-cells in autoimmunity [8,24,31,42,44] (Figures 4 and 6a); and 6) the ability of CD1d to bind phospholipid (PL) antigens to induce anti-phospholipid autoimmunity (Figure 5). RF, rheumatoid factor; APC, antigen presenting cell.

Mentions: Different MHC class I-related molecules associated with β2m play distinct roles in the development of different autoantibodies (Figure 7). A clear understanding of these roles may have implications for the development of novel therapies for the treatment of complex multi-system lupus disease. For example, inhibition or neutralization of FcRn may increase IgG catabolism [17], thus reducing the levels of pathogenic IgG autoantibodies, and the activation of regulatory CD8+ or iNKT-cells may protect against autoimmunity. Patients with SLE and related diseases have reduced numbers and/or functions of CD1d-reactive T-cells [9,49-51], so the boosting of CD1d-reactive T-cells should be explored as a therapeutic strategy in SLE. In fact, treatment with rituximab restores the numbers and functions of CD1d-reactive T-cells to near-normal levels in patients with SLE [50]. There is a need for caution, however, as some CD1d-restricted T-cells might activate anti-phospholipid B cells and might induce or worsen anti-phospholipid syndrome, which manifests with vascular thrombosis and loss of pregnancy [52]. Further studies are needed to dissect the roles of CD1d-restricted glycolipid-reactive vs phospholipid-reactive T-cells in conferring the protective vs pathogenic roles in SLE.


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)

Distinct roles of different β2 microglobulin (β2m)-associated glycoproteins in the regulation of humoral autoimmunity. The findings in this report and previous studies suggest that β2m may affect lupus-like autoimmunity via at least six possible mechanisms: 1) neonatal Fc receptor (FcRn) effects on immunoglobulin G (IgG) catabolism [17,18] (Figure 2); 2) Qa-1-restricted CD8+ regulatory or suppressor T-cells that can suppress autoimmunity [39]; 3) major histocompatability complex (MHC) class I-restricted CD8+ Ti cells (inhibitory T-cells) that suppress autoantibody production via production of transforming growth factor β [5,28]; 4) MHC class I-restricted CD8+ cytotoxic T lymphocytes (CTL) that can ablate autoreactive B-cells [6]; 5) protective role of CD1d-restricted glycolipid (GL)-reactive invariant natural killer T (iNKT)-cells in autoimmunity [8,24,31,42,44] (Figures 4 and 6a); and 6) the ability of CD1d to bind phospholipid (PL) antigens to induce anti-phospholipid autoimmunity (Figure 5). RF, rheumatoid factor; APC, antigen presenting cell.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3672782&req=5

Figure 7: Distinct roles of different β2 microglobulin (β2m)-associated glycoproteins in the regulation of humoral autoimmunity. The findings in this report and previous studies suggest that β2m may affect lupus-like autoimmunity via at least six possible mechanisms: 1) neonatal Fc receptor (FcRn) effects on immunoglobulin G (IgG) catabolism [17,18] (Figure 2); 2) Qa-1-restricted CD8+ regulatory or suppressor T-cells that can suppress autoimmunity [39]; 3) major histocompatability complex (MHC) class I-restricted CD8+ Ti cells (inhibitory T-cells) that suppress autoantibody production via production of transforming growth factor β [5,28]; 4) MHC class I-restricted CD8+ cytotoxic T lymphocytes (CTL) that can ablate autoreactive B-cells [6]; 5) protective role of CD1d-restricted glycolipid (GL)-reactive invariant natural killer T (iNKT)-cells in autoimmunity [8,24,31,42,44] (Figures 4 and 6a); and 6) the ability of CD1d to bind phospholipid (PL) antigens to induce anti-phospholipid autoimmunity (Figure 5). RF, rheumatoid factor; APC, antigen presenting cell.
Mentions: Different MHC class I-related molecules associated with β2m play distinct roles in the development of different autoantibodies (Figure 7). A clear understanding of these roles may have implications for the development of novel therapies for the treatment of complex multi-system lupus disease. For example, inhibition or neutralization of FcRn may increase IgG catabolism [17], thus reducing the levels of pathogenic IgG autoantibodies, and the activation of regulatory CD8+ or iNKT-cells may protect against autoimmunity. Patients with SLE and related diseases have reduced numbers and/or functions of CD1d-reactive T-cells [9,49-51], so the boosting of CD1d-reactive T-cells should be explored as a therapeutic strategy in SLE. In fact, treatment with rituximab restores the numbers and functions of CD1d-reactive T-cells to near-normal levels in patients with SLE [50]. There is a need for caution, however, as some CD1d-restricted T-cells might activate anti-phospholipid B cells and might induce or worsen anti-phospholipid syndrome, which manifests with vascular thrombosis and loss of pregnancy [52]. Further studies are needed to dissect the roles of CD1d-restricted glycolipid-reactive vs phospholipid-reactive T-cells in conferring the protective vs pathogenic roles in SLE.

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