Limits...
B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-O-acetyl sialic acid esterase.

Cariappa A, Takematsu H, Liu H, Diaz S, Haider K, Boboila C, Kalloo G, Connole M, Shi HN, Varki N, Varki A, Pillai S - J. Exp. Med. (2008)

Bottom Line: We show that the enzymatic acetylation and deacetylation of a cell surface carbohydrate controls B cell development, signaling, and immunological tolerance.The 9-O-acetylation state of sialic acid regulates the function of CD22, a Siglec that functions in vivo as an inhibitor of BCR signaling.These results describe a novel catalytic regulator of B cell signaling and underscore the crucial role of inhibitory signaling in the maintenance of immunological tolerance in the B lineage.

View Article: PubMed Central - PubMed

Affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.

ABSTRACT
We show that the enzymatic acetylation and deacetylation of a cell surface carbohydrate controls B cell development, signaling, and immunological tolerance. Mice with a mutation in sialate:O-acetyl esterase, an enzyme that specifically removes acetyl moieties from the 9-OH position of alpha2-6-linked sialic acid, exhibit enhanced B cell receptor (BCR) activation, defects in peripheral B cell development, and spontaneously develop antichromatin autoantibodies and glomerular immune complex deposits. The 9-O-acetylation state of sialic acid regulates the function of CD22, a Siglec that functions in vivo as an inhibitor of BCR signaling. These results describe a novel catalytic regulator of B cell signaling and underscore the crucial role of inhibitory signaling in the maintenance of immunological tolerance in the B lineage.

Show MeSH

Related in: MedlinePlus

Increased serum immunoglobulins and autoantibodies in Siae mutant mice. (A) Serum immunoglobulins of specific isotypes are increased in mutant mice. Immunoglobulin isotypes were quantitated by ELISA. Each data point represents a single mouse. Horizontal bars represent the mean. (B) Increased levels of autoantibodies in the serum of SiaeΔ2/Δ2 mice. ELISA was used to estimate the levels of various autoimmune antibodies in serum. Each data point represents one mouse. Horizontal bars represent the mean. Ages of mice in A and B ranged from 20–60 wk. The results presented A and B and in C and D are all from the same set of mice. (C) Siae mutant mice show histological features of glomerulonephritis. Paraffin-embedded sections of kidney from mutant and WT mice were stained with hematoxylin and eosin (top) and with periodic acid Schiff (PAS) reagent (bottom). The glomeruli of the mutant mice (top right) show mesangial hypercellularity and expansion caused by periodic acid Schiff–positive deposits (bottom). The magnification is marked on each image. Bars, 100 μm. Results are representative of mice described in A and B. (D) IgG immune complex deposition in glomeruli of SiaeΔ2/Δ2 mice. Immunofluorescence studies on frozen sections of kidney reveal enlarged glomeruli with IgG-positive deposits in the mesangium in SiaeΔ2/Δ2 mice. The magnification is marked on each image. Bars, 100 μm. These sections are from the same mice as those shown in C.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC2626685&req=5

fig6: Increased serum immunoglobulins and autoantibodies in Siae mutant mice. (A) Serum immunoglobulins of specific isotypes are increased in mutant mice. Immunoglobulin isotypes were quantitated by ELISA. Each data point represents a single mouse. Horizontal bars represent the mean. (B) Increased levels of autoantibodies in the serum of SiaeΔ2/Δ2 mice. ELISA was used to estimate the levels of various autoimmune antibodies in serum. Each data point represents one mouse. Horizontal bars represent the mean. Ages of mice in A and B ranged from 20–60 wk. The results presented A and B and in C and D are all from the same set of mice. (C) Siae mutant mice show histological features of glomerulonephritis. Paraffin-embedded sections of kidney from mutant and WT mice were stained with hematoxylin and eosin (top) and with periodic acid Schiff (PAS) reagent (bottom). The glomeruli of the mutant mice (top right) show mesangial hypercellularity and expansion caused by periodic acid Schiff–positive deposits (bottom). The magnification is marked on each image. Bars, 100 μm. Results are representative of mice described in A and B. (D) IgG immune complex deposition in glomeruli of SiaeΔ2/Δ2 mice. Immunofluorescence studies on frozen sections of kidney reveal enlarged glomeruli with IgG-positive deposits in the mesangium in SiaeΔ2/Δ2 mice. The magnification is marked on each image. Bars, 100 μm. These sections are from the same mice as those shown in C.

Mentions: Many phenotypic features of SiaeΔ2/Δ2 mice resemble those seen in the absence of CD22. These include enhanced BCR signaling, the loss of MZ B cells, and a reduction in perisinusoidal B cells. Subtle alterations in responses to synthetic T-dependent and T-independent antigens have been described in CD22- mice, and an altered spectrum of responsiveness to similar antigens was also noted in SiaeΔ2/Δ2 mice. Immunization with DNP-KLH resulted in diminished IgG2a, IgG2b, and IgG3 responses in Siae mutant mice (Fig. S12, available at http://www.jem.org/cgi/content/full/jem.20081399/DC1). SiaeΔ2/Δ2 mice spontaneously developed high levels of certain class-switched serum immunoglobulins, including IgE and IgG2b (Fig. 6 A), as well as high titers of antinuclear antibodies and circulating immune complexes as early as at 20 wk of age (Fig. 6 B). These mice also develop an immune complex glomerulonephritis (Fig. 6, C and D). Anti-DNA antibodies develop in CD22- mice after 9 mo of age, but glomerular immune complex deposits were not observed in these mice on a C57BL/6 background (45).


B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-O-acetyl sialic acid esterase.

Cariappa A, Takematsu H, Liu H, Diaz S, Haider K, Boboila C, Kalloo G, Connole M, Shi HN, Varki N, Varki A, Pillai S - J. Exp. Med. (2008)

Increased serum immunoglobulins and autoantibodies in Siae mutant mice. (A) Serum immunoglobulins of specific isotypes are increased in mutant mice. Immunoglobulin isotypes were quantitated by ELISA. Each data point represents a single mouse. Horizontal bars represent the mean. (B) Increased levels of autoantibodies in the serum of SiaeΔ2/Δ2 mice. ELISA was used to estimate the levels of various autoimmune antibodies in serum. Each data point represents one mouse. Horizontal bars represent the mean. Ages of mice in A and B ranged from 20–60 wk. The results presented A and B and in C and D are all from the same set of mice. (C) Siae mutant mice show histological features of glomerulonephritis. Paraffin-embedded sections of kidney from mutant and WT mice were stained with hematoxylin and eosin (top) and with periodic acid Schiff (PAS) reagent (bottom). The glomeruli of the mutant mice (top right) show mesangial hypercellularity and expansion caused by periodic acid Schiff–positive deposits (bottom). The magnification is marked on each image. Bars, 100 μm. Results are representative of mice described in A and B. (D) IgG immune complex deposition in glomeruli of SiaeΔ2/Δ2 mice. Immunofluorescence studies on frozen sections of kidney reveal enlarged glomeruli with IgG-positive deposits in the mesangium in SiaeΔ2/Δ2 mice. The magnification is marked on each image. Bars, 100 μm. These sections are from the same mice as those shown in C.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2626685&req=5

fig6: Increased serum immunoglobulins and autoantibodies in Siae mutant mice. (A) Serum immunoglobulins of specific isotypes are increased in mutant mice. Immunoglobulin isotypes were quantitated by ELISA. Each data point represents a single mouse. Horizontal bars represent the mean. (B) Increased levels of autoantibodies in the serum of SiaeΔ2/Δ2 mice. ELISA was used to estimate the levels of various autoimmune antibodies in serum. Each data point represents one mouse. Horizontal bars represent the mean. Ages of mice in A and B ranged from 20–60 wk. The results presented A and B and in C and D are all from the same set of mice. (C) Siae mutant mice show histological features of glomerulonephritis. Paraffin-embedded sections of kidney from mutant and WT mice were stained with hematoxylin and eosin (top) and with periodic acid Schiff (PAS) reagent (bottom). The glomeruli of the mutant mice (top right) show mesangial hypercellularity and expansion caused by periodic acid Schiff–positive deposits (bottom). The magnification is marked on each image. Bars, 100 μm. Results are representative of mice described in A and B. (D) IgG immune complex deposition in glomeruli of SiaeΔ2/Δ2 mice. Immunofluorescence studies on frozen sections of kidney reveal enlarged glomeruli with IgG-positive deposits in the mesangium in SiaeΔ2/Δ2 mice. The magnification is marked on each image. Bars, 100 μm. These sections are from the same mice as those shown in C.
Mentions: Many phenotypic features of SiaeΔ2/Δ2 mice resemble those seen in the absence of CD22. These include enhanced BCR signaling, the loss of MZ B cells, and a reduction in perisinusoidal B cells. Subtle alterations in responses to synthetic T-dependent and T-independent antigens have been described in CD22- mice, and an altered spectrum of responsiveness to similar antigens was also noted in SiaeΔ2/Δ2 mice. Immunization with DNP-KLH resulted in diminished IgG2a, IgG2b, and IgG3 responses in Siae mutant mice (Fig. S12, available at http://www.jem.org/cgi/content/full/jem.20081399/DC1). SiaeΔ2/Δ2 mice spontaneously developed high levels of certain class-switched serum immunoglobulins, including IgE and IgG2b (Fig. 6 A), as well as high titers of antinuclear antibodies and circulating immune complexes as early as at 20 wk of age (Fig. 6 B). These mice also develop an immune complex glomerulonephritis (Fig. 6, C and D). Anti-DNA antibodies develop in CD22- mice after 9 mo of age, but glomerular immune complex deposits were not observed in these mice on a C57BL/6 background (45).

Bottom Line: We show that the enzymatic acetylation and deacetylation of a cell surface carbohydrate controls B cell development, signaling, and immunological tolerance.The 9-O-acetylation state of sialic acid regulates the function of CD22, a Siglec that functions in vivo as an inhibitor of BCR signaling.These results describe a novel catalytic regulator of B cell signaling and underscore the crucial role of inhibitory signaling in the maintenance of immunological tolerance in the B lineage.

View Article: PubMed Central - PubMed

Affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.

ABSTRACT
We show that the enzymatic acetylation and deacetylation of a cell surface carbohydrate controls B cell development, signaling, and immunological tolerance. Mice with a mutation in sialate:O-acetyl esterase, an enzyme that specifically removes acetyl moieties from the 9-OH position of alpha2-6-linked sialic acid, exhibit enhanced B cell receptor (BCR) activation, defects in peripheral B cell development, and spontaneously develop antichromatin autoantibodies and glomerular immune complex deposits. The 9-O-acetylation state of sialic acid regulates the function of CD22, a Siglec that functions in vivo as an inhibitor of BCR signaling. These results describe a novel catalytic regulator of B cell signaling and underscore the crucial role of inhibitory signaling in the maintenance of immunological tolerance in the B lineage.

Show MeSH
Related in: MedlinePlus