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Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations.

Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, Tschopp J, Browning JL - J. Exp. Med. (1999)

Bottom Line: The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases.Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti-DNA autoantibodies, and immunoglobulin deposition in the kidneys.This phenotype is reminiscent of certain human autoimmune disorders and suggests that dysregulation of BAFF expression may be a critical element in the chain of events leading to autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Inflammation and Cell Biology, Biogen, Cambridge, Massachusetts 02142, USA. fabienne_mackay@biogen.com

ABSTRACT
The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases. BAFF, a new member of the TNF family, binds to B cells and costimulates their growth in vitro. Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti-DNA autoantibodies, and immunoglobulin deposition in the kidneys. This phenotype is reminiscent of certain human autoimmune disorders and suggests that dysregulation of BAFF expression may be a critical element in the chain of events leading to autoimmunity.

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Related in: MedlinePlus

Increased B cell numbers in BAFF-Tg mice. (A) Increased lymphocyte counts in BAFF-Tg mice. The graph compares 12 control littermates (left) with 12 BAFF-Tg mice (right). Lymphocyte counts (○) and granulocytes (including neutrophils, eosinophils, basophils; ⋄) are shown. (B) Increased proportion of B cells in PBL from BAFF-Tg mice. PBL were stained with both anti–B220-FITC and anti–CD4-PE for FACS® analysis and gated on live cells using the forward and side scatter profile. Percentages of CD4- and B220-positive cells are indicated. One control mouse (left) and two BAFF-Tg mice (right) are shown and the results were representative of seven animals analyzed in each group. (C) FACS® analysis of the ratio of B to T cells in PBL. The difference between control animals and BAFF-Tg mice in A and C was statistically significant (P < 0.001). (D) Increased MHC class II expression on B cells from BAFF-Tg mice PBL. MHC class II expression was analyzed by FACS®. (E) Increased Bcl-2 expression in B cells from BAFF-Tg mice PBL. Bcl-2 expression was measured by intracytoplasmic staining and cells were analyzed by FACS®. In both D and E, B220-positive cells were gated. Four control littermates (white bars) and four BAFF-Tg mice are shown and are representative of at least 12 animals analyzed for each group. MFI, mean of fluorescence intensity. The dotted line represents the average MFI for the control animals. The difference between control animals and BAFF-Tg mice was statistically significant (P < 0.005). (F) Increased expression of effector T cells in BAFF-Tg mice. PBL were stained with anti–CD4-CyChrome™, anti–CD44-FITC and anti–l-selectin-PE. Shown are CD4+-gated cells. Percentages of CD44hi/l-selectinlo cells are indicated. One control mouse (left) and two BAFF-Tg mice (right) are shown and the results were representative of eight animals analyzed in each group.
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Figure 1: Increased B cell numbers in BAFF-Tg mice. (A) Increased lymphocyte counts in BAFF-Tg mice. The graph compares 12 control littermates (left) with 12 BAFF-Tg mice (right). Lymphocyte counts (○) and granulocytes (including neutrophils, eosinophils, basophils; ⋄) are shown. (B) Increased proportion of B cells in PBL from BAFF-Tg mice. PBL were stained with both anti–B220-FITC and anti–CD4-PE for FACS® analysis and gated on live cells using the forward and side scatter profile. Percentages of CD4- and B220-positive cells are indicated. One control mouse (left) and two BAFF-Tg mice (right) are shown and the results were representative of seven animals analyzed in each group. (C) FACS® analysis of the ratio of B to T cells in PBL. The difference between control animals and BAFF-Tg mice in A and C was statistically significant (P < 0.001). (D) Increased MHC class II expression on B cells from BAFF-Tg mice PBL. MHC class II expression was analyzed by FACS®. (E) Increased Bcl-2 expression in B cells from BAFF-Tg mice PBL. Bcl-2 expression was measured by intracytoplasmic staining and cells were analyzed by FACS®. In both D and E, B220-positive cells were gated. Four control littermates (white bars) and four BAFF-Tg mice are shown and are representative of at least 12 animals analyzed for each group. MFI, mean of fluorescence intensity. The dotted line represents the average MFI for the control animals. The difference between control animals and BAFF-Tg mice was statistically significant (P < 0.005). (F) Increased expression of effector T cells in BAFF-Tg mice. PBL were stained with anti–CD4-CyChrome™, anti–CD44-FITC and anti–l-selectin-PE. Shown are CD4+-gated cells. Percentages of CD44hi/l-selectinlo cells are indicated. One control mouse (left) and two BAFF-Tg mice (right) are shown and the results were representative of eight animals analyzed in each group.

Mentions: The transgenic mouse population was found to have more lymphocytes in the blood when compared with control negative littermates, reaching values as high as 13,000 lymphocytes/μl of blood (Fig. 1 A). In contrast, the number of granulocytes per microliter of blood in both BAFF-Tg and control mice remained within normal limits (Fig. 1 A). The elevated lymphocyte levels resulted from an expanded B cell subset, since FACS® analysis, using anti–CD4 and –B220 antibodies, of peripheral blood cells (PBL) from 18 BAFF-Tg mice issued from six different founders showed increased B/T ratios (Fig. 1b and Fig. c). Likewise, combining the number of lymphocytes per microliter of blood with the percentage of circulating T cells, calculation of absolute numbers of CD4 circulating T cells revealed a 50% reduction of this T cell subset in BAFF-Tg mice when compared with control mice, and the same observation was made for the CD8 T cell subset (data not shown). All peripheral blood B cells from BAFF-Tg mice had increased MHC class II and Bcl-2 expression when compared with B cells from control mice (Fig. 1d and Fig. e, respectively), indicating some level of B cell activation in PBL of BAFF-Tg mice. T cells in the blood of BAFF-Tg mice did not express the early activation markers CD69 or CD25; however, 40–56% of CD4 or CD8 T cells were activated effector T cells with a CD44hi, l-selectinlo phenotype versus only 8–12% in control littermates (Fig. 1 F). Thus, BAFF-Tg mice clearly show signs of an expanded peripheral blood B cell compartment and global B cell activation along with T cell alterations.


Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations.

Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, Tschopp J, Browning JL - J. Exp. Med. (1999)

Increased B cell numbers in BAFF-Tg mice. (A) Increased lymphocyte counts in BAFF-Tg mice. The graph compares 12 control littermates (left) with 12 BAFF-Tg mice (right). Lymphocyte counts (○) and granulocytes (including neutrophils, eosinophils, basophils; ⋄) are shown. (B) Increased proportion of B cells in PBL from BAFF-Tg mice. PBL were stained with both anti–B220-FITC and anti–CD4-PE for FACS® analysis and gated on live cells using the forward and side scatter profile. Percentages of CD4- and B220-positive cells are indicated. One control mouse (left) and two BAFF-Tg mice (right) are shown and the results were representative of seven animals analyzed in each group. (C) FACS® analysis of the ratio of B to T cells in PBL. The difference between control animals and BAFF-Tg mice in A and C was statistically significant (P < 0.001). (D) Increased MHC class II expression on B cells from BAFF-Tg mice PBL. MHC class II expression was analyzed by FACS®. (E) Increased Bcl-2 expression in B cells from BAFF-Tg mice PBL. Bcl-2 expression was measured by intracytoplasmic staining and cells were analyzed by FACS®. In both D and E, B220-positive cells were gated. Four control littermates (white bars) and four BAFF-Tg mice are shown and are representative of at least 12 animals analyzed for each group. MFI, mean of fluorescence intensity. The dotted line represents the average MFI for the control animals. The difference between control animals and BAFF-Tg mice was statistically significant (P < 0.005). (F) Increased expression of effector T cells in BAFF-Tg mice. PBL were stained with anti–CD4-CyChrome™, anti–CD44-FITC and anti–l-selectin-PE. Shown are CD4+-gated cells. Percentages of CD44hi/l-selectinlo cells are indicated. One control mouse (left) and two BAFF-Tg mice (right) are shown and the results were representative of eight animals analyzed in each group.
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Related In: Results  -  Collection

Show All Figures
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Figure 1: Increased B cell numbers in BAFF-Tg mice. (A) Increased lymphocyte counts in BAFF-Tg mice. The graph compares 12 control littermates (left) with 12 BAFF-Tg mice (right). Lymphocyte counts (○) and granulocytes (including neutrophils, eosinophils, basophils; ⋄) are shown. (B) Increased proportion of B cells in PBL from BAFF-Tg mice. PBL were stained with both anti–B220-FITC and anti–CD4-PE for FACS® analysis and gated on live cells using the forward and side scatter profile. Percentages of CD4- and B220-positive cells are indicated. One control mouse (left) and two BAFF-Tg mice (right) are shown and the results were representative of seven animals analyzed in each group. (C) FACS® analysis of the ratio of B to T cells in PBL. The difference between control animals and BAFF-Tg mice in A and C was statistically significant (P < 0.001). (D) Increased MHC class II expression on B cells from BAFF-Tg mice PBL. MHC class II expression was analyzed by FACS®. (E) Increased Bcl-2 expression in B cells from BAFF-Tg mice PBL. Bcl-2 expression was measured by intracytoplasmic staining and cells were analyzed by FACS®. In both D and E, B220-positive cells were gated. Four control littermates (white bars) and four BAFF-Tg mice are shown and are representative of at least 12 animals analyzed for each group. MFI, mean of fluorescence intensity. The dotted line represents the average MFI for the control animals. The difference between control animals and BAFF-Tg mice was statistically significant (P < 0.005). (F) Increased expression of effector T cells in BAFF-Tg mice. PBL were stained with anti–CD4-CyChrome™, anti–CD44-FITC and anti–l-selectin-PE. Shown are CD4+-gated cells. Percentages of CD44hi/l-selectinlo cells are indicated. One control mouse (left) and two BAFF-Tg mice (right) are shown and the results were representative of eight animals analyzed in each group.
Mentions: The transgenic mouse population was found to have more lymphocytes in the blood when compared with control negative littermates, reaching values as high as 13,000 lymphocytes/μl of blood (Fig. 1 A). In contrast, the number of granulocytes per microliter of blood in both BAFF-Tg and control mice remained within normal limits (Fig. 1 A). The elevated lymphocyte levels resulted from an expanded B cell subset, since FACS® analysis, using anti–CD4 and –B220 antibodies, of peripheral blood cells (PBL) from 18 BAFF-Tg mice issued from six different founders showed increased B/T ratios (Fig. 1b and Fig. c). Likewise, combining the number of lymphocytes per microliter of blood with the percentage of circulating T cells, calculation of absolute numbers of CD4 circulating T cells revealed a 50% reduction of this T cell subset in BAFF-Tg mice when compared with control mice, and the same observation was made for the CD8 T cell subset (data not shown). All peripheral blood B cells from BAFF-Tg mice had increased MHC class II and Bcl-2 expression when compared with B cells from control mice (Fig. 1d and Fig. e, respectively), indicating some level of B cell activation in PBL of BAFF-Tg mice. T cells in the blood of BAFF-Tg mice did not express the early activation markers CD69 or CD25; however, 40–56% of CD4 or CD8 T cells were activated effector T cells with a CD44hi, l-selectinlo phenotype versus only 8–12% in control littermates (Fig. 1 F). Thus, BAFF-Tg mice clearly show signs of an expanded peripheral blood B cell compartment and global B cell activation along with T cell alterations.

Bottom Line: The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases.Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti-DNA autoantibodies, and immunoglobulin deposition in the kidneys.This phenotype is reminiscent of certain human autoimmune disorders and suggests that dysregulation of BAFF expression may be a critical element in the chain of events leading to autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Inflammation and Cell Biology, Biogen, Cambridge, Massachusetts 02142, USA. fabienne_mackay@biogen.com

ABSTRACT
The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases. BAFF, a new member of the TNF family, binds to B cells and costimulates their growth in vitro. Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti-DNA autoantibodies, and immunoglobulin deposition in the kidneys. This phenotype is reminiscent of certain human autoimmune disorders and suggests that dysregulation of BAFF expression may be a critical element in the chain of events leading to autoimmunity.

Show MeSH
Related in: MedlinePlus