Autoimmune-prone mice share a promoter haplotype associated with reduced expression and function of the Fc receptor FcγRII

NR Pritchard, AJ Cutler, S Uribe, SJ Chadban, Bernard J Morley, KGC Smith

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Abstract

Human autoimmune diseases thought to arise from the combined effects of multiple susceptibility genes include systemic lupus erythematosus (SLE) and autoimmune diabetes. Well-characterised polygenic mouse models closely resembling each of these diseases exist, and genetic evidence links receptors for the Fc portion of immunoglobulin G (FcR) with their pathogenesis in mice and humans [1-3]. FcRs may be activatory or inhibitory and regulate a variety of Immune and inflammatory processes [4,5]. FcγRII (CD32) negatively regulates activation of cells including B cells and macrophages [6]. FcγRII-deficient mice are prone to immune mediated disease [7-9]. The gene encoding Fc gamma RII, Fcgr2, is contained in genetic susceptibility Intervals in mouse models of SLE such as the New Zealand Black (NZB) contribution to the (NZB x New Zealand White (NZW)) F1 strain [1,10,11] and the BXSB strain [12], and in human SLE [1-3]. We therefore sequenced Fcgr2 and identified a haplotype defined by deletions in the Fcgr2 promoter region that is present in major SLE-prone mouse strains (NZB, BXSB, SB/Le, MRL, 129 [13]) and non-obese diabetic (NOD) mice but absent in control strains (BALB/c, C57BL/6, DBA/2, C57BL/10) and NZW mice. The autoimmune haplotype was associated with reduced cell-surface expression of FcγRII on macrophages and activated B cells and with hyperactive macrophages resembling those of Fc gamma RII-deficient mice, and is therefore likely to play an important role in the pathogenesis of SLE and possibly diabetes.
Original languageEnglish
Pages (from-to)227-230
Number of pages4
JournalCurrent Biology
Volume10
Issue number4
DOIs
Publication statusPublished - 15 Feb 2000

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Fc Receptors
Macrophages
lupus erythematosus
Haplotypes
IgG Receptors
haplotypes
promoter regions
New Zealand
Medical problems
Systemic Lupus Erythematosus
receptors
mice
Cells
Strain control
Immunoglobulin Fc Fragments
macrophages
Gene encoding
Genetic Promoter Regions
B-lymphocytes
pathogenesis

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Autoimmune-prone mice share a promoter haplotype associated with reduced expression and function of the Fc receptor FcγRII. / Pritchard, NR; Cutler, AJ; Uribe, S; Chadban, SJ; Morley, Bernard J; Smith, KGC.

In: Current Biology, Vol. 10, No. 4, 15.02.2000, p. 227-230.

Research output: Contribution to journalArticle

Pritchard, NR ; Cutler, AJ ; Uribe, S ; Chadban, SJ ; Morley, Bernard J ; Smith, KGC. / Autoimmune-prone mice share a promoter haplotype associated with reduced expression and function of the Fc receptor FcγRII. In: Current Biology. 2000 ; Vol. 10, No. 4. pp. 227-230.
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abstract = "Human autoimmune diseases thought to arise from the combined effects of multiple susceptibility genes include systemic lupus erythematosus (SLE) and autoimmune diabetes. Well-characterised polygenic mouse models closely resembling each of these diseases exist, and genetic evidence links receptors for the Fc portion of immunoglobulin G (FcR) with their pathogenesis in mice and humans [1-3]. FcRs may be activatory or inhibitory and regulate a variety of Immune and inflammatory processes [4,5]. FcγRII (CD32) negatively regulates activation of cells including B cells and macrophages [6]. FcγRII-deficient mice are prone to immune mediated disease [7-9]. The gene encoding Fc gamma RII, Fcgr2, is contained in genetic susceptibility Intervals in mouse models of SLE such as the New Zealand Black (NZB) contribution to the (NZB x New Zealand White (NZW)) F1 strain [1,10,11] and the BXSB strain [12], and in human SLE [1-3]. We therefore sequenced Fcgr2 and identified a haplotype defined by deletions in the Fcgr2 promoter region that is present in major SLE-prone mouse strains (NZB, BXSB, SB/Le, MRL, 129 [13]) and non-obese diabetic (NOD) mice but absent in control strains (BALB/c, C57BL/6, DBA/2, C57BL/10) and NZW mice. The autoimmune haplotype was associated with reduced cell-surface expression of FcγRII on macrophages and activated B cells and with hyperactive macrophages resembling those of Fc gamma RII-deficient mice, and is therefore likely to play an important role in the pathogenesis of SLE and possibly diabetes.",
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AB - Human autoimmune diseases thought to arise from the combined effects of multiple susceptibility genes include systemic lupus erythematosus (SLE) and autoimmune diabetes. Well-characterised polygenic mouse models closely resembling each of these diseases exist, and genetic evidence links receptors for the Fc portion of immunoglobulin G (FcR) with their pathogenesis in mice and humans [1-3]. FcRs may be activatory or inhibitory and regulate a variety of Immune and inflammatory processes [4,5]. FcγRII (CD32) negatively regulates activation of cells including B cells and macrophages [6]. FcγRII-deficient mice are prone to immune mediated disease [7-9]. The gene encoding Fc gamma RII, Fcgr2, is contained in genetic susceptibility Intervals in mouse models of SLE such as the New Zealand Black (NZB) contribution to the (NZB x New Zealand White (NZW)) F1 strain [1,10,11] and the BXSB strain [12], and in human SLE [1-3]. We therefore sequenced Fcgr2 and identified a haplotype defined by deletions in the Fcgr2 promoter region that is present in major SLE-prone mouse strains (NZB, BXSB, SB/Le, MRL, 129 [13]) and non-obese diabetic (NOD) mice but absent in control strains (BALB/c, C57BL/6, DBA/2, C57BL/10) and NZW mice. The autoimmune haplotype was associated with reduced cell-surface expression of FcγRII on macrophages and activated B cells and with hyperactive macrophages resembling those of Fc gamma RII-deficient mice, and is therefore likely to play an important role in the pathogenesis of SLE and possibly diabetes.

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