B cell inhibitory receptors and autoimmunity

Pritchard, Nicholas; Smith, Kenneth G. C.

doi:10.1046/j.1365-2567.2003.01592.x

Cited by 97 publications

(81 citation statements)

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“…The function of these inhibitory receptors is not redundant, as has been shown by studies using mice deficient for several Bcell inhibitory receptors (Pritchard and Smith, 2003). Despite the fact that expression levels may be low, inhibitory immune receptors play an important role in maintaining immune homeostasis since absence of inhibitory immune receptors results in increased activation of immune cells, in some cases leading to * Corresponding author.…”

Section: Introductionmentioning

confidence: 99%

The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes

Rijkers

Ruiter

Baridi

et al. 2008

Molecular Immunology

118

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To ensure an adequate response against pathogens and prevent unwanted self-reactivity, immune cells need to functionally express both activating and inhibitory receptors. CD200R is an inhibitory receptor mainly expressed on myeloid cells that down-modulates cellular activation both in vivo and in vitro. Although previously mainly studied as a regulator of myeloid function, we now show that CD200R is differentially expressed on human and mouse T-cell subsets. In both species, CD4 + T cells express higher amounts of CD200R than CD8 + T cells, and memory cells express higher amounts of CD200R than naïve or effector cells. CD200R expression is up-regulated on both CD4 + and CD8 + T cells after stimulation in vitro. Furthermore, we show CD200R expression on human and mouse B cells. In human tonsils, CD200R is differentially expressed on B cells, with high expression on memory cells and plasmablasts. Mice lacking the ligand for CD200R, CD200 −/− mice, do not show abnormal composition of the lymphocyte compartment and have normal B cell responses to antigenic challenge. Although the functional implications remain to be elucidated, the expression of CD200R on lymphocytes suggests a much broader role for CD200R-mediated immune regulation than previously anticipated.

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Section: Introductionmentioning

confidence: 99%

The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes

Rijkers

Ruiter

Baridi

et al. 2008

Molecular Immunology

118

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“…Inhibitory receptors play an important role in the regulation of immune cells. This is illustrated by the fact that mutations in inhibitory receptors or in the molecules through which they signal, are associated with autoimmune disease [1]. Most inhibitory receptors in the immune system contain one or several immunoreceptor tyrosine-based inhibitory motifs (ITIM).…”

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confidence: 99%

Leukocyte‐associated Ig‐like receptor‐1 has SH2 domain‐containing phosphatase‐independent function and recruits C‐terminal Src kinase

et al. 2005

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Most inhibitory receptors in the immune system contain one or several immunoreceptor tyrosine-based inhibitory motifs (ITIM) and recruit the SH2 domain-containing phosphatases SHP-1, SHP-2 and/or SHIP, which are generally believed to be essential for the inhibitory function. However, it has not been systematically investigated whether ITIM-bearing receptors exert their function through alternative interactions. Here we describe that leukocyte-associated Ig-like receptor (LAIR)-1 has inhibitory function in DT40 chicken B cells that lack both SHP-1 and SHP-2. In addition, we found that LAIR-1 did not recruit SHIP upon phosphorylation. Thus, LAIR-1 can function independently from SH2 domain-containing phosphatases and must recruit at least one other signaling molecule. Using a yeast-tri-hybrid system, we found that phosphorylated LAIR-1 bound the C-terminal Src kinase (Csk). The interaction required the SH2 domain of Csk and phosphorylation of the tyrosine in the N-terminal ITIM of LAIR-1. We propose that Csk is an additional player in the regulation of the immune system by ITIMbearing receptors. IntroductionAn appropriate response of the immune system depends on a balance between activating and inhibitory signals. Inhibitory receptors play an important role in the regulation of immune cells. This is illustrated by the fact that mutations in inhibitory receptors or in the molecules through which they signal, are associated with autoimmune disease [1]. Most inhibitory receptors in the immune system contain one or several immunoreceptor tyrosine-based inhibitory motifs (ITIM). This motif has the consensus sequence (I/V/L/S)-x-Y-x-x-(L/ V/I), where x represents any amino acid [2]. Upon engagement, ITIM-bearing receptors become phosphorylated and recruit the SH2 domain-containing inositol phosphatase SHIP and/or the SH2 domaincontaining tyrosine phosphatases SHP-1 and SHP-2. The phosphatases subsequently dephosphorylate and thereby inactivate key molecules involved in cellular activation [2,3]. It is widely believed that the recruitment of SH2 domain-containing phosphatases is required for the inhibitory function of ITIM-bearing receptors. However, several studies, including our previous work on leukocyte-associated Ig-like receptor (LAIR)-1, suggest that the phosphatases are not the sole down-stream effectors of ITIM-bearing receptors.LAIR-1 is an ITIM-bearing receptor that is broadly expressed in the immune system [4] and functions as an inhibitory receptor on NK cells, T cells and B cells [4][5][6][7][8][9]. In addition, LAIR-1 inhibits the differentiation of peripheral blood precursors towards dendritic cells [10] and induces apoptosis in myeloid leukemia cells [11,12] Here we show that LAIR-1 has an inhibitory capacity in SHP-1-and SHP-2-deficient DT40 chicken B cells and does not recruit SHIP. This indicates that, in contrast to the established dogma, LAIR-1 has an inhibitory function independent of SH2 domain-containing phosphatases. Therefore, we searched for other LAIR-1-interacting proteins. Using a yeast-tri...

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Section: Introductionmentioning

confidence: 99%

“…This defect is associated with a reduced surface expression of CD22 on resting B cells and reduced ability of LPS-activated B cells to up-regulate CD22. Therefore, data from the CD22-knockout mice link defects in CD22 expression to the development of autoimmunity [18,19].We have now extended these pioneering studies by utilizing our well-defined anti-DNA knock-in mouse lines, in which a single anti-DNA H chain (D42H of the NZB/NZW anti-DNA D42 hybridoma) or combinations of this H chain with different L chains (Vj1-Jj1 or Vj8-Jj5) have been targeted to the appropriate chromosomal loci in the mouse genome [20,21]. When expressed on a non-autoimmune mouse background, no anti-DNA activity was found in the serum of H chain-or H/L chain-targeted mice and the animals showed features of all three known mechanisms of B cell tolerance, i.e.…”

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Peripheral B cell receptor editing may promote the production of high‐affinity autoantibodies in CD22‐deficient mice

et al. 2006

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CD22-deficient mice are characterized by B cell hyperactivity and autoimmunity. We have constructed knock-in CD22 -/-mice, expressing an anti-DNA heavy (H) chain (D42), alone or combined with Vj1-Jj1 or Vj8-Jj5 light (L) chains. The Ig-targeted mice produced a lupus-like serology that was age-and sex-dependent. High-affinity IgG autoantibodies were largely dependent on the selection of B cells with a particular H/L combination, in which a non-transgenic, endogenous L chain was assembled by secondary rearrangements through the mechanism of receptor editing. Moreover, we present evidence that these secondary rearrangements are very prominent in splenic peripheral B cells. Since CD22 is primarily expressed on the surface of peripheral B cells, we propose a model for the development of a lupus-like autoimmune disease by a combination of peripheral receptor editing and abnormal B cell activation. IntroductionSystemic lupus erythematosus (SLE) is a rheumatic disease of unknown etiology, usually occurring in young women of childbearing age. The presence of serum antibodies to a variety of self components and their possible involvement in the development of severe kidney disease (glomerulonephritis) has made SLE a prototype of systemic autoimmune diseases [1]. The autoantibodies in lupus sera react with a large variety of nuclear antigens, including DNA, RNA and nuclear proteins. The antibodies to dsDNA are mostly highaffinity IgG that appear almost exclusively in SLE and very rarely in other diseases [2, 3].Several mouse models which spontaneously develop a lupus-like disease have been studied extensively [4]. The NZB/NZW F1 mouse is considered to be the murine model most closely resembling human SLE [5]. The lupus-like disease in these mice is more severe in females and is accompanied by high-affinity IgG anti-dsDNA autoantibodies. Both NZB and NZW parents contribute multiple susceptibility genes to the immune abnormalities of the F1 hybrid mouse [6]. Additional mouse models of SLE include mouse strains with deficiencies in antigen disposal mechanisms and mice that are deficient in proteins regulating the thresholds for tolerance and activation of B and T lymphocytes [7].CD22 is a B cell-specific surface glycoprotein of the Ig superfamily expressed on mature B cells [8, 9]. It functions as an adhesion molecule, as a signal-transducing molecule and as a modulator of intracellular signaling through the B cell receptor (BCR) complex. Negative regulatory roles for CD22 in BCR signaling are proposed to be critical for normal B cell activation, since immunoreceptor tyrosine-based inhibitory motifs with- in CD22 recruit SHP-1, a potent intracellular phosphatase with inhibitory functions in BCR signaling [10,11]. CD22-deficient mice [12][13][14][15] were reported to have decreased numbers of circulating B cells and slightly increased numbers of peritoneal B-1 cells, as well as higher levels of serum IgM [12,14]. Significantly, mature B cells from CD22-deficient mice had decreased expression of cell surface IgM and augmented i...

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B cell inhibitory receptors and autoimmunity

Cited by 97 publications

References 98 publications

The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes

The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes

Leukocyte‐associated Ig‐like receptor‐1 has SH2 domain‐containing phosphatase‐independent function and recruits C‐terminal Src kinase

Peripheral B cell receptor editing may promote the production of high‐affinity autoantibodies in CD22‐deficient mice

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