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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Allergy+Clin+Immunol
2014 ; 133
(4
): 1149-61
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Signaling lymphocytic activation molecule (SLAM)/SLAM-associated protein pathway
regulates human B-cell tolerance
#MMPMID24373350
Menard L
; Cantaert T
; Chamberlain N
; Tangye SG
; Riminton S
; Church JA
; Klion A
; Cunningham-Rundles C
; Nichols KE
; Meffre E
J Allergy Clin Immunol
2014[Apr]; 133
(4
): 1149-61
PMID24373350
show ga
BACKGROUND: Signaling lymphocytic activation molecule (SLAM)-associated protein
(SAP) can mediate the function of SLAM molecules, which have been proposed to be
involved in the development of autoimmunity in mice. OBJECTIVE: We sought to
determine whether the SLAM/SAP pathway regulates the establishment of human
B-cell tolerance and what mechanisms of B-cell tolerance could be affected by SAP
deficiency. METHODS: We tested the reactivity of antibodies isolated from single
B cells from SAP-deficient patients with X-linked lymphoproliferative disease
(XLP). The expressions of SAP and SLAM family members were assessed in human bone
marrow-developing B cells. We also analyzed regulatory T (Treg) cell function in
patients with XLP and healthy control subjects. RESULTS: We found that new
emigrant/transitional B cells from patients with XLP were enriched in
autoreactive clones, revealing a defective central B-cell tolerance checkpoint in
the absence of functional SAP. In agreement with a B cell-intrinsic regulation of
central tolerance, we identified SAP expression in a discrete subset of bone
marrow immature B cells. SAP colocalized with SLAMF6 only in association with
clustered B-cell receptors likely recognizing self-antigens, suggesting that
SLAM/SAP regulate B-cell receptor-mediated central tolerance. In addition,
patients with XLP displayed defective peripheral B-cell tolerance, which is
normally controlled by Treg cells. Treg cells in patients with XLP seem
functional, but SAP-deficient T cells were resistant to Treg cell-mediated
suppression. Indeed, SAP-deficient T cells were hyperresponsive to T-cell
receptor stimulation, which resulted in increased secretion of IL-2, IFN-?, and
TNF-?. CONCLUSIONS: SAP expression is required for the counterselection of
developing autoreactive B cells and prevents their T cell-dependent accumulation
in the periphery.
|*Immune Tolerance
[MESH]
|*Signal Transduction
[MESH]
|Antigens, CD/*metabolism
[MESH]
|Autoimmunity/genetics/immunology
[MESH]
|B-Cell Activating Factor/blood
[MESH]
|B-Lymphocytes/*immunology/*metabolism
[MESH]
|Gene Expression
[MESH]
|Humans
[MESH]
|Intracellular Signaling Peptides and Proteins/deficiency/genetics/*metabolism
[MESH]