TY - JOUR
T1 - Disturbed B-lymphocyte selection in autoimmune lymphoproliferative syndrome
AU - Janda, A
AU - Schwarz, K
AU - van der Burg, Mirjam
AU - Vach, W
AU - Ijspeert, Hanna
AU - Lorenz, MR
AU - Elgizouli, M
AU - Pieper, K
AU - Fisch, P
AU - Hagel, J
AU - Lorenzetti, R
AU - Seidl, M
AU - Roesler, J
AU - Hauck, F
AU - Traggiai, E
AU - Speckmann, C
AU - Rensing-Ehl, A
AU - Ehl, S
AU - Eibel, H
AU - Rizzi, M
PY - 2016
Y1 - 2016
N2 - Fas is a transmembrane receptor involved in the maintenance of tolerance and immune homeostasis. In murine models, it has been shown to be essential for deletion of autoreactive B cells in the germinal center. The role of Fas in human B-cell selection and in development of autoimmunity in patients carrying FAS mutations is unclear. We analyzed patients with either a somatic FAS mutation or a germline FAS mutation and somatic loss-of-heterozygosity, which allows comparing the fate of B cells with impaired vs normal Fas signaling within the same individual. Class-switched memory B cells showed: accumulation of FAS-mutated B cells; failure to enrich single V, D, J genes and single V-D, D-J gene combinations of the B-cell receptor variable region; increased frequency of variable regions with higher content of positively charged amino acids; and longer CDR3 and maintenance of polyreactive specificities. Importantly, Fas-deficient switched memory B cells showed increased rates of somatic hypermutation. Our data uncover a defect in B-cell selection in patients with FAS mutations, which has implications for the understanding of the pathogenesis of autoimmunity and lymphomagenesis of autoimmune lymphoproliferative syndrome.
AB - Fas is a transmembrane receptor involved in the maintenance of tolerance and immune homeostasis. In murine models, it has been shown to be essential for deletion of autoreactive B cells in the germinal center. The role of Fas in human B-cell selection and in development of autoimmunity in patients carrying FAS mutations is unclear. We analyzed patients with either a somatic FAS mutation or a germline FAS mutation and somatic loss-of-heterozygosity, which allows comparing the fate of B cells with impaired vs normal Fas signaling within the same individual. Class-switched memory B cells showed: accumulation of FAS-mutated B cells; failure to enrich single V, D, J genes and single V-D, D-J gene combinations of the B-cell receptor variable region; increased frequency of variable regions with higher content of positively charged amino acids; and longer CDR3 and maintenance of polyreactive specificities. Importantly, Fas-deficient switched memory B cells showed increased rates of somatic hypermutation. Our data uncover a defect in B-cell selection in patients with FAS mutations, which has implications for the understanding of the pathogenesis of autoimmunity and lymphomagenesis of autoimmune lymphoproliferative syndrome.
U2 - 10.1182/blood-2015-04-642488
DO - 10.1182/blood-2015-04-642488
M3 - Article
C2 - 26907631
SN - 0006-4971
VL - 127
SP - 2193
EP - 2202
JO - Blood
JF - Blood
IS - 18
ER -