ライフサイエンスコーパス: ALPS

1 ALPS insertion is severely hampered when monounsaturated

2 ALPS is a unique clinical syndrome in which in vitro abn

3 ALPS is subdivided into: 1) Type Ia, ALPS with mutant Fa

4 ALPS was diagnosed in 47% of patients tested.

5 ALPS was identified in 9 unrelated children as manifeste

6 We surveyed a cohort of 100 ALPS patients (including 33 splenectomized) and found th

7 otic Bcl-2 family members in T cells from 12 ALPS patients and determined the in vitro sensitivity of

8 e natural history and pathophysiology of 150 ALPS-FAS patients and 63 healthy mutation-positive relat

9 with Fas mutations were identified in 7 of 8 ALPS kindreds.

10 Spleen sections from 9 ALPS patients revealed double-negative T-cell (DN-T) inf

11 In addition, ALPS has been shown to be a more common condition, as pa

12 Recently, patients with an ALPS-like disease called RAS-associated autoimmune leuko

13 exes are common features in LGL leukemia and ALPS.

14 Probands and relatives with mutations and ALPS also showed a lower number of CD4(+)/CD25(+) T cell

15 followed by the relatives with mutations and ALPS.

16 ufficient to mildly induce Bim in normal and ALPS T cells via a Janus kinase/signal transducer and ac

17 New work now shows that alpha-synuclein and ALPS motifs represent two extreme types of amphipathic h

18 FAS ligand concentrations were determined as ALPS markers.

19 nt fraction of shared CDR3 sequences between ALPS DNT and both CD4(+) and CD8(+)TEMRA cells.

20 poptosis in vitro, accounting for biological ALPS phenotypes in vivo.

21 ype was also detected among CD4(+) or CD8(+) ALPS TEMRA cells.

22 F receptor superfamily proteins, but certain ALPS individuals have no such mutations.

23 ar-dynamics (MD) simulations to characterize ALPS binding to such lipid bilayers.

24 tives regardless of the presence of clinical ALPS, factors, other than modifiers of the Fas apoptosis

25 ofile predictive of the presence of clinical ALPS.

26 In conclusion, ALPS is marked by the presence of DR+ T cells that exhib

27 In contrast, ALPS patients' CD4-/CD8- T cells produced very low amoun

28 in autoimmune lymphoproliferative diseases (ALPS) and lpr or gld mice and attributed to CD95 and CD9

29 Finally, ALPS patients' peripheral monocytes/macrophages produced

30 s, but without all the required criteria for ALPS (n = 42), had expansions of CD8(+) T cells, alpha/b

31 sion of which is virtually pathognomonic for ALPS.

32 that children with ES should be screened for ALPS with DNTs.

33 stic algorithm and recommended treatment for ALPS have changed significantly, improving quality of li

34 e to the cytosolic leaflet is essential for +ALPS binding and vesicular transport between the EE and

35 eases Fas-induced cell death in T cells from ALPS and DALD patients in vitro; and (4) treatment with

36 for somatic FAS mutations in DNT cells from ALPS patients with no detectable germline mutation and a

37 ty for the abnormal allele, lymphocytes from ALPS patients showed markedly decreased FADD association

38 eas no patients with DNTs less than 2.5% had ALPS on apoptosis testing.

39 pothesized a subset of patients with ES have ALPS and tested 45 children at 22 institutions, measurin

40 e immune deficiency, have been found to have ALPS.

41 More than 300 families with hereditary ALPS have now been described; nearly 500 patients from t

42 r terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in v

43 Here we show that human ALPS DNT have features of terminally differentiated effe

44 ALPS is subdivided into: 1) Type Ia, ALPS with mutant Fas; 2) Type Ib, lymphadenopathy and mu

45 th systemic lupus erythematosus; 3) Type II, ALPS with mutant caspase 10; and 4) Type III, ALPS as ye

46 LPS with mutant caspase 10; and 4) Type III, ALPS as yet without any defined genetic cause.

47 In ALPS, defective lymphocyte apoptosis permits chronic, no

48 correlated significantly with serum IL-10 in ALPS patients, and IL-10 was sufficient to mildly induce

49 therapeutic target for DN T cell ablation in ALPS.

50 apoptosis defects underlying autoimmunity in ALPS type II.

51 ion, leads to organ-specific autoimmunity in ALPS, IPEX, and APS1.

52 ions in caspase-8 have not been described in ALPS, and homozygous caspase-8 deficiency causes embryon

53 roliferation and aberrant differentiation in ALPS.

54 biting Notch signaling would be effective in ALPS and SLE by reducing the production of abnormal DNTs

55 scription 3 pathway drives Bim expression in ALPS DNTC, which renders them sensitive to BH3 mimetics,

56 changes in Bcl-2 family member expression in ALPS to determine whether the Bcl-2 pathway might provid

57 lation of "double-negative" T cells found in ALPS.

58 d therapeutically to improve Fas function in ALPS and DALD.

59 and the Bcl-2 apoptotic pathway intersect in ALPS patients.

60 n the pathogenesis of lymphoproliferation in ALPS patients.

61 sufficiency as a common disease mechanism in ALPS patients with extracellular FAS mutations.

62 S can be disrupted by distinct mechanisms in ALPS.

63 Moreover, in ALPS patients with a germ line FAS mutation and somatic

64 gest that intracytoplasmic CD95 mutations in ALPS impair apoptosis chiefly by disrupting death-domain

65 Mutations in ALPS typically affect CD95 (Fas/APO-1)-mediated apoptosi

66 MZ in ALPS patients contained an abnormally thick layer of MAd

67 d-sparing treatments improves the outcome in ALPS-FAS patients.

68 t likely contribute to disease penetrance in ALPS.

69 ons of the cellular and cytokine profiles in ALPS show a prominent skewing toward a T-helper 2 phenot

70 e in vivo and in vitro cytokine secretion in ALPS to shed light on the relation of apoptosis defects

71 The responses seen in ALPS patients were profound, suggesting that sirolimus s

72 time to CR was often slower than was seen in ALPS.

73 toplasmic death domain from nine independent ALPS CD95 death-domain mutations result in a failure to

74 reducing GMAP-210 levels or redirecting its ALPS motif to mitochondria decreased liposome capture by

75 Finally, ABT-737 preferentially killed ALPS DNTC in vitro.

76 hydrophobic insertions along the monotonous ALPS sequence.

77 Most ALPS patients harbor mutations in the FAS gene, which re

78 pamycin is an effective treatment for murine ALPS and should be explored as treatment for affected hu

79 understanding of the genetics and biology of ALPS.

80 B12 is a reliable and accurate biomarker of ALPS-FAS, and the major causes of morbidity and mortalit

81 Most cases of ALPS are associated with germline mutations of the FAS g

82 Most cases of ALPS involve heterozygous mutations in the lymphocyte su

83 A defining characteristic of ALPS is the expansion of double negative T cells (DNTC).

84 monizing the diagnosis and classification of ALPS will foster collaborative research and better under

85 However, analysis of a large cohort of ALPS patients revealed that approximately 30% have mutat

86 after FAS inactivation and a major cohort of ALPS-affected patients were found to have hyper-IgE.

87 ested criteria to establish the diagnosis of ALPS.

88 de echogenicity may suggest the diagnosis of ALPS.

89 iently distinctive to suggest a diagnosis of ALPS.

90 thout a Fas mutation and with no features of ALPS (n = 65) demonstrated a small but significant expan

91 ounts for the humoral autoimmune features of ALPS and, perhaps, of other humoral autoimmune states.

92 We show here that the salient features of ALPS as well as a predisposition to hematological malign

93 plex kindred in which biological features of ALPS were found in the context of severe bacterial and v

94 mphocyte apoptosis, but clinical features of ALPS were not present in the vast majority of these indi

95 yte apoptosis and most had other features of ALPS.

96 parents who presented with a severe form of ALPS caused by FASLG deficiency.

97 Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and ac

98 We propose that the hypersensitivity of ALPS motifs to lipid packing defects results from the re

99 s to diagnosis, follow-up, and management of ALPS, its associated cytopenias, and other complications

100 Clinical manifestations of ALPS include autoimmune cytopenias, organomegaly, and ly

101 associated with the overt manifestations of ALPS.

102 RLlpr/lpr mice, which are an animal model of ALPS.

103 ested this hypothesis using murine models of ALPS and SLE.

104 pothesis using rapamycin in murine models of ALPS.

105 ly that better define the pathophysiology of ALPS, including the characterization of somatic FAS vari

106 th domain also showed a higher penetrance of ALPS phenotype features in mutation-bearing relatives.

107 DNTs (> or = 5%) were a strong predictor of ALPS (positive predictive value = 94%), whereas no patie

108 ycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4(+) or CD8(+) T cells in v

109 hildren with ES and documents a high rate of ALPS among pediatric ES patients.

110 s and determined the in vitro sensitivity of ALPS DNTC to the pro-apoptotic BH3 mimetic, ABT-737.

111 fluences the development and the severity of ALPS.

112 families show an ever-expanding spectrum of ALPS and its major complications: hypersplenism, autoimm

113 inical, genetic, and immunologic spectrum of ALPS, 9 patients and their families were extensively eva

114 The study of ALPS patients reveals the necessity of apoptosis for pre

115 clinical and laboratory phenotype to that of ALPS type Ia.

116 ed in clinical and basic science research on ALPS and related disorders.

117 One ALPS patient lacked a Fas gene mutation.

118 h somatic FAS mutations among a group of our ALPS patients with no detectable germline mutation and t

119 levated immunoglobulin levels also predicted ALPS.

120 ng both a Fas mutation and clinically proven ALPS (n = 28) showed significant expansion of CD8(+) T c

121 ntrinsic amphipathic lipid packaging sensor (ALPS) motif within HOPS Vps41, a target of the vacuolar

122 hat of the amphipathic lipid-packing sensor (ALPS) motif of GMAP-210: both preferred small (radius <

123 nsors, the Amphipathic Lipid Packing Sensor (ALPS) motif, does not seem to recognize the curved surfa

124 within an amphipathic lipid-packing sensor (ALPS) motif, which participates in targeting of synapsin

125 variant of the ArfGAP lipid packing sensor (+ALPS) motif for localization to TGN/EE membranes.

126 Significant ALPS-related morbidity occurred in 44% of relatives with

127 Since ALPS is caused by defective lymphocyte apoptosis, we hyp

128 imilar to ALPS type Ia patients, the somatic ALPS patients had increased DNT cell numbers and elevate

129 In parallel in vitro studies, ALPS patients CD4+ DR+ T cells stimulated either with an

130 In in vivo studies, ALPS patients manifested greatly increased circulating l

131 ith autoimmune lymphoproliferative syndrome (ALPS) achieved a durable complete response (CR), includi

132 The autoimmune lymphoproliferative syndrome (ALPS) affords novel insights into the mechanisms that re

133 ith autoimmune lymphoproliferative syndrome (ALPS) and dominantly interfere with apoptosis by an unkn

134 ith autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosis (SLE) have T-cell

135 the autoimmune lymphoproliferative syndrome (ALPS) are usually attributable to inherited mutations of

136 Autoimmune lymphoproliferative syndrome (ALPS) caused by impaired FAS-mediated apoptosis of lymph

137 ere autoimmune lymphoproliferative syndrome (ALPS) in humans.

138 Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caus

139 Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caus

140 Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of disrupted lymphocyte homeostasis,

141 Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immuno

142 Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas

143 Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder of T cell homeostasis caused b

144 Autoimmune lymphoproliferative syndrome (ALPS) is a human genetic disorder of lymphocyte apoptosi

145 Autoimmune Lymphoproliferative Syndrome (ALPS) is a recently recognized disease in which a geneti

146 Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder in which genetic defects

147 Autoimmune lymphoproliferative syndrome (ALPS) is caused by inactivating mutations in FAS or FASL

148 Autoimmune lymphoproliferative syndrome (ALPS) is characterized by childhood onset of lymphadenop

149 Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic nonmalignant lymphopro

150 The autoimmune lymphoproliferative syndrome (ALPS) is characterized by early-onset lymphadenopathy, s

151 se, Autoimmune Lymphoproliferative Syndrome (ALPS) is due to dominant-interfering mutations in the Fa

152 Autoimmune lymphoproliferative syndrome (ALPS) is marked by massive lymphadenopathy, hepatospleno

153 Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte a

154 the autoimmune lymphoproliferative syndrome (ALPS) met in Bethesda, Maryland on September 21-22, 2009

155 ith autoimmune lymphoproliferative syndrome (ALPS) patients and healthy mutation-positive relatives,

156 in autoimmune lymphoproliferative syndrome (ALPS) patients.

157 Autoimmune lymphoproliferative syndrome (ALPS) presents in childhood with nonmalignant lymphadeno

158 Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of apoptotic mechanisms to ma

159 the autoimmune lymphoproliferative syndrome (ALPS) reveals that formation of SPOTS can be disrupted b

160 Autoimmune lymphoproliferative syndrome (ALPS) type Ia is caused by inherited defects in apoptosi

161 ith autoimmune lymphoproliferative syndrome (ALPS) type II, characterized by abnormal lymphocyte and

162 ith autoimmune lymphoproliferative syndrome (ALPS), a congenital disease of defective apoptosis and a

163 of autoimmune lymphoproliferative syndrome (ALPS), a human disorder that is characterized by defecti

164 of autoimmune lymphoproliferative syndrome (ALPS), caused by mutation of the Fas death receptor, is

165 In autoimmune/lymphoproliferative syndrome (ALPS), defective Fas death receptor function causes lymp

166 the autoimmune lymphoproliferative syndrome (ALPS), which is caused by mutations in the FAS apoptotic

167 ith autoimmune lymphoproliferative syndrome (ALPS).

168 of autoimmune lymphoproliferative syndrome (ALPS).

169 ted autoimmune lymphoproliferative syndrome (ALPS).

170 ith autoimmune lymphoproliferative syndrome (ALPS; Canale-Smith syndrome), a disorder of lymphocyte h

171 tated in the congenital autoimmune syndrome, ALPS.

172 mon cause of this condition, which is termed ALPS-FAS.

173 s mediated exclusively by the amino-terminal ALPS motif.

174 The ALPS motif recognizes lipid-packing defects by a conserv

175 The ALPS type Ia probands (n = 31) and relatives having both

176 Among the ALPS-associated Fas mutants, dominant inhibition of apop

177 ion of Thr-87 interferes with folding of the ALPS motif, providing a means for regulating the associa

178 vesicles via the same mechanism whereby the ALPS motif senses lipid-packing defects at the vesicle s

179 ic leaflet, both of which are sensed by the +ALPS motif.

180 a potentially novel therapeutic approach to ALPS.

181 icate that these cytokines may contribute to ALPS and DALD: (1) recombinant IL-17A and IL-17F signifi

182 Some authors have referred to ALPS as Canale-Smith syndrome or lymphoproliferative syn

183 Similar to ALPS type Ia patients, the somatic ALPS patients had inc

184 e mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferati

185 hat rapamycin would be effective in treating ALPS.

186 rituximab have been shown to have unexpected ALPS-specific toxicities, and mycophenolate mofetil and

187 Of 17 unique APT1 mutations in unrelated ALPS probands, 12 (71%) occurred in exons 7-9, which enc

188 the characterization of somatic FAS variant ALPS, the identification of haploinsufficiency as a mech

189 ta revealed an unexpected mechanism by which ALPS results in anti-polysaccharide IgM antibody product

190 stasis but, unlike individuals affected with ALPS, also have defects in their activation of T lymphoc

191 findings in 166 members of 31 families with ALPS type Ia, associated with genetic mutations in the T

192 expression of Eomes in humans and mice with ALPS.

193 This work shows that patients with ALPS and DALD have high serum levels of interleukin 17A

194 When lymphocytes from patients with ALPS are cultured in vitro, they are resistant to apopto

195 Treatment options for patients with ALPS are limited.

196 and lymphoid tissues of these patients with ALPS contained significantly higher levels of IL-10 mess

197 Patients with ALPS demonstrate nonspecific but often dramatic imaging

198 Patients with ALPS have chronic enlargement of the spleen and lymph no

199 Most patients with ALPS have mutations in a gene now named TNFRSF6 (tumor n

200 Some patients with ALPS have relatives with these same apoptotic defects, h

201 e then, with approximately 500 patients with ALPS studied worldwide, significant advances in our unde

202 icantly higher (P <.001) in 21 patients with ALPS than in healthy controls.

203 Patients with ALPS typically present with no other clinical phenotype.

204 cal features in 19 consecutive patients with ALPS were performed.

205 optosis have been described in patients with ALPS, including the FAS ligand gene (FASLG) in rare case

206 as variants, not restricted to patients with ALPS, were identified.

207 Despite this progress, many patients with ALPS-like disease remain undefined genetically.

208 umoral autoimmunity typical of patients with ALPS.

209 3), and liver (n = 2) from 10 patients with ALPS.

210 apoptosis in only a subset of patients with ALPS.

211 ould be screened in patients presenting with ALPS features but lacking the usual markers, including p