PMID- 23843450
OWN - NLM
STAT- MEDLINE
DCOM- 20140519
LR  - 20130711
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Linking)
VI  - 5
IP  - 193
DP  - 2013 Jul 10
TI  - Plasmacytoid dendritic cells, interferon signaling, and FcgammaR contribute to 
      pathogenesis and therapeutic response in childhood immune thrombocytopenia.
PG  - 193ra89
LID - 10.1126/scitranslmed.3006277 [doi]
AB  - Immune thrombocytopenia (ITP) is an autoimmune disorder of childhood 
      characterized by immune-mediated destruction of platelets. The mechanisms 
      underlying the pathogenesis of ITP and the therapeutic efficacy of intravenous 
      immunoglobulins (IVIG) in this disorder remain unclear. We show that monocytes 
      from patients with ITP have a distinct gene expression profile, with increased 
      expression of type I interferon response (IR) genes. Plasma from ITP patients had 
      increased levels of several cytokines indicative of immune activation, including 
      an increase in interferon-alpha. ITP patients also had an increase in plasmacytoid 
      dendritic cells (pDCs) compared to healthy donors. Therapy-induced remission of 
      ITP was associated with abrogation of the IR gene signature in monocytes without 
      reduction in the levels of circulating interferon-alpha itself. IVIG altered the 
      ratio of activating/inhibitory Fcgamma receptors (FcgammaRs) in vivo primarily by 
      reducing FcgammaRIII (CD16). The engagement of activating FcgammaRs was required for 
      IVIG-mediated abrogation of monocyte response to exogenous interferon-alpha in 
      culture. Moreover, plasma from ITP patients led to activation of monocytes and 
      myeloid DCs in culture with an increase in T cell stimulatory capacity; this 
      activation depended on the engagement of activating FcgammaRs and interferon-alpha 
      receptor (IFNAR) and was inhibited by antibody-mediated blockade of these 
      pathways. These data point to a central role of type I interferon in the 
      pathogenesis of ITP and suggest targeting pDCs and blockade of IR as potential 
      therapeutic approaches in this disorder. They also provide evidence for the 
      capacity of IVIG to extinguish IR in vivo, which may contribute to its effects in 
      autoimmunity.
FAU - Sehgal, Kartik
AU  - Sehgal K
AD  - Yale Cancer Center, Yale University, New Haven, CT 06519, USA.
FAU - Guo, Xiuyang
AU  - Guo X
FAU - Koduru, Srinivas
AU  - Koduru S
FAU - Shah, Anumeha
AU  - Shah A
FAU - Lin, Aiping
AU  - Lin A
FAU - Yan, Xiting
AU  - Yan X
FAU - Dhodapkar, Kavita M
AU  - Dhodapkar KM
LA  - eng
GR  - R01 AI079222/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Chemokines)
RN  - 0 (Immunoglobulins, Intravenous)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Interferon-alpha)
RN  - 0 (Receptors, IgG)
RN  - 9008-11-1 (Interferons)
SB  - IM
MH  - Adolescent
MH  - Chemokines/metabolism
MH  - Child
MH  - Child, Preschool
MH  - Dendritic Cells/*metabolism
MH  - Female
MH  - Gene Expression Profiling
MH  - Humans
MH  - Immunoglobulins, Intravenous/therapeutic use
MH  - Intercellular Signaling Peptides and Proteins/metabolism
MH  - Interferon-alpha/blood/metabolism
MH  - Interferons/*metabolism
MH  - Lupus Erythematosus, Systemic/genetics
MH  - Male
MH  - Monocytes/metabolism
MH  - Purpura, Thrombocytopenic, Idiopathic/blood/*drug therapy/genetics/*immunology
MH  - Receptors, IgG/*metabolism
MH  - *Signal Transduction/genetics
MH  - Tissue Donors
MH  - Young Adult
EDAT- 2013/07/12 06:00
MHDA- 2014/05/20 06:00
CRDT- 2013/07/12 06:00
PHST- 2013/07/12 06:00 [entrez]
PHST- 2013/07/12 06:00 [pubmed]
PHST- 2014/05/20 06:00 [medline]
AID - 5/193/193ra89 [pii]
AID - 10.1126/scitranslmed.3006277 [doi]
PST - ppublish
SO  - Sci Transl Med. 2013 Jul 10;5(193):193ra89. doi: 10.1126/scitranslmed.3006277.