scholarly journals Disrupted Ca2+ homeostasis and immunodeficiency in patients with functional Inositol 1,4,5-trisphosphate receptor subtype 3 defects

2021 ◽  
Author(s):  
Julika Neumann ◽  
Erika van Nieuwenhove ◽  
Lara E Terry ◽  
Frederik Staels ◽  
Taylor R Knebel ◽  
...  
Keyword(s):  
Lymphocyte Activation ◽  
Cell Receptor ◽  
Receptor Subtype ◽  
Compound Heterozygous ◽  
Inborn Errors ◽  
Hematopoietic Stem ◽  
Inositol 1,4,5 Trisphosphate ◽  
Severe Immunodeficiency ◽  
Compound Heterozygous Variants ◽  
Trisphosphate Receptor

Calcium signaling is essential for lymphocyte activation, with genetic disruptions resulting in severe immunodeficiency. The inositol 1,4,5-trisphosphate receptor (IP3R), formed from homo- or hetero-tetramers of the IP3R isoforms 1-3, amplifies lymphocyte signaling by releasing Ca2+ from ER stores into the cytosol following antigen-stimulation. While knockout of all 3 IP3R isoforms results in immunodeficiency in mice, the seeming redundancy of subunits was thought to explain the absence of IP3R mutation as a cause of human immunodeficiency. Here, we identify compound heterozygous variants in ITPR3 in two unrelated Caucasian patients presenting with combined immunodeficiency, in one case requiring hematopoietic stem cell transplantation. We observed disrupted Calcium homeostasis in patient-derived fibroblasts and immune cells, with abnormal proliferation and activation responses following B and T cell receptor stimulation. Reconstitution of IP3R knockout cell lines identified the variants as functional hypomorphs with reduced discrimination between homeostatic and induced states, validating a link between genotype and phenotype. These results demonstrate a functional linkage between defective ER Ca2+ channels and immunodeficiency, and identify IP3Rs as diagnostic targets for patients with specific inborn errors of immunity.

scholarly journals A function for tyrosine phosphorylation of type 1 inositol 1,4,5-trisphosphate receptor in lymphocyte activation

2007 ◽  
Vol 179 (5) ◽  
pp. 923-934 ◽  
Author(s):  
Nikhil deSouza ◽  
Jie Cui ◽  
Miroslav Dura ◽  
Thomas V. McDonald ◽  
Andrew R. Marks
Keyword(s):  
T Cells ◽  
Tyrosine Phosphorylation ◽  
Lymphocyte Activation ◽  
Cell Receptor ◽  
Scaffolding Protein ◽  
Activated T Cells ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor ◽  
Ca2 Channels

Sustained elevation of intracellular calcium by Ca2+ release–activated Ca2+ channels is required for lymphocyte activation. Sustained Ca2+ entry requires endoplasmic reticulum (ER) Ca2+ depletion and prolonged activation of inositol 1,4,5-trisphosphate receptor (IP3R)/Ca2+ release channels. However, a major isoform in lymphocyte ER, IP3R1, is inhibited by elevated levels of cytosolic Ca2+, and the mechanism that enables the prolonged activation of IP3R1 required for lymphocyte activation is unclear. We show that IP3R1 binds to the scaffolding protein linker of activated T cells and colocalizes with the T cell receptor during activation, resulting in persistent phosphorylation of IP3R1 at Tyr353. This phosphorylation increases the sensitivity of the channel to activation by IP3 and renders the channel less sensitive to Ca2+-induced inactivation. Expression of a mutant IP3R1-Y353F channel in lymphocytes causes defective Ca2+ signaling and decreased nuclear factor of activated T cells activation. Thus, tyrosine phosphorylation of IP3R1-Y353 may have an important function in maintaining elevated cytosolic Ca2+ levels during lymphocyte activation.

Neonatal-Onset Familial Mediterranean Fever in an Infant with Human Parainfluenza Virus-4 Infection

Neonatology ◽  
2021 ◽  
pp. 1-5
Author(s):  
Alexandre Michev ◽  
Alessandro Borghesi ◽  
Caterina Tretti ◽  
Maddalena Martella ◽  
Amelia Di Comite ◽  
...  
Keyword(s):  
Familial Mediterranean Fever ◽  
Parainfluenza Virus ◽  
Compound Heterozygous ◽  
Inborn Errors ◽  
Immunological Responses ◽  
Inflammatory Conditions ◽  
Neonatal Onset ◽  
Mediterranean Fever ◽  
Compound Heterozygous Variants ◽  
Human Parainfluenza Virus

Unusual, severe infections or inflammatory episodes in newborns and infants are largely unexplained and often attributed to immature immune responses. Inborn errors of immunity (IEI) are increasingly recognized as the etiology of life-threatening inflammatory and infectious diseases in infancy. We describe a patient with a unique neonatal-onset Familial Mediterranean Fever (FMF) due to compound heterozygous variants in <i>MEFV</i>, presenting as pleuritis following human parainfluenza virus-4 infection. Diagnostic challenges of FMF in infancy include the interpretation of the attacks as infectious episodes. Newborns and infants with acute, recurrent, or chronic, unusually severe infectious or inflammatory conditions should be screened for IEI, including both disorders with defective immunological responses and autoinflammatory disorders.

scholarly journals T-cell-receptor signalling in inositol 1,4,5-trisphosphate receptor (IP3R) type-1-deficient mice: is IP3R type 1 essential for T-cell-receptor signalling?

1998 ◽  
Vol 333 (3) ◽  
pp. 615-619 ◽  
Author(s):  
Junji HIROTA ◽  
Masashi BABA ◽  
Mineo MATSUMOTO ◽  
Teiichi FURUICHI ◽  
Kiyoshi TAKATSU ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Cell Phenotype ◽  
Receptor Signalling ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

Stimulation of T-cells via the T-cell receptor (TCR) complex is accompanied by an increase in intracellular Ca2+ concentration ([Ca2+]i). Recently, it was reported that a stable transformant of the human T-cell line, Jurkat, expressing an antisense cDNA construct of inositol 1,4,5-trisphosphate receptor (IP3R) type 1 (IP3R1), failed to demonstrate increased [Ca2+]i or interleukin-2 production after TCR stimulation and was also resistant to apoptotic stimuli. This cell line lacked IP3R1 expression, but expressed the type-2 and -3 receptors, IP3R2 and IP3R3 respectively [Jayaraman, Ondriasova, Ondrias, Harnick and Marks (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 6007–6011, and Jayaraman and Marks (1997) Mol. Cell. Biol. 17, 3005–3012]. The authors concluded that IP3R1 is essential for TCR signalling and suggested that Ca2+ release via IP3R1 is a critical mediator of apoptosis. To establish whether a loss of IP3R1 function in T-cells occurred in vivo and in vitro, we investigated Ca2+ signalling after TCR stimulation and the properties of T-cells using IP3R1-deficient (IP3R1-/-) mice. As IP3R1-/- mice die at weaning, we transplanted bone marrow cells of IP3R1-/- mice into irradiated wild-type mice. Western blot analysis showed that the recipient IP3R1-containing (IP3R1+/+) lymphocytes were replaced by the donor IP3R1-/- lymphocytes after transplantation and that expression of IP3R2 and IP3R3 was unaltered. In contrast with the previous reports, T-cells lacking IP3R1 were able to mobilize Ca2+ from intracellular Ca2+ stores after stimulation via the TCR. We observed no significant differences between IP3R1+/+ and IP3R1-/- T-cells in terms of the number of thymocytes and splenocytes, the proportion of the T-cell phenotype, proliferative response to anti-CD3 monoclonal antibody (mAb) stimulation and cell viability. Therefore IP3R1 is not essential for T-cell development and function.

scholarly journals Inositol 1,4,5-Trisphosphate Receptor Subtype-Specific Regulation of Calcium Oscillations

2011 ◽  
Vol 36 (7) ◽  
pp. 1175-1185 ◽  
Author(s):  
Songbai Zhang ◽  
Nicolas Fritz ◽  
Cristian Ibarra ◽  
Per Uhlén
Keyword(s):  
Calcium Oscillations ◽  
Receptor Subtype ◽  
Inositol 1,4,5 Trisphosphate ◽  
Specific Regulation ◽  
Trisphosphate Receptor

scholarly journals T cells deficient in inositol 1,4,5-trisphosphate receptor are resistant to apoptosis.

1997 ◽  
Vol 17 (6) ◽  
pp. 3005-3012 ◽  
Author(s):  
T Jayaraman ◽  
A R Marks
Keyword(s):  
T Cells ◽  
Intracellular Calcium ◽  
Calcium Release ◽  
Calcium Influx ◽  
Cell Receptor ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Inositol 1,4,5 Trisphosphate ◽  
Intracellular Calcium Release ◽  
Trisphosphate Receptor

The type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) calcium release channel is present on the endoplasmic reticulum of most cell types. T lymphocytes which have been made deficient in IP3R1 lack detectable IP3-induced intracellular calcium release and exhibit defective signaling via the T-cell receptor (TCR) (T. Jayaraman, E. Ondriasova, K. Ondrias, D. Harnick, and A. R. Marks, Proc. Natl. Acad. Sci. USA 92:6007-6011, 1995). We now show that IP3R1-deficient T cells are resistant to apoptosis induced by dexamethasone, TCR stimulation, ionizing radiation, and Fas. Resistance to TCR-mediated apoptosis in IP3R1-deficient cells is reversed by pharmacologically raising cytoplasmic calcium levels. TCR-mediated apoptosis can be induced in calcium-free media, indicating that extracellular calcium influx is not required. These findings suggest that intracellular calcium release via the IP3R1 is a critical mediator of apoptosis.

A function for tyrosine phosphorylation of type 1 inositol 1,4,5-trisphosphate receptor in lymphocyte activation

2007 ◽  
Vol 204 (13) ◽  
pp. i30-i30
Author(s):  
Nikhil deSouza ◽  
Jie Cui ◽  
Miroslav Dura ◽  
Thomas V. McDonald ◽  
Andrew R. Marks
Keyword(s):  
Tyrosine Phosphorylation ◽  
Lymphocyte Activation ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

scholarly journals Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Jingjing Liang ◽  
Jun Lyu ◽  
Meng Zhao ◽  
Dan Li ◽  
Mingzhu Zheng ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Calcium Signalling ◽  
Cell Receptor ◽  
Proximal Region ◽  
Thymocyte Development ◽  
Crucial Component ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

Abstract Thymocyte-expressed, positive selection-associated 1 (Tespa1) is important in T cell receptor (TCR)-driven thymocyte development. Downstream of the TCR, Tespa1 is a crucial component of the linker for activation of T cells (LAT) signalosome, facilitating calcium signalling and subsequent MAPK activation. However, it is unknown how Tespa1 elicits calcium signalling. Here, we show that inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) is crucial for Tespa1-optimized, TCR-induced Ca2+ flux and thymocyte development. Upon TCR stimulation, Tespa1 directly interacts with IP3R1 and recruits it to the TCR complex, where IP3R1 is phosphorylated at Y353 by Fyn. This Tespa1-IP3R1 interaction is mediated by the F187 and F188 residues of Tespa1 and the amino-terminus of IP3R1. Tespa1-F187A/F188A mutant mice phenocopy Tespa1-deficient mice with impaired late thymocyte development due to reduced IP3R1 translocation to the TCR-proximal region. Our work elucidates the function of Tespa1 in T cell development and the regulation of TCR-induced Ca2+ signalling through IP3R1.

scholarly journals Germline Compound Heterozygous Variants Identified in the STXBP2 Gene Leading to a Familial Hemophagocytic Lymphohistiocytosis Type 5: A Case Report

2021 ◽  
Vol 9 ◽  
Author(s):  
Vera Maria Dantas ◽  
Cassandra Teixeira Valle ◽  
Roberta Piccin de Oliveira ◽  
Mylena Taíse Azevedo L. Bezerra ◽  
Cleia Teixeira do Amaral ◽  
...  
Keyword(s):  
Hemophagocytic Lymphohistiocytosis ◽  
Pathogenic Mutation ◽  
Recurrent Fever ◽  
Compound Heterozygous ◽  
Acceptor Site ◽  
Hematopoietic Stem ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Variant Of Uncertain Significance ◽  
Uncertain Significance ◽  
Compound Heterozygous Variants

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, potentially fatal autosomal-recessive immunodeficiency, and STXBP2 mutations have been associated with FHL type 5 (FHL-5). Here, we report a case of a 2-year-old boy who presented with recurrent fever, hepatosplenomegaly, pancytopenia, hyperferritinemia, and hypofibrinogenemia since 4 months of age. His genetic analysis revealed a compound heterozygosity of the STXBP2 gene with a described pathogenic mutation, c.1247-1G&gt;C (splicing acceptor site), harbored by his father and a likely pathogenic variant of uncertain significance (VUS), c.704G&gt;A (p.Arg235Gln), harbored by his mother. He was diagnosed as compound heterozygous for FHL-5 and was treated with the HLH-2004 protocol. Since treatment, this patient has been in remission, and he is being evaluated for a hematopoietic stem cell transplantation (HSCT).

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