scholarly journals Adaptive Immunodeficiency in WHIM Syndrome

2018 ◽  
Vol 20 (1) ◽  
pp. 3 ◽  
Author(s):  
Shamik Majumdar ◽  
Philip Murphy
Keyword(s):  
Chemokine Receptor ◽  
Autosomal Dominant ◽  
Whim Syndrome ◽  
C Terminus ◽  
Immunodeficiency Disorder ◽  
Chemokine Ligand ◽  
Chemokine Receptor 4 ◽  
The Impact ◽  
G Protein Coupled ◽  
Increased Susceptibility

Cysteine-X-cysteine chemokine receptor 4 (CXCR4) is a broadly expressed and multifunctional G protein-coupled chemokine receptor critical for organogenesis, hematopoiesis, and antimicrobial host defense. In the hematopoietic system, the binding of CXCR4 to its cognate chemokine ligand, CXCL12, mediates leukocyte trafficking, distribution, survival, activation, and proliferation. Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, autosomal dominant, combined immunodeficiency disorder caused by mutations in the C-terminus of CXCR4 that prevent receptor downregulation and therefore result in pathologically increased signaling. The “M” in the acronym WHIM refers to myelokathexis, the retention of neutrophils in the bone marrow resulting in neutropenia, which explains in part the increased susceptibility to bacterial infection. However, WHIM patients also present with B and T lymphopenia, which may explain the susceptibility to human papillomavirus (HPV), the cause of warts. The impact of WHIM mutations on lymphocytes and adaptive immunity has received less attention than myelokathexis and is the focus of this review.

scholarly journals WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4

Blood ◽  
2012 ◽  
Vol 120 (1) ◽  
pp. 181-189 ◽  
Author(s):  
Qian Liu ◽  
Haoqian Chen ◽  
Teresa Ojode ◽  
Xiangxi Gao ◽  
Sandra Anaya-O'Brien ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitution ◽  
Chemokine Receptor ◽  
Autosomal Dominant ◽  
Calcium Flux ◽  
Single Amino Acid ◽  
Whim Syndrome ◽  
Terminal Domain ◽  
Chemokine Receptor Cxcr4 ◽  
C Terminus

Abstract WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder so-named because it is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (defective neutrophil egress from the BM). Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G → A). This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor. Accordingly, like CXCR4R334X, the most common truncation mutation in WHIM syndrome, CXCR4E343K mediated approximately 2-fold increased signaling in calcium flux and chemotaxis assays relative to wild-type CXCR4; however, CXCR4E343K had a reduced effect on blocking normal receptor down-regulation from the cell surface. Therefore, in addition to truncating mutations in the C-terminal domain of CXCR4, WHIM syndrome may be caused by a single charge-changing amino acid substitution in this domain, E343K, that results in increased receptor signaling.

scholarly journals G protein subtype–specific signaling bias in a series of CCR5 chemokine analogs

2018 ◽  
Vol 11 (552) ◽  
pp. eaao6152 ◽  
Author(s):  
Emily Lorenzen ◽  
Emilie Ceraudo ◽  
Yamina A. Berchiche ◽  
Carlos A. Rico ◽  
Alexandre Fürstenberg ◽  
...  
Keyword(s):  
G Protein ◽  
Chemokine Receptor ◽  
General Feature ◽  
G Protein Coupled Receptors ◽  
Second Messenger Pathways ◽  
Chemokine Receptor 4 ◽  
Ligand Bias ◽  
G Protein Coupled ◽  
Hiv 1 ◽  
The Ideal

Chemokines and some chemical analogs of chemokines prevent cellular HIV-1 entry when bound to the HIV-1 coreceptors C-C chemokine receptor 5 (CCR5) or C-X-C chemokine receptor 4 (CXCR4), which are G protein–coupled receptors (GPCRs). The ideal HIV-1 entry blocker targeting the coreceptors would display ligand bias and avoid activating G protein–mediated pathways that lead to inflammation. We compared CCR5-dependent activation of second messenger pathways in a single cell line. We studied two endogenous chemokines [RANTES (also known as CCL5) and MIP-1α (also known as CCL3)] and four chemokine analogs of RANTES (5P12-, 5P14-, 6P4-, and PSC-RANTES). We found that CCR5 signaled through both Gi/o and Gq/11. IP1 accumulation and Ca2+ flux arose from Gq/11 activation, rather than from Gβγ subunit release after Gi/o activation as had been previously proposed. The 6P4- and PSC-RANTES analogs were superagonists for Gq/11 activation, whereas the 5P12- and 5P14-RANTES analogs displayed a signaling bias for Gi/o. These results demonstrate that RANTES analogs elicit G protein subtype–specific signaling bias and can cause CCR5 to couple preferentially to Gq/11 rather than to Gi/o signaling pathways. We propose that G protein subtype–specific signaling bias may be a general feature of GPCRs that can couple to more than one G protein family.

scholarly journals Role of C-X-C chemokine ligand 12/C-X-C chemokine receptor 4 in the progression of hepatocellular carcinoma

2017 ◽  
Vol 14 (2) ◽  
pp. 1905-1910 ◽  
Author(s):  
Kuo-Shyang Jeng ◽  
Chi-Juei Jeng ◽  
Wen-Juei Jeng ◽  
Chiung-Fang Chang ◽  
I-Shyan Sheen
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chemokine Receptor ◽  
Chemokine Ligand ◽  
Chemokine Receptor 4

scholarly journals CXCL12/CXCR4-Axis Dysfunctions: Markers of the Rare Immunodeficiency Disorder WHIM Syndrome

2010 ◽  
Vol 29 (3-4) ◽  
pp. 189-198 ◽  
Author(s):  
Françoise Bachelerie
Keyword(s):  
Bacterial Infections ◽  
Receptor Internalization ◽  
Gene Encoding ◽  
Whim Syndrome ◽  
Papillomavirus Infection ◽  
Immunodeficiency Disorder ◽  
T Cell Lymphopenia ◽  
Chemokine Cxcl12 ◽  
G Protein Coupled ◽  
Cxcr4 Axis

The WHIM syndrome features susceptibility to human Papillomavirus infection-induced warts and carcinomas, hypogammaglobulinemia, recurrent bacterial infections, B and T-cell lymphopenia, and neutropenia associated with retention of senescent neutrophils in the bone marrow (i.e. myelokathexis). This rare disorder is mostly linked to inherited heterozygous autosomal dominant mutations in the gene encodingCXCR4, a G protein coupled receptor with a unique ligand, the chemokine CXCL12/SDF-1. Some individuals who have full clinical forms of the syndrome carry a wild typeCXCR4gene. In spite of this genetic heterogeneity, leukocytes from WHIM patients share in common dysfunctions of the CXCR4-mediated signaling pathway upon exposure to CXCL12. Dysfunctions are characterized by impaired desensitization and receptor internalization, which are associated with enhanced responses to the chemokine. Our increasing understanding of the mechanisms that account for the aberrant CXCL12/CXCR4-mediated responses is beginning to provide insight into the pathogenesis of the disorder. As a result we can expect to identify markers of the WHIM syndrome, as well as other disorders with WHIM-like features that are associated with dysfunctions of the CXCL12/CXCR4 axis.

scholarly journals Preferential involvement of CX chemokine receptor 4 and CX chemokine ligand 12 in T-Cell migration toward melanoma cells

2006 ◽  
Vol 5 (10) ◽  
pp. 1304-1312 ◽  
Author(s):  
Tianqian Zhang ◽  
Rajasekharan Somasundaram ◽  
Carol Berking ◽  
Laura Caputo ◽  
Patricia Van Belle ◽  
...  
Keyword(s):  
Cell Migration ◽  
T Cell ◽  
Chemokine Receptor ◽  
Melanoma Cells ◽  
T Cell Migration ◽  
Chemokine Ligand ◽  
Chemokine Receptor 4

Insights into the binding modes of CC chemokine receptor 4 (CCR4) inhibitors: a combined approach involving homology modelling, docking, and molecular dynamics simulation studies

2015 ◽  
Vol 11 (2) ◽  
pp. 618-634 ◽  
Author(s):  
Changdev G. Gadhe ◽  
Mi-hyun Kim
Keyword(s):  
Chemokine Receptor ◽  
Cell Lymphoma ◽  
Homology Modelling ◽  
Vital Role ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Binding Modes ◽  
Cc Chemokine ◽  
Chemokine Receptor 4 ◽  
G Protein Coupled

CC chemokine receptor 4 (CCR4), a G protein-coupled receptor (GPCR), plays a vital role in the progression of asthma, T-cell lymphoma, inflammation, and Alzheimer's disease.

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