Publications by authors named "Philip M Murphy"

149 Publications

Obituary for Prof. Dr. Ulrich Siebenlist.

Biomedicines 2021 Mar 1;9(3). Epub 2021 Mar 1.

Laboratory of Molecular Immunology, NIAID, NIH, Bethesda, MD 20892, USA.

Ulrich Siebenlist, Ph [...].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines9030244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000846PMC
March 2021

Ulrich Siebenlist (1951-2020).

Immunity 2021 Mar;54(3):391-392

Laboratory of Immune Systems Biology, NIAID, NIH, Bethesda, MD, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2021.02.009DOI Listing
March 2021

Protean Regulation of Leukocyte Function by Nuclear Lamins.

Trends Immunol 2021 Apr 27;42(4):323-335. Epub 2021 Feb 27.

Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), Rockville, MD 20892, USA. Electronic address:

The leukocyte nucleus must be sufficiently elastic to squeeze through tissue barriers during migration, but not so collapsible as to risk damaging chromatin. The proper balance is struck in part by the composition of the nuclear lamina, a flexible meshwork composed mainly of intermediate filaments woven from type A and type B lamin proteins, that is located subjacent to the inner nuclear membrane. There is now increasing evidence that, in addition to influencing nuclear shape and stiffness and cell migration, lamins and lamin-interacting proteins may also interact functionally with chromatin to influence leukocyte gene expression, differentiation, and effector function, including T cell differentiation, B cell somatic hypermutation, and the formation of neutrophil extracellular traps (NETosis).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.it.2021.02.005DOI Listing
April 2021

Chemokine Regulation During Epidemic Coronavirus Infection.

Front Pharmacol 2020 4;11:600369. Epub 2021 Feb 4.

Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, United States.

SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus-2) is the third coronavirus to emerge as a cause of severe and frequently fatal pneumonia epidemics in humans, joining SARS-CoV and MERS-CoV (Middle East Respiratory Syndrome-coronavirus). As with many infectious diseases, the immune response to coronavirus infection may act as a double-edged sword: necessary for promoting antiviral host defense, but, if not appropriately regulated, also able to incite life-threatening immunopathology. Key immunoregulatory mediators include the chemokines, a large family of leukocyte chemoattractants that coordinate leukocyte infiltration, positioning and activation in infected tissue by acting at specific G protein-coupled receptors. Here, we compare the involvement of chemokines and chemokine receptors during infection with the three epidemic coronaviruses and discuss their potential value as biomarkers and targets for therapeutic development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.600369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890195PMC
February 2021

Structural and functional analysis of Ccr1l1, a Rodentia-restricted eosinophil-selective chemokine receptor homologue.

J Biol Chem 2021 Feb 3:100373. Epub 2021 Feb 3.

Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Bethesda, Maryland, USA. Electronic address:

Mouse Ccr1l1 (Ccr1-like 1) encodes an orphan G protein-coupled receptor (GPCR) with highest homology to the inflammatory and highly promiscuous chemokine receptors Ccr1 and Ccr3 (70 and 50% amino acid identity, respectively). Ccr1l1 was first cloned in 1995, yet current knowledge of this putative chemokine receptor is limited to its gene organization and chromosomal localization. Here we report that Ccr1l1 is a Rodentia-specific gene selectively expressed in eosinophils. However, eosinophil phenotypes, development and responsiveness to chemokines were all normal in naïve Ccr1l1 knockout mice. We demonstrate for the first time that recombinant Ccr1l1 is expressed on the plasma membrane of transfected cells and contains an extracellular N-terminus and an intracellular C-terminus, consistent with GPCR topology. Using receptor internalization, β-arrestin recruitment, calcium flux and chemotaxis assays, we excluded all 37 available mouse chemokines, including Ccr1 ligands, and two viral chemokines as Ccr1l1 ligands, and demonstrated that mouse Ccr1, but not Ccr1l1, exhibits constitutive signaling activity. However, sequence analysis and structural modeling revealed that Ccr1l1 is well-equipped to act as a classical signaling GPCR, with N-terminal sulfotyrosines as the only signaling and chemokine-binding determinant absent in Ccr1l1. Hereof, we show that a sulfatable N-terminal Ccr1 Y residue is essential for chemotaxis and calcium responses induced by Ccl3 and Ccl9/10 but substituting the corresponding Ccr1l1 F residue with tyrosine failed to confer responsiveness to Ccr1 ligands. Although Ccr1l1 remains an extreme outlier in the chemokine receptor family, our study supports it might respond to unidentified mouse chemokine ligands in eosinophil-driven immune responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbc.2021.100373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949164PMC
February 2021

Leukocyte chemotactic receptor Fpr1 protects against aging-related posterior subcapsular cataract formation.

FASEB J 2021 Feb;35(2):e21315

Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Cataracts are a common consequence of aging; however, pathogenesis remains poorly understood. Here, we observed that after 3 months of age mice lacking the G protein-coupled leukocyte chemotactic receptor Fpr1 (N-formyl peptide receptor 1) began to develop bilateral posterior subcapsular cataracts that progressed to lens rupture and severe degeneration, without evidence of either systemic or local ocular infection or inflammation. Consistent with this, Fpr1 was detected in both mouse and human lens in primary lens epithelial cells (LECs), the only cell type present in the lens; however, expression was confined to subcapsular LECs located along the anterior hemispheric surface. To maximize translucency, LECs at the equator proliferate and migrate posteriorly, then differentiate into lens fiber cells by nonclassical apoptotic signaling, which results in loss of nuclei and other organelles, including mitochondria which are a rich source of endogenous N-formyl peptides. In this regard, denucleation and posterior migration of LECs were abnormal in lenses from Fpr1 mice, and direct stimulation of LECs with the prototypic N-formyl peptide agonist fMLF promoted apoptosis. Thus, Fpr1 is repurposed beyond its immunoregulatory role in leukocytes to protect against cataract formation and lens degeneration during aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.202002135RDOI Listing
February 2021

Bcl-3 suppresses differentiation of RORγt regulatory T cells.

Immunol Cell Biol 2021 Feb 1. Epub 2021 Feb 1.

Laboratory of Molecular Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Regulatory T cells (Tregs) exert inhibitory function under various physiological conditions and adopt diverse characteristics following environmental cues. Multiple subsets of Tregs expressing master transcription factors of helper T cells such as RORγt, T-bet, Gata3 and PPARγ have been characterized, but the molecular mechanism governing the differentiation of these subsets remains largely unknown. Here we report that the atypical IκB protein family member Bcl-3 suppresses RORγt Treg accumulation. The suppressive effect of Bcl-3 was particularly evident in the mouse immune tolerance model of anti-CD3 therapy. Using conditional knockout mice, we illustrate that loss of Bcl-3 specifically in Tregs was sufficient to boost RORγt Treg formation and resistance of mice to dextran sulfate sodium-induced colitis. We further demonstrate the suppressive effect of Bcl-3 on RORγt Treg differentiation in vitro. Our results reveal a novel role of nuclear factor-kappa B signaling pathways in Treg subset differentiation that may have clinical implications in immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imcb.12441DOI Listing
February 2021

The NF-κB regulator Bcl-3 restricts terminal differentiation and promotes memory cell formation of CD8+ T cells during viral infection.

PLoS Pathog 2021 Jan 28;17(1):e1009249. Epub 2021 Jan 28.

Immune Activation Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

Bcl-3 is an atypical member of the IκB family that acts in the nucleus to modulate transcription of many NF-κB targets in a highly context-dependent manner. Accordingly, complete Bcl-3-/- mice have diverse defects in both innate and adaptive immune responses; however, direct effects of Bcl-3 action in individual immune cell types have not been clearly defined. Here, we document a cell-autonomous role for Bcl-3 in CD8+ T cell differentiation during the response to lymphocytic choriomeningitis virus infection. Single-cell RNA-seq and flow cytometric analysis of virus-specific Bcl3-/- CD8+ T cells revealed that differentiation was skewed towards terminal effector cells at the expense of memory precursor effector cells (MPECs). Accordingly, Bcl3-/- CD8+ T cells exhibited reduced memory cell formation and a defective recall response. Conversely, Bcl-3-overexpression in transgenic CD8+ T cells enhanced MPEC formation but reduced effector cell differentiation. Together, our results establish Bcl-3 as an autonomous determinant of memory/terminal effector cell balance during CD8+ T cell differentiation in response to acute viral infection. Our results provide proof-of-principle for targeting Bcl-3 pharmacologically to optimize adaptive immune responses to infectious agents, cancer cells, vaccines and other stimuli that induce CD8+ T cell differentiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1009249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872245PMC
January 2021

Correction to: TREC Screening for WHIM Syndrome.

J Clin Immunol 2021 Apr;41(3):629-630

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-021-00976-xDOI Listing
April 2021

Aberrant type 1 immunity drives susceptibility to mucosal fungal infections.

Science 2021 01;371(6526)

Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, USA.

Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)- and signal transducer and activator of transcription 1 (STAT1)-dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)-STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell-dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aay5731DOI Listing
January 2021

TREC Screening for WHIM Syndrome.

J Clin Immunol 2021 Apr 7;41(3):621-628. Epub 2021 Jan 7.

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Purpose: T cell receptor excision circle (TREC) quantification is a recent addition to newborn screening (NBS) programs and is intended to identify infants with severe combined immunodeficiencies (SCID). However, other primary immunodeficiency diseases (PID) have also been identified as the result of TREC screening. We recently reported a newborn with a low TREC level on day 1 of life who was diagnosed with WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome, a non-SCID primary immunodeficiency caused by mutations in the chemokine receptor CXCR4.

Methods: We have now retrospectively reviewed the birth and clinical histories of all known WHIM infants born after the implementation of NBS for SCID.

Results: We identified six infants with confirmed WHIM syndrome who also had TREC quantification on NBS. Three of the six WHIM infants had low TREC levels on NBS. All six patients were lymphopenic but only one infant had a T cell count below 1,500 cells/μL. The most common clinical manifestation was viral bronchiolitis requiring hospitalization. One infant died of complications related to Tetralogy of Fallot, a known WHIM phenotype.

Conclusion: The results suggest that WHIM syndrome should be considered in the differential diagnosis of newborns with low NBS TREC levels.

Trial Registration: Not applicable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-020-00921-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925426PMC
April 2021

Editorial: Atypical Functions of Leukocyte Chemoattractant Receptors.

Front Immunol 2020 9;11:596902. Epub 2020 Oct 9.

Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.596902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581779PMC
October 2020

Chromoanasynthesis as a cause of Jacobsen syndrome.

Am J Med Genet A 2020 11 25;182(11):2533-2539. Epub 2020 Aug 25.

Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.

Jacobsen syndrome (MIM #147791) is a rare multisystem genomic disorder involving craniofacial abnormalities, intellectual disability, other neurodevelopmental defects, and terminal truncation of chromosome 11q, typically deleting ~170 to >340 genes. We describe the first case of Jacobsen syndrome caused by congenital chromoanasynthesis, an extreme form of complex chromosomal rearrangement. Six duplications and five deletions occurred on one copy of chromosome 11q with microhomology signatures in the breakpoint junctions, indicating an all-at-once replication-based rearrangement mechanism in a gametocyte or early post-zygotic cell. Eighteen genes were deleted from the Jacobsen region, including KIRREL3, which is associated with intellectual disability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61824DOI Listing
November 2020

Absence of mucosal-associated invariant T cells in a person with a homozygous point mutation in .

Sci Immunol 2020 07;5(49)

Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.

The role unconventional T cells play in protective immunity in humans is unclear. Mucosal-associated invariant T (MAIT) cells are an unconventional T cell subset restricted to the antigen-presenting molecule MR1. Here, we report the discovery of a patient homozygous for a rare Arg31His (R9H in the mature protein) mutation in MR1 who has a history of difficult-to-treat viral and bacterial infections. MR1 was unable to present the potent microbially derived MAIT cell stimulatory ligand. The MR1 crystal structure revealed that the stimulatory ligand cannot bind due to the mutation lying within, and causing structural perturbation to, the ligand-binding domain of MR1. While MR1 could bind and be up-regulated by a MAIT cell inhibitory ligand, the patient lacked circulating MAIT cells. This shows the importance of the stimulatory ligand for MAIT cell selection in humans. The patient had an expanded γδ T cell population, indicating a compensatory interplay between these unconventional T cell subsets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciimmunol.abc9492DOI Listing
July 2020

A Critical Role of Formyl Peptide Receptors in Host Defense against .

J Immunol 2020 05 27;204(9):2464-2473. Epub 2020 Mar 27.

Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702;

Formyl peptide receptors (FPRs, mouse Fprs) belong to the G protein-coupled receptor superfamily and mediate phagocyte migration in response to bacteria- and host-derived chemoattractants; however, knowledge about their in vivo roles in bacterial pathogenesis is limited. In this study, we investigated the role of Fpr1 and Fpr2 in host defense against infection. In vitro, we found that supernatants from cultures induced chemotaxis of wild-type (WT) mouse bone marrow-derived neutrophils and that the activity was significantly reduced in cells genetically deficient in either Fpr1 or Fpr2 and was almost absent in cells lacking both receptors. Consistent with this, supernatants induced chemotaxis and MAPK phosphorylation in HEK293 cells expressing either recombinant Fpr1 or Fpr2 but not untransfected parental cells. WT bone marrow -derived neutrophils could actively phagocytose and kill , whereas both activities were diminished in cells lacking Fpr1 or Fpr2; again, an additive effect was observed in cells lacking both receptors. In vivo, Fpr1 and Fpr2 deficiency resulted in reduced recruitment of neutrophils in the liver and peritoneal cavity of mice infected with inactivated Moreover, and mice had significantly increased mortality compared with WT mice after i.p. challenge with a virulent clinical isolate. These results indicate a critical role of Fprs in host defense against infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1900430DOI Listing
May 2020

Discovery of several thousand highly diverse circular DNA viruses.

Elife 2020 02 4;9. Epub 2020 Feb 4.

Lab of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, United States.

Although millions of distinct virus species likely exist, only approximately 9000 are catalogued in GenBank's RefSeq database. We selectively enriched for the genomes of circular DNA viruses in over 70 animal samples, ranging from nematodes to human tissue specimens. A bioinformatics pipeline, Cenote-Taker, was developed to automatically annotate over 2500 complete genomes in a GenBank-compliant format. The new genomes belong to dozens of established and emerging viral families. Some appear to be the result of previously undescribed recombination events between ssDNA and ssRNA viruses. In addition, hundreds of circular DNA elements that do not encode any discernable similarities to previously characterized sequences were identified. To characterize these 'dark matter' sequences, we used an artificial neural network to identify candidate viral capsid proteins, several of which formed virus-like particles when expressed in culture. These data further the understanding of viral sequence diversity and allow for high throughput documentation of the virosphere.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.51971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000223PMC
February 2020

Mouse Cytomegalovirus Differentially Exploits Cell Surface Glycosaminoglycans in a Cell Type-Dependent and MCK-2-Independent Manner.

Viruses 2019 12 27;12(1). Epub 2019 Dec 27.

Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Many viruses initiate interaction with target cells by binding to cell surface glycosaminoglycans (GAGs). Heparan sulfate (HS) appears to be particularly important in fibroblasts, epithelial cells and endothelial cells, where it represents the dominant GAG. How GAGs influence viral infectivity in HS-poor target cells such as macrophages has not been clearly defined. Here, we show that mouse cytomegalovirus (MCMV) targets HS in susceptible fibroblasts and cultured salivary gland acinar cells (SGACs), but not in macrophage cell lines and primary bone marrow-derived macrophages, where chondroitin sulfate was the dominant virus-binding GAG. MCK-2, an MCMV-encoded GAG-binding chemokine that promotes infection of macrophages as part of a gH/gL/MCK-2 entry complex, was dispensable for MCMV attachment to the cell surface and for direct infection of SGACs. Thus, MCMV tropism for target cells is markedly influenced by differential GAG expression, suggesting that the specificity of anti-GAG peptides now under development as HCMV therapeutics may need to be broadened for effective application as anti-viral agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/v12010031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019585PMC
December 2019

Low-level Cxcr4-haploinsufficient HSC engraftment is sufficient to correct leukopenia in WHIM syndrome mice.

JCI Insight 2019 12 19;4(24). Epub 2019 Dec 19.

Molecular Signaling Section, Laboratory of Molecular Immunology, and.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome immunodeficiency is caused by autosomal dominant gain-of-function mutations in chemokine receptor CXCR4. Patient WHIM-09 was spontaneously cured by chromothriptic deletion of 1 copy of 164 genes, including the CXCR4WHIM allele, presumably in a single hematopoietic stem cell (HSC) that repopulated HSCs and the myeloid lineage. Testing the specific contribution of CXCR4 hemizygosity to her cure, we previously demonstrated enhanced engraftment of Cxcr4+/o HSCs after transplantation in WHIM (Cxcr4+/w) model mice, but the potency was not quantitated. We now report graded-dose competitive transplantation experiments using lethally irradiated Cxcr4+/+ recipients in which mixed BM cells containing approximately 5 Cxcr4+/o HSCs and a 100-fold excess of Cxcr4+/w HSCs achieved durable 50% Cxcr4+/o myeloid and B cell chimerism in blood and approximately 20% Cxcr4+/o HSC chimerism in BM. In Cxcr4+/o/Cxcr4+/w parabiotic mice, we observed 80%-100% Cxcr4+/o myeloid and lymphoid chimerism in the blood and 15% Cxcr4+/o HSC chimerism in BM from the Cxcr4+/w parabiont, which was durable after separation from the Cxcr4+/o parabiont. Thus, CXCR4 haploinsufficiency likely significantly contributed to the selective repopulation of HSCs and the myeloid lineage from a single chromothriptic HSC in WHIM-09. Moreover, the results suggest that WHIM allele silencing of patient HSCs is a viable gene therapy strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.132140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975255PMC
December 2019

Abnormal Newborn Screen in a WHIM Syndrome Infant.

J Clin Immunol 2019 11 6;39(8):839-841. Epub 2019 Sep 6.

Walter Reed National Military Medical Center, 13101 Conover Dr., Silver Spring, Bethesda, MD, 20902, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-019-00686-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868327PMC
November 2019

Case Report: Ocular toxoplasmosis in a WHIM syndrome immunodeficiency patient.

F1000Res 2019 2;8. Epub 2019 Jan 2.

Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.

A patient with WHIM syndrome immunodeficiency presented with sudden painless right eye blindness associated with advanced retinal and optic nerve damage. was detected by PCR in vitreous fluid but not serum.  The patient was treated with pyrimethamine/sulfadiazine for 6 weeks due to evidence of active ocular inflammation and then received prophylaxis with trimethoprim-sulfamethoxazole due to his immunosuppression.  Vision did not return; however, the infection did not spread to involve other sites.  Toxoplasmosis is rare in primary immunodeficiency disorders and is the first protozoan infection reported in WHIM syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12688/f1000research.16825.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587139PMC
June 2020

WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure.

J Clin Immunol 2019 08 16;39(6):532-556. Epub 2019 Jul 16.

Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.

WHIM syndrome is a rare combined primary immunodeficiency disease named by acronym for the diagnostic tetrad of warts, hypogammaglobulinemia, infections, and myelokathexis. Myelokathexis is a unique form of non-cyclic severe congenital neutropenia caused by accumulation of mature and degenerating neutrophils in the bone marrow; monocytopenia and lymphopenia, especially B lymphopenia, also commonly occur. WHIM syndrome is usually caused by autosomal dominant mutations in the G protein-coupled chemokine receptor CXCR4 that impair desensitization, resulting in enhanced and prolonged G protein- and β-arrestin-dependent responses. Accordingly, CXCR4 antagonists have shown promise as mechanism-based treatments in phase 1 clinical trials. This review is based on analysis of all 105 published cases of WHIM syndrome and covers current concepts, recent advances, unresolved enigmas and controversies, and promising future research directions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-019-00665-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698215PMC
August 2019

Plerixafor for the Treatment of WHIM Syndrome. Reply.

N Engl J Med 2019 04;380(16):e25

National Institute of Allergy and Infectious Diseases, Bethesda, MD

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMc1901646DOI Listing
April 2019

IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to .

Elife 2019 04 16;8. Epub 2019 Apr 16.

Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States.

Methicillin-resistant (MRSA) is a major hospital- and community-acquired pathogen, but the mechanisms underlying host-defense to MRSA remain poorly understood. Here, we investigated the role of IL-21 in this process. When administered intra-tracheally into wild-type mice, IL-21 induced granzymes and augmented clearance of pulmonary MRSA but not when neutrophils were depleted or a granzyme B inhibitor was added. Correspondingly, IL-21 induced MRSA killing by human peripheral blood neutrophils. Unexpectedly, however, basal MRSA clearance was also enhanced when IL-21 signaling was blocked, both in KO mice and in wild-type mice injected with IL-21R-Fc fusion-protein. This correlated with increased type I interferon and an IFN-related gene signature, and indeed anti-IFNAR1 treatment diminished MRSA clearance in these animals. Moreover, we found that IFNβ induced granzyme B and promoted MRSA clearance in a granzyme B-dependent fashion. These results reveal an interplay between IL-21 and type I IFN in the innate immune response to MRSA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.45501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504231PMC
April 2019

Low-Level Parasite Persistence Drives Vasculitis and Myositis in Skeletal Muscle of Mice Chronically Infected with Trypanosoma cruzi.

Infect Immun 2019 06 21;87(6). Epub 2019 May 21.

Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

In chronic infection, the cause of Chagas disease, life-threatening inflammatory diseases develop over time in the heart, esophagus, and colon of some patients. C57BL/6 mice infected with the myotropic Colombiana strain of model many of the immunological and parasitological features of human infection but succumb to chronic paralyzing myositis and skeletal muscle vasculitis, not cardiomyopathy or gastrointestinal disease. Here we show that T cell depletion in the chronic phase of this model increased tissue parasitism to acute-phase levels and induced neutrophilic skeletal muscle inflammation. Conversely, after daily treatment with the trypanocide benznidazole for 8 weeks during the chronic phase, viable parasites were no longer detectable, myositis completely resolved, vasculitis was ∼80% reduced, fibrosis was reduced, and myofiber morphology normalized. After the drug was discontinued, parasitism rebounded, and immunopathology recurred. The parasite load was statistically strongly correlated with the severity of inflammation. Thus, both T cell immunity and trypanocidal pharmacotherapy suppress to very low levels, but do not cure, infection, which is necessary and possibly sufficient to induce crippling chronic skeletal muscle myositis and vasculitis in the model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/IAI.00081-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529661PMC
June 2019

Hematopoietic chimerism and donor-specific skin allograft tolerance after non-genotoxic CD117 antibody-drug-conjugate conditioning in MHC-mismatched allotransplantation.

Nat Commun 2019 02 6;10(1):616. Epub 2019 Feb 6.

Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, 20892, MD, USA.

Hematopoietic chimerism after allogeneic bone marrow transplantation may establish a state of donor antigen-specific tolerance. However, current allotransplantation protocols involve genotoxic conditioning which has harmful side-effects and predisposes to infection and cancer. Here we describe a non-genotoxic conditioning protocol for fully MHC-mismatched bone marrow allotransplantation in mice involving transient immunosuppression and selective depletion of recipient hematopoietic stem cells with a CD117-antibody-drug-conjugate (ADC). This protocol resulted in multilineage, high level (up to 50%), durable, donor-derived hematopoietic chimerism after transplantation of 20 million total bone marrow cells, compared with ≤ 2.1% hematopoietic chimerism from 50 million total bone marrow cells without conditioning. Moreover, long-term survival of bone marrow donor-type but not third party skin allografts is achieved in CD117-ADC-conditioned chimeric mice without chronic immunosuppression. The only observed adverse event is transient elevation of liver enzymes in the first week after conditioning. These results provide proof-of-principle for CD117-ADC as a non-genotoxic, highly-targeted conditioning agent in allotransplantation and tolerance protocols.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-08202-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365540PMC
February 2019

Plerixafor for the Treatment of WHIM Syndrome.

N Engl J Med 2019 01;380(2):163-170

From the Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (D.H.M., D.V., E.C., Q.L., P.M.M.), the Laboratories of Cellular Oncology (D.V.P., C.B.B.) and Pathology (S.P.), National Cancer Institute, the Department of Laboratory Medicine, Clinical Center (K.R.C.), the National Institute of Dental and Craniofacial Research (P.J.G.), and the National Institute on Deafness and Other Communication Disorders (D.A.B.), National Institutes of Health, and Kozloff and Trout MDs (H.H.T.), Bethesda, MD; the Infectious Diseases Unit and Primary Immunodeficiencies Unit, Hospital Dona Estefânia, Pediatric University Hospital (J.F.N.), and Centro de Imunodeficiências Primárias, Academic Medical Center of Lisbon (S.L.S.), Lisbon, Portugal; and the University of Chicago Medical Center, Chicago (E.A.B., E.M.L.).

WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), a primary immunodeficiency disorder involving panleukopenia, is caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Myelokathexis is neutropenia caused by neutrophil retention in bone marrow. Patients with WHIM syndrome are often treated with granulocyte colony-stimulating factor (G-CSF), which can increase neutrophil counts but does not affect cytopenias other than neutropenia. In this investigator-initiated, open-label study, three severely affected patients with WHIM syndrome who could not receive G-CSF were treated with low-dose plerixafor, a CXCR4 antagonist, for 19 to 52 months. Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus-associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly. Adverse events were mainly infections attributable to the underlying immunodeficiency. One patient died from complications of elective reconstructive surgery. (Funded by the National Institutes of Health.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1808575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425947PMC
January 2019

Adaptive Immunodeficiency in WHIM Syndrome.

Int J Mol Sci 2018 Dec 20;20(1). Epub 2018 Dec 20.

Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.

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 -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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20010003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337672PMC
December 2018

WHIM syndrome: Immunopathogenesis, treatment and cure strategies.

Immunol Rev 2019 01;287(1):91-102

Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

WHIM syndrome is a rare, autosomal dominant immunodeficiency which is named for the four key manifestations: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. It results from heterozygous gain-of-function mutations in the chemokine receptor CXCR4 which is widely expressed on leukocytes and has profound influences on immune system homeostasis and organogenesis. New treatments for the disease using drugs to reduce CXCR4 function are excellent examples of precision medicine. Since CXCR4 and its ligand CXCL12 play an important role in a variety of infectious, inflammatory, autoimmune, and malignant diseases, the study of WHIM syndrome provides important insights into both the physiologic and disease roles of these molecules.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imr.12719DOI Listing
January 2019

Metagenomic Discovery of 83 New Human Papillomavirus Types in Patients with Immunodeficiency.

mSphere 2018 12 12;3(6). Epub 2018 Dec 12.

Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, Maryland, USA.

Several immunodeficiencies are associated with high susceptibility to persistent and progressive human papillomavirus (HPV) infection leading to a wide range of cutaneous and mucosal lesions. However, the HPV types most commonly associated with such clinical manifestations in these patients have not been systematically defined. Here, we used virion enrichment, rolling circle amplification, and deep sequencing to identify circular DNA viruses present in skin swabs and/or wart biopsy samples from 48 patients with rare genetic immunodeficiencies, including patients with warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome, or epidermodysplasia verruciformis (EV). Their profiles were compared with the profiles of swabs from 14 healthy adults and warts from 6 immunologically normal children. Individual patients were typically infected with multiple HPV types; up to 26 different types were isolated from a single patient (multiple anatomical sites, one time point). Among these, we identified the complete genomes of 83 previously unknown HPV types and 35 incomplete genomes representing possible additional new types. HPV types in the genus were common in WHIM patients, whereas EV patients mainly shed HPVs from the genus Preliminary evidence based on three WHIM patients treated with plerixafor, a leukocyte mobilizing agent, suggest that longer-term therapy may correlate with decreased HPV diversity and increased predominance of HPV types associated with childhood skin warts. Although some members of the viral family cause benign skin warts (papillomas), many human papillomavirus (HPV) infections are not associated with visible symptoms. For example, most healthy adults chronically shed () virions from apparently healthy skin surfaces. To further explore the diversity of papillomaviruses, we performed viromic surveys on immunodeficient individuals suffering from florid skin warts. Our results nearly double the number of known HPV types and suggest that WHIM syndrome patients are uniquely susceptible to HPV-associated skin warts. Preliminary results suggest that treatment with the drug plerixafor may promote resolution of the unusual HPV skin warts observed in WHIM patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSphereDirect.00645-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291628PMC
December 2018

Chemokine Subversion by Human Herpesviruses.

J Innate Immun 2018 30;10(5-6):465-478. Epub 2018 Aug 30.

Inflammation, Repair and Development Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United

Viruses use diverse molecular mechanisms to exploit and evade the immune response. Herpesviruses, in particular, encode functional chemokine and chemokine receptor homologs pirated from the host, as well as secreted chemokine-binding proteins with unique structures. Multiple functions have been described for herpesvirus chemokine components, including attraction of target cells, blockade of leukocyte migration, and modulation of gene expression and cell entry by the virus. Here we review current concepts about how human herpesvirus chemokines, chemokine receptors, and chemokine-binding proteins may be used to shape a proviral state in the host.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000492161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289880PMC
October 2019