Vadim I Pivniouk

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• Pivniouk, V. I., Gimenes-Junior, J. A., Ezeh, P., Michael, A., Pivniouk, O. N., Abidov, A., Anderson, D., Gozdz, J., DeVries, A., Martinez, F., Pasquali, C., & Vercelli, D. (2021). Airway administration of OM-85, a bacterial lysate, blocks experimental asthma by targeting dendritic cells and the epithelium/IL-33/ILC2 axis. The Journal of Allergy and Clinical Immunology. doi:10.1016/j.jaci.2021.09.013
• Pivniouk, V. I., Pivniouk, O., DeVries, A., Uhrlaub, J. L., Michael, A., Pivniouk, D., VanLinden, S. R., Conway, M. Y., Hahn, S., Malone, S. P., Ezeh, P., Churko, J., Anderson, D., Kraft, M., Nikolich-Zugich, J., & Vercelli, D. (2021). The OM-85 bacterial lysate inhibits SARS-CoV-2 infection of epithelial cells by downregulating SARS-CoV-2 receptor expression. The Journal of Allergy and Clinical Immunology. doi:10.1016/j.jaci.2021.11.019
• Stein, M. M., Hrusch, C. L., Gozdz, J., Igartua, C., Pivniouk, V., Murray, S. E., Ledford, J. G., Marques dos Santos, M., Anderson, R. L., Metwali, N., Neilson, J. W., Maier, R. M., Gilbert, J. A., Holbreich, M., Thorne, P. S., Martinez, F. D., von Mutius, E., Vercelli, D., Ober, C., & Sperling, A. I. (2016). Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children. The New England journal of medicine, 375(5), 411-21.
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  The Amish and Hutterites are U.S. agricultural populations whose lifestyles are remarkably similar in many respects but whose farming practices, in particular, are distinct; the former follow traditional farming practices whereas the latter use industrialized farming practices. The populations also show striking disparities in the prevalence of asthma, and little is known about the immune responses underlying these disparities.
• Lantz, R. C., Chau, B., Sarihan, P., Witten, M. L., Pivniouk, V. I., & Chen, G. J. (2009). In utero and postnatal exposure to arsenic alters pulmonary structure and function. Toxicology and applied pharmacology, 235(1), 105-13.
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  In addition to cancer endpoints, arsenic exposures can also lead to non-cancerous chronic lung disease. Exposures during sensitive developmental time points can contribute to the adult disease. Using a mouse model, in utero and early postnatal exposures to arsenic (100 ppb or less in drinking water) were found to alter airway reactivity to methacholine challenge in 28 day old pups. Removal of mice from arsenic exposure 28 days after birth did not reverse the alterations in sensitivity to methacholine. In addition, adult mice exposed to similar levels of arsenic in drinking water did not show alterations. Therefore, alterations in airway reactivity were irreversible and specific to exposures during lung development. These functional changes correlated with protein and gene expression changes as well as morphological structural changes around the airways. Arsenic increased the whole lung levels of smooth muscle actin in a dose dependent manner. The level of smooth muscle mass around airways was increased with arsenic exposure, especially around airways smaller than 100 microm in diameter. This increase in smooth muscle was associated with alterations in extracellular matrix (collagen, elastin) expression. This model system demonstrates that in utero and postnatal exposure to environmentally relevant levels of arsenic can irreversibly alter pulmonary structure and function in the adults.
• Kettner, A., Kumar, L., Antón, I. M., Sasahara, Y., de la Fuente, M., Pivniouk, V. I., Falet, H., Hartwig, J. H., & Geha, R. S. (2004). WIP regulates signaling via the high affinity receptor for immunoglobulin E in mast cells. The Journal of experimental medicine, 199(3), 357-68.
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  Wiskott-Aldrich syndrome protein-interacting protein (WIP) stabilizes actin filaments and is important for immunoreceptor-mediated signal transduction leading to actin cytoskeleton rearrangement in T and B cells. Here we report a role for WIP in signaling pathways downstream of the high affinity receptor for immunoglobulin (Ig)E (FcepsilonRI) in mast cells. WIP-deficient bone marrow-derived mast cells (BMMCs) were impaired in their capacity to degranulate and secrete interleukin 6 after FcepsilonRI ligation. Calcium mobilization, phosphorylation of Syk, phospholipase C-g2, and c-Jun NH2-terminal kinase were markedly decreased in WIP-deficient BMMCs. WIP was found to associate with Syk after FcepsilonRI ligation and to inhibit Syk degradation as evidenced by markedly diminished Syk levels in WIP-deficient BMMCs. WIP-deficient BMMCs exhibited no apparent defect in their subcortical actin network and were normal in their ability to form protrusions when exposed to an IgE-coated surface. However, the kinetics of actin changes and the cell shape changes that follow FcepsilonRI signaling were altered in WIP-deficient BMMCs. These results suggest that WIP regulates FcepsilonRI-mediated mast cell activation by regulating Syk levels and actin cytoskeleton rearrangement.
• Kettner, A., Pivniouk, V., Kumar, L., Falet, H., Lee, J. S., Mulligan, R., & Geha, R. S. (2003). Structural requirements of SLP-76 in signaling via the high-affinity immunoglobulin E receptor (Fc epsilon RI) in mast cells. Molecular and cellular biology, 23(7), 2395-406.
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  The adapter SLP-76 plays an essential role in Fc epsilon RI signaling, since SLP-76(-/-) bone marrow-derived mast cells (BMMC) fail to degranulate and release interleukin-6 (IL-6) following Fc epsilon RI ligation. To define the role of SLP-76 domains and motifs in Fc epsilon RI signaling, SLP-76(-/-) BMMC were retrovirally transduced with SLP-76 and SLP-76 mutants. The SLP-76 N-terminal and Gads binding domains, but not the SH2 domain, were critical for Fc epsilon RI-mediated degranulation and IL-6 secretion, whereas all three domains are essential for T-cell proliferation following T-cell receptor (TCR) ligation. Unexpectedly, the three tyrosine residues in SLP-76 critical for TCR signaling, Y112, Y128, and Y145, were not essential for IL-6 secretion, but were required for degranulation and mitogen-activated protein kinase activation. Furthermore, a Y112/128F SLP-76 mutant, but not a Y145F mutant, strongly reconstituted mast cell degranulation, suggesting a critical role for Y145 in Fc epsilon RI-mediated exocytosis. These results point to important differences in the function of SLP-76 between T cells and mast cells.
• Pivniouk, V. I., Snapper, S. B., Kettner, A., Alenius, H., Laouini, D., Falet, H., Hartwig, J., Alt, F. W., & Geha, R. S. (2003). Impaired signaling via the high-affinity IgE receptor in Wiskott-Aldrich syndrome protein-deficient mast cells. International immunology, 15(12), 1431-40.
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  Wiskott-Aldrich syndrome protein (WASP) is the product of the gene deficient in boys with X-linked Wiskott-Aldrich syndrome. We assessed the role of WASP in signaling through the high-affinity IgE receptor (FcepsilonRI) using WASP-deficient mice. IgE-dependent degranulation and cytokine secretion were markedly diminished in bone marrow-derived mast cells from WASP-deficient mice. Upstream signaling events that include FcepsilonRI-triggered total protein tyrosine phosphorylation, and protein tyrosine phosphorylation of FcepsilonRIbeta and Syk were not affected by WASP deficiency. However, tyrosine phosphorylation of phospholipase Cgamma and Ca(2+) mobilization were diminished. IgE-dependent activation of c-Jun N-terminal kinase, cell spreading and redistribution of cellular F-actin in mast cells were reduced in the absence of WASP. We conclude that WASP regulates FcepsilonRI-mediated granule exocytosis, cytokine production and cytoskeletal changes in mast cells.
• Jabara, H., Laouini, D., Tsitsikov, E., Mizoguchi, E., Bhan, A., Castigli, E., Dedeoglu, F., Pivniouk, V., Brodeur, S., & Geha, R. (2002). The binding site for TRAF2 and TRAF3 but not for TRAF6 is essential for CD40-mediated immunoglobulin class switching. Immunity, 17(3), 265-76.
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  To define the role of TRAF proteins in CD40-dependent isotype switching in B cells, we introduced wild-type (WT) and mutant CD40 transgenes that lacked the binding motifs for TRAF6 (CD40deltaTRAF6), TRAF2 and TRAF3 (CD40deltaTRAF2/3), or both (CD40deltaTRAFs) into B cells of CD40(-/-) mice. The in vivo isotype switch defect in CD40(-/-) mice was fully corrected by WT and CD40deltaTRAF6, partially by CD40deltaTRAF2/3, and not at all by CD40deltaTRAFs transgenes. CD40-mediated isotype switching, proliferation, and activation of p38, JNK, and NFkappaB in B cells were normal in WT and CD40deltaTRAF6 mice, severely impaired in CD40deltaTRAF2/3, and absent in CD40deltaTRAFs mice. These results suggest that binding to TRAF2 and/or TRAF3 but not TRAF6 is essential for CD40 isotype switching and activation in B cells.
• Kumar, L., Pivniouk, V., de la Fuente, M. A., Laouini, D., & Geha, R. S. (2002). Differential role of SLP-76 domains in T cell development and function. Proceedings of the National Academy of Sciences of the United States of America, 99(2), 884-9.
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  The adapter SLP-76 is essential for thymocyte development. SLP-76(-/-) mice were reconstituted with SLP-76 deletion mutant transgenes to examine the role of SLP-76 domains in T cell development and function. The N-terminal domain deletion mutant completely failed to restore thymocyte development. Mice reconstituted with Gads-binding site and SH2 domain deletion mutants had decreased thymic cellularity, impaired transition from double to single positive thymocytes, and decreased numbers of mature T cells in the spleen. Calcium mobilization and extracellular signal-regulated protein kinase activation were decreased in the Gads-binding site mutant but almost normal in the SH2 domain mutant. T cells from both mutants failed to proliferate following T cell antigen receptor ligation. Nevertheless, both mutants mounted partial cutaneous hypersensitivity responses and normal T cell dependent IgG1 antibody responses. These results indicate differential roles for SLP-76 domains in T cell development, proliferation and effector functions.
• Bonilla, F. A., Fujita, R. M., Pivniouk, V. I., Chan, A. C., & Geha, R. S. (2000). Adapter proteins SLP-76 and BLNK both are expressed by murine macrophages and are linked to signaling via Fcgamma receptors I and II/III. Proceedings of the National Academy of Sciences of the United States of America, 97(4), 1725-30.
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  The SLP-76 (Src homology 2 domain-containing leukocyte protein of 76 kDa) adapter protein is expressed in T cells and myeloid cells, whereas its homologue BLNK (B cell linker protein) is expressed in B cells. SLP-76 and BLNK link immunoreceptor tyrosine-based activation motif-containing receptors to signaling molecules that include phospholipase C-gamma, mitogen-activated protein kinases, and the GTPases Ras and Rho. SLP-76 plays a critical role in T cell receptor, FcvarepsilonRI and gpVI collagen receptor signaling, and participates in signaling via FcgammaR and killer cell inhibitory receptors. BLNK plays a critical role in B cell receptor signaling. We show that murine bone marrow-derived macrophages express both SLP-76 and BLNK. Selective ligation of FcgammaRI and FcgammaRII/III resulted in tyrosine phosphorylation of both SLP-76 and BLNK. SLP-76(-/-) bone marrow-derived macrophages display FcgammaR-mediated tyrosine phosphorylation of Syk, phospholipase C-gamma2, and extracellular signal regulated kinases 1 and 2, and normal FcgammaR-dependent phagocytosis. These data suggest that both SLP-76 and BLNK are coupled to FcgammaR signaling in murine macrophages.
• Falet, H., Barkalow, K. L., Pivniouk, V. I., Barnes, M. J., Geha, R. S., & Hartwig, J. H. (2000). Roles of SLP-76, phosphoinositide 3-kinase, and gelsolin in the platelet shape changes initiated by the collagen receptor GPVI/FcR gamma-chain complex. Blood, 96(12), 3786-92.
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  How platelet shape change initiated by a collagen-related peptide (CRP) specific for the GPVI/FcR gamma-chain complex (GPVI/FcR gamma-chain) is coupled to SLP-76, phosphoinositide (PI) 3-kinase, and gelsolin is reported. As shown by video microscopy, platelets rapidly round and grow dynamic filopodial projections that rotate around the periphery of the cell after they contact a CRP-coated surface. Lamellae subsequently spread between the projections. All the actin-driven shape changes require SLP-76 expression. SLP-76 is essential for the Ca(++) mobilization induced by CRP, whereas PI 3-kinase only modulates it. The extension of lamellae requires net actin assembly and an exposure of actin filament barbed ends downstream of PI 3-kinase. Gelsolin expression is also required for the extension of lamellae, but not for the formation of filopodia. Altogether, the data describe the role of SLP-76 in the platelet activation initiated by GPVI/FcR gamma-chain and the roles of PI 3-kinase and gelsolin in lamellae spreading. (Blood. 2000;96:3786-3792)
• Pivniouk, V. I., & Geha, R. S. (2000). The role of SLP-76 and LAT in lymphocyte development. Current opinion in immunology, 12(2), 173-8.
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  SLP-76 and LAT are two recently identified adapter proteins that are involved in the signal transduction cascade initiated by engagement of the TCR. The role of these two molecules in thymocyte development has become clearer following studies of gene targeted mice. The data indicate that SLP-76 and LAT are each critical for the expansion and differentiation of double-negative thymocytes and that SLP-76 is essential for allelic exclusion at the TCRbeta locus.
• Aifantis, I., Pivniouk, V. I., Gärtner, F., Feinberg, J., Swat, W., Alt, F. W., von Boehmer, H., & Geha, R. S. (1999). Allelic exclusion of the T cell receptor beta locus requires the SH2 domain-containing leukocyte protein (SLP)-76 adaptor protein. The Journal of experimental medicine, 190(8), 1093-102.
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  Signaling via the pre-T cell receptor (TCR) is required for the proliferative expansion and maturation of CD4(-)CD8(-) double-negative (DN) thymocytes into CD4(+)CD8(+) double-positive (DP) cells and for TCR-beta allelic exclusion. The adaptor protein SH2 domain-containing leukocyte protein (SLP)-76 has been shown to play a crucial role in thymic development, because thymocytes of SLP-76(-/-) mice are arrested at the CD25(+)CD44(-) DN stage. Here we show that SLP-76(-/-) DN thymocytes express the pre-TCR on their surfaces and that introduction of a TCR-alpha/beta transgene into the SLP-76(-/-) background fails to cause expansion of DN thymocytes or developmental progression to the DP stage. Moreover, analysis of TCR-beta rearrangement in SLP-76(-/-) TCR-transgenic mice or in single CD25(+)CD44(-) DN cells from SLP-76(-/-) mice indicates an essential role of SLP-76 in TCR-beta allelic exclusion.
• Pivniouk, V. I., Martin, T. R., Lu-Kuo, J. M., Katz, H. R., Oettgen, H. C., & Geha, R. S. (1999). SLP-76 deficiency impairs signaling via the high-affinity IgE receptor in mast cells. The Journal of clinical investigation, 103(12), 1737-43.
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  SLP-76 is an adapter protein expressed in T cells and myeloid cells that is a substrate for ZAP-70 and Syk. SLP-76-deficient mice exhibit a profound block in T-cell development. We found that although SLP-76 is expressed in mouse mast cells, SLP-76(-/-) mice have normal numbers of mast cells in their skin and bronchi. SLP-76(-/-) mice are resistant to IgE-mediated passive anaphylaxis. SLP-76(-/-) mice sensitized with IgE anti-dinitrophenyl (DNP) and then challenged with DNP-HSA developed only mild and transient tachycardia, failed to increase their plasma histamine level, and all survived the antigen challenge. Bone marrow-derived mast cells (BMMCs) from SLP76(-/-) mice failed to release beta-hexosaminidase and to secrete IL-6 after FcepsilonRI cross-linking. Tyrosine phosphorylation of phospholipase C-gamma1 (but not of Syk) and calcium mobilization in response to IgE cross-linking were reduced in SLP-76-deficient BMMCs. These results suggest that SLP-76 plays an important role in FcepsilonRI-mediated signaling in mast cells.
• Pivniouk, V., Tsitsikov, E., Swinton, P., Rathbun, G., Alt, F. W., & Geha, R. S. (1998). Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76. Cell, 94(2), 229-38.
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  The adaptor protein SLP-76 is expressed in T lymphocytes and myeloid cells and is a substrate for ZAP-70 and Syk. We generated a SLP-76 null mutation in mice by homologous recombination in embryonic stem cells to evaluate the role of SLP-76 in T cell development and activation. SLP-76-deficient mice exhibited subcutaneous and intraperitoneal hemorrhaging and impaired viability. Analysis of lymphoid cells revealed a profound block in thymic development with absence of double-positive CD4+8+ thymocytes and of peripheral T cells. This block could not be overcome by in vivo treatment with anti-CD3. V-D-J rearrangement of the TCRbeta locus was not obviously affected. B cell development was normal. These results indicate that SLP-76 collects all pre-TCR signals that drive the development and expansion of double-positive thymocytes.
• Kaĭgorodov, V. A., Ptitsyn, L. R., Pivniuk, V. I., Kondrat'eva, I. A., Al'tman, I. B., & Vasilov, R. G. (1996). [Expression of human IgE-binding factor (sCD23) in Escherichia coli cells]. Biulleten' eksperimental'noi biologii i meditsiny, 121(6), 690-4.
• Chelidze, L. K., Lebedin, I. S., Tsytsikov, E. N., Pivniuk, V. I., & Vasilov, R. G. (1994). [Effect of recombinant interleukin-4 on immunoglobulin synthesis in cultured human peripheral blood mononuclear cells]. Biulleten' eksperimental'noi biologii i meditsiny, 118(10), 426-8.
• Pivniuk, V. I., Chelidze, L. K., Martsen, E. O., Tsytsikov, E. N., & Vasilov, R. G. (1994). [Low affinity human IgE receptor: cloning cDNA from B-lymphocytes of cell line 1B and study of its expression in peripheral blood B-cells]. Molekuliarnaia biologiia, 28(4), 840-5.
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  Previously, the cDNA coding for human low-affinity receptor for IgE (FcERII/CD23) was cloned by three independent groups. Using oligonucleotide probes corresponding to the published cDNA sequence of CD23, we have isolated cDNA clones encoding FcERII from the cDNA library of B-lymphoblastoid cell line 1B obtained in our laboratory. Cloned nucleotide sequences of FcERII were shown to be identical to those from the RPMI8866 cell line. Using a DNA fragment containing the full-length cDNA copy of CD23 as a probe, CD23 expression in highly purified peripheral blood B lymphocytes was shown to be induced by recombinant human IL4 in a clearly dose-dependent manner.
• Vasilov, R. G., Chelidze, L. K., Lebedin, I. S., Chukanov, S. V., Tsytsikov, E. N., & Pivniuk, V. I. (1994). [Interconnection between expression of surface markers and synthesis of immunoglobulin E by peripheral blood mononuclear cells under the effect of recombinant interleukin-4]. Biulleten' eksperimental'noi biologii i meditsiny, 118(10), 421-5.

Proceedings Publications

• Pivniouk, V. I., Rosenbaum, D., Herrell, A., Pivniouk, O., Rafaels, N., Mathias, R., Barnes, K., & Vercelli, D. (2016, May). Differential regulation of human and mouse IL33 expression in the lungs of human IL33 BAC transgenic mice.. In AAI Annual Meeting - Immunology 2016.
• Pivniouk, V. I., Rosenbaum, D., Pivniouk, O., & Vercelli, D. (2016, May). Downregulation of human IL4 and IL13 expression by CRISPR/Cas9-mediated deletion of DNase I hypersensitive site HS11/12 from a transgenic human Th2 cytokine locus. In AAI Annual Meeting - Immunology 2016.
• Pivniouk, V. I., Pivniouk, V. I., Rosenbaum, D., Rosenbaum, D., Aryanpur, P., Aryanpur, P., Pivniouk, O., Pivniouk, O., Stern, D., Stern, D., Halonen, M., Halonen, M., Vercelli, D., & Vercelli, D. (2013, January). Asthma/allergy-associated single nucleotide polymorphisms (SNPs) in IL13 strongly dysregulate human IL4 expression and IgE production. In Keystone Symposium: Type 2 Immunity: Initiation, Maintenance, Homeostasis and Pathology.

Presentations

• Pivniouk, V. I., Hahn, S., Pivniouk, O., Michael, A. N., VanLinden, S. R., Banskar, S., Han, R., Ezeh, P., Malone, S. P., & Vercelli, D. (2023, October).

  Preventive but not Therapeutic Administration of a Bacterial Lysate Suppresses Experimental Allergic Asthma

  . 33rd Biennial Symposium of the Collegium Internationale Allergologicum. Montréal, Canada: Collegium Internationale Allergologicum.
• Pivniouk, V. I., Pivniouk, O., Uhrlaub, J. L., Molzahn, A., Kimura, H., Ledford, J., Kraft, M., Nikolich-Zugich, J. Z., & Vercelli, D. (2023).

  IL-13 protects epithelial cells from SARS-CoV-2 infection by inhibiting early ACE2-mediated events

  . Immunology2023, The AAI Annual Meeting. Washington, DC: AAI.
• Vercelli, D., Gilbert, J. A., Ober, C., von Mutius, E., Holbreich, M., Stein, M. M., Igartua, C., Pivniouk, V. I., Horner, A. N., Gimenes, Jr, J. A., Patil, K., Theriault, B., Gozdz, J., Sharma, A., & Honeker, L. K. (2019, May 17-22). Gut microbiota from Amish but not Hutterite pre-school children protect germ-free mice from experimental asthma. International Conference, American Thoracic Society. Dallas, TX.
• Pivniouk, V. I., Rosenbaum, D., Pivniouk, O., & Vercelli, D. (2016, July). Regulation of human Th2 cytokine expression: Combining BAC transgenesis with CRISPR/Cas9 genome editing. FASEB SRC: IgE and Allergy, 50 Years & Onward.

Poster Presentations

• Pivniouk, V. I., Banskar, S., Pivniouk, O., Ezeh, P., Ledford, J., Chu, H. W., Kraft, M., & Vercelli, D. (2023). INTRANASAL ADMINISTRATION OF AMISH FARM DUST EXTRACTS PREVENTS RV1B-INDUCED LUNG NEUTROPHILIA. 2023 Asthma and Allergic Diseases Cooperative Research Centers Annual Meeting. Rockville, MD: NIAID.
• Pivniouk, V. I., Gimenes, Jr, J. A., Ezeh, P., Michael, A. N., Pivniouk, O., Abidov, A., Gozdz, J., DeVries, A., Pasquali, C., & Vercelli, D. (2020, May 15-20). Intra-nasal administration of the OM-85 bacterial lysate strongly protects from experimental asthma by targeting multiple innate and adaptive immune processes. International Conference, American Thoracic Society. Philadelphia, PA.
• Pivniouk, V. I., Rosenbaum, D., Herrell, A., Pivniouk, O., Rafaels, N., Mathias, R., Barnes, K., & Vercelli, D. (2016, May). Differential regulation of human and mouse IL33 expression in the lungs of human IL33 BAC transgenic mice.. AAI Annual Meeting - Immunology 2016.
• Pivniouk, V. I., Rosenbaum, D., Pivniouk, O., & Vercelli, D. (2016, May). Downregulation of human IL4 and IL13 expression by CRISPR/Cas9-mediated deletion of DNase I hypersensitive site HS11/12 from a transgenic human Th2 cytokine locus. AAI Annual Meeting - Immunology 2016.

Reviews

• Pivniouk, V. I., & Vercelli, D. (2023. The om-85 bacterial lysate: a new tool against sars-cov-2?. Multidisciplinary Respiratory Medicine.