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A Systematic Re-Examination Of Processing Of Mhci-Bound Antigenic Peptide Precursors By Er Aminopeptidase 1, George Mavridis, Richa Arya, Alexander Domnick, Jerome Zoidakis, Manousos Makridakis, Antonia Vlahou, Anastasia Mpakali, Angelos Lelis, Dimitris Georgiadis, Robert Tampe, Athanasios Papakyriakou, Lawrence J. Stern, Efstratios Stratikos 2020 National Center for Scientific Research Demokritos

A Systematic Re-Examination Of Processing Of Mhci-Bound Antigenic Peptide Precursors By Er Aminopeptidase 1, George Mavridis, Richa Arya, Alexander Domnick, Jerome Zoidakis, Manousos Makridakis, Antonia Vlahou, Anastasia Mpakali, Angelos Lelis, Dimitris Georgiadis, Robert Tampe, Athanasios Papakyriakou, Lawrence J. Stern, Efstratios Stratikos

Open Access Articles

Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims antigenic peptide precursors to generate mature antigenic peptides for presentation by major histocompatibility complex class I (MHCI) molecules and regulates adaptive immune responses. ERAP1 has been proposed to trim peptide precursors both in solution and in pre-formed MHCI-peptide complexes, but which mode is more relevant to its biological function remains controversial. Here, we compared ERAP1-mediated trimming of antigenic peptide precursors in solution or when bound to three MHCI alleles, HLA-B*58, HLA-B*08 and HLA-A*02. For all MHCI-peptide combinations, peptide binding onto MHCI protected against ERAP1-mediated trimming. In only a single MHCI-peptide combination ...


Regulation Of Adipose Tissue Inflammation By Interleukin 6, Myoung Souk Han, Alexis White, Rachel J. Perry, Joao-Paulo Camporez, Juan Hidalgo, Gerald I. Shulman, Roger J. Davis 2020 University of Massachusetts Medical School

Regulation Of Adipose Tissue Inflammation By Interleukin 6, Myoung Souk Han, Alexis White, Rachel J. Perry, Joao-Paulo Camporez, Juan Hidalgo, Gerald I. Shulman, Roger J. Davis

Open Access Articles

Obesity is associated with a chronic state of low-grade inflammation and progressive tissue infiltration by immune cells and increased expression of inflammatory cytokines. It is established that interleukin 6 (IL6) regulates multiple aspects of metabolism, including glucose disposal, lipolysis, oxidative metabolism, and energy expenditure. IL6 is secreted by many tissues, but the role of individual cell types is unclear. We tested the role of specific cells using a mouse model with conditional expression of the Il6 gene. We found that IL6 derived from adipocytes increased, while IL6 derived from myeloid cells and muscle suppressed, macrophage infiltration of adipose tissue. These ...


Co-Administration Of Injected And Oral Vaccine Candidates Elicits Improved Immune Responses Over Either Route Alone, Celine A. Hayden, Danilo Landrock, Chiung Yu Hung, Gary R. Ostroff, Gina M. Fake, John H. Walker, Ann Kier, John A. Howard 2020 Applied Biotechnology Institute

Co-Administration Of Injected And Oral Vaccine Candidates Elicits Improved Immune Responses Over Either Route Alone, Celine A. Hayden, Danilo Landrock, Chiung Yu Hung, Gary R. Ostroff, Gina M. Fake, John H. Walker, Ann Kier, John A. Howard

Open Access Articles

Infectious diseases continue to be a significant cause of morbidity and mortality, and although efficacious vaccines are available for many diseases, some parenteral vaccines elicit little or no mucosal antibodies which can be a significant problem since mucosal tissue is the point of entry for 90% of pathogens. In order to provide protection for both serum and mucosal areas, we have tested a combinatorial approach of both parenteral and oral administration of antigens for diseases caused by a viral pathogen, Hepatitis B, and a fungal pathogen, Coccidioides. We demonstrate that co-administration by the parenteral and oral routes is a useful ...


Agi-134: A Fully Synthetic Alpha-Gal Glycolipid That Converts Tumors Into In Situ Autologous Vaccines, Induces Anti-Tumor Immunity And Is Synergistic With An Anti-Pd-1 Antibody In Mouse Melanoma Models, Stephen M. Shaw, Kim Wigglesworth, Giles F. Whalen, Arik A. Zur 2019 Agalimmune Ltd.

Agi-134: A Fully Synthetic Alpha-Gal Glycolipid That Converts Tumors Into In Situ Autologous Vaccines, Induces Anti-Tumor Immunity And Is Synergistic With An Anti-Pd-1 Antibody In Mouse Melanoma Models, Stephen M. Shaw, Kim Wigglesworth, Giles F. Whalen, Arik A. Zur

Open Access Articles

Background: Treatments that generate T cell-mediated immunity to a patient's unique neoantigens are the current holy grail of cancer immunotherapy. In particular, treatments that do not require cumbersome and individualized ex vivo processing or manufacturing processes are especially sought after. Here we report that AGI-134, a glycolipid-like small molecule, can be used for coating tumor cells with the xenoantigen Galalpha1-3Galbeta1-4GlcNAc (alpha-Gal) in situ leading to opsonization with pre-existing natural anti-alpha-Gal antibodies (in short anti-Gal), which triggers immune cascades resulting in T cell mediated anti-tumor immunity.

Methods: Various immunological effects of coating tumor cells with alpha-Gal via AGI-134 in vitro ...


Systemic Rage Ligands Are Upregulated In Tuberculosis Individuals With Diabetes Co-Morbidity And Modulated By Anti-Tuberculosis Treatment And Metformin Therapy, Nathella Pavan Kumar, Kadar Moideen, Arul Nancy, Vijay Viswanathan, Basavaradhya S. Shruthi, Shanmugam Sivakumar, Syed Hissar, Hardy Kornfeld, Subash Babu 2019 National Institutes of Health-NIRT- International Center for Excellence in Research

Systemic Rage Ligands Are Upregulated In Tuberculosis Individuals With Diabetes Co-Morbidity And Modulated By Anti-Tuberculosis Treatment And Metformin Therapy, Nathella Pavan Kumar, Kadar Moideen, Arul Nancy, Vijay Viswanathan, Basavaradhya S. Shruthi, Shanmugam Sivakumar, Syed Hissar, Hardy Kornfeld, Subash Babu

Open Access Articles

BACKGROUND: Ligands of the receptor for advanced glycation end products (RAGE) are key signalling molecules in the innate immune system but their role in tuberculosis-diabetes comorbidity (TB-DM) has not been investigated.

METHODS: We examined the systemic levels of soluble RAGE (sRAGE), advanced glycation end products (AGE), S100A12 and high mobility group box 1 (HMGB1) in participants with either TB-DM, TB, DM or healthy controls (HC).

RESULTS: Systemic levels of AGE, sRAGE and S100A12 were significantly elevated in TB-DM and DM in comparison to TB and HC. During follow up, AGE, sRAGE and S100A12 remained significantly elevated in TB-DM compared to ...


Functionally Overlapping Variants Control Tuberculosis Susceptibility In Collaborative Cross Mice, Clare M. Smith, Megan K. Proulx, Rocky Lai, Michael C. Kiritsy, Timothy A. Bell, Pablo Hock, Fernando Pardo-Manuel de Villena, Martin T. Ferris, Richard E. Baker, Samuel M. Behar, Christopher M. Sassetti 2019 University of Massachusetts Medical School

Functionally Overlapping Variants Control Tuberculosis Susceptibility In Collaborative Cross Mice, Clare M. Smith, Megan K. Proulx, Rocky Lai, Michael C. Kiritsy, Timothy A. Bell, Pablo Hock, Fernando Pardo-Manuel De Villena, Martin T. Ferris, Richard E. Baker, Samuel M. Behar, Christopher M. Sassetti

Open Access Articles

Host genetics plays an important role in determining the outcome of Mycobacterium tuberculosis infection. We previously found that Collaborative Cross (CC) mouse strains differ in their susceptibility to M. tuberculosis and that the CC042/GeniUnc (CC042) strain suffered from a rapidly progressive disease and failed to produce the protective cytokine gamma interferon (IFN-gamma) in the lung. Here, we used parallel genetic and immunological approaches to investigate the basis of CC042 mouse susceptibility. Using a population derived from a CC001/Unc (CC001) x CC042 intercross, we mapped four quantitative trait loci (QTL) underlying tuberculosis immunophenotypes (Tip1 to Tip4). These included QTL ...


Differential Skewing Of Donor-Unrestricted And Gammadelta T Cell Repertoires In Tuberculosis-Infected Human Lungs, Paul Ogongo, Adrie Jc. Steyn, Farina Karim, Kaylesh J. Dullabh, Ismael Awala, Rajhmun Madansein, Alasdair Leslie, Samuel M. Behar 2019 University of KwaZulu-Natal

Differential Skewing Of Donor-Unrestricted And Gammadelta T Cell Repertoires In Tuberculosis-Infected Human Lungs, Paul Ogongo, Adrie Jc. Steyn, Farina Karim, Kaylesh J. Dullabh, Ismael Awala, Rajhmun Madansein, Alasdair Leslie, Samuel M. Behar

Open Access Articles

Unconventional T cells that recognize mycobacterial antigens are of great interest as potential vaccine targets against tuberculosis (TB). This includes donor-unrestricted T cells (DURTs), such as mucosa-associated invariant T cells (MAITs), CD1-restricted T cells, and gammadelta T cells. We exploited the distinctive nature of DURTs and gammadelta T cell receptors (TCRs) to investigate the involvement of these T cells during TB in the human lung by global TCR sequencing. Making use of surgical lung resections, we investigated the distribution, frequency, and characteristics of TCRs in lung tissue and matched blood from individuals infected with TB. Despite depletion of MAITs and ...


In Vivo Clonal Expansion And Phenotypes Of Hypocretin-Specific Cd4(+) T Cells In Narcolepsy Patients And Controls, Wei Jiang, James R. Birtley, Grant C. Weaver, Liying Lu, Lawrence J. Stern, Elizabeth D. Mellins 2019 Stanford University

In Vivo Clonal Expansion And Phenotypes Of Hypocretin-Specific Cd4(+) T Cells In Narcolepsy Patients And Controls, Wei Jiang, James R. Birtley, Grant C. Weaver, Liying Lu, Lawrence J. Stern, Elizabeth D. Mellins

Open Access Articles

Individuals with narcolepsy suffer from abnormal sleep patterns due to loss of neurons that uniquely supply hypocretin (HCRT). Previous studies found associations of narcolepsy with the human leukocyte antigen (HLA)-DQ6 allele and T-cell receptor alpha (TRA) J24 gene segment and also suggested that in vitro-stimulated T cells can target HCRT. Here, we present evidence of in vivo expansion of DQ6-HCRT tetramer(+)/TRAJ24(+)/CD4(+) T cells in DQ6(+) individuals with and without narcolepsy. We identify related TRAJ24(+) TCRalphabeta clonotypes encoded by identical alpha/beta gene regions from two patients and two controls. TRAJ24-G allele(+) clonotypes only expand in the two ...


Redirection Of Skn-1 Abates The Negative Metabolic Outcomes Of A Perceived Pathogen Infection, James D. Nhan, Christian D. Turner, Sarah M. Anderson, Chia-An Yen, Hans M. Dalton, Hilary K. Cheesman, Dana L. Ruter, Nandhitha Uma Naresh, Cole M. Haynes, Alexander A. Soukas, Read Pukkila-Worley, Sean P. Curran 2019 University of Southern California

Redirection Of Skn-1 Abates The Negative Metabolic Outcomes Of A Perceived Pathogen Infection, James D. Nhan, Christian D. Turner, Sarah M. Anderson, Chia-An Yen, Hans M. Dalton, Hilary K. Cheesman, Dana L. Ruter, Nandhitha Uma Naresh, Cole M. Haynes, Alexander A. Soukas, Read Pukkila-Worley, Sean P. Curran

Open Access Articles

Early host responses toward pathogens are essential for defense against infection. In Caenorhabditis elegans, the transcription factor, SKN-1, regulates cellular defenses during xenobiotic intoxication and bacterial infection. However, constitutive activation of SKN-1 results in pleiotropic outcomes, including a redistribution of somatic lipids to the germline, which impairs health and shortens lifespan. Here, we show that exposing C. elegans to Pseudomonas aeruginosa similarly drives the rapid depletion of somatic, but not germline, lipid stores. Modulating the epigenetic landscape refines SKN-1 activity away from innate immunity targets, which alleviates negative metabolic outcomes. Similarly, exposure to oxidative stress redirects SKN-1 activity away from ...


Common Nodes Of Virus-Host Interaction Revealed Through An Integrated Network Analysis, Korbinian Bosl, Richard K. Kandasamy 2019 Norwegian University of Science and Technology

Common Nodes Of Virus-Host Interaction Revealed Through An Integrated Network Analysis, Korbinian Bosl, Richard K. Kandasamy

Open Access Articles

Viruses are one of the major causes of acute and chronic infectious diseases and thus a major contributor to the global burden of disease. Several studies have shown how viruses have evolved to hijack basic cellular pathways and evade innate immune response by modulating key host factors and signaling pathways. A collective view of these multiple studies could advance our understanding of virus-host interactions and provide new therapeutic perspectives for the treatment of viral diseases. Here, we performed an integrative meta-analysis to elucidate the 17 different host-virus interactomes. Network and bioinformatics analyses showed how viruses with small genomes efficiently achieve ...


Evaluation Of Il-1 Blockade As A Host-Directed Therapy For Tuberculosis In Mice And Macaques, Caylin G. Winchell, Bibhuti B. Mishra, University of Massachusetts Medical School, Samantha J. Nelson, Christopher M. Sassetti, JoAnne L. Flynn 2019 University of Pittsburgh

Evaluation Of Il-1 Blockade As A Host-Directed Therapy For Tuberculosis In Mice And Macaques, Caylin G. Winchell, Bibhuti B. Mishra, University Of Massachusetts Medical School, Samantha J. Nelson, Christopher M. Sassetti, Joanne L. Flynn

University of Massachusetts Medical School Faculty Publications

In 2017, there were over 550,000 estimated new cases of multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB), emphasizing a need for new treatment strategies. Linezolid (LZD) is a potent antibiotic for antibiotic-resistant Gram-positive infections and is an effective treatment for TB. However, extended LZD use can lead to LZD-associated host toxicities, most commonly bone marrow suppression. LZD toxicities may be mediated by IL-1, a pathway important for early immunity during M. tuberculosis infection that later contributes to pathology. We hypothesized LZD efficacy could be enhanced by modulation of IL-1 pathway to reduce BM toxicity and TB associated-inflammation. We used two ...


Plasma Eicosanoid Levels In Tuberculosis And Tuberculosis-Diabetes Co-Morbidity Are Associated With Lung Pathology And Bacterial Burden, Nathella Pavan Kumar, Kadar Moideen, Arul Nancy, Vijay Viswanathan, Basavaradhya S. Shruthi, Sivakumar Shanmugam, Syed Hissar, Hardy Kornfeld, Subash Babu 2019 National Institutes of Health

Plasma Eicosanoid Levels In Tuberculosis And Tuberculosis-Diabetes Co-Morbidity Are Associated With Lung Pathology And Bacterial Burden, Nathella Pavan Kumar, Kadar Moideen, Arul Nancy, Vijay Viswanathan, Basavaradhya S. Shruthi, Sivakumar Shanmugam, Syed Hissar, Hardy Kornfeld, Subash Babu

Open Access Articles

Host eicosanoids are lipid mediators of inflammation that are commonly accepted as important modulators of the host immune response in Mycobacterium tuberculosis infection. During active tuberculosis (TB), eicosanoids may play an important role in the regulation of inflammatory responses. However, a detailed investigation of the relationship of eicosanoids in TB and TB-diabetes comorbidity (TB-DM) and association to disease pathology or bacterial burdens has not been studied. To study this, we examined the plasma levels of Lipoxin A4 (LXA4), 15-epi-LXA4, Leukotriene B4 (LTB4), and Prostaglandin E2 (PGE2) in individuals with either TB-DM, TB, diabetes mellitus (DM) or healthy controls (HC). Plasma ...


Chitosan Biosynthesis And Virulence In The Human Fungal Pathogen Cryptococcus Gattii, Woei C. Lam, Rajendra Upadhya, Charles A. Specht, Abigail E. Ragsdale, Camaron R. Hole, Stuart M. Levitz, Jennifer K. Lodge 2019 Washington University in St. Louis

Chitosan Biosynthesis And Virulence In The Human Fungal Pathogen Cryptococcus Gattii, Woei C. Lam, Rajendra Upadhya, Charles A. Specht, Abigail E. Ragsdale, Camaron R. Hole, Stuart M. Levitz, Jennifer K. Lodge

University of Massachusetts Medical School Faculty Publications

Cryptococcus gattii R265 is a hyper-virulent fungal strain responsible for the major outbreak of cryptococcosis in Vancouver Island of British Columbia in 1999. It differs significantly from C. neoformans in its natural environment, its preferred site in the mammalian host, and in the nature and mode of pathogenesis. Our previous studies in C. neoformans have shown that the presence of chitosan, the deacetylated form of chitin, in the cell wall attenuates inflammatory responses in the host, while its absence induces robust immune responses, which in turn facilitate clearance of the fungus and induces a protective response. The results of the ...


Postnatal Zika Virus Infection Of Nonhuman Primate Infants Born To Mothers Infected With Homologous Brazilian Zika Virus, Nicholas J. Maness, Diogo Magnani 2019 Tulane University

Postnatal Zika Virus Infection Of Nonhuman Primate Infants Born To Mothers Infected With Homologous Brazilian Zika Virus, Nicholas J. Maness, Diogo Magnani

Open Access Articles

Recent data in a nonhuman primate model showed that infants postnatally infected with Zika virus (ZIKV) were acutely susceptible to high viremia and neurological damage, suggesting the window of vulnerability extends beyond gestation. In this pilot study, we addressed the susceptibility of two infant rhesus macaques born healthy to dams infected with Zika virus during pregnancy. Passively acquired neutralizing antibody titers dropped below detection limits between 2 and 3 months of age, while binding antibodies remained detectable until viral infection at 5 months. Acute serum viremia was comparatively lower than adults infected with the same Brazilian isolate of ZIKV (n ...


Systemic Inflammation Impairs Microglial Abeta Clearance Through Nlrp3 Inflammasome, Dario Tejera, Dilek Mercan, Juan M. Sanchez-Caro, Mor Hanan, David Greenberg, Hermona Soreq, Eicke Latz, Douglas T. Golenbock, Michael T. Heneka 2019 University Hospitals Bonn

Systemic Inflammation Impairs Microglial Abeta Clearance Through Nlrp3 Inflammasome, Dario Tejera, Dilek Mercan, Juan M. Sanchez-Caro, Mor Hanan, David Greenberg, Hermona Soreq, Eicke Latz, Douglas T. Golenbock, Michael T. Heneka

Open Access Articles

Alzheimer's disease is the most prevalent type of dementia and is caused by the deposition of extracellular amyloid-beta and abnormal tau phosphorylation. Neuroinflammation has emerged as an additional pathological component. Microglia, representing the brain's major innate immune cells, play an important role during Alzheimer's. Once activated, microglia show changes in their morphology, characterized by a retraction of cell processes. Systemic inflammation is known to increase the risk for cognitive decline in human neurogenerative diseases including Alzheimer's. Here, we assess for the first time microglial changes upon a peripheral immune challenge in the context of aging and ...


Ak002, A Humanized Sialic Acid-Binding Immunoglobulin-Like Lectin-8 Antibody That Induces Antibody-Dependent Cell-Mediated Cytotoxicity Against Human Eosinophils And Inhibits Mast Cell-Mediated Anaphylaxis In Mice, Bradford A. Youngblood, Emily C. Brock, John Leung, Rustom Falahati, Paul J. Bryce, Jessica Bright, Jason Williams, Leonard D. Shultz, Dale L. Greiner, Michael A. Brehm, Christopher Bebbington, Nenad Tomasevic 2019 Allakos, Inc.

Ak002, A Humanized Sialic Acid-Binding Immunoglobulin-Like Lectin-8 Antibody That Induces Antibody-Dependent Cell-Mediated Cytotoxicity Against Human Eosinophils And Inhibits Mast Cell-Mediated Anaphylaxis In Mice, Bradford A. Youngblood, Emily C. Brock, John Leung, Rustom Falahati, Paul J. Bryce, Jessica Bright, Jason Williams, Leonard D. Shultz, Dale L. Greiner, Michael A. Brehm, Christopher Bebbington, Nenad Tomasevic

Open Access Articles

INTRODUCTION: Pathologic accumulation and activation of mast cells and eosinophils are implicated in allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is an inhibitory receptor selectively expressed on mast cells, eosinophils and, at a lower extent, basophils. When engaged with an antibody, Siglec-8 can induce apoptosis of activated eosinophils and inhibit mast cell activation. AK002 is a humanized, non-fucosylated IgG1 anti-Siglec-8 antibody undergoing clinical investigation for treatment of allergic, inflammatory, and proliferative diseases. Here we examine the human tissue selectivity of AK002 and evaluate the in vitro, ex vivo, and in vivo activity of AK002 on eosinophils and ...


Nuclear Magnetic Resonance Solution Structure And Functional Behavior Of The Human Proton Channel, Monika Bayrhuber, Innokentiy Maslennikov, Witek Kwiatkowski, Alexander Sobol, Christoph Wierschem, Cédric Eichmann, Lukas Frey, Roland Riek 2019 ETH Zürich

Nuclear Magnetic Resonance Solution Structure And Functional Behavior Of The Human Proton Channel, Monika Bayrhuber, Innokentiy Maslennikov, Witek Kwiatkowski, Alexander Sobol, Christoph Wierschem, Cédric Eichmann, Lukas Frey, Roland Riek

Pharmacy Faculty Articles and Research

The human voltage-gated proton channel [Hv1(1) or VSDO(2)] plays an important role in the human innate immune system. Its structure differs considerably from those of other cation channels. It is built solely of a voltage-sensing domain and thus lacks the central pore domain, which is essential for other cation channels. Here, we determined the solution structure of an N- and C-terminally truncated human Hv1 (Δ-Hv1) in the resting state by nuclear magnetic resonance (NMR) spectroscopy. Δ-Hv1 comprises the typical voltage-sensing antiparallel four-helix bundle (S1–S4) preceded by an amphipathic helix (S0). The solution structure corresponds to an intermediate ...


Cxcr3 Chemokine Receptor Guides Trypanosoma Cruzi-Specific T-Cells Triggered By Dna/Adenovirus Asp2 Vaccine To Heart Tissue After Challenge, Camila Pontes Ferreira, Leonardo Moro Cariste, Barbara Ferri Moraschi, Bianca Ferrarini Zanetti, Sang Won Han, Daniel Araki Ribeiro, Alexandre Vieira Machado, Joseli Lannes-Vieira, Ricardo T. Gazzinelli, Jose Ronnie Vasconcelos Carvalho 2019 Federal University of São Paulo

Cxcr3 Chemokine Receptor Guides Trypanosoma Cruzi-Specific T-Cells Triggered By Dna/Adenovirus Asp2 Vaccine To Heart Tissue After Challenge, Camila Pontes Ferreira, Leonardo Moro Cariste, Barbara Ferri Moraschi, Bianca Ferrarini Zanetti, Sang Won Han, Daniel Araki Ribeiro, Alexandre Vieira Machado, Joseli Lannes-Vieira, Ricardo T. Gazzinelli, Jose Ronnie Vasconcelos Carvalho

Open Access Articles

CD8+ T lymphocytes play an important role in controlling infections by intracellular pathogens. Chemokines and their receptors are crucial for the migration of CD8+ T-lymphocytes, which are the main IFNgamma producers and cytotoxic effectors cells. Although the participation of chemokine ligands and receptors has been largely explored in viral infection, much less is known in infection by Trypanosoma cruzi, the causative agent of Chagas disease. After T. cruzi infection, CXCR3 chemokine receptor is highly expressed on the surface of CD8+ T-lymphocytes. Here, we hypothesized that CXCR3 is a key molecule for migration of parasite-specific CD8+ T-cells towards infected tissues, where ...


Alternative Splicing Regulates Stochastic Nlrp3 Activity, Florian Hoss, James L. Mueller, Francisca Rojas Ringeling, Juan F. Rodriguez-Alcazar, Rebecca Brinkschulte, Gerald Seifert, Rainer Stahl, Lori Broderick, Chris D. Putnam, Richard D. Kolodner, Stefan Canzar, Matthias Geyer, Hal M. Hoffman, Eicke Latz 2019 University of Bonn

Alternative Splicing Regulates Stochastic Nlrp3 Activity, Florian Hoss, James L. Mueller, Francisca Rojas Ringeling, Juan F. Rodriguez-Alcazar, Rebecca Brinkschulte, Gerald Seifert, Rainer Stahl, Lori Broderick, Chris D. Putnam, Richard D. Kolodner, Stefan Canzar, Matthias Geyer, Hal M. Hoffman, Eicke Latz

Open Access Articles

Leucine-rich repeat (LRR) domains are evolutionarily conserved in proteins that function in development and immunity. Here we report strict exonic modularity of LRR domains of several human gene families, which is a precondition for alternative splicing (AS). We provide evidence for AS of LRR domain within several Nod-like receptors, most prominently the inflammasome sensor NLRP3. Human NLRP3, but not mouse NLRP3, is expressed as two major isoforms, the full-length variant and a variant lacking exon 5. Moreover, NLRP3 AS is stochastically regulated, with NLRP3 exon 5 lacking the interaction surface for NEK7 and hence loss of activity. Our data thus ...


A Permethrin Metabolite Is Associated With Adaptive Immune Responses In Gulf War Illness, Utsav Joshi, Lawrence J. Stern, Laila Abdullah 2019 The Open University

A Permethrin Metabolite Is Associated With Adaptive Immune Responses In Gulf War Illness, Utsav Joshi, Lawrence J. Stern, Laila Abdullah

Open Access Articles

Gulf War Illness (GWI), affecting 30% of veterans from the 1991 Gulf War (GW), is a multi-symptom illness with features similar to those of patients with autoimmune diseases. The objective of the current work is to determine if exposure to GW-related pesticides, such as permethrin (PER), activates peripheral and central nervous system (CNS) adaptive immune responses. In the current study, we focused on a PER metabolite, 3-phenoxybenzoic acid (3-PBA), as this is a common metabolite previously shown to form adducts with endogenous proteins. We observed the presence of 3-PBA and 3-PBA modified lysine of protein peptides in the brain, blood ...


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