Publications by authors named "Carol Hoffman"

Introduction: In the era of next-generation sequencing, clinicians frequently encounter variants of unknown significance (VUS) in genetic testing. VUS may be reclassified over time as genetic knowledge grows. We know little about how best to approach VUS in the maturity-onset diabetes of the young (MODY).

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Susceptibility to brucellosis remains prevalent, even in herds vaccinated with conventional vaccines. Efforts are underway to develop an improved brucellosis vaccine, and possibly a universal vaccine, given that species are highly homologous. To this end, two mutants were developed, znBM- (znBMZ) and znBM-mCherry (znBM-mC), and were tested for their ability to confer systemic immunity against virulent challenge.

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Sjögren's Syndrome (SjS) results in loss of salivary and lacrimal gland excretion due to an autoimmune attack on these secretory glands. Conventional SjS treatments address the symptoms, but not the cause of disease. Recognizing this deficit of treatments to reverse SjS disease, studies were pursued using the fimbriae from enterotoxigenic E.

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The Brucella abortus double-mutant (ΔznuA ΔnorD Brucella abortus-lacZ [znBAZ]) was assessed for its protective efficacy after vaccination with a single nasal dose. Superior protection was achieved in znBAZ-vaccinated mice against pulmonary, wild-type B. abortus 2308 challenge when compared with conventional livestock Brucella abortus vaccines, the smooth S19 (smooth B.

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Brucellosis is a disease of livestock that is commonly asymptomatic until an abortion occurs. Disease in humans results from contact of infected livestock or consumption of contaminated milk or meat. zoonosis is primarily caused by one of three species that infect livestock, in cattle, in goats and sheep, and in pigs.

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Re-emerging zoonotic pathogen spp. continues to impact developing countries and persists in expanding populations of wildlife species in the US, constantly threatening infection of our domestic herds. The development of improved animal and human vaccines remains a priority.

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Small extracellular vesicles (sEVs) produced by antigen-presenting cells represent a novel mechanism of cell-to-cell communication. The sEVs have been shown to drive Th1-type adaptive immune responses against intracellular infections such as Salmonella. In this study, we have demonstrated that an administration of sEVs produced by Salmonella-infected macrophages to BALB/c mice that were then challenged with Salmonella infection decreased bacterial load in infected animals and led to protection against a lethal dose of Salmonella.

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Colonization factor antigen I (CFA/I) fimbria, an adhesin from enterotoxigenic Escherichia coli, confers protection in murine autoimmune models for type 1 diabetes (T1D), multiple sclerosis, and rheumatoid arthritis. Although CFA/I fimbriae's initial mode of action is in a bystander or in an antigen (Ag)-independent fashion, protection is ultimately dependent upon the induction and/or activation of auto-Ag-specific regulatory T cells (Tregs). However, little is known about how protection transitions from bystander suppression to Ag-specific Tregs.

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Past studies with the live, double-mutant  (znBAZ) strain resulted in nearly complete protection of mice against pulmonary challenge with wild-type (wt) a dominant CD8 T cell response. To understand the contribution innate immune cells in priming CD8 T cell responses, mice were nasally dosed with wt , smooth vaccine strain 19 (S19), or znBAZ, and examined for innate immune cell activation. Flow cytometric analysis revealed that znBAZ, but not wt nor S19 infection, induces up to a 5-fold increase in the frequency of IFN-γ-producing NK cells in mouse lungs.

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Salmonella Typhimurium is a causative agent of nontyphoidal salmonellosis, for which there is a lack of a clinically approved vaccine in humans. As an intracellular pathogen, Salmonella impacts many cellular pathways. However, the intercellular communication mechanism facilitated by host-derived small extracellular vesicles (EVs), such as exosomes, is an overlooked aspect of the host responses to this infection.

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Article Synopsis
  • Sjögren's syndrome (SjS) is a common autoimmune disease affecting mainly women, leading to damage in salivary and lacrimal glands, with no current cure or vaccine available.
  • In a study, researchers treated genetically modified mice with an oral treatment called LL-CFA/I to see if it could induce immune tolerance and suppress inflammation.
  • Results showed that LL-CFA/I maintained salivary flow in the mice for longer periods and reduced inflammation significantly, suggesting its potential as a therapy for SjS in the future.*
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Understanding the migration of lymphocytes to nonintestinal mucosal sites is fundamental to developing mucosal vaccination strategies. Studies have shown that nasal and oral immunization with cholera toxin (CT) stimulates, in addition to α4β7 , the induction of αE (CD103)β7 B cells. To determine the extent to which αE-associated β7 contributes to antigen (Ag)-specific immunoglobulin (Ig)A responses in the upper respiratory tract, nasal CT vaccination was performed in wild-type (wt) and β7 mice.

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Antigen (Ag)-specific tolerization prevents type 1 diabetes (T1D) in non-obese diabetic (NOD) mice but proved less effective in humans. Several auto-Ags are fundamental to disease development, suggesting T1D etiology is heterogeneous and may limit the effectiveness of Ag-specific therapies to distinct disease endotypes. Colonization factor antigen I (CFA/I) fimbriae from Escherichia coli can inhibit autoimmune diseases in murine models by inducing bystander tolerance.

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Brucellosis remains the most common zoonotic disease globally. Currently no vaccines for humans exist, and conventional brucellosis vaccines for livestock fail to confer complete protection; hence, an improved vaccine is needed. Although Brucella infections primarily occur following a mucosal exposure, vaccines are administered parenterally.

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Background: Human granulocytic anaplasmosis (HGA) is a tick-borne disease caused by the etiologic agent Anaplasma phagocytophilum. HGA was designated a nationally notifiable disease in the United States in 1998. Currently there are no vaccines available against HGA.

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IL-35, a relatively newly discovered cytokine belonging to the larger IL-12 family, shows unique anti-inflammatory properties, believed to be associated with dedicated receptors and signaling pathways. IL-35 plays a pivotal role in the development and the function of both regulatory B (Bregs) and T cells (Tregs). In order to further its therapeutic potential, a dairy strain was engineered to express murine IL-35 (LL-IL35), and this recombinant strain was applied to suppress collagen-induced arthritis (CIA).

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Background: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia, and elucidating its genetic underpinnings is critical. FTLD research centers typically recruit patient cohorts that are limited by the center's specialty and the ways in which its geographic location affects the ethnic makeup of research participants. Novel sources of data are needed to get population estimates of the contribution of variants in known FTLD-associated genes.

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Brucellosis remains burdensome for livestock and humans worldwide. Better vaccines for protection are needed to reduce disease incidence. Immunity to brucellosis and barriers to protection are discussed.

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There remains a need for an improved livestock vaccine for brucellosis since conventional vaccines are only ∼70% efficacious, making some vaccinated animals susceptible to Brucella infections. To address this void, a vaccine capable of evoking protective immunity, while still being sufficiently attenuated to produce minimal disease, is sought. In this pursuit, the ΔnorD ΔznuA B.

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Regulatory T cells (Tregs) induced during autoimmunity often become quiescent and unable to resolve disease, suggesting inadequate activation. Resolution of established experimental autoimmune encephalomyelitis (EAE) can be achieved with myelin oligodendrocyte glycoprotein (MOG) fused to reovirus protein σ1 (MOG-pσ1), which activates Tregs, restoring protection, but requiring other regulatory cells to revitalize them. B cells have a dichotomous role in both the pathogenesis and recovery from EAE.

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Unlabelled: Recurrent outbreaks of bacterial gastroenteritis linked to the consumption of fresh fruits and vegetables highlight the paucity of understanding of the ecology of Salmonella enterica under crop production and postharvest conditions. These gaps in knowledge are due, at least in part, to the lack of suitable surrogate organisms for studies for which biosafety level 2 is problematic. Therefore, we constructed and validated an avirulent strain of Salmonella enterica serovar Typhimurium.

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We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies collected from internal and external sources. Scores were calculated by trained scientists using a quantitative framework that assigned differential weighting to these five types of data.

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We compare molecular combing to Southern blot in the analysis of the facioscapulohumeral muscular dystrophy type 1 locus (FSHD1) on chromosome 4q35-qter (chr 4q) in genomic DNA specimens sent to a clinical laboratory for FSHD testing. A de-identified set of 87 genomic DNA specimens determined by Southern blot as normal (n = 71), abnormal with D4Z4 macrosatellite repeat array contractions (n = 7), indeterminate (n = 6), borderline (n = 2), or mosaic (n = 1) was independently re-analyzed by molecular combing in a blinded fashion. The molecular combing results were identical to the Southern blot results in 75 (86%) of cases.

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We report the frequency, positive rate, and type of mutations in 14 genes (PMP22, GJB1, MPZ, MFN2, SH3TC2, GDAP1, NEFL, LITAF, GARS, HSPB1, FIG4, EGR2, PRX, and RAB7A) associated with Charcot-Marie-Tooth disease (CMT) in a cohort of 17,880 individuals referred to a commercial genetic testing laboratory. Deidentified results from sequencing assays and multiplex ligation-dependent probe amplification (MLPA) were analyzed including 100,102 Sanger sequencing, 2338 next-generation sequencing (NGS), and 21,990 MLPA assays. Genetic abnormalities were identified in 18.

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Smoking during pregnancy is associated with a variety of untoward effects on the offspring. However, recent epidemiological studies have brought into question whether the association between neurobehavioral deficits and maternal smoking is causal. We utilized an animal model of maternal smoking to determine the effects of prenatal cigarette smoke (CS) exposure on neurobehavioral development.

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