Papers by Peter Velazquez
PMC, Apr 24, 2018
The immune response to (LM) is Background Listeria monocytogenes characterized by formation of le... more The immune response to (LM) is Background Listeria monocytogenes characterized by formation of leukocyte rich foci of infection in liver and spleen. Although much has been gained in our understanding of immune response through the study of LM, little is known about spatio-temporal regulation of immune response to Listeria in liver. We utilize a combination of molecular, genetic and intravital Methods: microscopic approaches to gain insight into the dynamics of foci and leukocyte behavior during hepatic Listeriosis. : LM foci efficiently exclude blood flow, indicating the presence of a Results barrier separating the foci and healthy tissue. Despite this barrier, sinusoidal myelomonocytic cells readily enter or transiently interact with cells at the edge of foci of infection. Next, utilizing L9.6 transgenic CD8 T cells specific for an endogenously processed LM antigen, p60 217-225, along with LM deficient in this epitope, we define the role of TCR in T cell migratory behavior in infected liver. Surprisingly, T cell behavior varies with micro-anatomic locale. Near foci, non-specific adhesion mechanisms dominate lymphocyte behavior. Antigen specific effects on motility became detectable only distal to foci. These data suggest that LM antigens act in a paracrine manner Conclusions: to mediate protection from Listeriosis in the liver.
American Journal of Cancer Research, 2022
Springer Seminars in Immunopathology, 2004
Mucosal lymphocyte homeostasis involves the dynamic interaction of enteric microbiota, the intest... more Mucosal lymphocyte homeostasis involves the dynamic interaction of enteric microbiota, the intestinalflora and host epithelium, and the mucosal immune system. Multiple host components play critical roles in mediating this homeostasis. Dyisregulation of mucosal lymphocyte homeostasis results in a variety of instestinalintestinal disorders, notably inflammatory bowel diseases like ulcerative colitis and Crohn's disease. that strike at over onemillion people annually in the United states. One key cellular compartment incomponent regulating homeostasis areis comprised of the B-lymphocytes (B-cells) that reside in gut associated lymphoid tissue (GALT). This tissue compartment includes Ppeyer's Ppatch, isolated lymphoid follicles,tissue lamina propria, and mesenteric lymph nodes. Recent data has pointed to two new and exciting aspects of B-cells in the gut. First, there has been progress on identification and functional analysis of abundant isolated lymphoid follicle B-cell that are key mediators of IgA genesis. Second, the several groups have now clarified the functional identification and characterization of immunoregulatory B-cells in the gut. This review examines the novel aspects of these B-cells and examines how each play a role in mediating mucosal homeostasis in this bacterial laden compartment.
Molecular Genetics and Metabolism, 2013
Acute febrile illness is a common cause of hospital admission, and its associated infectious caus... more Acute febrile illness is a common cause of hospital admission, and its associated infectious causes contribute to substantial morbidity and death among children worldwide, especially in low-and middle-income countries. Declining transmission of malaria in many regions, combined with the increasing use of rapid diagnostic tests for malaria, has led to the increasing recognition of leptospirosis, rickettsioses, respiratory viruses, and arboviruses as etiologic agents of fevers. However, clinical discrimination between these etiologies can be difficult. Overtreatment with antimalarial drugs is common, even in the setting of a negative test result, as is overtreatment with empiric antibacterial drugs. Viral etiologies remain underrecognized and poorly investigated. Moresensitive diagnostics have led to additional dilemmas in discriminating whether a positive test result reflects a causative pathogen. Here, we review and summarize the current epidemiology and focus particularly on children and the challenges for future research.
Journal of Leukocyte Biology, 2012
FIVM has provided many insights into the regulation of immunity. We report the validation of an a... more FIVM has provided many insights into the regulation of immunity. We report the validation of an approach for visualizing murine small bowel via single-and multiphoton FIVM. Tissue damage is limited to ϳ200 m, immediately adjacent to the incision, as confirmed by intravital PI staining. Treatment with 10 KDa dextran-FITC and 70 KDa dextran-TR confirms that perfusion is intact. Selective filtration of 10 KDa but not 70 KDa dextran from the blood indicated that kidney function is also intact. Interestingly, lamina propria vasculature is semipermeable to 10 KDa dextran. Next, reporter mice expressing egfp from the CX3CR1 locus, egfp from the FoxP3 locus, or RFP from the IL-17F locus were used to track DC subsets, FoxP3 ϩ Tregs, or Th17f cells, respectively. Resident cx3cr1 ϩ/egfp cells were sessile but actively probed the surrounding microenvironment. Both T cell populations patrol the lamina propria, but the Th17f cells migrate more rapidly than Tregs. Together, these data demonstrate intact vascular perfusion, while intravitally visualizing the mucosal surface of the small bowel. Lastly, the cx3cr1 ϩ DCs and T cells display activity similar to that found in steady-state, secondary lymphoid organs.
The Journal of Immunology, 2010
Recruitment of CCR2 + Ly6C high monocytes to sites of infection is essential for efficient cleara... more Recruitment of CCR2 + Ly6C high monocytes to sites of infection is essential for efficient clearance of microbial pathogens. Although CCR2-mediated signals promote monocyte emigration from bone marrow, the contribution of CCR2 to later stages of monocyte recruitment remains unresolved. In this article, we show that CCR2 deficiency markedly worsens hepatic Listeria monocytogenes infection because Ly6C high monocytes are retained in the bone marrow. Intravenously transferred, CCR2-deficient Ly6C high monocytes traffic normally to hepatic foci of infection and contribute to bacterial clearance. Pertussis toxin treatment of adoptively transferred monocytes does not impair their intrahepatic trafficking, suggesting that chemokine signaling, once CCR2 + Ly6C high monocytes emigrate from the bone marrow, is not required for monocyte localization to sites of bacterial infection in the liver. Expression of ICAM-1 is induced in close proximity to foci of bacterial infection in the liver, including on CD31 + endothelial cells, and blockade of CD11b and CD44 diminishes monocyte localization to these hepatic foci. Our studies demonstrated that Ly6C high monocyte recruitment from the bloodstream to the L. monocytogenes-infected liver does not require chemokine receptormediated signals but instead is principally dependent on integrin-and extracellular matrix-mediated monocyte adhesion.
Immunogenetics, 2006
A recent and surprising body of research has linked changes in immune function to biologic and th... more A recent and surprising body of research has linked changes in immune function to biologic and therapeutic targeting of cannabinoid receptors, which prototypically respond to delta-9 tetrahydrocannabinol. The peripheral cannabinoid receptor CB2 is highly expressed in immune cell types (macrophages, dendritic cells, and B cells), and pharmacologically alters their cytokine production and responsiveness. Accordingly, cannabinoid agonists can powerfully alter susceptibility to certain microbial infections, atherosclerosis, and cancer immunotherapy. What is unknown is the physiologic role of natural levels of endocannabinoids and their receptors in normal immune homeostasis. Gαi2−/− mice are deficient in the formation of certain B and T cell subsets and are susceptible to immune dysregulation, notably developing inflammatory bowel disease. A key issue is the identity of the Gi-coupled receptors relevant to this Gαi2-signaling pathway. We find that mice deficient in CB2, the Gi-coupled peripheral endocannabinoid receptor, have profound deficiencies in splenic marginal zone, peritoneal B1a cells, splenic memory CD4 + T cells, and intestinal natural killer cells and natural killer T cells. These findings partially phenocopy and extend the lymphocyte developmental disorder associated with the Gαi2−/− genotype, and suggest that the endocannabinoid system is required for the formation of T and B cell subsets involved in immune homeostasis. This noncompensatable requirement for physiologic function of the endocannabinoid system is novel. Because levels of endocannabinoids are highly restricted microanatomically, local regulation of their production and receptor expression offers a new principle for regional immune homeostasis and disease susceptibility, and extends and refines the rationale for CB2-targeted immunotherapy in immune and inflammatory diseases.
Gastroenterology, 2003
reguhtion and immunolocafization studies revealed Hsp110 expression in subsets of human IEC's in ... more reguhtion and immunolocafization studies revealed Hsp110 expression in subsets of human IEC's in vivo. Recombinant human Hsp 110 induced CDld expression on the T84 cell line. Conversely, anti-Hsp110 monoclonal antibodies blocked CDld induction by crude LC. Conclusion: These data support the presence of a novel autocrine pathway of CD 1 d regulation by Hspll0 further emphasizing the linkage between CDld and innate immunity.
Clinical Immunology, 2005
The epidemiologic risk of certain systemic immunologic diseases is affected by commensal or envir... more The epidemiologic risk of certain systemic immunologic diseases is affected by commensal or environmental microbiota, but the cellular basis of the ''hygiene hypothesis'' is poorly understood. In this study, we demonstrate that composition of the commensal microbiota affects the functional state of the peripheral naïve (CD62L hi CD44 lo) T lymphocyte populations. Restricted flora (RF) mice (stably colonized with excess nonpathogenic Clostridium sp., and changes in other bacterial and fungal taxa) were distinguished after the neonatal period by a progressive deficiency in absolute numbers of naïve CD4 + and CD8 + T lymphocytes. SPF and RF mice had comparable levels of memory CD4 + and CD8 + T cells. This phenotype was attributable to the altered levels of certain commensals and their products, since germ-free mice had normal absolute numbers of splenic CD4 + and CD8 + T cells and their respective naïve and memory subsets. The naïve CD4 + T cell subset was functionally distinguished in RF mice versus SPF mice by TCR hyperresponsiveness, pro-inflammatory cytokine production, and increased activation-induced cell death. Biochemically, these traits were associated with higher basal phosphorylation of the TCR signaling proteins ZAP-70, Lck, and LAT. These findings indicate that enteric microbial products, through unknown cellular circuitry, influence steps in CD4 T cell differentiation moderating basal TCR signaling and immune responsiveness.
Journal of Biological Chemistry, 1997
Wellcome open research, 2018
The immune response to (LM) is Background Listeria monocytogenes characterized by formation of le... more The immune response to (LM) is Background Listeria monocytogenes characterized by formation of leukocyte rich foci of infection in liver and spleen. Although much has been gained in our understanding of immune response through the study of LM, little is known about spatio-temporal regulation of immune response to Listeria in liver. We utilize a combination of molecular, genetic and intravital Methods: microscopic approaches to gain insight into the dynamics of foci and leukocyte behavior during hepatic Listeriosis. : LM foci efficiently exclude blood flow, indicating the presence of a Results barrier separating the foci and healthy tissue. Despite this barrier, sinusoidal myelomonocytic cells readily enter or transiently interact with cells at the edge of foci of infection. Next, utilizing L9.6 transgenic CD8 T cells specific for an endogenously processed LM antigen, p60 217-225, along with LM deficient in this epitope, we define the role of TCR in T cell migratory behavior in infected liver. Surprisingly, T cell behavior varies with micro-anatomic locale. Near foci, non-specific adhesion mechanisms dominate lymphocyte behavior. Antigen specific effects on motility became detectable only distal to foci. These data suggest that LM antigens act in a paracrine Conclusions: manner to mediate protection from Listeriosis in the liver.
The Journal of Immunology, Apr 1, 2010
The Faseb Journal, Mar 1, 2008
The Journal of Immunology, Apr 1, 2009
The Faseb Journal, Mar 1, 2008
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Papers by Peter Velazquez