Publications by authors named "Leopoldo Flores-Romo"

47 Publications

Germinal Center Cells Turning to the Dark Side: Neoplasms of B Cells, Follicular Helper T Cells, and Follicular Dendritic Cells.

Front Oncol 2020 15;10:587809. Epub 2021 Jan 15.

Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

Gaining knowledge of the neoplastic side of the three main cells-B cells, Follicular Helper T (Tfh) cells, and follicular dendritic cells (FDCs) -involved in the germinal center (GC) reaction can shed light toward further understanding the microuniverse that is the GC, opening the possibility of better treatments. This paper gives a review of the more complex underlying mechanisms involved in the malignant transformations that take place in the GC. Whilst our understanding of the biology of the GC-related B cell lymphomas has increased-this is not reviewed in detail here-the dark side involving neoplasms of Tfh cells and FDCs are poorly studied, in great part, due to their low incidence. The aggressive behavior of Tfh lymphomas and the metastatic potential of FDCs sarcomas make them clinically relevant, merit further attention and are the main focus of this review. Tfh cells and FDCs malignancies can often be misdiagnosed. The better understanding of these entities linked to their molecular and genetic characterization will lead to prediction of high-risk patients, better diagnosis, prognosis, and treatments based on molecular profiles.
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http://dx.doi.org/10.3389/fonc.2020.587809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843373PMC
January 2021

Crosstalk Between Dermal Fibroblasts and Dendritic Cells During Dengue Virus Infection.

Front Immunol 2020 23;11:538240. Epub 2020 Oct 23.

Departamento de Biomedicina Molecular Centro de Investigación y de Estudios Avanzados, del Instituto Politécnico Nacional, Ciudad de México, México.

Dengue virus infection (DENV-2) is transmitted by infected mosquitoes the skin, where many dermal and epidermal cells are potentially susceptible to infection. Most of the cells in an area of infection will establish an antiviral microenvironment to control viral replication. Although cumulative studies report permissive DENV-2 infection in dendritic cells, keratinocytes, and fibroblasts, among other cells also infected, little information is available regarding cell-to-cell crosstalk and the effect of this on the outcome of the infection. Therefore, our study focused on understanding the contribution of fibroblast and dendritic cell crosstalk to the control or promotion of dengue. Our results suggest that dendritic cells promote an antiviral state over fibroblasts by enhancing the production of type I interferon, but not proinflammatory cytokines. Infected and non-infected fibroblasts promoted partial dendritic cell maturation, and the fibroblast-matured cells were less permissive to infection and showed enhanced type I interferon production. We also observed that the soluble mediators produced by non-infected or Poly (I:C) transfected fibroblasts induced allogenic T cell proliferation, but mediators produced by DENV-2 infected fibroblasts inhibited this phenomenon. Additionally, the effects of fibroblast soluble mediators on CD14 monocytes were analyzed to assess whether they affected the differentiation of monocyte derived dendritic cells (moDC). Our data showed that mediators produced by infected fibroblasts induced variable levels of monocyte differentiation into dendritic cells, even in the presence of recombinant GM-CSF and IL-4. Cells with dendritic cell-like morphology appeared in the culture; however, flow cytometry analysis showed that the mediators did not fully downregulate CD14 nor did they upregulate CD1a. Our data revealed that fibroblast-dendritic cell crosstalk promoted an antiviral response mediated manly by type I interferons over fibroblasts. Furthermore, the maturation of dendritic cells and T cell proliferation were promoted, which was inhibited by DENV-2-induced mediators. Together, our results suggest that activation of the adaptive immune response is influenced by the crosstalk of skin resident cells and the intensity of innate immune responses established in the microenvironment of the infected skin.
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http://dx.doi.org/10.3389/fimmu.2020.538240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645109PMC
April 2021

Outer Membrane Vesicles From Modulate Immune Response and Induce Cytoskeleton Rearrangement in Peripheral Blood Mononuclear Cells.

Front Microbiol 2020 19;11:556795. Epub 2020 Oct 19.

Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico.

Similar to what has been described in other Gram-negative bacteria, releases outer membrane vesicles (OMVs). OMVs from 16M and the rough-mutant VTRM1 were able to induce a protective immune response against virulent in mice models. The presence of some proteins which had previously been reported to induce protection against were found in the proteome of OMVs from 16M. However, the proteome of OMVs from VTRM1 had not previously been determined. In order to be better understand the role of OMVs in host-cell interactions, the aim of this work was to compare the proteomes of OMVs from 16M and the derived rough-mutant VTRM1, as well as to characterize the immune response induced by vesicles on host cells. Additionally, the effect of SDS and proteinase K on the stability of OMVs was analyzed. OMVs from 16M (smooth strain) and the VTRM1 rough mutant (lacking the -polysaccharide side chain) were analyzed through liquid chromatography-mass spectrometry (LC-MS/MS). OMVs were treated with proteinase K, sodium deoxycholate, and SDS, and then their protein profile was determined using SDS-PAGE. Furthermore, PBMCs were treated with OMVs in order to measure their effect on cytoskeleton, surface molecules, apoptosis, DNA damage, proliferation, and cytokine-induction. A total of 131 proteins were identified in OMVs from 16M, and 43 in OMVs from VTRM1. Proteome comparison showed that 22 orthologous proteins were common in vesicles from both strains, and their core proteome contained Omp31, Omp25, GroL, and Omp16. After a subsequent detergent and enzyme treatment, OMVs from VTRM1 exhibited higher sensitive compared to OMVs from the 16M strain. Neither OMVs induced IL-17, proliferation, apoptosis or DNA damage. Nonetheless, OMVs from the smooth and rough strains induced overproduction of TNFα and IL-6, as well as actin and tubulin rearrangements in the cytoskeleton. Moreover, OMVs from both strains inhibited PD-L1 expression in T-cells. These data revealed significant differences in OMVs derived from the rough and smooth strains, among which, the presence or absence of complete LPS appeared to be crucial to protect proteins contained within vesicles and to drive the immune response.
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http://dx.doi.org/10.3389/fmicb.2020.556795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604303PMC
October 2020

Langerhans Cells From Mice at Birth Express Endocytic- and Pattern Recognition-Receptors, Migrate to Draining Lymph Nodes Ferrying Antigen and Activate Neonatal T Cells .

Front Immunol 2020 27;11:744. Epub 2020 Apr 27.

Department of Cell Biology, Center for Advanced Research, The National Polytechnic Institute, Cinvestav-IPN, Mexico City, Mexico.

Antigen capturing at the periphery is one of the earliest, crucial functions of antigen-presenting cells (APCs) to initiate immune responses. Langerhans cells (LCs), the epidermal APCs migrate to draining lymph nodes (DLNs) upon acquiring antigens. An arsenal of endocytic molecules is available to this end, including lectins and pathogen recognition receptors (PRRs). However, cutaneous LCs are poorly defined in the early neonatal period. We assessed endocytic molecules expression : Mannose (CD206)-, Scavenger (SRA/CD204)-, Complement (CD2l, CDllb)-, and Fc-Receptors (CD16/32, CD23) as well as CD1d, CD14, CD205, Langerin (CD207), MHCII, and TLR4 in unperturbed epidermal LCs from both adult and early neonatal mice. As most of these markers were negative at birth (day 0), LC presence was revealed with the conspicuous, epidermal LC-restricted ADPase (and confirmed with CD45) staining detecting that they were as numerous as adult ones. Unexpectedly, most LCs at day 0 expressed CD14 and CD204 while very few were MHCII+ and TLR4+. In contrast, adult LCs lacked all these markers except Langerin, CD205, CD11b, MHCII and TLR4. Intriguingly, the CD204+ and CD14+ LCs predominant at day 0, apparently disappeared by day 4. Upon cutaneous FITC application, LCs were reduced in the skin and a CD204+MHCII+FITC+ population with high levels of CD86 subsequently appeared in DLNs, with a concomitant increased percentage of CD3+CD69+ T cells, strongly suggesting that neonatal LCs were able both to ferry the cutaneous antigen into DLNs and to activate neonatal T cells . Cell cycle analysis indicated that neonatal T cells in DLNs responded with proliferation. Our study reveals that epidermal LCs are present at birth, but their repertoire of endocytic molecules and PRRs differs to that of adult ones. We believe this to be the first description of CDl4, CD204 and TLR4 in neonatal epidermal LCs . Newborns' LCs express molecules to detect antigens during early postnatal periods, are able to take up local antigens and to ferry them into DLNs conveying the information to responsive neonatal T cells.
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http://dx.doi.org/10.3389/fimmu.2020.00744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197463PMC
March 2021

Cutaneous Dengue Virus Inoculation Triggers Strong B Cell Reactions but Contrastingly Poor T Cell Responses.

Virol Sin 2020 Oct 20;35(5):575-587. Epub 2020 Apr 20.

Department of Cell Biology, Center for Advanced Research (CINVESTAV-IPN), The National Polytechnic Institute, 07360, Mexico City, Mexico.

Dengue is a global health problem without current specific treatment nor safe vaccines available. While severe dengue is related to pre-existing non-neutralizing dengue virus (DENV) antibodies, the role of T cells in protection or pathology is unclear. Using cutaneous DENV infection in immunocompetent mice we previously showed the generation of PNA+ germinal centers (GCs), now we assessed the activation and proliferation of B and T cells in draining lymph nodes (DLNs). We found a drastic remodelling of DLN compartments from 7 to 14 days post-infection (dpi) with greatly enlarged B cell follicles, occupying almost half of the DLN area compared to ~24% in naïve conditions. Enormous clusters of proliferating (Ki-67+) cells inside B follicles were found 14 dpi, representing ~33% of B cells in DLNs but only ~2% in non-infected mice. Inside GCs, we noticed an important recruitment of tingle body macrophages removing apoptotic cells. In contrast, the percentage of paracortex area and total T cells decreased by 14-16 dpi, compared to controls. Scattered randomly distributed Ki-67+ T cells were found, similar to non-infected mice. CD69 expression by CD4+ and CD8+ T cells was minor, while it was remarkable in B cells, representing 1764.7% of change from basal levels 3 dpi. The apparent lack of T cell responses cannot be attributed to apoptosis since no significant differences were observed compared to non-infected mice. This study shows massive B cell activation and proliferation in DLNs upon DENV infection. In contrast, we found very poor, almost absent CD4+ and CD8+ T cell responses.
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http://dx.doi.org/10.1007/s12250-020-00213-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168571PMC
October 2020

Proteomic Analysis of Membrane Blebs of 2308 and RB51 and Their Evaluation as an Acellular Vaccine.

Front Microbiol 2019 29;10:2714. Epub 2019 Nov 29.

Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico.

Membrane blebs are released from Gram-negative bacteria, however, little is known about blebs. This work pursued two objectives, the first was to determine and identify the proteins in the membrane blebs by proteomics and analysis. The second aim was to evaluate the use of membrane blebs of 2308 and RB51 as an acellular vaccine and . To achieve these aims, membrane blebs from 2308 and RB51 were obtained and then analyzed by liquid chromatography coupled to mass spectrometry. membrane blebs were used as a "vaccine" to induce an immune response in BALB/c mice, using the strain RB51 as a positive vaccine control. After subsequent challenge with 2308, CFUs in spleens were determined; and immunoglobulins IgG1 and IgG2a were measured in murine serum by ELISA. Also, activation and costimulatory molecules induced by membrane blebs were analyzed in splenocytes by flow cytometry. Two hundred and twenty eight proteins were identified in 2308 membrane blebs and 171 in RB51 blebs, some of them are well-known immunogens such as SodC, Omp2b, Omp2a, Omp10, Omp16, and Omp19. Mice immunized with membrane blebs from rough or smooth induced similar protective immune responses as well as the vaccine RB51 after the challenge with virulent strain 2308 ( < 0.05). The levels of IgG2a in mice vaccinated with 2308 membrane blebs were higher than those vaccinated with RB51 membrane blebs or RB51 post-boosting. Moreover, mice immunized with 2308 blebs increased the percentage of activated B cells (CD19CD69) Therefore, membrane blebs are potential candidates for the development of an acellular vaccine against brucellosis, especially those derived from the rough strains so that serological diagnostic is not affected.
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http://dx.doi.org/10.3389/fmicb.2019.02714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895012PMC
November 2019

Multiparameter flow cytometry analysis of leukocyte markers for diagnosis in preterm neonatal sepsis.

J Matern Fetal Neonatal Med 2019 Sep 19:1-11. Epub 2019 Sep 19.

Faculty of Medicine, Combined Studies Plan in Medicine, National Autonomous University of Mexico , Mexico City , Mexico.

Neonatal sepsis is an important public health concern worldwide due to its immediate lethality and long-term morbidity rates, Clinical evaluation and laboratory analyses are indispensable for diagnosis of neonatal sepsis. However, assessing multiple biomarkers in neonates is difficult due to limited blood availability. The aim is to investigate if the neonatal sepsis in preterm could be identified by multiparameter analysis with flow cytometry. The expression of activation-related molecules was evaluated by flow cytometry in newborn with or without risk factors for sepsis. Our analysis revealed that several markers could be useful for sepsis diagnosis, such as CD45RA, CD45RO, or CD71 on T cells; HLA-DR on NKT or classic monocytes, and TREM-1 on non-classic monocytes or neutrophils. However, ROC analysis shows that the expression of CD45RO on T lymphocytes is the only useful biomarker for diagnosis of neonatal late-onset sepsis. Also, decision tree analyses showed that CD45RO plus CD27 could help differentiate the preterm septic neonates from those with risk factors. Our study shows a complementary and practical strategy for biomarker assessment in neonatal sepsis.
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http://dx.doi.org/10.1080/14767058.2019.1666100DOI Listing
September 2019

Dendritic cells and Brucella spp. interaction: the sentinel host and the stealthy pathogen.

Folia Microbiol (Praha) 2020 Feb 19;65(1):1-16. Epub 2019 Feb 19.

Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala S/N, Santo Tomás, 11340, Mexico city, Mexico.

As dendritic cells (DCs) are among the first cells to encounter antigens, these cells trigger both innate and T cell responses, and are the most potent antigen-presenting cells. Brucella spp., which is an intracellular facultative and stealthy pathogen, is able to evade the bactericidal activities of professional phagocytes. Several studies have demonstrated that Brucella can survive and replicate intracellularly, thereby provoking impaired maturation of DCs. Therefore, the interaction between DCs and Brucella becomes an interesting model to study the immune response. In this review, we first will describe the most common techniques for DCs differentiation in vitro as well as general features of brucellosis. Then, the interaction of DCs and Brucella, including pathogen recognition, molecular mechanisms of bacterial pathogenesis, and intracellular trafficking of Brucella to subvert innate response, will be reviewed. Finally, we will debate diversity in immunological DC response and the controversial role of DC activation against Brucella infection.
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http://dx.doi.org/10.1007/s12223-019-00691-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224029PMC
February 2020

The Outer Membrane Vesicles of ATCC 7966: A Proteomic Analysis and Effect on Host Cells.

Front Microbiol 2018 16;9:2765. Epub 2018 Nov 16.

Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico.

Gram-negative bacteria release outer membrane vesicles (OMVs) into the extracellular environment. OMVs have been studied extensively in bacterial pathogens, however, information related with the composition of OMVs is missing. In this study we analyzed the composition of purified OMVs from ATCC 7966 by proteomics. Also we studied the effect of OMVs on human peripheral blood mononuclear cells (PBMCs). Vesicles were grown in agar plates and then purified through ultracentrifugation steps. Purified vesicles showed an average diameter of 90-170 nm. Moreover, 211 unique proteins were found in OMVs from ; some of them are well-known as virulence factors such as: haemolysin Ahh1, RtxA toxin, extracellular lipase, HcpA protein, among others. OMVs from ATCC 7966 induced lymphocyte activation and apoptosis in monocytes, as well as over-expression of pro-inflammatory cytokines. This work contributed to the knowledge of the composition of the vesicles of ATCC 7966 and their interaction with the host cell.
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http://dx.doi.org/10.3389/fmicb.2018.02765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250952PMC
November 2018

Human keratinocyte cultures (HaCaT) can be infected by DENV, triggering innate immune responses that include IFNλ and LL37.

Immunobiology 2018 11 6;223(11):608-617. Epub 2018 Jul 6.

Department of Molecular Biomedicine, Av. IPN # 2508 Col. San Pedro Zacatenco, 07360 México, D.F., Mexico. Electronic address:

The skin is the first anatomical region that dengue virus (DENV) encounters during the natural infection. Although the role of some skin resident cells like dendritic cells and fibroblasts has been demonstrated to be crucial to elucidate the role of resident cells and molecules participating during the early events of the innate immune response, the participation of keratinocytes during DENV infection has not been fully elucidated. In this paper we aimed to evaluate the use of the HaCaT cell line as a model to study the immune responses of skin keratinocytes to DENV infection. We demonstrated productive DENV-2 infection of HaCaT cells and their capability to establish an antiviral response through production of type I and type III interferons (IFN-β and IFN-λ). The production of these cytokines by HaCaT cells correlated with upregulation of IFN-inducible transmembrane protein-3 (IFITM3) and viperin in bystander, uninfected cells. We also observed an increase in secretion of IL-6 and IL-8. Skin keratinocytes are known to secrete antimicrobial peptides (AMPs) during viral infections. In our model, DENV-2 infected HaCaT cells upregulate the production of cytoplasmic LL-37. We evaluated the dual role of LL-37, HBD2, and HBD3 antiviral activity and immunoregulation during DENV-2 infection of HaCaT cells and found that LL-37 significantly reduced DENV-2 replication. This indicates that the HaCaT cell line can be used as a model for studying the innate response of keratinocytes to DENV infection. Our results also suggest that skin keratinocytes play an important role in the skin microenvironment after DENV infection by secreting molecules like type I and type III IFNs, pro-inflammatory molecules, and LL-37, which may contribute to the protection against arboviral infections.
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http://dx.doi.org/10.1016/j.imbio.2018.07.006DOI Listing
November 2018

Competitive suppression of dengue virus replication occurs in chikungunya and dengue co-infected Mexican infants.

Parasit Vectors 2018 Jul 3;11(1):378. Epub 2018 Jul 3.

Department of Molecular Biomedicine, CINVESTAV-IPN, México City, México.

Background: Co-circulation of dengue virus (DENV) and chikungunya virus (CHIKV) is increasing worldwide but information on the viral dynamics and immune response to DENV-CHIKV co-infection, particularly in young infants, is scant.

Methods: Blood samples were collected from 24 patients, aged 2 months to 82 years, during a CHIKV outbreak in Mexico. DENV and CHIKV were identified by RT-PCR; ELISA was used to detect IgM and IgG antibodies. CHIKV PCR products were cloned, sequenced and subjected to BLAST analysis. To address serological findings, HMEC-1 and Vero cells were inoculated with DENV-1, DENV-2 and CHIKV alone and in combination (DENV-2-CHIKV and DENV-1-CHIKV); viral titers were measured at 24, 48 and 72 h.

Results: Nine patients (38%) presented co-infection, of who eight were children. None of the patients presented severe illness. Sequence analysis showed that the circulating CHIKV virus belonged to the Asian lineage. Seroconversion to both viruses was only observed in the four patients five years or older, while the five infants under two years of age only seroconverted to CHIKV. Viral titers in the CHIKV mono-infected cells were greater than in the DENV-1 and DENV-2 mono-infected cells. Furthermore, we observed significantly increased CHIKV progeny and reduction of DENV progeny in the co-infected cells.

Conclusions: In our population, DENV-CHIKV co-infection was not associated with increased clinical severity. Our in vitro assay findings strongly suggest that the lack of DENV IgG conversion in the co-infected infants is due to suppression of DENV replication by the Asian lineage CHIKV. The presence of maternal antibody and immature immune responses in the young infants may also play a role.
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http://dx.doi.org/10.1186/s13071-018-2942-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029041PMC
July 2018

Catalase Inhibits the Formation of Mast Cell Extracellular Traps.

Front Immunol 2018 28;9:1161. Epub 2018 May 28.

Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, México City, Mexico.

Tuberculosis is one of the leading causes of human morbidity and mortality. (Mtb) employs different strategies to evade and counterattack immune responses persisting for years. Mast cells are crucial during innate immune responses and help clear infections inflammation or by direct antibacterial activity through extracellular traps (MCETs). Whether Mtb induce MCETs production is unknown. In this study, we report that viable Mtb did not induce DNA release by mast cells, but heat-killed Mtb (HK-Mtb) did. DNA released by mast cells after stimulation with HK-Mtb was complexed with histone and tryptase. MCETs induced with PMA and HK-Mtb were unable to kill live Mtb bacilli. Mast cells stimulated with HK-Mtb induced hydrogen peroxide production, whereas cells stimulated with viable Mtb did not. Moreover, MCETs induction by HK-Mtb was dependent of NADPH oxidase activity, because its blockade resulted in a diminished DNA release by mast cells. Interestingly, catalase-deficient Mtb induced a significant production of hydrogen peroxide and DNA release by mast cells, indicating that catalase produced by Mtb prevents MCETs release by degrading hydrogen peroxide. Our findings show a new strategy employed by Mtb to overcome the immune response through inhibiting MCETs formation, which could be relevant during early stages of infection.
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http://dx.doi.org/10.3389/fimmu.2018.01161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985745PMC
August 2019

Corrigendum: Anti-Lipid IgG Antibodies Are Produced Germinal Centers in a Murine Model Resembling Human Lupus.

Front Immunol 2017 12;8:440. Epub 2017 Apr 12.

Department of Cell Biology, Center for Research and Advanced Studies, CINVESTAV-IPN, Instituto Politécnico Nacional (IPN) , Mexico City , Mexico.

[This corrects the article on p. 396 in vol. 7, PMID: 27746783.].
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http://dx.doi.org/10.3389/fimmu.2017.00440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388691PMC
April 2017

Immunization of Newborn Mice Accelerates the Architectural Maturation of Lymph Nodes, But AID-Dependent IgG Responses Are Still Delayed Compared to the Adult.

Front Immunol 2017 19;8:13. Epub 2017 Jan 19.

Department of Cell Biology, Center for Advanced Research, The National Polytechnic Institute, Cinvestav-IPN , Mexico City , Mexico.

Lymph nodes (LNs) have evolved to maximize antigen (Ag) collection and presentation as well as lymphocyte proliferation and differentiation-processes that are spatially regulated by stromal cell subsets, including fibroblastic reticular cells (FRCs) and follicular dendritic cells (FDCs). Here, we showed that naïve neonatal mice have poorly organized LNs with few B and T cells and undetectable FDCs, whereas adult LNs have numerous B cells and large FDC networks. Interestingly, immunization on the day of birth accelerated B cell accumulation and T cell recruitment into follicles as well as FDC maturation and FRC organization in neonatal LNs. However, compared to adults, the formation of germinal centers was both delayed and reduced following immunization of neonatal mice. Although immunized neonates poorly expressed activation-induced cytidine deaminase (AID), they were able to produce Ag-specific IgGs, but with lower titers than adults. Interestingly, the Ag-specific IgM response in neonates was similar to that in adults. These results suggest that despite an accelerated structural maturation of LNs in neonates following vaccination, the B cell response is still delayed and reduced in its ability to isotype switch most likely due to poor AID expression. Of note, naïve pups born to Ag-immunized mothers had high titers of Ag-specific IgGs from day 0 (at birth). These transferred antibodies confirm a mother-derived coverage to neonates for Ags to which mothers (and most likely neonates) are exposed, thus protecting the neonates while they produce their own antibodies. Finally, the type of Ag used in this study and the results obtained also indicate that T cell help would be operating at this stage of life. Thus, neonatal immune system might not be intrinsically immature but rather evolutionary adapted to cope with Ags at birth.
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http://dx.doi.org/10.3389/fimmu.2017.00013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5243854PMC
January 2017

Anti-Lipid IgG Antibodies Are Produced Germinal Centers in a Murine Model Resembling Human Lupus.

Front Immunol 2016 29;7:396. Epub 2016 Sep 29.

Department of Cell Biology, Center for Research and Advanced Studies, CINVESTAV-IPN, National Polytechnic Institute , Mexico City , Mexico.

Anti-lipid IgG antibodies are produced in some mycobacterial infections and in certain autoimmune diseases [such as anti-phospholipid syndrome, systemic lupus erythematosus (SLE)]. However, few studies have addressed the B cell responses underlying the production of these immunoglobulins. Anti-lipid IgG antibodies are consistently found in a murine model resembling human lupus induced by chlorpromazine-stabilized non-bilayer phospholipid arrangements (NPA). NPA are transitory lipid associations found in the membranes of most cells; when NPA are stabilized they can become immunogenic and induce specific IgG antibodies, which appear to be involved in the development of the mouse model of lupus. Of note, anti-NPA antibodies are also detected in patients with SLE and leprosy. We used this model of lupus to investigate the cellular mechanisms that lead to the production of anti-lipid, class-switched IgG antibodies. In this murine lupus model, we found plasma cells (Gr1, CD19, CD138) producing NPA-specific IgGs in the draining lymph nodes, the spleen, and the bone marrow. We also found a significant number of germinal center B cells (IgD, CD19, PNA) specific for NPA in the draining lymph nodes and the spleen, and we identified the presence of NPA in these germinal centers. By contrast, very few NPA-specific, extrafollicular reaction B cells (B220, Blimp1) were found. Moreover, when assessing the anti-NPA IgG antibodies produced during the experimental protocol, we found that the affinity of these antibodies progressively increased over time. Altogether, our data indicate that, in this murine model resembling human lupus, B cells produce anti-NPA IgG antibodies mainly via germinal centers.
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http://dx.doi.org/10.3389/fimmu.2016.00396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5040728PMC
September 2016

Listeria monocytogenes induces mast cell extracellular traps.

Immunobiology 2017 02 6;222(2):432-439. Epub 2016 Aug 6.

Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, Mexico; Unidad de Desarrollo e Investigación en Bioprocesos (UDIBI), Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, Mexico. Electronic address:

Mast cells play an essential role in different immunological phenomena including allergy and infectious diseases. Several bacteria induce mast cell activation leading to degranulation and the production of several cytokines and chemokines. However, mast cells also have different microbicidal activities such as phagocytosis and the release of DNA with embedded granular proteins known as Mast Cell Extracellular Traps (MCETs). Although previous reports indicate that extracellular bacteria are able to induce MCETs little is known if intracellular bacteria can induce these structures. In this work, we evaluated MCETs induction by the intracellular bacteria Listeria monocytogenes. We found that mast cells released DNA after stimulation with L. monocytogenes, and this DNA was complexed to histone and tryptase. Before extracellular DNA release, L. monocytogenes induced modifications to the mast cell nuclear envelope and DNA was detected outside the nucleus. L. monocytogenes stimulated mast cells to produce significant amounts of reactive oxygen species (ROS) and blocking NADPH oxidase diminished DNA release by mast cells. Finally, MCETs showed antimicrobial activity against L. monocytogenes that was partially blocked when β-hexosaminidase activity was inhibited. These results show that L. monocytogenes induces mast cells to produce microbicidal MCETs, suggesting a role for mast cells in containing infection beyond the induction of inflammation.
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http://dx.doi.org/10.1016/j.imbio.2016.08.006DOI Listing
February 2017

The Cellular Bases of Antibody Responses during Dengue Virus Infection.

Front Immunol 2016 6;7:218. Epub 2016 Jun 6.

Department of Cell Biology, Center for Advanced Research, The National Polytechnic Institute, Cinvestav-IPN , Mexico City , Mexico.

Dengue virus (DENV) is one of the most significant human viral pathogens transmitted by mosquitoes and can cause from an asymptomatic disease to mild undifferentiated fever, classical dengue, and severe dengue. Neutralizing memory antibody (Ab) responses are one of the most important mechanisms that counteract reinfections and are therefore the main aim of vaccination. However, it has also been proposed that in dengue, some of these class-switched (IgG) memory Abs might worsen the disease. Although these memory Abs derive from B cells by T-cell-dependent processes, we know rather little about the (acute, chronic, or memory) B cell responses and the complex cellular mechanisms generating these Abs during DENV infections. This review aims to provide an updated and comprehensive perspective of the B cell responses during DENV infection, starting since the very early events such as the cutaneous DENV entrance and the arrival into draining lymph nodes, to the putative B cell activation, proliferation, and germinal centers (GCs) formation (the source of affinity-matured class-switched memory Abs), till the outcome of GC reactions such as the generation of plasmablasts, Ab-secreting plasma cells, and memory B cells. We discuss topics very poorly explored such as the possibility of B cell infection by DENV or even activation-induced B cell death. The current information about the nature of the Ab responses to DENV is also illustrated.
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http://dx.doi.org/10.3389/fimmu.2016.00218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893500PMC
July 2016

Nonbilayer Phospholipid Arrangements Are Toll-Like Receptor-2/6 and TLR-4 Agonists and Trigger Inflammation in a Mouse Model Resembling Human Lupus.

J Immunol Res 2015 19;2015:369462. Epub 2015 Oct 19.

Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute (IPN), 11340 Mexico City, DF, Mexico.

Systemic lupus erythematosus is characterized by dysregulated activation of T and B cells and autoantibodies to nuclear antigens and, in some cases, lipid antigens. Liposomes with nonbilayer phospholipid arrangements induce a disease resembling human lupus in mice, including IgM and IgG antibodies against nonbilayer phospholipid arrangements. As the effect of these liposomes on the innate immune response is unknown and innate immune system activation is necessary for efficient antibody formation, we evaluated the effect of these liposomes on Toll-like receptor (TLR) signaling, cytokine production, proinflammatory gene expression, and T, NKT, dendritic, and B cells. Liposomes induce TLR-4- and, to a lesser extent, TLR-2/TLR-6-dependent signaling in TLR-expressing human embryonic kidney (HEK) cells and bone marrow-derived macrophages. Mice with the lupus-like disease had increased serum concentrations of proinflammatory cytokines, C3a and C5a; they also had more TLR-4-expressing splenocytes, a higher expression of genes associated with TRIF-dependent TLR-4-signaling and complement activation, and a lower expression of apoptosis-related genes, compared to healthy mice. The percentage of NKT and the percentage and activation of dendritic and B2 cells were also increased. Thus, TLR-4 and TLR-2/TLR-6 activation by nonbilayer phospholipid arrangements triggers an inflammatory response that could contribute to autoantibody production and the generation of a lupus-like disease in mice.
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http://dx.doi.org/10.1155/2015/369462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629040PMC
September 2016

Soluble flagellin coimmunization attenuates Th1 priming to Salmonella and clearance by modulating dendritic cell activation and cytokine production.

Eur J Immunol 2015 Aug 24;45(8):2299-311. Epub 2015 Jun 24.

Division of Immunity and Infection, Institute of Biomedical Research, University of Birmingham, Birmingham, UK.

Soluble flagellin (sFliC) from Salmonella Typhimurium (STm) can induce a Th2 response to itself and coadministered antigens through ligation of TLR5. These properties suggest that sFliC could potentially modulate responses to Th1 antigens like live STm if both antigens are given concurrently. After coimmunization of mice with sFliC and STm there was a reduction in Th1 T cells (T-bet(+) IFN-γ(+) CD4 T cells) compared to STm alone and there was impaired clearance of STm. In contrast, there was no significant defect in the early extrafollicular B-cell response to STm. These effects are dependent upon TLR5 and flagellin expression by STm. The mechanism for these effects is not related to IL-4 induced to sFliC but rather to the effects of sFliC coimmunization on DCs. After coimmunization with STm and sFliC, splenic DCs had a lower expression of costimulatory molecules and profoundly altered kinetics of IL-12 and TNFα expression. Ex vivo experiments using in vivo conditioned DCs confirmed the effects of sFliC were due to altered DC function during a critical window in the coordinated interplay between DCs and naïve T cells. This has marked implications for understanding how limits in Th1 priming can be achieved during infection-induced, Th1-mediated inflammation.
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http://dx.doi.org/10.1002/eji.201545564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973836PMC
August 2015

Germinal center reaction following cutaneous dengue virus infection in immune-competent mice.

Front Immunol 2015 24;6:188. Epub 2015 Apr 24.

Department of Cell Biology, Center for Advanced Research, National Polytechnic Institute, Cinvestav-IPN , Mexico City , Mexico.

Dengue virus (DENV) has four serotypes, which can cause from asymptomatic disease to severe dengue. Heterologous secondary infections have been associated to a greater risk of potentially fatal dengue due to non-neutralizing memory antibodies (Abs), which facilitate the infection, such as anti-precursor membrane (prM) Abs, among other mechanisms. Usually, class-switched memory Abs are generated mainly through germinal centers (GCs). However, the cellular events underlying these Ab responses to DENV, especially during repeated/secondary infections, have been poorly studied. We wanted to know whether there is involvement of GC reactions during cutaneous DENV infection and whether there is any sort of preferential Ab responses to defined viral proteins. Intradermal DENV inoculation at a relatively low dose efficiently infects immune-competent BALB/c mice, inducing higher quantities of DENV-specific GC B cells and larger GCs than the control conditions. Interestingly, GCs exhibited as much prM as envelope (E) and non-structural 3 viral proteins in situ. Intriguingly, despite the much larger abundance of E protein than of prM protein in the virions, infected animals showed similar amounts of circulating Abs and Ag-specific GC B cells both for prM and for E proteins, even significantly higher for prM. To the best of our knowledge, there are no reports of the GC responses during DENV infection. This relatively stronger anti-prM response could be triggered by DENV to preferentially promote Abs against certain viral proteins, which might favor infections by facilitating DENV invasion of host cells. It is thus conceivably that DENV might have evolved to induce this kind of Ab responses.
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http://dx.doi.org/10.3389/fimmu.2015.00188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408864PMC
May 2015

ESAT-6 Targeting to DEC205+ Antigen Presenting Cells Induces Specific-T Cell Responses against ESAT-6 and Reduces Pulmonary Infection with Virulent Mycobacterium tuberculosis.

PLoS One 2015 27;10(4):e0124828. Epub 2015 Apr 27.

Department of Cell Biology, Cinvestav-IPN, Ciudad de México, Mexico.

Airways infection with Mycobacterium tuberculosis (Mtb) is contained mostly by T cell responses, however, Mtb has developed evasion mechanisms which affect antigen presenting cell (APC) maturation/recruitment delaying the onset of Ag-specific T cell responses. Hypothetically, bypassing the natural infection routes by delivering antigens directly to APCs may overcome the pathogen's naturally evolved evasion mechanisms, thus facilitating the induction of protective immune responses. We generated a murine monoclonal fusion antibody (α-DEC-ESAT) to deliver Early Secretory Antigen Target (ESAT)-6 directly to DEC205+ APCs and to assess its in vivo effects on protection associated responses (IFN-γ production, in vivo CTL killing, and pulmonary mycobacterial load). Treatment with α-DEC-ESAT alone induced ESAT-6-specific IFN-γ producing CD4+ T cells and prime-boost immunization prior to Mtb infection resulted in early influx (d14 post-infection) and increased IFN-γ+ production by specific T cells in the lungs, compared to scarce IFN-γ production in control mice. In vivo CTL killing was quantified in relevant tissues upon transferring target cells loaded with mycobacterial antigens. During infection, α-DEC-ESAT-treated mice showed increased target cell killing in the lungs, where histology revealed cellular infiltrate and considerably reduced bacterial burden. Targeting the mycobacterial antigen ESAT-6 to DEC205+ APCs before infection expands specific T cell clones responsible for early T cell responses (IFN-γ production and CTL activity) and substantially reduces lung bacterial burden. Delivering mycobacterial antigens directly to APCs provides a unique approach to study in vivo the role of APCs and specific T cell responses to assess their potential anti-mycobacterial functions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124828PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4411092PMC
February 2016

Prolonged exposure to neutrophil extracellular traps can induce mitochondrial damage in macrophages and dendritic cells.

Springerplus 2015 2;4:161. Epub 2015 Apr 2.

Department of Cell Biology, Cinvestav-IPN. AV. IPN No 2508, Zacatenco, C.P. 07330 D.F México.

Neutrophils are one the earliest, crucial innate defenses against innumerable pathogens. Their main microbicidal activities include phagocytosis and degranulation, with many pharmacologically active molecules contributing to inflammation. Recently, a novel antimicrobial mechanism was discovered; the Neutrophil Extracelullar Traps (NETs) formed by extrusion of DNA and associated molecules (histones, elastase, antimicrobial peptides, among others) which trap and kill microorganisms. Since NETs were recently described, research has focused on their induction and microbicidal properties, and recently on disease involvement. However, the functional consequences of NETs interacting with other immune cells, either resident or recruited during early inflammation, have not been assessed. We therefore investigated the consequences of exposing two major APCs, macrophages (Mfs) and conventional Dendritic Cells (cDCs) to NETs. Our data revealed that at early times (30 min), both Antigen Presenting Cells (APCs) showed induction of important costimulatory molecules (CD80, CD86). Unexpectedly, however, at later times (6 and 24 hours) NETs apparently triggered a cell death process in these APCs by a caspase- and Apoptosis induced factor (AIF)-dependent pathway, suggesting mitochondrial damage. By rhodamine-123 labelling we found that in both APCs, relatively prolonged exposure to NETs or their components importantly decreased the mitochondrial membrane potential. Ultrastructural analysis confirmed mitochondrial alterations in both APCs. Our results would suggest that early in inflammation, NETs can activate the two main APCs (Mfs and cDCs), but as the process continues, NETs can then initiate apoptosis of these cells through mitochondrial harm. Conceivable, this "late" induction of cell death in these two APCs might start limiting an ongoing inflammatory process to control it.
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http://dx.doi.org/10.1186/s40064-015-0932-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392041PMC
April 2015

Novel monoclonal antibody against alphaX subunit from horse CD11c/CD18 integrin.

Vet Immunol Immunopathol 2015 Apr 12;164(3-4):220-6. Epub 2015 Feb 12.

Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia - Universidad Nacional Autonoma de Mexico, Avenida Universidad, 2001, Colonia Chamilpa, Apartado Postal 510-3, Cuernavaca, Morelos, Mexico. Electronic address:

The αX I-domain of the horse integrin CD11c was successfully expressed in Escherichia coli, purified, biochemically characterized and used as immunogen to generate murine monoclonal antibodies against horse CD11c, which are not yet commercially available. One monoclonal antibody mAb-1C4 against the αX I-domain, is an IgG2a able to interact with the recombinant I-domain, showing an EC50=2.4ng according to ELISA assays. By western blot with horse PBMCs lysates the mAb-1C4 recognized a protein of 150kDa which corresponds well with the CD11c molecule. Using immunohistochemistry in horse lymph node tissue sections, mAb-1C4 marked cells in situ, some with apparent dendritic morphology. Thus the mAb generated to a recombinant epitope from horse CD11c identified the molecule in intact cells within horse lymphoid tissue. By the labelling intensity, the histological location (paracortical and interfollicular areas) and the apparent morphology of the marked cells, we can say that these are putative horse dendritic cells (DCs). The development of a mAb to horse CD11c provides a new tool to better study the horse DC biology and opens other biotechnological avenues, such as DC targeting-based vaccines.
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http://dx.doi.org/10.1016/j.vetimm.2015.02.002DOI Listing
April 2015

Differential activation of dendritic cells by Mycobacterium tuberculosis Beijing genotype.

Immunol Invest 2014 21;43(5):436-46. Epub 2014 Mar 21.

Department of Immunology, Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional , ENCB-IPN , México .

Mycobacterium tuberculosis (Mtb) inhibits dendritric cells (DC) function in order to delay T cell response. Furthermore, there is increasing evidence that genetic diversity of Mtb strains can affect their interaction with the immune system. Beijing genotype has attracted attention because of its high prevalence and multi-drug resistance. Although it is known that this genotype is hypervirulent and differentially activates macrophages when compared to other genotypes, little is known about its interaction with DC. In order to address this issue, murine bone marrow derived DC (BMDC) were stimulated with soluble extracts (SE) from BCG, H37Rv, Canetti and Beijing genotypes. We observed that unlike other mycobacteria strains, SE-Beijing was unable to induce maturation of DC as assessed by cell surface MHC-II expression. DC stimulated with SE-Beijing failed to produce IL-12 and TNF-α, but did secrete IL-10. Interestingly, SE-Beijing induced CCR7 and PDL-1 on BMDC, but did not induce the expression of CD86. When BMDC stimulated with SE-Beijing were used to activate CD4+ cells they were unable to induce a Th1 response when compared with less virulent genotypes. These results indicate that Beijing is able to modulate DC activation and function, which may be related to the pathogenesis induced by this genotype.
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http://dx.doi.org/10.3109/08820139.2014.880120DOI Listing
January 2015

Mycobacterium tuberculosis manipulates pulmonary APCs subverting early immune responses.

Immunobiology 2013 Mar 24;218(3):393-401. Epub 2012 May 24.

Department of Cell Biology, Center for Advanced Research CINVESTAV-IPN, Mexico City, Mexico.

Alveolar macrophages (AM) and dendritic cells (DCs) are the main antigen presenting cells (APCs) in the respiratory tract. Whereas macrophages have been extensively studied in tuberculosis, in situ interactions of DC with Mycobacterium tuberculosis (Mtb) are poorly explored. We aimed to characterize lung APCs during pulmonary tuberculosis in Balb/C mice infected with Mtb H37Rv. Mtb-infection via the airways induced a delayed and continuous accumulation of DCs and AM in the lungs. While lung DCs increased after day 3 post-infection, macrophages increased after 2-3 weeks. Although both populations accumulated in lungs during the infection, DCs decreased in the late stages. Infection induced differential expression of co-stimulatory molecules in these lung APCs, decreasing to basal levels in both APCs in the late stages. A remarkable segregation was found regarding bacillary burden. Many macrophages contained numerous bacilli, but DC contained scarce mycobacteria or none. Mtb-infection also induced delayed accumulation of DC in draining lymph nodes. This delayed recruitment was not associated with a lack of IL-12p40, which was detected from day 3 post-infection. Although AM and lung DCs behave differently during pulmonary tuberculosis, Mtb apparently manipulates both lung APCs subverting early protective responses resulting in disease progression.
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http://dx.doi.org/10.1016/j.imbio.2012.05.022DOI Listing
March 2013

Activation of the innate immune response against DENV in normal non-transformed human fibroblasts.

PLoS Negl Trop Dis 2011 Dec 20;5(12):e1420. Epub 2011 Dec 20.

Departamento de Biomedicina Molecular Centro de Investigación y de Estudios Avanzados, México Distrito Federal, Mexico.

Background: When mosquitoes infected with DENV are feeding, the proboscis must traverse the epidermis several times ("probing") before reaching a blood vessel in the dermis. During this process, the salivary glands release the virus, which is likely to interact first with cells of the various epidermal and dermal layers, cells which could be physiologically relevant to DENV infection and replication in humans. However, important questions are whether more abundant non-hematopoietic cells such as fibroblasts become infected, and whether they play any role in antiviral innate immunity in the very early stages of infection, or even if they might be used by DENV as primary replication cells.

Methodology/principal Findings: Fibroblasts freshly released from healthy skin and infected 12 hours after their isolation show a positive signal for DENV. In addition, when primary skin fibroblast cultures were established and subsequently infected, we showed DENV-2 antigen-positive intracellular signal at 24 hours and 48 hours post-infection. Moreover, the fibroblasts showed productive infection in a conventional plaque assay. The skin fibroblasts infected with DENV-2 underwent potent signaling through both TLR3 and RIG- 1, but not Mda5, triggering up-regulation of IFNβ, TNFα, defensin 5 (HB5) and β defensin 2 (HβD2). In addition, DENV infected fibroblasts showed increased nuclear translocation of interferon (IFN) regulatory factor 3 (IRF3), but not interferon regulatory factor 7 (IRF7), when compared with mock-infected fibroblasts.

Conclusions/significance: In this work, we demonstrated the high susceptibility to DENV infection by primary fibroblasts from normal human skin, both in situ and in vitro. Our results suggest that these cells may contribute to the pro-inflammatory and anti-viral microenvironment in the early stages of interaction with DENV-2. Furthermore, the data suggest that fibroblast may also be used as a primary site of DENV replication and provide viral particles that may contribute to subsequent viral dissemination.
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http://dx.doi.org/10.1371/journal.pntd.0001420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243703PMC
December 2011

Neonate antigen presenting cells within murine intestinal muscular layer.

Immunol Invest 2012 23;41(1):104-16. Epub 2011 Jun 23.

Department of Cell Biology, Center for Advanced Research, CINVESTAV-IPN, Mexico City, Mexico.

The intestinal mucosa is exposed to a vast antigenic contact. Several antigen presenting cell (APCs) have been described within the gut associated lymphoid tissue (GALT) (Peyer's patches, lamina propria, mesenteric lymph nodes, muscular layer); however, this has been done almost exclusively in adult organisms. As there is no characterization of intestinal muscular layer's APCs during early neonate development we adapted the conventional technique used in adults, to the neonate intestine. We obtained the intestinal muscular layer from early neonates (days 0-3 upon birth) and from young mice (2 and 3 weeks after birth). A planar network of CD45(+), MHC-II(+), DEC-205(+) cells with irregular, some with prominent dendritic morphology was found at birth under basal physiological conditions, whereas Langerin(+) DCs appeared after two weeks. The variations seen in CD45(+), MHC-II(+) and DEC-205(+) cells along the early neonatal development, could be related to the new challenges by intestinal antigen exposure from the newborn diet (breast milk, solid food), and to important environmental changes (start walking, exploring the surroundings, etc). Our study reveals the presence of APCs in intestinal muscular layer at birth, and their subsequent changes in physiological, non-induced conditions, contributing basic information about these cells in the neonate intestinal immune system.
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http://dx.doi.org/10.3109/08820139.2011.586394DOI Listing
March 2012

Reduced in vivo cytotoxicity and increased Mycobacterial burden are associated with virulent Mycobacterium tuberculosis strains during lung infection.

Immunol Invest 2012 2;41(1):51-60. Epub 2011 Jun 2.

Department of Cell Biology Cinvestav-IPN.

Cytotoxic cellular responses are crucial for clearing intracellular pathogens and generating host resistance. Experimental pulmonary tuberculosis is associated with an early delay in T cell responses and with elevated lung bacterial burden during chronic infection. In this study we quantified the in vivo cytotoxicity and the mycobacterial burden from two pertinent tissues in groups of mice infected each with a mycobacterial strain of different virulence. None of the strains induced cytotoxic responses during early (day 14) infection. Interestingly, at 21 and 60 days post-infection, Mycobacterium canettii (lowest virulence) triggered the strongest in vivo cytotoxicity both in lungs and mediastinal lymph nodes. In contrast, Mycobacterium tuberculosis H37Rv (intermediate virulence) and Beijing strains (highest virulence) induced lower cytotoxic responses, and exhibited high bacterial growth, especially in lungs. These in vivo data suggest that virulence of Mycobacterium strains are somehow associated with subverting cytotoxic responses, thus contributing to early bacterial replication and subsequent persistence in the lungs.
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http://dx.doi.org/10.3109/08820139.2011.580408DOI Listing
March 2012

Rotavirus infection activates dendritic cells from Peyer's patches in adult mice.

J Virol 2010 Feb 9;84(4):1856-66. Epub 2009 Dec 9.

Facultad de Medicina, Universidad Autonoma del Estado de Morelos, 62210 Morelos, Mexico.

This study used an in vivo mouse model to analyze the response of dendritic cells (DCs) in Peyer's patches (PPs) within the first 48 h of infection with the wild-type murine rotavirus EDIM (EDIM(wt)). After the infection, the absolute number of DCs was increased by 2-fold in the PPs without a modification of their relative percentage of the total cell number. Also, the DCs from PPs of infected mice showed a time-dependent migration to the subepithelial dome (SED) and an increase of the surface activation markers CD40, CD80, and CD86. This response was more evident at 48 h postinfection (p.i.) and depended on viral replication, since DCs from PPs of mice inoculated with UV-treated virus did not show this phenotype. As a result of the activation, the DCs showed an increase in the expression of mRNA for the proinflammatory cytokines interleukin-12/23p40 (IL-12/23p40), tumor necrosis factor alpha (TNF-alpha), and beta interferon (IFN-beta), as well as for the regulatory cytokine IL-10. These results suggest that, a short time after rotavirus infection, the DCs from PPs play a critical role in controlling the infection and, at the same time, avoiding an excessive inflammatory immune response.
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http://dx.doi.org/10.1128/JVI.02640-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812372PMC
February 2010