International Journal of Molecular Sciences

Research

Jump to: Review

16 pages, 2754 KiB

Open AccessArticle

Sex Differences in the Frequencies of B and T Cell Subpopulations of Human Cord Blood

by Michelle Bous, Charline Schmitt, Muriel Charlotte Hans, Regine Weber, Nasenien Nourkami-Tutdibi, Sebastian Tenbruck, Bashar Haj Hamoud, Gudrun Wagenpfeil, Elisabeth Kaiser, Erich-Franz Solomayer, Michael Zemlin and Sybelle Goedicke-Fritz

Int. J. Mol. Sci. 2023, 24(14), 11511; https://doi.org/10.3390/ijms241411511 - 15 Jul 2023

Cited by 1 | Viewed by 1649

Abstract

Cord blood represents a link between intrauterine and early extrauterine development. Cord blood cells map an important time frame in human immune imprinting processes. It is unknown whether the sex of the newborn affects the lymphocyte subpopulations in the cord blood. Nine B [...] Read more.

Cord blood represents a link between intrauterine and early extrauterine development. Cord blood cells map an important time frame in human immune imprinting processes. It is unknown whether the sex of the newborn affects the lymphocyte subpopulations in the cord blood. Nine B and twenty-one T cell subpopulations were characterized using flow cytometry in human cord blood from sixteen male and twenty-one female newborns, respectively. Except for transitional B cells and naïve B cells, frequencies of B cell counts across all subsets was higher in the cord blood of male newborns than in female newborns. The frequency of naïve thymus-negative Th cells was significantly higher in male cord blood, whereas the remaining T cell subpopulations showed a higher count in the cord blood of female newborns. Our study is the first revealing sex differences in the B and T cell subpopulations of human cord blood. These results indicate that sex might have a higher impact for the developing immune system, urging the need to expand research in this area. Full article

(This article belongs to the Special Issue Neonatal Immunology)

► Show Figures

Figure 1

13 pages, 1462 KiB

Open AccessArticle

Increased Expression of Anaphylatoxin C5a-Receptor-1 in Neutrophils and Natural Killer Cells of Preterm Infants

by Hannah Boeckel, Christian M. Karsten, Wolfgang Göpel, Egbert Herting, Jan Rupp, Christoph Härtel and Annika Hartz

Int. J. Mol. Sci. 2023, 24(12), 10321; https://doi.org/10.3390/ijms241210321 - 19 Jun 2023

Viewed by 1197

Abstract

Preterm infants are susceptible to infection and their defense against pathogens relies largely on innate immunity. The role of the complement system for the immunological vulnerability of preterm infants is less understood. Anaphylatoxin C5a and its receptors C5aR1 and -2 are known to [...] Read more.

Preterm infants are susceptible to infection and their defense against pathogens relies largely on innate immunity. The role of the complement system for the immunological vulnerability of preterm infants is less understood. Anaphylatoxin C5a and its receptors C5aR1 and -2 are known to be involved in sepsis pathogenesis, with C5aR1 mainly exerting pro-inflammatory effects. Our explorative study aimed to determine age-dependent changes in the expression of C5aR1 and C5aR2 in neonatal immune cell subsets. Via flow cytometry, we analyzed the expression pattern of C5a receptors on immune cells isolated from peripheral blood of preterm infants (n = 32) compared to those of their mothers (n = 25). Term infants and healthy adults served as controls. Preterm infants had a higher intracellular expression of C5aR1 on neutrophils than control individuals. We also found a higher expression of C5aR1 on NK cells, particularly on the cytotoxic CD56^dim subset and the CD56^- subset. Immune phenotyping of other leukocyte subpopulations revealed no gestational-age-related differences for the expression of and C5aR2. Elevated expression of C5aR1 on neutrophils and NK cells in preterm infants may contribute to the phenomenon of “immunoparalysis” caused by complement activation or to sustained hyper-inflammatory states. Further functional analyses are needed to elucidate the underlying mechanisms. Full article

(This article belongs to the Special Issue Neonatal Immunology)

► Show Figures

Figure 1

17 pages, 3186 KiB

Open AccessArticle

Complement Drives Chronic Inflammation and Progressive Hydrocephalus in Murine Neonatal Germinal Matrix Hemorrhage

by Mohammed Alshareef, Devin Hatchell, Tyler Vasas, Khalil Mallah, Aakash Shingala, Jonathan Cutrone, Ali Alawieh, Chunfang Guo, Stephen Tomlinson and Ramin Eskandari

Int. J. Mol. Sci. 2023, 24(12), 10171; https://doi.org/10.3390/ijms241210171 - 15 Jun 2023

Cited by 1 | Viewed by 1502

Abstract

Germinal matrix hemorrhage (GMH) is a pathology that occurs in infancy, with often devastating long-term consequences. Posthemorrhagic hydrocephalus (PHH) can develop acutely, while periventricular leukomalacia (PVL) is a chronic sequala. There are no pharmacological therapies to treat PHH and PVL. We investigated different [...] Read more.

Germinal matrix hemorrhage (GMH) is a pathology that occurs in infancy, with often devastating long-term consequences. Posthemorrhagic hydrocephalus (PHH) can develop acutely, while periventricular leukomalacia (PVL) is a chronic sequala. There are no pharmacological therapies to treat PHH and PVL. We investigated different aspects of the complement pathway in acute and chronic outcomes after murine neonatal GMH induced at postnatal day 4 (P4). Following GMH-induction, the cytolytic complement membrane attack complex (MAC) colocalized with infiltrating red blood cells (RBCs) acutely but not in animals treated with the complement inhibitor CR2-Crry. Acute MAC deposition on RBCs was associated with heme oxygenase-1 expression and heme and iron deposition, which was reduced with CR2-Crry treatment. Complement inhibition also reduced hydrocephalus and improved survival. Following GMH, there were structural alterations in specific brain regions linked to motor and cognitive functions, and these changes were ameliorated by CR2-Crry, as measured at various timepoints through P90. Astrocytosis was reduced in CR2-Crry-treated animals at chronic, but not acute, timepoints. At P90, myelin basic protein and LAMP-1 colocalized, indicating chronic ongoing phagocytosis of white matter, which was reduced by CR2-Crry treatment. Data indicate acute MAC-mediated iron-related toxicity and inflammation exacerbated the chronic effects of GMH. Full article

(This article belongs to the Special Issue Neonatal Immunology)

► Show Figures

Figure 1

13 pages, 2489 KiB

Open AccessArticle

Depletion of Ly6G-Expressing Neutrophilic Cells Leads to Altered Peripheral T-Cell Homeostasis and Thymic Development in Neonatal Mice

by Jessica Rühle, Marco Ginzel, Stefanie Dietz, Julian Schwarz, Trim Lajqi, Sandra Beer-Hammer, Christian F. Poets, Christian Gille and Natascha Köstlin-Gille

Int. J. Mol. Sci. 2023, 24(9), 7763; https://doi.org/10.3390/ijms24097763 - 24 Apr 2023

Cited by 1 | Viewed by 1665

Abstract

Newborns and especially preterm infants are much more susceptible to infections than adults. Due to immature adaptive immunity, especially innate immune cells play an important role in a newborn’s infection defense. Neonatal neutrophils exhibit profound differences in their functionality compared to neutrophils of [...] Read more.

Newborns and especially preterm infants are much more susceptible to infections than adults. Due to immature adaptive immunity, especially innate immune cells play an important role in a newborn’s infection defense. Neonatal neutrophils exhibit profound differences in their functionality compared to neutrophils of adults. In particular, neonates possess a relevant population of suppressive neutrophils, which not only inhibit but also specifically modulate the function of T-cells. In this study, we investigated whether neonatal neutrophils are already involved in T-cell development in the thymus. For this purpose, we used a newly developed model of antibody-mediated immune cell depletion in which we administered a depleting antibody to pregnant and then lactating dams. Using this method, we were able to sufficiently deplete Ly6G-positive neutrophils in offspring. We demonstrated that the depletion of neutrophils in newborn mice resulted in altered peripheral T-cell homeostasis with a decreased CD4+/CD8+ T-cell ratio and decreased expression of CD62L. Neutrophil depletion even affected T-cell development in the thymus, with increased double positive thymocytes and a decreased CD4+/CD8+ single positive thymocyte ratio. Altogether, we demonstrated a previously unknown mechanism mediating neutrophils’ immunomodulatory effects in newborns. Full article

(This article belongs to the Special Issue Neonatal Immunology)

► Show Figures

Figure 1

13 pages, 5288 KiB

Open AccessArticle

PD-1/PD-L1 Control of Antigen-Specifically Activated CD4 T-Cells of Neonates

by Christiane Majer, Holger Lingel, Aditya Arra, Hans-Gert Heuft, Dirk Bretschneider, Silke Balk, Katrin Vogel and Monika C. Brunner-Weinzierl

Int. J. Mol. Sci. 2023, 24(6), 5662; https://doi.org/10.3390/ijms24065662 - 16 Mar 2023

Cited by 4 | Viewed by 1840

Abstract

Newborns are highly susceptible to infections; however, the underlying mechanisms that regulate the anti-microbial T-helper cells shortly after birth remain incompletely understood. To address neonatal antigen-specific human T-cell responses against bacteria, Staphylococcus aureus (S. aureus) was used as a model pathogen [...] Read more.

Newborns are highly susceptible to infections; however, the underlying mechanisms that regulate the anti-microbial T-helper cells shortly after birth remain incompletely understood. To address neonatal antigen-specific human T-cell responses against bacteria, Staphylococcus aureus (S. aureus) was used as a model pathogen and comparatively analyzed in terms of the polyclonal staphylococcal enterotoxin B (SEB) superantigen responses. Here, we report that neonatal CD4 T-cells perform activation-induced events upon S. aureus/APC-encounter including the expression of CD40L and PD-1, as well as the production of Th1 cytokines, concomitant to T-cell proliferation. The application of a multiple regression analysis revealed that the proliferation of neonatal T-helper cells was determined by sex, IL-2 receptor expression and the impact of the PD-1/PD-L1 blockade. Indeed, the treatment of S. aureus-activated neonatal T-helper cells with PD-1 and PD-L1 blocking antibodies revealed the specific regulation of the immediate neonatal T-cell responses with respect to the proliferation and frequencies of IFNγ producers, which resembled in part the response of adults’ memory T-cells. Intriguingly, the generation of multifunctional T-helper cells was regulated by the PD-1/PD-L1 axis exclusively in the neonatal CD4 T-cell lineage. Together, albeit missing memory T-cells in neonates, their unexperienced CD4 T-cells are well adapted to mount immediate and strong anti-bacterial responses that are tightly controlled by the PD-1/PD-L1 axis, thereby resembling the regulation of recalled memory T-cells of adults. Full article

(This article belongs to the Special Issue Neonatal Immunology)

► Show Figures

Figure 1

18 pages, 3574 KiB

Open AccessArticle

Imbalanced Inflammatory Responses in Preterm and Term Cord Blood Monocytes and Expansion of the CD14⁺CD16⁺ Subset upon Toll-like Receptor Stimulation

by Kirsten Glaser, David Kern, Christian P. Speer, Nicolas Schlegel, Michael Schwab, Ulrich H. Thome, Christoph Härtel and Clyde J. Wright

Int. J. Mol. Sci. 2023, 24(5), 4919; https://doi.org/10.3390/ijms24054919 - 3 Mar 2023

Viewed by 1593

Abstract

Developmentally regulated features of innate immunity are thought to place preterm and term infants at risk of infection and inflammation-related morbidity. Underlying mechanisms are incompletely understood. Differences in monocyte function including toll-like receptor (TLR) expression and signaling have been discussed. Some studies point [...] Read more.

Developmentally regulated features of innate immunity are thought to place preterm and term infants at risk of infection and inflammation-related morbidity. Underlying mechanisms are incompletely understood. Differences in monocyte function including toll-like receptor (TLR) expression and signaling have been discussed. Some studies point to generally impaired TLR signaling, others to differences in individual pathways. In the present study, we assessed mRNA and protein expression of pro- and anti-inflammatory cytokines in preterm and term cord blood (CB) monocytes compared with adult controls stimulated ex vivo with Pam3CSK4, zymosan, polyinosinic:polycytidylic acid, lipopolysaccharide, flagellin, and CpG oligonucleotide, which activate the TLR1/2, TLR2/6, TLR3, TLR4, TLR5, and TLR9 pathways, respectively. In parallel, frequencies of monocyte subsets, stimulus-driven TLR expression, and phosphorylation of TLR-associated signaling molecules were analyzed. Independent of stimulus, pro-inflammatory responses of term CB monocytes equaled adult controls. The same held true for preterm CB monocytes—except for lower IL-1β levels. In contrast, CB monocytes released lower amounts of anti-inflammatory IL-10 and IL-1ra, resulting in higher ratios of pro-inflammatory to anti-inflammatory cytokines. Phosphorylation of p65, p38, and ERK1/2 correlated with adult controls. However, stimulated CB samples stood out with higher frequencies of intermediate monocytes (CD14⁺CD16⁺). Both pro-inflammatory net effect and expansion of the intermediate subset were most pronounced upon stimulation with Pam3CSK4 (TLR1/2), zymosan (TR2/6), and lipopolysaccharide (TLR4). Our data demonstrate robust pro-inflammatory and yet attenuated anti-inflammatory responses in preterm and term CB monocytes, along with imbalanced cytokine ratios. Intermediate monocytes, a subset ascribed pro-inflammatory features, might participate in this inflammatory state. Full article

(This article belongs to the Special Issue Neonatal Immunology)

► Show Figures

Graphical abstract

10 pages, 2276 KiB

Open AccessArticle

Epigenetic Immune Cell Counting to Analyze Potential Biomarkers in Preterm Infants: A Proof of Principle in Necrotizing Enterocolitis

by Michiel H. D. Schoenaker, Mara O. Zuiderwijk, Vincent Bekker, Robbert G. M. Bredius, Jeannette Werner, Janika J. Schulze, Mirjam van der Burg and Maartje Blom

Int. J. Mol. Sci. 2023, 24(3), 2372; https://doi.org/10.3390/ijms24032372 - 25 Jan 2023

Cited by 1 | Viewed by 1615

Abstract

Epigenetic immune cell counting is a DNA (de)methylation-based technique which can be used to quantify lymphocyte subsets on dried blood spots (DBS). The foregoing techniques allow for a retrospective investigation of immune cell profiles in newborns. In this study, we used this technique [...] Read more.

Epigenetic immune cell counting is a DNA (de)methylation-based technique which can be used to quantify lymphocyte subsets on dried blood spots (DBS). The foregoing techniques allow for a retrospective investigation of immune cell profiles in newborns. In this study, we used this technique for determining lymphocyte subcounts as a potential biomarker for necrotizing enterocolitis (NEC). We investigated whether this technique can be implemented in the field of neonatology, by testing whether regulatory T cell (Treg) levels are pre-existently low in preterms with NEC. Newborn screening (NBS) cards from 32 preterms with NEC and 32 age- and weight-matched preterm controls, and 60 healthy term newborns, were analyzed. Relative and absolute cell counts were determined for CD3+, CD4+, CD8+, Th17, and Treg T cells. For both relative and absolute cell counts of CD3+, CD4+, CD8+, and Th17 T cells, significant differences were found between healthy term controls and both preterm groups, but not between preterm groups. For Tregs, no significant differences were found in either relative or absolute counts between any of the newborn groups. This study demonstrates the principle of epigenetic immune cell counting to analyze lymphocyte subsets in preterm neonates. Full article

(This article belongs to the Special Issue Neonatal Immunology)

► Show Figures

Figure 1

Review

Jump to: Research

21 pages, 755 KiB

Open AccessReview

Antimicrobial Peptides (AMPs) and the Microbiome in Preterm Infants: Consequences and Opportunities for Future Therapeutics

by Janina Marissen, Lilith Reichert, Christoph Härtel, Mats Ingmar Fortmann, Kirstin Faust, Delfina Msanga, Jürgen Harder, Michael Zemlin, Mercedes Gomez de Agüero, Katja Masjosthusmann and Alexander Humberg

Int. J. Mol. Sci. 2024, 25(12), 6684; https://doi.org/10.3390/ijms25126684 - 18 Jun 2024

Viewed by 399

Abstract

Antimicrobial peptides (AMPs) are crucial components of the innate immune system in various organisms, including humans. Beyond their direct antimicrobial effects, AMPs play essential roles in various physiological processes. They induce angiogenesis, promote wound healing, modulate immune responses, and serve as chemoattractants for [...] Read more.

Antimicrobial peptides (AMPs) are crucial components of the innate immune system in various organisms, including humans. Beyond their direct antimicrobial effects, AMPs play essential roles in various physiological processes. They induce angiogenesis, promote wound healing, modulate immune responses, and serve as chemoattractants for immune cells. AMPs regulate the microbiome and combat microbial infections on the skin, lungs, and gastrointestinal tract. Produced in response to microbial signals, AMPs help maintain a balanced microbial community and provide a first line of defense against infection. In preterm infants, alterations in microbiome composition have been linked to various health outcomes, including sepsis, necrotizing enterocolitis, atopic dermatitis, and respiratory infections. Dysbiosis, or an imbalance in the microbiome, can alter AMP profiles and potentially lead to inflammation-mediated diseases such as chronic lung disease and obesity. In the following review, we summarize what is known about the vital role of AMPs as multifunctional peptides in protecting newborn infants against infections and modulating the microbiome and immune response. Understanding their roles in preterm infants and high-risk populations offers the potential for innovative approaches to disease prevention and treatment. Full article

(This article belongs to the Special Issue Neonatal Immunology)

► Show Figures

Figure 1

15 pages, 1051 KiB

Open AccessReview

New Insights in Immunometabolism in Neonatal Monocytes and Macrophages in Health and Disease

by Renske de Jong, Klaus Tenbrock and Kim Ohl

Int. J. Mol. Sci. 2023, 24(18), 14173; https://doi.org/10.3390/ijms241814173 - 16 Sep 2023

Cited by 1 | Viewed by 1384

Abstract

It is well established that the neonatal immune system is different from the adult immune system. A major task of the neonatal immune system is to bridge the achievement of tolerance towards harmless antigens and commensal bacteria while providing protection against pathogens. This [...] Read more.

It is well established that the neonatal immune system is different from the adult immune system. A major task of the neonatal immune system is to bridge the achievement of tolerance towards harmless antigens and commensal bacteria while providing protection against pathogens. This is highly important because neonates are immunologically challenged directly after birth by a rigorous change from a semi-allogeneic sterile environment into a world rich with microbes. A so called disease tolerogenic state is typical for neonates and is anticipated to prevent immunopathological damage potentially at the cost of uncontrolled pathogen proliferation. As a consequence, neonates are more susceptible than adults to life-threatening infections. At the basis of a well-functioning immune response, both for adults and neonates, innate immune cells such as monocytes and monocyte-derived macrophages play an essential role. A well-responsive monocyte will alter its cellular metabolism to subsequently induce certain immune effector function, a process which is called immunometabolism. Immunometabolism has received extensive attention in the last decade; however, it has not been broadly studied in neonates. This review focuses on carbohydrate metabolism in monocytes and macrophages in neonates. We will exhibit pathways involving glycolysis, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation and their role in shaping neonates’ immune systems to a favorable tolerogenic state. More insight into these pathways will elucidate potential treatments targets in life-threatening conditions including neonatal sepsis or expose potential targets which can be used to induce tolerance in conditions where tolerance is harmfully impaired such as in autoimmune diseases. Full article

(This article belongs to the Special Issue Neonatal Immunology)

► Show Figures

Figure 1

17 pages, 1613 KiB

Open AccessReview

Regulatory T Cells in Development and Prediction of Necrotizing Enterocolitis in Preterm Neonates: A Scoping Review

by Mara O. Zuiderwijk, Mirjam van der Burg, Vincent Bekker and Michiel H. D. Schoenaker

Int. J. Mol. Sci. 2022, 23(18), 10903; https://doi.org/10.3390/ijms231810903 - 18 Sep 2022

Cited by 5 | Viewed by 2434

Abstract

Necrotizing enterocolitis (NEC) is a leading cause of mortality in premature infants. However, the pathophysiology and influence of regulatory T cells (Tregs) have not been sufficiently elucidated. We performed a scoping review to investigate current knowledge on the influence of Tregs in NEC, [...] Read more.

Necrotizing enterocolitis (NEC) is a leading cause of mortality in premature infants. However, the pathophysiology and influence of regulatory T cells (Tregs) have not been sufficiently elucidated. We performed a scoping review to investigate current knowledge on the influence of Tregs in NEC, and to investigate the predictive value of Treg number in NEC development. Pubmed, Embase, Prospero and Cochrane Library were searched during December 2020. Primary research articles discussing Tregs and NEC development written in English were selected. Two reviewers screened title and abstract for relevance, after which full-text screening was performed. A total of 20 articles were selected—13 of the articles discussed studies performed in animal models, while 8 used human neonate data. One study discussed both animal and human data. It was shown that after NEC diagnosis or induction, Treg levels were decreased while Th17 levels were increased. No studies were found which investigated the predictive value of Treg number in NEC development. A reduced Treg level is found in animals and neonates with NEC. The question remains whether this effect is a factor on the causal pathway of NEC development or a bystander effect. Future research focusing on the pathophysiological timeline of NEC and the involvement of Tregs is required for better understanding of this disease. Full article

(This article belongs to the Special Issue Neonatal Immunology)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Neonatal Immunology

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (10 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI