VEGF-C prophylaxis favors lymphatic drainage and modulates neuroinflammation in a stroke model.

Meningeal lymphatic vessels (MLVs) promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelial growth factor-C (VEGF-C) regulates MLV development and maintenance and has therapeutic potential for treating neurological disorders. Herein, we investigated the effects of VEGF-C overexpression on brain fluid drainage and ischemic stroke outcomes in mice. Intracerebrospinal administration of an adeno-associated virus expressing mouse full-length VEGF-C (AAV-mVEGF-C) increased CSF drainage to the deep cervical lymph nodes (dCLNs) by enhancing lymphatic growth and upregulated neuroprotective signaling pathways identified by single nuclei RNA sequencing of brain cells. In a mouse model of ischemic stroke, AAV-mVEGF-C pretreatment reduced stroke injury and ameliorated motor performances in the subacute stage, associated with mitigated microglia-mediated inflammation and increased BDNF signaling in brain cells. Neuroprotective effects of VEGF-C were lost upon cauterization of the dCLN afferent lymphatics and not mimicked by acute post-stroke VEGF-C injection. We conclude that VEGF-C prophylaxis promotes multiple vascular, immune, and neural responses that culminate in a protection against neurological damage in acute ischemic stroke.

X-linked intellectual developmental disorder with onset of neonatal heart failure: A case report and literature review.

X-linked intellectual developmental disorder is a rare X-linked genetic disease, manifested as heart disease, intellectual impairment, and developmental disorders. We report a male infant who presented with dyspnea after birth. Physical examination on admission revealed poor responsiveness, deep eye sockets, a small mandible, abnormalities of the outer ears, and reduced limb muscle tone. The child was moaning with shortness of breath and a positive three-concave sign without pulmonary rales. The heart sounds were weak with a grade 2/6 diastolic heart murmur. Echocardiography showed an enlarged heart with increased trabeculae in the left ventricular muscle wall. X-linked mental retardation syndrome type 34(MRXS34, OMIM# 300967) was diagnosed after exome sequencing showed a c.1131G > A hemizygous variant in the NONO gene. After timely therapy including respiratory support, cardiac glycosides, and diuresis, the child's condition improved and he was discharged at one month of age. A literature review showed that, to date, 22 live births with X-linked mental retardation have been reported. The NONO-related phenotype can be summarized as a neurological and cardiac developmental disorder, which may be accompanied by multisystem malformations. The present case enriches the knowledge of X-linked intellectual developmental syndromes.

Compartmentalized ocular lymphatic system mediates eye-brain immunity.

The eye, an anatomical extension of the central nervous system (CNS), exhibits many molecular and cellular parallels to the brain. Emerging research demonstrates that changes in the brain are often reflected in the eye, particularly in the retina1. Still, the possibility of an immunological nexus between the posterior eye and the rest of the CNS tissues remains unexplored. Here, studying immune responses to herpes simplex virus in the brain, we observed that intravitreal immunization protects mice against intracranial viral challenge. This protection extended to bacteria and even tumours, allowing therapeutic immune responses against glioblastoma through intravitreal immunization. We further show that the anterior and posterior compartments of the eye have distinct lymphatic drainage systems, with the latter draining to the deep cervical lymph nodes through lymphatic vasculature in the optic nerve sheath. This posterior lymphatic drainage, like that of meningeal lymphatics, could be modulated by the lymphatic stimulator VEGFC. Conversely, we show that inhibition of lymphatic signalling on the optic nerve could overcome a major limitation in gene therapy by diminishing the immune response to adeno-associated virus and ensuring continued efficacy after multiple doses. These results reveal a shared lymphatic circuit able to mount a unified immune response between the posterior eye and the brain, highlighting an understudied immunological feature of the eye and opening up the potential for new therapeutic strategies in ocular and CNS diseases.

Combined gestational age and serum fucose for early prediction of risk for bronchopulmonary dysplasia in premature infants.

OBJECTIVE: As the predominant complication in preterm infants, Bronchopulmonary Dysplasia (BPD) necessitates accurate identification of infants at risk and expedited therapeutic interventions for an improved prognosis. This study evaluates the potential of Monosaccharide Composite (MC) enriched with environmental information from circulating glycans as a diagnostic biomarker for early-onset BPD, and, concurrently, appraises BPD risk in premature neonates. MATERIALS AND METHODS: The study incorporated 234 neonates of ≤32 weeks gestational age. Clinical data and serum samples, collected one week post-birth, were meticulously assessed. The quantification of serum-free monosaccharides and their degraded counterparts was accomplished via High-performance Liquid Chromatography (HPLC). Logistic regression analysis facilitated the construction of models for early BPD diagnosis. The diagnostic potential of various monosaccharides for BPD was determined using Receiver Operating Characteristic (ROC) curves, integrating clinical data for enhanced diagnostic precision, and evaluated by the Area Under the Curve (AUC). RESULTS: Among the 234 neonates deemed eligible, BPD development was noted in 68 (29.06%), with 70.59% mild (48/68) and 29.41% moderate-severe (20/68) cases. Multivariate analysis delineated several significant risk factors for BPD, including gestational age, birth weight, duration of both invasive mechanical and non-invasive ventilation, Patent Ductus Arteriosus (PDA), pregnancy-induced hypertension, and concentrations of two free monosaccharides (Glc-F and Man-F) and five degraded monosaccharides (Fuc-D, GalN-D, Glc-D, and Man-D). Notably, the concentrations of Glc-D and Fuc-D in the moderate-to-severe BPD group were significantly diminished relative to the mild BPD group. A potent predictive capability for BPD development was exhibited by the conjunction of gestational age and Fuc-D, with an AUC of 0.96. CONCLUSION: A predictive model harnessing the power of gestational age and Fuc-D demonstrates promising efficacy in foretelling BPD development with high sensitivity (95.0%) and specificity (94.81%), potentially enabling timely intervention and improved neonatal outcomes.

Metabolic fitness of IgA+ plasma cells in the gut requires DOCK8.

Dedicator of cytokinesis 8 (DOCK8) mutations lead to a primary immunodeficiency associated with recurrent gastrointestinal infections and poor antibody responses but, paradoxically, heightened IgE to food antigens, suggesting that DOCK8 is central to immune homeostasis in the gut. Using Dock8-deficient mice, we found that DOCK8 was necessary for mucosal IgA production to multiple T cell-dependent antigens, including peanut and cholera toxin. Yet DOCK8 was not necessary in T cells for this phenotype. Instead, B cell-intrinsic DOCK8 was required for maintenance of antigen-specific IgA-secreting plasma cells (PCs) in the gut lamina propria. Unexpectedly, DOCK8 was not required for early B cell activation, migration, or IgA class switching. An unbiased interactome screen revealed novel protein partners involved in metabolism and apoptosis. Dock8-deficient IgA+ B cells had impaired cellular respiration and failed to engage glycolysis appropriately. These results demonstrate that maintenance of the IgA+ PC compartment requires DOCK8 and suggest that gut IgA+ PCs have unique metabolic requirements for long-term survival in the lamina propria.

Escape from the pore.

Perforin-2 mediates endocytic escape in cross-presenting dendritic cells.

An outbreak of nosocomial infection of neonatal aseptic meningitis caused by echovirus 18.

We describe an outbreak of echovirus 18 infection involving 10 patients in our neonatal intensive care unit (an attack rate of 33%). The mean age at the onset of illness was 26.8 days. Eighty percent were preterm infants. All were discharged home without sequelae. There were no differences in gestation age, birth weight, delivery mode, use of antibiotics, and parenteral nutrition between the enterovirus (EV) group and non-EV group, but the rate of breastfeeding was significantly higher in the EV group. Separation care and reinforcement of hand-washing seemed to be effective in preventing further spread of the virus. Visiting policy, hygiene practice, and handling of expressed breastmilk should be reinforced.

Infantile Pompe disease with intrauterine onset: a case report and literature review.

BACKGROUND: Pompe disease is a rare autosomal recessive disease. Acid alpha-glucosidase (GAA) deficiency leads to glycogen storage in lysosomes, causing skeletal, cardiac, and smooth muscle lesions. Pompe disease is progressive, and its severity depends on the age of onset. Classic infantile Pompe disease, the most severe form, is characterized by an age of onset before 12 months. Pompe disease with intrauterine onset has rarely been reported. CASE PRESENTATION: The proband was born at a gestational age of 40 weeks and 3 days and admitted to our hospital because of intrauterine cardiac hypertrophy, shortness of breath, and cyanosis until 13 min postnatally. Physical examination at admission revealed poor responsiveness, pale skin, shortness of breath, reduced limb muscle tone, and bilateral pedal edema. The heart sounds were weak, and no heart murmur was heard. Echocardiography showed left (9 mm) and right (5 mm) ventricular hypertrophies. The patient was subjected to non-invasive ventilator-assisted respiration, fluid restriction, diuresis, and metoprolol treatment. Infantile Pompe disease was diagnosed on day 16 with a GAA enzymatic activity of 0.31 µmol/L/h and with the full-penetrance genetic test showing the homozygous gene mutation c.1844G>T(p.Gly615Val). Enzyme replacement therapy was refused by the patient's parents, and the patient died at seven months of age from cardiopulmonary failure. CONCLUSION: Infants with intrauterine-onset Pompe disease usually have early manifestations of heart disease. Prompt GAA enzymatic activity determination and molecular genetic testing are helpful in aiding the parents' decision and planning the treatment.

Combining bulk RNA-sequencing and single-cell RNA-sequencing data to reveal the immune microenvironment and metabolic pattern of osteosarcoma.

Background: Osteosarcoma (OS) is a kind of solid tumor with high heterogeneity at tumor microenvironment (TME), genome and transcriptome level. In view of the regulatory effect of metabolism on TME, this study was based on four metabolic models to explore the intertumoral heterogeneity of OS at the RNA sequencing (RNA-seq) level and the intratumoral heterogeneity of OS at the bulk RNA-seq and single cell RNA-seq (scRNA-seq) level. Methods: The GSVA package was used for single-sample gene set enrichment analysis (ssGSEA) analysis to obtain a glycolysis, pentose phosphate pathway (PPP), fatty acid oxidation (FAO) and glutaminolysis gene sets score. ConsensusClusterPlus was employed to cluster OS samples downloaded from the Target database. The scRNA-seq and bulk RNA-seq data of immune cells from GSE162454 dataset were analyzed to identify the subsets and types of immune cells in OS. Malignant cells and non-malignant cells were distinguished by large-scale chromosomal copy number variation. The correlations of metabolic molecular subtypes and immune cell types with four metabolic patterns, hypoxia and angiogenesis were determined by Pearson correlation analysis. Results: Two metabolism-related molecular subtypes of OS, cluster 1 and cluster 2, were identified. Cluster 2 was associated with poor prognosis of OS, active glycolysis, FAO, glutaminolysis, and bad TME. The identified 28608 immune cells were divided into 15 separate clusters covering 6 types of immune cells. The enrichment scores of 5 kinds of immune cells in cluster-1 and cluster-2 were significantly different. And five kinds of immune cells were significantly correlated with four metabolic modes, hypoxia and angiogenesis. Of the 28,608 immune cells, 7617 were malignant cells. The four metabolic patterns of malignant cells were significantly positively correlated with hypoxia and negatively correlated with angiogenesis. Conclusion: We used RNA-seq to reveal two molecular subtypes of OS with prognosis, metabolic pattern and TME, and determined the composition and metabolic heterogeneity of immune cells in OS tumor by bulk RNA-seq and single-cell RNA-seq.

Oral anaphylaxis to peanut in a mouse model is associated with gut permeability but not with Tlr4 or Dock8 mutations.

BACKGROUND: The etiology of food allergy is poorly understood; mouse models are powerful systems to discover immunologic pathways driving allergic disease. C3H/HeJ mice are a widely used model for the study of peanut allergy because, unlike C57BL/6 or BALB/c mice, they are highly susceptible to oral anaphylaxis. However, the immunologic mechanism of this strain's susceptibility is not known. OBJECTIVE: We aimed to determine the mechanism underlying the unique susceptibility to anaphylaxis in C3H/HeJ mice. We tested the role of deleterious Toll-like receptor 4 (Tlr4) or dedicator of cytokinesis 8 (Dock8) mutations in this strain because both genes have been associated with food allergy. METHODS: We generated C3H/HeJ mice with corrected Dock8 or Tlr4 alleles and sensitized and challenged them with peanut. We then characterized the antibody response to sensitization, anaphylaxis response to both oral and systemic peanut challenge, gut microbiome, and biomarkers of gut permeability. RESULTS: In contrast to C3H/HeJ mice, C57BL/6 mice were resistant to anaphylaxis after oral peanut challenge; however, both strains undergo anaphylaxis with intraperitoneal challenge. Restoring Tlr4 or Dock8 function in C3H/HeJ mice did not protect from anaphylaxis. Instead, we discovered enhanced gut permeability resulting in ingested allergens in the bloodstream in C3H/HeJ mice compared to C57BL/6 mice, which correlated with an increased number of goblet cells in the small intestine. CONCLUSIONS: Our work highlights the potential importance of gut permeability in driving anaphylaxis to ingested food allergens; it also indicates that genetic loci outside of Tlr4 and Dock8 are responsible for the oral anaphylactic susceptibility of C3H/HeJ mice.

Preparation of cellulose nanospheres via combining ZnCl2·3H2O pretreatment and p-toluenesulfonic hydrolysis as a two-step method.

Spherical nanocelluloses, also known as cellulose nanospheres (CNS), have controllable morphology and have shown advantages as green template material, emulsion stabilizer. Herein, CNS were prepared via a new two-step method, first pretreatment of microcrystalline cellulose (MCC) using ZnCl2·3H2O and then acid hydrolysis of regenerated cellulose (RC) via p-toluenesulfonic acid (p-TsOH). The shape, size, crystallinity of MCC were changed, and nubbly RC with smallest size (942 nm) was obtained after 2 h pretreatment by ZnCl2·3H2O. CNS with high 61.3% yield were produced after acid hydrolysis (67 wt% p-TsOH) of RC at 80 °C, 6 h. The analysis of Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM) showed that CNS had an average diameter of 347 nm. CNS were present in precipitate after high-speed centrifugation, due to the high Zeta potential of -12 mV and large size. The structure of CNS was tested by Fourier Transfer Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), Nuclear Magnetic Resonance (NMR), CNS had high crystallinity (cellulose II) of 61%. Thermal Gravimetric Analysis (TGA) indicated that CNS had high thermal stability (Tonset 303.3 °C, Tmax 332 °C). CNS showed poor re-dispersibility in water/ethanol/THF, 1 wt% CNS could be dissolved in ZnCl2·3H2O. 7.37% rod-like CNC were obtained after 6 h hydrolysis. FTIR proved that p-TsOH was recovered by re-crystallization. This study provided a novel, sustainable two-step method for the preparation of spherical CNS.

Dendritic Cell Regulation of T Helper Cells.

As the professional antigen-presenting cells of the immune system, dendritic cells (DCs) sense the microenvironment and shape the ensuing adaptive immune response. DCs can induce both immune activation and immune tolerance according to the peripheral cues. Recent work has established that DCs comprise several phenotypically and functionally heterogeneous subsets that differentially regulate T lymphocyte differentiation. This review summarizes both mouse and human DC subset phenotypes, development, diversification, and function. We focus on advances in our understanding of how different DC subsets regulate distinct CD4+ T helper (Th) cell differentiation outcomes, including Th1, Th2, Th17, T follicular helper, and T regulatory cells. We review DC subset intrinsic properties, local tissue microenvironments, and other immune cells that together determine Th cell differentiation during homeostasis and inflammation.

Torn between type 1 and type 2 immunity.

DOCK8 uncovers a link between cell integrity and TH2 skewing.

Antigen-Presenting Cells in Food Tolerance and Allergy.

Food allergy now affects 6%-8% of children in the Western world; despite this, we understand little about why certain people become sensitized to food allergens. The dominant form of food allergy is mediated by food-specific immunoglobulin E (IgE) antibodies, which can cause a variety of symptoms, including life-threatening anaphylaxis. A central step in this immune response to food antigens that differentiates tolerance from allergy is the initial priming of T cells by antigen-presenting cells (APCs), primarily different types of dendritic cells (DCs). DCs, along with monocyte and macrophage populations, dictate oral tolerance versus allergy by shaping the T cell and subsequent B cell antibody response. A growing body of literature has shed light on the conditions under which antigen presentation occurs and how different types of T cell responses are induced by different APCs. We will review APC subsets in the gut and discuss mechanisms of APC-induced oral tolerance versus allergy to food identified using mouse models and patient samples.

IL-10-Dependent Crosstalk between Murine Marginal Zone B Cells, Macrophages, and CD8α+ Dendritic Cells Promotes Listeria monocytogenes Infection.

Type 1 CD8α+ conventional dendritic cells (cDC1s) are required for CD8+ T cell priming but, paradoxically, promote splenic Listeria monocytogenes infection. Using mice with impaired cDC2 function, we ruled out a role for cDC2s in this process and instead discovered an interleukin-10 (IL-10)-dependent cellular crosstalk in the marginal zone (MZ) that promoted bacterial infection. Mice lacking the guanine nucleotide exchange factor DOCK8 or CD19 lost IL-10-producing MZ B cells and were resistant to Listeria. IL-10 increased intracellular Listeria in cDC1s indirectly by reducing inducible nitric oxide synthase expression early after infection and increasing intracellular Listeria in MZ metallophilic macrophages (MMMs). These MMMs trans-infected cDC1s, which, in turn, transported Listeria into the white pulp to prime CD8+ T cells. However, this also facilitated bacterial expansion. Therefore, IL-10-mediated crosstalk between B cells, macrophages, and cDC1s in the MZ promotes both Listeria infection and CD8+ T cell activation.

Low-Rank Sparse Preserving Projections for Dimensionality Reduction.

Learning an efficient projection to map high-dimensional data into a lower dimensional space is a rather challenging task in the community of pattern recognition and computer vision. Manifold learning is widely applied because it can disclose the intrinsic geometric structure of data. However, it only concerns the geometric structure and may lose its effectiveness in case of corrupted data. To address this challenge, we propose a novel dimensionality reduction method by combining the manifold learning and low-rank sparse representation, termed low-rank sparse preserving projections (LSPP), which can simultaneously preserve the intrinsic geometric structure and learn a robust representation to reduce the negative effects of corruptions. Therefore, LSPP is advantageous to extract robust features. Because the formulated LSPP problem has no closed-form solution, we use the linearized alternating direction method with adaptive penalty and eigen-decomposition to obtain the optimal projection. The convergence of LSPP is proven, and we also analyze its complexity. To validate the effectiveness and robustness of LSPP in feature extraction and dimensionality reduction, we make a critical comparison between LSPP and a series of related dimensionality reduction methods. The experimental results demonstrate the effectiveness of LSPP.

Impact of Xenon on CLIC4 and Bcl-2 Expression in Lipopolysaccharide and Hypoxia-Ischemia-Induced Periventricular White Matter Damage.

BACKGROUND: Premature birth is a significant health care burden. Xenon (Xe) is a general anesthetic with neuroprotective effects. OBJECTIVES: Here, we investigate the neuroprotective role of Xe in a lipopolysaccharide (LPS)- and hypoxia-ischemia (HI)-induced white matter damage (WMD) model. METHODS: Three-day-old Sprague-Dawley rats were randomly divided into a sham group (group A, n = 24), an LPS + HI group (group B, n = 24), and an LPS + HI + Xe group (group C, n = 72). The onset of Xe inhalation started at 0, 2, and 5 h in subgroups C1, C2, and C3, respectively. Next, we performed TUNEL and hematoxylin and eosin (HE) staining; and examined the expression of CLIC4 and Bcl-2 in brain tissues. RESULTS: HE staining revealed distorted cytoarchitecture, tangled nerve fibers, and pyknosis in group B, while Xe treatment improved these histological alterations in the group C pups. Following LPS and HI insult, the number of apoptotic cells significantly increased in group B at 48 and 72 h (p < 0.05), and Xe significantly alleviated apoptosis (p < 0.001) at 24, 48, and 72 h, respectively. Similarly, CLIC4 mRNA expression was significantly increased in group B (p < 0.05), and Xe produced a marked reduction in CLIC4 mRNA expression in group C subgroups (p < 0.05). Western blotting demonstrated enhanced Bcl-2 expression in group C when compared to group B (p < 0.05). CONCLUSIONS: These results demonstrate that LPS and HI successfully induced WMD, and Xe decreased neuronal apoptosis via Bcl-2- and CLIC4-mediated pathways. Moreover, the therapeutic time window of Xe extended for up to 5 h. These findings suggest that Xe can be used as a protective treatment for WMD in premature infants.

EgoNet identifies differential ego-modules and pathways related to prednisolone resistance in childhood acute lymphoblastic leukemia.

PURPOSE: To extract feature ego-modules and pathways in childhood acute lymphoblastic leukemia (ALL) resistant to prednisolone treatment, and further to explore the mechanisms behind prednisolone resistance. MATERIALS AND METHODS: EgoNet algorithm was used to identify candidate ego-network modules, mainly via constructing differential co-expression network (DCN); selecting ego genes; collecting ego-network modules; refining candidate modules. Afterwards, statistical significance was calculated for these candidate modules. Biological functions of differential ego-network modules were identified using Reactome database. To verify this proposed method can lead to truly positive findings in clinical settings, support vector machine (SVM) was utilized to compute the AUC values for each significant pathway using 3-fold cross-validation method. To predict the reliability of our findings, another established method (attract) was used to identify the differential attractor modules using the same microarray profile. RESULTS: After eliminating the modules with classification accuracy < 0.9 and node number < 15, only ego-network module 30 was eligible. After significance calculation, module 30 was significant. Module 30 was enriched in APC/C-mediated degradation of cell cycle proteins. The AUC for the significant pathway of APC/C-mediated degradation of cell cycle proteins was 0.915. Although the attract method obtained more modules, the module identified by our proposed method owned more gene nodes, and had more classification ability (AUC = 0.915). CONCLUSION: One differential ego-network module identified in childhood ALL resistance to prednisolone based on DCN and EgoNet, might be helpful to reveal the mechanisms underlying prednisolone resistance in childhood ALL.

The binding of a monoclonal antibody to the apical region of SCARB2 blocks EV71 infection.

Entero virus 71 (EV71) causes hand, foot, and mouth disease (HFMD) and occasionally leads to severe neurological complications and even death. Scavenger receptor class B member 2 (SCARB2) is a functional receptor for EV71, that mediates viral attachment, internalization, and uncoating. However, the exact binding site of EV71 on SCARB2 is unknown. In this study, we generated a monoclonal antibody (mAb) that binds to human but not mouse SCARB2. It is named JL2, and it can effectively inhibit EV71 infection of target cells. Using a set of chimeras of human and mouse SCARB2, we identified that the region containing residues 77-113 of human SCARB2 contributes significantly to JL2 binding. The structure of the SCARB2-JL2 complex revealed that JL2 binds to the apical region of SCARB2 involving α-helices 2, 5, and 14. Our results provide new insights into the potential binding sites for EV71 on SCARB2 and the molecular mechanism of EV71 entry.

Human Blood CD1c+ Dendritic Cells Encompass CD5high and CD5low Subsets That Differ Significantly in Phenotype, Gene Expression, and Functions.

There are three major dendritic cell (DC) subsets in both humans and mice, that is, plasmacytoid DCs and two types of conventional DCs (cDCs), cDC1s and cDC2s. cDC2s are important for polarizing CD4+ naive T cells into different subsets, including Th1, Th2, Th17, Th22, and regulatory T cells. In mice, cDC2s can be further divided into phenotypically and functionally distinct subgroups. However, subsets of human cDC2s have not been reported. In the present study, we showed that human blood CD1c+ cDCs (cDC2s) can be further separated into two subpopulations according to their CD5 expression status. Comparative transcriptome analyses showed that the CD5high DCs expressed higher levels of cDC2-specific genes, including IFN regulatory factor 4, which is essential for the cDC2 development and its migration to lymph nodes. In contrast, CD5low DCs preferentially expressed monocyte-related genes, including the lineage-specific transcription factor MAFB. Furthermore, compared with the CD5low subpopulation, the CD5high subpopulation showed stronger migration toward CCL21 and overrepresentation among migratory DCs in lymph nodes. Additionally, the CD5high DCs induced naive T cell proliferation more potently than did the CD5low DCs. Moreover, CD5high DCs induced higher levels of IL-10-, IL-22-, and IL-4-producing T cell formation, whereas CD5low DCs induced higher levels of IFN-γ-producing T cell formation. Thus, we show that human blood CD1c+ cDC2s encompass two subsets that differ significantly in phenotype, that is, gene expression and functions. We propose that these two subsets of human cDC2s could potentially play contrasting roles in immunity or tolerance.