HLA-DR expression on neonatal monocytes is associated with allergen-specific immune responses

doi:10.1016/j.jaci.2004.06.051

Journal of Allergy and Clinical Immunology

Volume 114, Issue 5, November 2004, Pages 1202-1208

https://doi.org/10.1016/j.jaci.2004.06.051 Get rights and content

Background

The specific mechanisms regulating priming of T-cell immunity to common allergens during early childhood remain to be elucidated, though increasing evidence indicates that antigen-presenting cell function is impaired in childhood.

Objective

Examine the relationship between HLA-DR expression on monocytes and B cells, allergen-specific T-cell responses at birth, and clinical outcomes at 2 years of age.

Methods

Blood mononuclear cells were obtained from 36 healthy neonates who were followed up clinically to the age of 2 years. Expression of HLA-DR by monocytes and B cells was determined at baseline and after in vitro exposure to IFN-γ, a cytokine that is known to upregulate the expression of HLA-DR. Mononuclear cells were stimulated with endotoxin or a panel of inhalant and food allergens, and cytokine responses and lymphoproliferation were determined after 1 and 5 days, respectively.

Results

The magnitude of HLA-DR upregulation on IFN-γ–stimulated cord blood CD14⁺ monocytes was consistently correlated with allergen-induced, but not mitogen-induced, lymphoproliferation at birth. HLA-DR upregulation on monocytes was also positively associated with endotoxin-induced IL-12 p70 synthesis (τ = 0.46; P < .001) but inversely related to mite- and ovalbumin-induced IL-13 synthesis (P = .0006 and P < .003, respectively). HLA-DR expression on unstimulated cord blood monocytes was inversely associated with symptoms of atopic disease at the 2-year follow-up (P = .015). In contrast, HLA-DR expression on B cells was not associated with these parameters of immune function.

Conclusions

These findings suggest that the maturity of neonatal monocytes and their responsiveness to external stimuli are linked to differing patterns of immune reactivity at birth and to the risk of allergic symptoms in early childhood.

Section snippets

Study population

Samples from a group of 36 healthy babies were included in this study. These were selected from a previously recruited cohort¹⁸ on the basis that there were sufficient cryopreserved MNCs to conduct the proposed additional in vitro studies presented here. The infants were originally recruited as part of a prospective study examining the development of allergen-specific immune responses in early childhood.5., 18. Their mothers were recruited from antenatal clinics at the King Edward Memorial

IFN-γ induces upregulation of HLA-DR expression on cord blood monocytes

We first examined the capacity of cord blood monocytes and B cells to undergo maturation in response to IFN-γ, a cytokine that is known to upregulate class II MHC expression on APCs. As shown in Fig 1, A, IFN-γ induced specific upregulation of HLA-DR expression on cord blood CD14⁺ monocytes. The intensity of HLA-DR expression on monocytes exposed to IFN-γ was significantly greater than that seen on cord blood monocytes studied at baseline or after culture in medium alone (P < .001 for both

Discussion

The specific mechanisms regulating the emergence of either T_H2-dominated CD4⁺ T-cell memory (allergy) or tolerance to common allergens during early childhood remain to be elucidated. Because the maturation of APC function is considered a rate-limiting step in the development of adaptive immunity in early postnatal life,11., 12., 22. we examined the relationship between cord blood monocyte and B-cell function, allergen specific immune responses, and clinical outcomes in a cohort of children

References (38)

N. Reider et al.
Dendritic cells contribute to the development of atopy by an insufficiency in IL-12 production
J Allergy Clin Immunol
(2002)
H.N. Trivedi et al.
Analysis of neonatal T cell and antigen presenting cell functions
Hum Immunol
(1997)
D.W. Hunt et al.
Studies of human cord blood dendritic cells: evidence for functional immaturity
Blood
(1994)
G. Delespesse et al.
Maturation of human neonatal CD4+ and CD8+ T lymphocytes into Th1/Th2 effectors
Vaccine
(1998)
S.L. Prescott et al.
Development of allergen-specific T-cell memory in atopic and normal children
Lancet
(1999)
B. Min et al.
Differential control of neonatal tolerance by antigen dose versus extended exposure and adjuvant
Cell Immunol
(2000)
T.L. Guo et al.
Regulation of HLA-DR and invariant chain expression by human peripheral blood mononuclear cells with lead, interferon-gamma, or interleukin-4
Cell Immunol
(1996)
B. Koppelman et al.
Interleukin-10 down-regulates MHC class II alphabeta peptide complexes at the plasma membrane of monocytes by affecting arrival and recycling
Immunity
(1997)
A. Yabuhara et al.
TH2-polarized immunological memory to inhalant allergens in atopics is established during infancy and early childhood
Clin Exp Allergy
(1997)
C. Macaubas et al.
Regulation of T-helper cell responses to inhalant allergen during early childhood
Clin Exp Allergy
(1999)

J.A. Warner et al.

Is deficiency of interferon gamma production by allergen triggered cord blood cells a predictor of atopic eczema?

Clin Exp Allergy

(1994)

F.I. Smillie et al.

Lymphoproliferative responses in cord blood and at one year: no evidence for the effect of in utero exposure to dust mite allergens

Clin Exp Allergy

(2001)

S.L. Prescott et al.

Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile

J Immunol

(1998)

G. Devereux et al.

In utero priming of allergen-specific helper T cells

Clin Exp Allergy

(2001)

H. Hammad et al.

Monocyte-derived dendritic cells induce a house dust mite-specific Th2 allergic inflammation in the lung of humanized SCID mice: involvement of CCR7

J Immunol

(2002)

A.S. Charbonnier et al.

Der p 1-pulsed myeloid and plasmacytoid dendritic cells from house dust mite-sensitized allergic patients dysregulate the T cell response

J Leukoc Biol

(2003)

A. Snijders et al.

Enhanced prostaglandin E2 production by monocytes in atopic dermatitis (AD) is not accompanied by enhanced production of IL-6, IL-10 or IL-12

Clin Exp Immunol

(1998)

J.P. Ridge et al.

Neonatal tolerance revisited: turning on newborn T cells with dendritic cells

Science

(1996)

N.C. Matthews et al.

Sustained expression of CD154 (CD40L) and proinflammatory cytokine production by alloantigen-stimulated umbilical cord blood T cells

J Immunol

(2000)

Cited by (28)

Genome-wide association study of asthma, total IgE, and lung function in a cohort of Peruvian children
2021, Journal of Allergy and Clinical Immunology
Citation Excerpt :
We found a strong association between the HLA-DQA1 region and total serum IgE levels. Although the most significant SNP in the region, namely, rs3135348, has not been previously reported in the GWAS literature or the GWAS catalog, the MHC region on Chr6, which harbors HLA genes, has consistently been documented to be associated with asthma46-48 and total serum IgE levels40,49-53 in diverse populations. In the GABRIEL consortium which looked at genetic signals for asthma, the SNP with the strongest association, rs9271300, was located in the MHC region between HLA-DRB1 and HLA-DQA1.46
Genetic ancestry plays a role in asthma health disparities.
Our aim was to evaluate the impact of ancestry on and identify genetic variants associated with asthma, total serum IgE level, and lung function.
A total of 436 Peruvian children (aged 9-19 years) with asthma and 291 without asthma were genotyped by using the Illumina Multi-Ethnic Global Array. Genome-wide proportions of indigenous ancestry populations from continental America (NAT) and European ancestry from the Iberian populations in Spain (IBS) were estimated by using ADMIXTURE. We assessed the relationship between ancestry and the phenotypes and performed a genome-wide association study.
The mean ancestry proportions were 84.7% NAT (case patients, 84.2%; controls, 85.4%) and 15.3% IBS (15.8%; 14.6%). With adjustment for asthma, NAT was associated with higher total serum IgE levels (P < .001) and IBS was associated with lower total serum IgE levels (P < .001). NAT was associated with higher FEV₁ percent predicted values (P < .001), whereas IBS was associated with lower FEV₁ values in the controls but not in the case patients. The HLA-DR/DQ region on chromosome 6 (Chr6) was strongly associated with total serum IgE (rs3135348; P = 3.438 × 10^–10) and was independent of an association with the haplotype HLA-DQA1∼HLA-DQB1:04.01∼04.02 (P = 1.55 × 10^–05). For lung function, we identified a locus (rs4410198; P = 5.536 × 10^–11) mapping to Chr19, near a cluster of zinc finger interacting genes that colocalizes to the long noncoding RNA CTD-2537I9.5. This novel locus was replicated in an independent sample of pediatric case patients with asthma with similar admixture from Brazil (P = .005).
This study confirms the role of HLA in atopy, and identifies a novel locus mapping to a long noncoding RNA for lung function that may be specific to children with NAT.
Innate immunity at birth: Implications for inflammation and infection in newborns
2017, Immunity and Inflammation in Health and Disease: Emerging Roles of Nutraceuticals and Functional Foods in Immune Support
The development of immunity at birth is vital and it involves several complex mechanisms. Since prior antigenic experience is limited, the adaptive immunity requires time for development. The newborns depend heavily on their innate immunity for survival during early life. The microbiome with the commensal flora contributes to the development of immunity in newborns. Maternal antibodies at the various mucosal surfaces are the primary checkpoints which provide immunity in the neonatal period. The reduced chemotaxis, phagocytosis and sustained activation of neonatal neutrophils and monocytes increase the susceptibility of newborns to infection. The quantitative and qualitative characteristics of dendritic cells are subset specific and their varied ontogeny and functions impair antigen presentation and reduce the vaccine responsiveness in early life. The natural killer cell functions like degranulation and release of lytic factors are reduced in early life which makes the newborns more prone to viral infections. Dietary limitation during lactation has shown to modify the functions of immune cells and increase the susceptibility to pathogenic invasion. Dietary supplements like lactoferrrin have shown to increase the levels of immunoglobulins and improve the mucosal and systemic immune response in early life.
The mechanism or mechanisms driving atopic asthma initiation: The infant respiratory microbiome moves to center stage
2015, Journal of Allergy and Clinical Immunology
Developments over the last 5 to 10 years, principally from studies on comprehensively phenotyped prospective birth cohorts, have highlighted the important role of viral respiratory tract infections during infancy and early childhood, particularly those occurring against a background of pre-existing sensitization to perennial aeroallergens, in driving the development of early-onset atopic asthma. Although debate surrounding the mechanism or mechanisms governing this causal pathway remains intense, demonstration of the capacity of pretreatment with anti-IgE antibody to blunt seasonal virus-associated asthma exacerbations in children provides strong support for the underlying concept. However, emerging data appear set to further complicate this picture. Notably, a combination of culture-based studies and complementary population-wide bacterial metagenomic data suggests that parallel host-bacteria interactions during infancy might play an additional role in modulating this causal pathway, as well as contributing independently to pathogenesis. These and related issues surrounding development of immune competence during the crucial early postnatal period, when these pathways are maximally active, are discussed below.
Effect of mite allergen immunotherapy on the altered phenotype of dendritic cells in allergic asthmatic children
2013, Annals of Allergy, Asthma and Immunology
Citation Excerpt :
Monocyte-derived DCs from atopic patients express low levels of HLA-DR.24 This finding implies that the low level of HLA-DR expression in atopic patients participates in their TH2 responses. In another study, HLA-DR expression on cord blood monocytes from individuals who manifested clinical allergic disease by 2 years of age was significantly reduced.25 However, immature monocyte-derived DCs from allergic asthmatic patients have higher HLA-DR levels compared with controls.26
Allergic asthma is a T_H2 inflammatory disease. Dendritic cells (DCs) play key roles in the T_H1/T_H2 balance. Allergen specific immunotherapy (SIT) has the potential to modify the course of allergy because the ratio of T_H1 to T_H2 cytokines produced is increased after SIT.
To determine how SIT affects DCs in children and to define novel parameters of this treatment.
We investigated the changes of phenotypic and functional variations of monocyte-derived DCs from allergic asthmatic children undergoing complete mite SIT. Peripheral blood monocytes from SIT allergic asthmatic children, allergic asthmatic controls, and healthy controls were cultured with granulocyte-macrophage colony-stimulating factor and interleukin 4 and then stimulated with Dermatophagoides pteronyssinus (Der p) allergen or lipopolysaccharide (LPS). The expressions of surface molecules on monocyte-derived DCs were assessed by flow cytometry. Cytokine production by cultured monocyte-derived DCs was determined by enzyme-linked immunosorbent assay.
After LPS stimulation, monocyte-derived DCs of the allergic asthmatic group had a higher CD86 and lower HLA-DR expression than the healthy controls. In SIT patients, the expression was similar to that of the healthy controls. After Der p stimulation monocyte-derived DCs of the allergic asthmatic patients displayed lower Toll-like receptor 4 (TLR4), whereas again in SIT patients the expression was similar to that of healthy controls.
These findings indicate that SIT normalizes the expression of CD86, HLA-DR, and TLR4 on DCs. Moreover, CD86, HLA-DR, and TLR4 may be useful parameters for monitoring SIT. Decreased TLR4 expression in allergic asthmatic patients might be compensated by TLR4 agonists, with the potential of amplifying the effects of SIT.
Neonatal antigen-presenting cells are functionally more quiescent in children born under traditional compared with modern environmental conditions
2012, Journal of Allergy and Clinical Immunology
Citation Excerpt :
Exposed animals had IL-10–producing tolerogenic DCs that, in line with our findings for PNG neonatal APCs, had enhanced expression of activation markers but a reduced ability to induce T-cell proliferation.11,44 Likewise, others have reported an inverse association between baseline HLA-DR expression on cord blood monocytes and development of atopic disease.45 Furthermore, we have recently shown in Australian cohorts that reduced neonatal innate inflammatory cytokine production is associated with reduced allergy risk.46,47
One explanation for the high burden of allergic and autoimmune diseases in industrialized countries is inappropriate immune development under modern environmental conditions. There is increasing evidence that the process of immune deviation already begins in utero, but the underlying immunologic mechanisms are not clear.
We sought to identify differences in the function of neonatal antigen-presenting cells (APCs) in children born in settings that are more traditional versus those of modern societies.
Cord blood mononuclear cells were collected from newborns from Papua New Guinea (PNG; traditional) and Australia (modern) and compared for differences in APCs and T-cell phenotype and function.
Australian cord naive T cells (CD4⁺CD25⁻CD127⁺ cells) showed an enhanced and more rapid proliferative response in an autologous, APC-dependent culture system, a result of differences in neonatal APCs rather than T-cell function. This included an increased capacity to process antigen and to upregulate activation markers after stimulation. In contrast, resting PNG APCs exhibited higher baseline levels of activation and inhibitory markers and were less responsive or nonresponsive to stimulation in vitro.
This study supports the hypothesis that prenatal environments can influence the developing immune system in utero. Children born under modern environmental conditions exhibit increased APC reactivity at birth compared with children born under traditional environmental conditions. The functionally more quiescent nature of PNG neonatal APCs might protect against the development of harmful inflammatory responses in early life.
Plasmacytoid dendritic cells during infancy are inversely associated with childhood respiratory tract infections and wheezing
2009, Journal of Allergy and Clinical Immunology
Citation Excerpt :
Although some alterations in infant immune function have been described in those children who later have asthma or allergic sensitization, most reports have focused on reduced capacity to produce IFN-γ2-8 or other aspects of T-cell function.30 Little attention has been paid to antigen-presenting cell function in this context, although we recently showed an association between HLA-DR expression on cord blood monocytes and the subsequent risk of clinical allergic disease.31 In relation to DCs and asthma, several cross-sectional studies in adults and older children have described changes in DC subsets in patients with asthma,17,18,20 although all these studies have been performed well after asthma was first diagnosed.
It has been proposed that immune dysfunction during early childhood plays an important role in asthma pathogenesis. However, it is not known specifically whether changes in dendritic cells (DCs) during infancy antedate the development of respiratory tract infections, asthma, and related clinical phenotypes.
We sought to assess the association between the level of blood DCs during the first year and the subsequent development of respiratory tract infections, wheezing, and allergic sensitization.
A community-based cohort of children with a family history of atopy was followed to age 5 years. Children were monitored intensively for respiratory tract infections. History of wheeze and asthma was collected annually, atopy was documented at 5 years, and flow cytometry was used to identify DC subsets in blood samples collected when children were well.
Levels of plasmacytoid DCs (pDCs) during infancy were inversely correlated with symptoms of lower respiratory tract infections, parent-reported wheezing, and the cumulative rate of physician-diagnosed asthma up to age 5 years. These relationships were independent of atopy, as determined by allergy skin test results and total and specific IgE levels. In contrast, levels of myeloid DCs were not associated with respiratory tract infections, asthma, or wheezing but were associated with total IgE levels at age 5 years.
In children with a family history of atopy, relative deficiency of circulating pDCs during infancy appears to be a risk factor for more frequent and more severe respiratory tract infections, wheezing, and a diagnosis of asthma. Infants with higher numbers of pDCs are protected against these outcomes.

View all citing articles on Scopus

: Supported by grants from the National Health & Medical Research Council (Australia).

View full text

Basic and clinical immunologyHLA-DR expression on neonatal monocytes is associated with allergen-specific immune responses

Background

Objective

Methods

Results

Conclusions

Section snippets

Study population

IFN-γ induces upregulation of HLA-DR expression on cord blood monocytes

Discussion

J Allergy Clin Immunol

Hum Immunol

Blood

Vaccine

Lancet

Cell Immunol

Cell Immunol

Immunity

TH2-polarized immunological memory to inhalant allergens in atopics is established during infancy and early childhood

Clin Exp Allergy

Regulation of T-helper cell responses to inhalant allergen during early childhood

Clin Exp Allergy

Is deficiency of interferon gamma production by allergen triggered cord blood cells a predictor of atopic eczema?

Clin Exp Allergy

Lymphoproliferative responses in cord blood and at one year: no evidence for the effect of in utero exposure to dust mite allergens

Clin Exp Allergy

Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile

J Immunol

In utero priming of allergen-specific helper T cells

Clin Exp Allergy

Monocyte-derived dendritic cells induce a house dust mite-specific Th2 allergic inflammation in the lung of humanized SCID mice: involvement of CCR7

J Immunol

Der p 1-pulsed myeloid and plasmacytoid dendritic cells from house dust mite-sensitized allergic patients dysregulate the T cell response

J Leukoc Biol

Enhanced prostaglandin E2 production by monocytes in atopic dermatitis (AD) is not accompanied by enhanced production of IL-6, IL-10 or IL-12

Clin Exp Immunol

Neonatal tolerance revisited: turning on newborn T cells with dendritic cells

Science

Sustained expression of CD154 (CD40L) and proinflammatory cytokine production by alloantigen-stimulated umbilical cord blood T cells

J Immunol

Basic and clinical immunology
HLA-DR expression on neonatal monocytes is associated with allergen-specific immune responses