British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults.

Iron deficiency anaemia (IDA) is a major cause of morbidity and burden of disease worldwide. It can generally be diagnosed by blood testing and remedied by iron replacement therapy (IRT) using the oral or intravenous route. The many causes of iron deficiency include poor dietary intake and malabsorption of dietary iron, as well as a number of significant gastrointestinal (GI) pathologies. Because blood is iron-rich it can result from chronic blood loss, and this is a common mechanism underlying the development of IDA-for example, as a consequence of menstrual or GI blood loss.Approximately a third of men and postmenopausal women presenting with IDA have an underlying pathological abnormality, most commonly in the GI tract. Therefore optimal management of IDA requires IRT in combination with appropriate investigation to establish the underlying cause. Unexplained IDA in all at-risk individuals is an accepted indication for fast-track secondary care referral in the UK because GI malignancies can present in this way, often in the absence of specific symptoms. Bidirectional GI endoscopy is the standard diagnostic approach to examination of the upper and lower GI tract, though radiological scanning is an alternative in some situations for assessing the large bowel. In recurrent or refractory IDA, wireless capsule endoscopy plays an important role in assessment of the small bowel.IDA may present in primary care or across a range of specialties in secondary care, and because of this and the insidious nature of the condition it has not always been optimally managed despite the considerable burden of disease- with investigation sometimes being inappropriate, incorrectly timed or incomplete, and the role of IRT for symptom relief neglected. It is therefore important that contemporary guidelines for the management of IDA are available to all clinicians. This document is a revision of previous British Society of Gastroenterology guidelines, updated in the light of subsequent evidence and developments.

Differential Gene Expression of Lymphocytes Stimulated with Rhinovirus A and C in Children with Asthma.

Rationale: Individuals with asthma have heightened antibody responses to rhinoviruses (RVs), although those specific for RV-C are lower than responses specific for RV-A, suggesting poor immunity to this species.Objectives: To ascertain and compare T-cell memory responses induced by RV-A and RV-C in children with and without asthma.Methods: Peripheral blood mononuclear cells from 17 children with asthma and 19 control subjects without asthma were stimulated in vitro with peptide formulations to induce representative species-specific responses to RV-A and RV-C. Molecular profiling (RNA sequencing) was used to identify enriched pathways and upstream regulators.Measurements and Main Results: Responses to RV-A showed higher expression of IFNG and STAT1 compared with RV-C, and significant expression of CXCL9, 10, and 11 was not found for RV-C. There was no reciprocal increase of T-helper cell type 2 (Th2) cytokine genes or the Th2 chemokine genes CCL11, CCL17, and CCL22. RV-C induced higher expression of CCL24 (eotaxin-2) than RV-A in the responses of children with and without asthma. Upstream regulator analysis showed both RV-A and, although to a lesser extent, RV-C induced predominant Th1 and inflammatory cytokine expression. The responses of children with asthma compared with those without asthma were lower for both RV-A and RV-C while retaining the pattern of gene expression and upstream regulators characteristic of each species. All groups showed activation of the IL-17A pathway.Conclusions: RV-C induced memory cells with a lower IFN-γ-type response than RV-A without T-helper cell type 2 (Th2) upregulation. Children with asthma had lower recall responses than those without asthma while largely retaining the same gene activation profile for each species. RV-A and RV-C, therefore, induce qualitatively different T-cell responses.

Immunodominant T-Cell Epitopes in the VP1 Capsid Protein of Rhinovirus Species A and C.

Rhinovirus (RV) species A and C are the most frequent cause of respiratory viral illness worldwide, and RV-C has been linked to more severe exacerbations of asthma in young children. Little is known about the immune responses to the different RV species, although studies comparing IgG1 antibody titers found impaired antibody responses to RV-C. Therefore, the aim of this study was to assess whether T-cell immunity to RV-C is similarly impaired. We measured T-cell proliferation to overlapping synthetic peptides covering the entire VP1 capsid protein of an RV-A and RV-C genotype for 20 healthy adult donors. Human leukocyte antigen (HLA) was typed in all the donors in order to investigate possible associations between the HLA type and RV peptide recognition. Total and specific IgG1 antibody titers to the VP1 proteins of both RV-A and RV-C were also measured to examine associations between the antibody and T-cell responses. We identified T-cell epitopes that are specific to and representative of each RV-A and RV-C species. These epitopes stimulated CD4+-specific T-cell proliferation, with similar magnitudes of response for both RV species. All the donors, independent of their HLA-DR or -DQ type, were able to recognize the immunodominant RV-A and -C regions of VP1. Furthermore, the presence or absence of specific antibody titers was not related to changes in T-cell recognition. Our results indicate a dissociation between the antibody and T-cell responses to rhinoviruses. The species-representative T-cell epitopes identified in this study are valuable tools for future studies investigating T-cell responses to the different RV species. IMPORTANCE: Rhinoviruses (RVs) are mostly associated with the common cold and asthma exacerbations, although their contributions to most upper and lower respiratory tract diseases have increasingly been reported. Species C (RV-C) has been associated with more frequent and severe asthma exacerbations in young children and, along with RV-A, is the most clinically relevant species. Little is known about how our immune system responds to rhinoviruses, and there are limited tools to study specific adaptive immunity against each rhinovirus species. In this study, we identified immunodominant T-cell epitopes of the VP1 proteins of RV-A and RV-C, which are representative of each species. The study found that T-cell responses to RV-A and RV-C were of similar magnitudes, in contrast with previous findings showing RV-C-specific antibody responses were low. These findings will provide the basis for future studies on the immune response to rhinoviruses and can help elucidate the mechanisms of severity of rhinovirus-induced infections.

Diagnosis and Management of Iron Deficiency in CKD: A Summary of the NICE Guideline Recommendations and Their Rationale.

The UK-based National Institute for Health and Care Excellence (NICE) has updated its guidance on iron deficiency and anemia management in chronic kidney disease. This report outlines the recommendations regarding iron deficiency and their rationale. Serum ferritin alone or transferrin saturation alone are no longer recommended as diagnostic tests to assess iron deficiency. Red blood cell markers (percentage hypochromic red blood cells, reticulocyte hemoglobin content, or reticulocyte hemoglobin equivalent) are better than ferritin level alone at predicting responsiveness to intravenous iron. When red blood cell markers are not available, a combination of transferrin saturation < 20% and ferritin level < 100ng/mL is an alternative. In comparisons of the cost-effectiveness of different iron status testing and treatment strategies, using percentage hypochromic red blood cells > 6% was the most cost-effective strategy for both hemodialysis and nonhemodialysis patients. A trial of oral iron replacement is recommended in people not receiving an erythropoiesis-stimulating agent (ESA) and not on hemodialysis therapy. For children receiving ESAs, but not treated by hemodialysis, oral iron should be considered. In adults and children receiving ESAs and/or on hemodialysis therapy, intravenous iron should be offered. When giving intravenous iron, high-dose low-frequency administration is recommended. For all children and for adults receiving in-center hemodialysis, low-dose high-frequency administration may be more appropriate.

House Dust Mite Allergens: New Discoveries and Relevance to the Allergic Patient.

PURPOSE OF REVIEW: Recent findings on house dust allergens and their contribution to knowledge that will significantly impact on current and future allergy treatments are appraised. RECENT FINDINGS: Quantitation of IgE binding to a spectrum of allergen components in several independent studies in varying locations has largely affirmed the main components as the groups 1 and 2 and possibly 23 allergens with mid-tier contributions from the groups 4, 5, 7, and 21. Prevalent binding to Der p 23 has been recapitulated sometimes with low titers. The IgE of non-asthmatic atopic subjects binds at lower titer and to fewer components than that of asthmatics, and their IgG binding relative to IgE is higher especially for children hospitalized for exacerbation. The higher IgG ratios were associated with increased IL-10 a cytokine more readily induced from T cells of allergic subjects. Peptides representing the groups 1 and 2 allergens can be used to stimulate ex vivo T cells showing responses correlating with IgE binding and providing a valuable tool for ascertaining the contribution of IgE and T cells to disease. Also, the induction of Th2 and follicular helper T cells are shown to make different contributions in mice. Cross-reactivity of IgE binding assays with high-titer cross-reactive antibodies induced by scabies is a problem in the many areas of the world where scabies is highly prevalent and endemic and from recent increases in immigration. In the last few years, allergen research has produced results that warrant rapid translation into diagnostic tools and the formulation of allergen components for immunotherapy.

Chronic cat allergen exposure induces a TH2 cell-dependent IgG4 response related to low sensitization.

BACKGROUND: In human subjects, allergen tolerance has been observed after high-dose allergen exposure or after completed allergen immunotherapy, which is related to the accumulation of anti-inflammatory IgG4. However, the specific T-cell response that leads to IgG4 induction during chronic allergen exposure remains poorly understood. OBJECTIVE: We sought to evaluate the relationship between cat allergen-specific T-cell frequency, cat allergen-specific IgE and IgG4 titers, and clinical status in adults with cat allergy with and without cat ownership and the cellular mechanism by which IgG4 is produced. METHODS: Fel d 1-, Fel d 4-, Fel d 7-, and Fel d 8-specific T-cell responses were characterized by CD154 expression after antigen stimulation. RESULTS: In allergic subjects without cat ownership, the frequency of cat allergen (Fel d 1 and Fel d 4)-specific TH2 (sTH2) cells correlates with higher IgE levels and is linked to asthma. Paradoxically, we observed that subjects with cat allergy and chronic cat exposure maintain a high frequency of sTH2 cells, which correlates with higher IgG4 levels and low sensitization. B cells from allergic, but not nonallergic subjects, are able to produce IgG4 after cognate interactions with sTH2 clones and Fel d 1 peptide or the Fel d 1 recombinant protein. CONCLUSION: These experiments suggest that (1) allergen-experienced B cells with the capacity to produce IgG4 are present in allergic subjects and (2) cat allergen exposure induces an IgG4 response in a TH2 cell-dependent manner. Thus IgG4 accumulation could be mediated by chronic activation of the TH2 response, which in turn drives desensitization.

Multivariate analysis to evaluate genetic groups and production traits of crossbred Holstein × Zebu cows.

The objective of this research was to try to unveil the relationship between production traits and genotypic proportions of crossbred dairy cattle using principal component analysis (PCA) and cluster analysis. The herd consists of crossbred animals of Holstein (H) and Zebu (Z) (Gir and Guzerat) in different genotypic proportions; the composition of which varies from 12.5 to 100.0 % of the genetic group H. For this study, 834 milk production records from 257 cows from the years 1997 to 2014 were analyzed. The animals were all managed at a farm located in northeastern Brazil. The variables in the PCA were total milk yield per lactation (MY), milk yield adjusted to 305 days (MY305), lactation length (LL), and proportion of H and Z breeding. This analysis reduced the size of the sample space from the original five variables to two principal components (PCs) that together explained 89.4 % of the total variation. MY, MY305, LL, and genotypic proportion of H all contributed positively to PC1. The genotypic proportion of Z contributed negatively, which established a contrast between H and Z. Further cluster analysis identified two distinct groups when considering production performance and genotype of the animals. The high-performance group was predominantly Holstein breeding, while the lower performing group consisted mostly of Zebu. Under the environmental and management conditions in which this research was conducted, the best performances for the traits considered were achieved from cows whose genotypic proportion was between 38.0 and 94.0 % Holstein breeding.

Identification of Der p 23, a peritrophin-like protein, as a new major Dermatophagoides pteronyssinus allergen associated with the peritrophic matrix of mite fecal pellets.

The house dust mite (HDM) Dermatophagoides pteronyssinus is one of most important allergen sources and a major elicitor of allergic asthma. We screened a D. pteronyssinus expression cDNA library with IgE Abs from HDM allergic patients. A cDNA coding for a new major allergen was isolated, which showed sequence homology to peritrophins, which contain chitin-binding domains and are part of the peritrophic matrix lining the gut of arthropods. The mature Der p 23 allergen was expressed in Escherichia coli as an 8-kDa protein without its hydrophobic leader sequence and purified to homogeneity. It reacted with IgE Abs from 74% of D. pteronyssinus allergic patients (n = 347) at levels comparable to the two major HDM allergens, Der p 1 and Der p 2. Thus, Der p 23 represents a new major D. pteronyssinus allergen. Furthermore, rDer p 23 exhibited high allergenic activity as demonstrated by upregulation of CD203c expression on basophils from D. pteronyssinus allergic patients. Immunogold electron microscopy localized the allergen in the peritrophic matrix lining the midgut of D. pteronyssinus as well as on the surface of the fecal pellets. Thus, we identified a new major D. pteronyssinus allergen as peritrophin-like protein. The high allergenic activity of Der p 23 and its frequent recognition as respiratory allergen may be explained by the fact that it becomes airborne and respirable through its association with mite feces. Der p 23 may be an essential component for diagnosis and specific immunotherapy of HDM allergy.

Recombinant house dust mite allergens.

House dust mites (HDM) are a globally important source of allergen responsible for the sensitization of more than 50% of allergic patients. Specific immunotherapy with HDM extracts is effective but allergen extracts cannot be fully standardized and severe side-effects can occur during the protracted course of treatment. The introduction of molecular biological techniques into allergy research allowed the indentification of more than 20 groups of HDM allergens. Recombinant HDM allergens can be produced in defined concentrations and consistent quality and allow the development of vaccines for HDM allergy with reduced allergenic activity and retained immunogenicity. The immunotherapy trials in pollen allergic patients with recombinant pollen allergens/hypoallergenic allergen derivatives have shown that this treatment is effective and indicated that recombinant HDM vaccines might improve immunotherapy of HDM allergic patients. Here we report the steps for the development of vaccines for HDM allergy. After selection of the most prevalent HDM species, the panel of allergens to be included into a therapeutic vaccine for HDM allergy needs to be determined. HDM allergens with high IgE-binding frequency and clinical relevance will be modified into hypoallergenic variants and evaluated for their allergenic activity and immunogenicity. Derivatives with reduced allergenic activity but with retained immunogenicity would be good candidates for a HDM vaccine for safe and efficient immunotherapy.

Comparison of rhinovirus antibody titers in children with asthma exacerbations and species-specific rhinovirus infection.

BACKGROUND: Asthma exacerbations are associated with human rhinovirus (HRV) infections, and more severe exacerbations are associated with HRV-C. We have previously shown that the HRV-C-specific antibody response is low in healthy adult sera and that most of the antibody to HRV-C is cross-reactive with HRV-A. OBJECTIVES: To compare the antibody response to each HRV species in asthmatic and nonasthmatic children in whom the type of HRV infection was known. METHODS: Total and specific IgG1 binding to HRV viral capsid protein antigens of HRV-A, -B, and -C were tested in the plasma from nonasthmatic children (n = 47) and children presenting to the emergency department with asthma exacerbations (n = 96). HRV, found in most of the children at the time of their exacerbation (72%), was analyzed using molecular typing. RESULTS: Asthmatic children had higher antibody responses to HRV. The titers specific to HRV-A, and to a lesser extent HRV-B, were higher than in nonasthmatic controls. The species-specific responses to HRV-C were markedly lower than titers to HRV-A and HRV-B in both asthmatic and nonasthmatic children (P < .001). The titers both at presentation and after convalescence were not associated with the HRV genotype detected during the exacerbation. CONCLUSIONS: The higher total anti-HRV antibody titers of asthmatic children and their higher anti-HRV-A and -B titers show their development of a heightened antiviral immune response. The low species-specific HRV-C titers found in all groups, even when the virus was found, point to a different and possibly less efficacious immune response to this species.

Hierarchy and molecular properties of house dust mite allergens.

The allergenic load of house dust mite allergy is largely constituted by a few proteins with a hierarchical pattern of allergenicity. The serodominant specificities are the group 1&2 and the group 23 faecal allergens. The collective IgE binding to the group 1&2 allergens can measure unequivocal HDM sensitisation better than HDM extracts although discrepancies have been found in regions with complex acarofauna suggesting a need to investigate the specificity with allergen components. The group 4, 5, 7&21 allergens that each induce responses in about 40% of subjects are mid-tier allergens accounting for most of the remaining IgE binding. Their titres are proportional to the concomitant responses to Der p1&2. Group 2 allergen variants have different antibody binding. Body proteins only occasionally induce sensitisation although a higher prevalence of binding by atopic dermatitis patients provides a new avenue of research. A broad spectrum of IgE binding has been associated with diverse symptoms but not with the severity of asthma which is associated with low IgG antibody. Some allergens such as the group 14 large lipid binding proteins and the recently described proteins Der f 24-33, need further investigation but with the cognoscence that other denominated allergens have been found to be minor sensitisers by comparative quantitative analyses. Scabies is a confounder for diagnosis with extracts, inducing cross-reactive antibodies with Der p 4&20 as is seafood allergy with cross reactivity to Der p 10 a minor HDM allergen. The HDM genome sequence can now be used to verify allelic and paralogous variations.

Allergen ligands in the initiation of allergic sensitization.

As investigations into the innate immune responses that lead to allergic sensitization become better defined, there is a need to determine how allergens could interact with pattern recognition receptors that bind non-proteinaceous moieties. Many important allergens are not covalently bound to lipid or carbohydrate, but have structures belonging to lipid, glycan and glycolipid-binding families. These include ML-domain proteins, lipopolysaccharide-binding/cell permeability-increasing proteins, von Ebner gland lipocalins, salivary lipocalins/major urinary proteins, plant pathogenesis-related proteins PR-5 and -10, uteroglobins, non-specific lipid transfer proteins, large lipid transfer proteins and proteins with chitin and other carbohydrate-binding modules. The binding expected is overviewed with regard to importance of the allergens and their ability to elicit responses proposed from experimental models. The evidence compiled showing that allergens from the same source sensitize for different types of adaptive immune responses supports the concept that individual allergens within these sources have their own distinctive interactions with innate immunity.

SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability.

The N-Myc oncoprotein is a critical factor in neuroblastoma tumorigenesis which requires additional mechanisms converting a low-level to a high-level N-Myc expression. N-Myc protein is stabilized when phosphorylated at Serine 62 by phosphorylated ERK protein. Here we describe a novel positive feedback loop whereby N-Myc directly induced the transcription of the class III histone deacetylase SIRT1, which in turn increased N-Myc protein stability. SIRT1 binds to Myc Box I domain of N-Myc protein to form a novel transcriptional repressor complex at gene promoter of mitogen-activated protein kinase phosphatase 3 (MKP3), leading to transcriptional repression of MKP3, ERK protein phosphorylation, N-Myc protein phosphorylation at Serine 62, and N-Myc protein stabilization. Importantly, SIRT1 was up-regulated, MKP3 down-regulated, in pre-cancerous cells, and preventative treatment with the SIRT1 inhibitor Cambinol reduced tumorigenesis in TH-MYCN transgenic mice. Our data demonstrate the important roles of SIRT1 in N-Myc oncogenesis and SIRT1 inhibitors in the prevention and therapy of N-Myc-induced neuroblastoma.

Quantitation of IgE binding to the chitinase and chitinase-like house dust mite allergens Der p 15 and Der p 18 compared to the major and mid-range allergens.

BACKGROUND: The prevalence of IgE binding to the group 15 and 18 house dust mite (HDM) allergens of the Dermatophagoides species is reported to be >50% and they are the major allergens of HDM-sensitised dogs. The objective was to quantitate the IgE titres to Der p 15 and Der p 18 and evaluate their importance in human HDM sensitisation compared to the known major and mid-tier allergens. METHODS: Der p 15 and Der p 18 were produced in Pichia pastoris, and their structure validated by circular dichroism. IgE binding was measured in 37 Australian HDM-allergic adults using a quantitative DELFIA™ assay. RESULTS: The prevalence of IgE titres to Der p 15 and Der p 18 >0.1 ng/ml was low (38%) and only one subject had a titre >10 ng/ml to either allergen. The mean anti-Der p 15 and Der p 18 titres were 1.2 and 2.6 ng/ml, respectively, i.e. approximately 10- to 20-fold lower than the response to the major Der p 1 and Der p 2 allergens (p < 0.001). The IgE responses to Der p 15 and Der p 18 were lower than the mid-tier allergens Der p 5 and Der p 7 and although they correlated with each other, they did not correlate with titres to either the major or mid-tier allergens. CONCLUSIONS: Sensitisation to Der p 15 and Der p 18 makes a minor contribution to anti-HDM IgE titres, and the titres do not correlate with the size of the response to the major allergens.

Hypoallergenic Der p 1/Der p 2 combination vaccines for immunotherapy of house dust mite allergy.

BACKGROUND: More than 50% of allergic patients have house dust mite (HDM) allergy. Group 1 and 2 allergens are the major HDM allergens. OBJECTIVE: We sought to produce and perform preclinical characterization of a recombinant hypoallergenic combination vaccine for specific immunotherapy of HDM allergy. METHODS: Synthetic genes coding for 2 hybrid proteins consisting of reassembled Der p 1 and Der p 2 fragments with (recombinant Der p 2 [rDer p 2]/1C) and without (rDer p 2/1S) cysteines were expressed in Escherichia coli and purified to homogeneity by means of affinity chromatography. Protein fold was determined by using circular dichroism analysis, allergenic activity was determined by testing IgE reactivity and using basophil activation assays, and the presence of T-cell epitopes was determined based on lymphoproliferation in allergic patients. Mice and rabbits were immunized to study the molecules' ability to induce an allergic response and whether they induce allergen-specific IgG capable of inhibiting allergic patients' IgE binding to the allergens, respectively. RESULTS: rDer p 2/1C and rDer p 2/1S were expressed in large amounts in E coli as soluble and folded proteins. Because of the lack of disulfide bonds, rDer p 2/1S did not form aggregates and was obtained as a monomeric protein, whereas rDer p 2/1C did form aggregates. Both hypoallergens lacked relevant IgE reactivity and had reduced ability to induce allergic inflammation and allergic responses but induced similar T-cell proliferation as the wild-type allergens. Immunization with the hypoallergens (rDer p 2/1S > rDer p 2/1C) induced IgG antibodies in rabbits that inhibited the IgE reactivity of patients with HDM allergy to Der p 1 and Der p 2. CONCLUSION: The preclinical characterization indicates that particularly rDer p 2/1S can be used as a safe hypoallergenic molecule for both tolerance and vaccination approaches to treat HDM allergy.

Clinical Outcome of Minimally Manipulated, Mechanically Isolated Autologous Adipose Tissue-Derived Stromal Vascular Fraction (Sahaj Therapy®) in Knee Osteoarthritis-Randomized Controlled Trial.

Introduction: Regenerative therapy has shown promising results in the treatment of osteoarthritis (OA) knee with Kellgren-Lawrence (KL) Grades I-III. We compared the safety, efficacy, functional, and clinical outcomes of intra-articular implantation of autologous adipose tissue-derived stromal vascular fraction (SVF) isolated using direct ultrasonic cavitation (Sahaj therapy-Cell Innovation Patented Technology) and saline injection in knee osteoarthritis. Materials and Methods: The present prospective observational study was conducted over 3 years. We enrolled 120 patients in our study, where four patients got excluded as they did not meet the inclusion criteria. The remaining 116 patients were randomized into two groups, one with autologous adipose tissue-derived SVF and the other group with saline injection. A comparison of mean KOOS and VAS scores at different follow-ups was done using Paired 't' test. A p value of < 0.05 was considered significant. Results: The results show that the SVF group had significantly higher KOOS scores (78.49 ± 6.54 in the SVF group vs 59.19 ± 5.14 in the saline group), respectively (p < 0.001). Similarly, the SVF group had significantly lesser VAS scores (3.17 ± 0.94 in the SVF group vs 3.89 ± 1.04 in the saline group), respectively (p < 0.001). Conclusions: Autologous adipose tissue-derived SVF is a better choice for treating knee osteoarthritis. For individuals with degenerative osteoarthritis, autologous SVF grafting in the same surgical procedure is an innovative and promising treatment modality. Even after 3 years of follow-up, the study participants with OA knee have shown a good clinical and functional outcome.

Antibacterial antibody responses associated with the development of asthma in house dust mite-sensitised and non-sensitised children.

BACKGROUND: Infants who develop house dust mite (HDM) allergy and HDM-sensitised children with severe persistent asthma have low antibody responses to the P6 antigen of Haemophilus influenzae. OBJECTIVE: To measure the development of antibody to two ubiquitous bacteria of the respiratory mucosa in a prospective birth cohort at high risk of allergic disease and to assess which responses are associated with asthma and atopy. METHODS: IgG1 and IgG4 antibody to H influenzae (P4 and P6) and Streptoccocus pneumoniae (PspA and PspC) surface antigens was measured in yearly blood samples of children aged 1-5 years. IgE to the P6 antigen was examined for the 5-year group. The children were stratified based on HDM sensitisation and asthma at 5 years of age. RESULTS: HDM-sensitised children had lower IgG1 antibody titres to the bacterial antigens, and early responses (<3 years and before the development of HDM sensitisation and asthma) corrected for multiple antigens were significantly reduced for P4, P6 and PspC (p=0.008, p=0.004 and p=0.028, respectively). Similar associations with asthma were also found (p=0.008, p=0.004 and p=0.032 for P4, P6 and PspC, respectively). The IgG4 antibody titre and prevalence were similar in both HDM-sensitised and non-sensitised groups, but sensitised children had a slower downregulation of the IgG4 response. Children with asthma (27/145 at 5 years) had lower anti-P6 IgE responses (p<0.05). CONCLUSIONS: HDM-sensitised children have early defective antibody responses to bacteria that are associated with asthma. Surprisingly, antibacterial IgE was associated with a reduced risk for asthma.