Functional iron‐deficiency in women with allergic rhinitis is associated with symptoms after nasal provocation and lack of iron‐sequestering microbes

Petje, Lisa‐Marie; Jensen, Sebastian A.; Szikora, Sebastian; Sulzbacher, Martin; Bartosik, Tina; Pjevac, Petra; Hausmann, Bela; Hufnagl, Karin; Untersmayr, Eva; Fischer, Lisa; Vyskocil, Erich; Eckl‐Dorna, Julia; Jensen‐Jarolim, Erika; Hofstetter, Gerlinde; Afify, Sheriene Moussa; Krenn, Claus G.; Rivelles, Elisa; Hann, Stephan; Roth‐Walter, Franziska

doi:10.1111/all.14960

Cited by 26 publications

(22 citation statements)

References 6 publications

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“…Antibiotic treatment also aggravated atopic dermatitis in a murine model ( 291 , 292 ). In line, it is well established that individuals with atopic diseases (rhinitis, asthma, dermatitis, food allergy) have a reduced microbial (fungal and bacterial) diversity ( 108 , 293 – 303 ), which may result in a diminished nutritional support by the commensal microbiota. The microbiota strongly manipulates the immune system.…”

Section: Sequestration Strategies and Defense Mechanisms In Microbes ...mentioning

confidence: 97%

“…Virtually, every immune activation results in functional iron deficiency ( 4 , 104 – 108 ), where, despite sufficient iron stores in the liver and mononuclear phagocyte system (macrophages), iron mobilization is inhibited and dietary iron absorption is decreased by hepcidin, the master regulator of iron uptake. As such, even in healthy adults, iron deficiency is a driver of low-grade chronic inflammation ( 109 ).…”

Section: Iron Deficiency In Humansmentioning

confidence: 99%

“…Persons with functional iron deficiencies usually suffer from underlying chronic or metabolic diseases such as autoimmune ( 110 , 111 ) and atopic diseases ( 108 , 112 – 115 ), chronic kidney diseases ( 56 , 116 , 117 ), congestive heart failure ( 118 – 120 ), chronic pulmonary diseases ( 121 – 123 ), and obesity ( 124 , 125 ), in which iron deficiency is associated with a worsened prognosis and outcome ( 103 , 104 , 126 – 133 ). Interestingly, iron deficiency is also associated with an increased risk for thrombosis ( 134 , 135 ).…”

Section: Iron Deficiency In Humansmentioning

confidence: 99%

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Iron-Deficiency in Atopic Diseases: Innate Immune Priming by Allergens and Siderophores

Roth‐Walter

2022

Front. Allergy

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Although iron is one of the most abundant elements on earth, about a third of the world's population are affected by iron deficiency. Main drivers of iron deficiency are beside the chronic lack of dietary iron, a hampered uptake machinery as a result of immune activation. Macrophages are the principal cells distributing iron in the human body with their iron restriction skewing these cells to a more pro-inflammatory state. Consequently, iron deficiency has a pronounced impact on immune cells, favoring Th2-cell survival, immunoglobulin class switching and primes mast cells for degranulation. Iron deficiency during pregnancy increases the risk of atopic diseases in children, while both children and adults with allergy are more likely to have anemia. In contrast, an improved iron status seems to protect against allergy development. Here, the most important interconnections between iron metabolism and allergies, the effect of iron deprivation on distinct immune cell types, as well as the pathophysiology in atopic diseases are summarized. Although the main focus will be humans, we also compare them with innate defense and iron sequestration strategies of microbes, given, particularly, attention to catechol-siderophores. Similarly, the defense and nutritional strategies in plants with their inducible systemic acquired resistance by salicylic acid, which further leads to synthesis of flavonoids as well as pathogenesis-related proteins, will be elaborated as both are very important for understanding the etiology of allergic diseases. Many allergens, such as lipocalins and the pathogenesis-related proteins, are able to bind iron and either deprive or supply iron to immune cells. Thus, a locally induced iron deficiency will result in immune activation and allergic sensitization. However, the same proteins such as the whey protein beta-lactoglobulin can also transport this precious micronutrient to the host immune cells (holoBLG) and hinder their activation, promoting tolerance and protecting against allergy. Since 2019, several clinical trials have also been conducted in allergic subjects using holoBLG as a food for special medical purposes, leading to a reduction in the allergic symptom burden. Supplementation with nutrient-carrying lipocalin proteins can circumvent the mucosal block and nourish selectively immune cells, therefore representing a new dietary and causative approach to compensate for functional iron deficiency in allergy sufferers.

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Section: Sequestration Strategies and Defense Mechanisms In Microbes ...mentioning

confidence: 97%

Section: Iron Deficiency In Humansmentioning

confidence: 99%

Section: Iron Deficiency In Humansmentioning

confidence: 99%

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Iron-Deficiency in Atopic Diseases: Innate Immune Priming by Allergens and Siderophores

Roth‐Walter

2022

Front. Allergy

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“…The concept of targeted micronutrition to correct micronutritional deficiencies in immune cells of allergic patients, the main attribute of mode-of-action of loaded beta-lactoglobulin (holoBLG), has been unravelled only recently [3][4][5][6]. There are multiple studies showing that atopy is associated with iron deficiencies [7][8][9][10][11] and/or vitamin deficiencies [12][13][14][15]. These deficiencies turn the immune system into a hyperreactive state, contributing to the atopic state [8,15].…”

Section: Introductionmentioning

confidence: 99%

Long-term benefits of targeted micronutrition with the holoBLG lozenge in house dust mite allergic patients

Bergmann

Raab²,

Krause

et al. 2022

Allergo J Int

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Summary Purpose The long-term effects of targeted micronutrition with the holoBLG lozenge in house dust mite (HDM) allergic rhinoconjunctivitis (ARC) patients were evaluated at a follow-up visit in an allergen exposure chamber (AEC). Methods Patients who were supplemented for 3‑months with the holoBLG lozenge in a previous study with two controlled HDM-AEC challenges [visits: V1, V3] were recruited for a third AEC challenge (V5) 7–8 months after cessation of supplementation. Symptoms (nose, conjunctival, bronchial, others), well-being, and lung function parameters were recorded exactly as in the previous study. Primary endpoint was change in median Total Nasal Symptom Score (TNSS) at V5 compared to V1. Secondary endpoints included e.g. change in median Total Symptom Score (TSS) and the exploratory analysis of temporal evolution of symptom scores using linear mixed effects models. Results Of the 32 patients included in the original study, 27 could be recruited for the follow-up visit with a third AEC challenge. An improvement of 20% (p = 0.15) in the primary endpoint TNSS [V1: 2.5 (interquartile range [IQR]: 1–4), V5: 2.0 (IQR: 1–3)] was observed; 40% (p = 0.04) improvement was seen for the TSS [V1: 5.0 (IQR: 3–9), V5: 3.0 (IQR: 2–5.5)]. Analysis of temporal evolution of all symptom scores, and the personal well-being revealed sustained, clinically meaningful improvement at V5 compared to V1. No relevant lung function parameter differences were observed. Conclusions Sustained long-term reduction of TNSS (primary endpoint) and sustained long-term improvement of secondary endpoints (temporal evolution of all symptom scores and well-being) were demonstrated 7–8 months after cessation of holoBLG supplementation, indicative of a long-lasting nature of immune resilience induced by holoBLG. Trial registration The study was registered at clinicaltrials.gov (NCT04872868).

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“…Presumably, there are patients with a history of Fe therapy among those individuals as well, the more since Fe‐deficient anemia is relatively common, and frequently treated with use of (temporary) oral supplementation 35 . According to some authors, it seems that Fe deficiency, and resultant anemia, are associated with the onset of type I allergy, such as allergic rhinocunjunctivitis, 36,37 whereas a corrected Fe status might prevent the formation of a type I allergy. In their review on this issue, Roth‐Walter et al 38 described that: “Fe deficiency affects more T‐helper (Th)1 than Th2 immune cells,” that is, the “proliferative phase of T cells is dependent on Fe supply” and “Th1‐associated cytokines IFN‐y and the IL‐12/IL18‐mediated proliferation was found to be severely affected by iron chelators.” Conversely, it might be possible that this is balanced by normal Fe homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Contact sensitization to iron: A potentially underestimated metal allergen and elicitor of complications in patients with metal implants

et al. 2022

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Background: Little is known about sensitization to iron (Fe) in private, occupational, and medical settings, particulary implantology.Objectives: To investigate sensitization to metals, particularly to Fe, both in preimplant individuals with presumed metal allergy and in patients with suspected metal implant allergy. To further characterize Fe-sensitized individuals.Methods: Analysis of patch test reactions to an Fe (II) sulfate-containing metal series in 183 consecutive patients (41 pre-implant, 142 metal implant bearers). Test readings were on day (D)2, D3, and D6. Evaluation of questionnaire-aided history of metal reactivity patterns and demographics of Fe reactors.Results: Metal reactivity in pre-implant/implant/total group was: to nickel 39%/30%/32%; to cobalt 17%/15%/15%; and to chromium 7%/13%/11%.Co-sensitizations cobalt/nickel (19/58) and cobalt/chromium (11/21) were significant at P < .001; co-sensitizations Fe/nickel (4/10) and chromium/knee arthroplasty (11/73) at P = .03. Ten of 183 (5.5%) reacted to Fe (2 of 41 pre-implant patients, 8 of 142 implant bearers), with 10 reacting only on D6. Fe reactivity was highest in complicated knee arthroplasty (7/73). Further peculiarities of Fe reactors included frequent isolated Fe reactivity (6/10), occupational metal exposure (7/10), previous (par)enteral Fe substitution (6/10).Conclusions: The 5.5% prevalence of Fe reactions suggests a potentially underestimated role of this metal allergen in general and in implant bearers. The latter also shows a distinct metal sensitization pattern.

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Functional iron‐deficiency in women with allergic rhinitis is associated with symptoms after nasal provocation and lack of iron‐sequestering microbes

Cited by 26 publications

References 6 publications

Iron-Deficiency in Atopic Diseases: Innate Immune Priming by Allergens and Siderophores

Iron-Deficiency in Atopic Diseases: Innate Immune Priming by Allergens and Siderophores

Long-term benefits of targeted micronutrition with the holoBLG lozenge in house dust mite allergic patients

Contact sensitization to iron: A potentially underestimated metal allergen and elicitor of complications in patients with metal implants

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