Abstract
The lipocalin beta-lactoglobulin (BLG) is a major protein compound in cow’s milk, and we detected it in cattle stable dust. BLG may be a novel player in the farm protective effect against atopic sensitization and hayfever. In previous studies, we demonstrated that only the ligand-filled holo-form of BLG prevented sensitization to itself. Here, we investigated whether holo-BLG could, in an innate manner, also protect against allergic sensitization to unrelated birch pollen allergens using a murine model. BALB/c mice were nasally pretreated four times in biweekly intervals with holo-BLG containing quercetin–iron complexes as ligands, with empty apo-BLG, or were sham-treated. Subsequently, mice were intraperitoneally sensitized two times with apo-BLG or with the unrelated birch pollen allergen apo-Bet v 1, adjuvanted with aluminum hydroxide. After subsequent systemic challenge with BLG or Bet v 1, body temperature drop was monitored by anaphylaxis imaging. Specific antibodies in serum and cytokines of BLG- and Bet v 1-stimulated splenocytes were analyzed by ELISA. Additionally, human peripheral blood mononuclear cells of pollen allergic subjects were stimulated with apo- versus holo-BLG before assessment by FACS. Prophylactic treatment with the holo-BLG resulted in protection against allergic sensitization and clinical reactivity also to Bet v 1 in an unspecific manner. Pretreatment with holo-BLG resulted in significantly lower BLG-as well as Bet v 1-specific antibodies and impaired antigen-presentation with significantly lower numbers of CD11c+MHCII+ cells expressing CD86. Pretreatment with holo-BLG also reduced the release of Th2-associated cytokines from Splenocytes in BLG-sensitized mice. Similarly, in vitro stimulation of PBMCs from birch pollen allergic subjects with holo-BLG resulted in a relative decrease of CD3+CD4+ and CD4+CRTh2 cells, but not of CD4+CD25+CD127− Treg cells, compared to apo-BLG stimulation. In conclusion, prophylactic treatment with holo-BLG protected against allergy in an antigen-specific and -unspecific manner by decreasing antigen presentation, specific antibody production and abrogating a Th2-response. Holo-BLG therefore promotes immune resilience against pollen allergens in an innate manner and may thereby contribute to the farm protective effect against atopic sensitization.
Highlights
Cow’s milk allergy (CMA) is associated with a low quality of life in children and their families, as milk and milk products are considered essential food in early lifetime
Other factors in milk, such as microbial components, fatty acids, TGF-beta, IL-10, IgG, microRNA and oligosaccharides have been discussed to contribute to the protective farm effect [33]
We showed that proper loading of the lipocalin BLG, the major whey compound of milk, with iron– flavonoid complexes can modulate immune-reactivity and induce immune resilience
Summary
Cow’s milk allergy (CMA) is associated with a low quality of life in children and their families, as milk and milk products are considered essential food in early lifetime. The phenomenon of CMA is in striking contrast to studies showing that consumption of unprocessed cow’s milk is considered to represent an important factor associated with the protective effect of cattle farms against atopic sensitization, asthma, and hayfever [10,11,12,13]. Heating milk above 65°C structurally alters the thermolabile milk proteins, in particular the whey fraction, and causes aggregates [16]. This leads to an increase in the antigenicity of the whey protein beta-lactoglobulin (BLG) [16] and the appearance of several new epitopes on BLG [17] during protein unfolding [18]. During the defatting process involving centrifugation and homogenization, the milk lipid fraction, e.g. w-3 polyunsaturated fatty acids, which is considered to be a precursor of anti-inflammatory mediators [19], is diminished
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