nBos d 5, β-lactoglobulin Milk
Allergen
Cow's milk is popularly consumed throughout the world. Allergy to cow's milk is prevalent among infants and young children during the first year of life, affecting 0.5-3% at the age of 1 year. Bos d 5 (β-lactoglobulin) has been reported as a major allergenic protein in cow's milk. Sensitization to Bos d 5 has been reported to range between 13-76% in cow’s milk allergy patients. Milk whey proteins (like Bos d 5) are heat-labile and therefore are likely to be destroyed after extensive cooking and baking of milk. Thus, specific immunoglobulin E (sIgE) to Bos d 5 might help assess the tolerance to cooked or baked milk. Further, a lower level of sIgE against Bos d 5 has been reported to indicate tolerance towards cow’s milk. Clinical manifestations of Bos d 5-mediated allergy majorly include anaphylaxis and atopic dermatitis. Moreover, sIgE testing with Bos d 5 has been considered vital in diagnosing a cow’s milk protein allergy. Cross-reactivity has been observed between antibodies against bovine Bos d 5 and α-lactalbumin in cow's milk due to the shared amino acid sequence. Moreover, Bos d 5 from cow's milk has been found to exhibit sequence homology with other mammalian milk proteins (like water buffalo, ewe, goat, pig, donkey, and horse).
Epidemiology
Worldwide distribution
Cow's milk is popularly consumed throughout the world. However, allergy to cow’s milk is prevalent among infants and young children during the first year of life, affecting 0.5-3% at the age of 1 year. Bos d 5 (β-lactoglobulin; BLG) has been reported as a major allergenic protein in cow's milk. Sensitization to Bos d 5 has been reported to range between 13-76% in cow’s milk allergy patients.
According to a study, 61% of patients (n=92) allergic to cow's milk have reported sensitization toward Bos d 5.
A Taiwan-based retrospective study reported sensitization towards Bos d 5 among 46.8% (89/190) of individuals with specific immunoglobulin E (sIgE) towards whole cow's milk. Furthermore, a study conducted in Poland among 291 children (2-14 years) with a history of cow's milk allergy (CMA) reported sensitization towards Bos d 5 in 53.6% (37/69) of children.
According to a study conducted in Japan on 83 children (0.8-15.8 years) with suspected CMA, the clinically diagnosed CMA children (n=61) were reported to possess considerably elevated levels of Bos d 5 sIgE compared to the non-CMA children. In addition, allergy against Bos d 5 was reported in 63.4% of patients with CMA (n=86) in an Iran-based study.
A Netherland-based study included 30 (≥16 years) patients with CMA [18 assessed via skin prick test (SPT) and 10 via double-blind placebo-controlled food challenge (DBPCFC)] in the study group and 25 individuals in the control group (cow milk sensitized but tolerant individuals). The study reported significantly higher reactivity (through SPT) towards Bos d 5 (p=0.004) among patients in the study group compared to the control group. Furthermore, sIgE towards Bos d 5 was observed in 56% (10/18) of CMA patients.
A study in Germany and Denmark used crossed radioimmunoelectrophoresis (CRIE) technique to determine the level of serum IgE to cow milk antigenic components in the sera of 21 CMA patients and detected IgE antibodies against Bos d 5 in the sera of all patients.
Clinical Relevance
Cow milk allergy is regarded as a major common pediatric food allergy. Milk allergy can be either IgE-mediated or non-IgE-mediated. The clinical manifestations of cow's milk protein allergy are reported to be of two types such as immediate (shortly after consumption) and delayed (after hours or days of consumption) responses. The immediate reactions are generally IgE-mediated and can lead to angioedema, urticaria, aggravation of atopic dermatitis (AD), vomiting, in some cases, anaphylaxis, as well as respiratory symptoms (breathing, wheezing, coughing). On the other hand, most delayed reactions are non-IgE mediated and can lead to gastrointestinal symptoms (like enteropathy or proctocolitis) or skin reactions (such as AD).
Milk whey proteins such as Bos d 5 are heat-labile and therefore destroyed during the extensive cooking and baking of milk. Thus, the sIgE level to Bos d 5 may help assess the likelihood of tolerance to cooked or baked milk, and 75% of children with CMA may actually tolerate baked milk products such as muffins, waffles, cakes and bread. High sIgE levels of Bos d 5 indicate an allergy to all forms of milk, and low sIgE levels of Bos d 5 may indicate the development of tolerance.
According to a study, anaphylaxis was reported in 6/15 patients after ingestion of cow's milk. Furthermore, sIgE against Bos d 5 (15.3 ± 16.2 kU/L; median: 7.2, range: 0.14–53) was observed in these patients.
In a Korea-based study, 950 children with clinically diagnosed AD reported that 52.5% (245/471) of children affected with AD and sensitized to cow's milk (n=471) exhibited positive sIgE towards Bos d 5.
Cross-reactive molecules
A prospective cohort study conducted on 38 children (age <14 years) with CMA-associated symptoms reported cross-sensitization (SPT-based) between goat and cow milk.
Diagnostics
Disease Severity
Bos d 5-sIgE has been considered essential in diagnosing cow milk protein allergy. According to a study, the level of sIgE to Bos d 5 and Bos d 5 sIgE/IgG4 ratios were significantly elevated in patients who were reactive to baked milk compared to patients who were tolerant to baked milk.
According to a study, the level of sIgE against Bos d 5 has been anticipated to be associated with immediate reactions, family history and the eosinophil percentage.
The presence of several IgE-binding linear epitopes on Bos d 5 may suggest the significance of its particular peptides to be used as molecular markers to diagnose persistent CMA.
Exposure
Cow milk allergy mainly occurs through ingestion.
Cross-Reactivity
Cow, goat, and sheep milk consists of homologous proteins with similar structures and functions, thereby leading to cross-reactivity between the milk proteins.
Bos d 5 from cow's milk protein shows sequence homology with other mammalian milk, including water buffalo (96.7%), ewe (93.9%), goat (94.4%), pig (63.9%), donkey (56.9%), and horse (59.4%).
Additionally, antibodies against bovine Bos d 5 have been reported to exhibit cross-reactivity with ALA both in the native and denatured state. This cross-reactivity is reported to occur due to the shared amino acid sequence between these two proteins.
Explained Results
Allergen Information
Bos d 5 (β-lactoglobulin) is considered a major allergenic protein in cow's milk.
Clinical information
Characteristic symptoms of CMA include skin reactions (angioedema, urticaria, and atopic dermatitis), gastrointestinal symptoms, respiratory systems, and in some cases, anaphylaxis.
Cross-reactivity
Antibodies against bovine Bos d 5 show cross-reactivity with ALA present in cow's milk due to shared amino acid sequence. In addition, Bos d 5 in cow's milk shows sequence homology with other mammalian milk proteins, including water buffalo, ewe, goat, pig, donkey, and horse.