Phl p 4
Summary
Phl p 4, a glycosylated protein, is a component of timothy grass (Phleum pratense) pollen. Its protein moiety is cross-reactive with other grass pollen group 4 allergens, while the cross-reactive carbohydrate determinants (CCD) support cross-reactivity with unrelated CCD-bearing allergenic molecules and whole allergens. Based on findings in a Swedish birth cohort, sensitization to Phl p 4 has been proposed as an early predictor of allergic rhinitis, but confirmation is needed.
Epidemiology
Worldwide distribution
Grass pollens are the principal causes of respiratory allergic disease globally. Timothy grass has a widespread distribution in the temperate climate and is often the predominant grass pollen in such European and Asian regions, less so in Australia. Timothy grass pollen induces allergic rhinitis (AR), allergic rhinoconjunctivitis (ARC), and exacerbates asthma in sensitized individuals. There is a high degree of cross-reactivity between timothy grass and other grass pollens.
Native Phl p 4 was identified as a major allergen of timothy grass pollen, binding IgE from 75%-82% of grass-allergic patients. In grass allergic Brazilian subjects, the prevalence of sensitization to microarrayed Phl p 4 was 64%. Recombinant Phl p 4 showed IgE binding with 31 of 32 nPhl p 4-reactive sera, but an important part of reactivity might be lost. Upon exposure of predisposed individuals to grass pollen, sensitization to Phl p 4 develops early in life. In the Swedish birth cohort BAMSE, sensitization to Phl p 4 was the second most frequent among timothy grass molecular allergens, aside from Phl p 1, growing from 3.9% at the age of 4 years to 13.0% at 8 years and 19.0% at 16 years. Apparent monosensitization to Phl p 4 during childhood was reported in the Swedish BAMSE birth cohort, but not in the German MAS birth cohort.
Clinical Relevance
Disease severity and prediction
Complex sensitization profiles, including sensitization to Phl p 4, are associated with a higher risk for symptomatic AR, high atopic features and increasing probability of reporting AR symptoms by the age of 16 years. In the Swedish birth cohort BAMSE, early sensitization to native Phl p 4 was identified as an early predictor of grass allergy, an epidemiological finding awaiting pathophysiological explanation given the glycosylated nature and hence extended cross-reactivity of Phl p 4.
Cross-reactive molecules
Phl p 4 exhibits sequence identity of 50% or higher with similar proteins from other grass species showing extensive similarity among members but not with other allergen families.
Other topics
The natural glycosylated form nPhl p 4 exhibits lower allergenicity than rPhl p 4 when assessed with skin prick tests or basophil activation test despite more effective IgE-binding.
Diagnostics
Disease Severity
Sensitization to Phl p 4 has been associated with more complex sensitization profiles, hence with a higher risk for AR
Cross-Reactivity
Phl p 4 shows sequence identity with similar proteins from other temperate and subtropical grass species. Cross-reactivity has been demonstrated with the major ragweed allergen defensin Amb a 1 and may extend outside grass and weed allergens if nPhl p 4 is used but can be avoided by using rPhl p 4.
AIT Prescription
Phl p 1 and Phl p 5, but not Phl p 4, are usually employed when grass pollen allergen immunotherapy is considered, both as biomarkers for therapeutic response and in trials with molecular allergen immunotherapy
Exposure
The main route of exposure is through inhalation of timothy grass pollen.
References
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