Table of Contents

g208 Phl p 4 Scientific Information Summary Epidemiology Environmental Characteristics Clinical Relevance Molecular Aspects Diagnostic Relevance Compiled By

Component

g208 Phl p 4

g208 Phl p 4 Scientific Information

Type:

Component

Name; WHO/IUIS:

Phl p 4

Biological function:

Berberin-bridge enzyme-like protein

Allergen code:

g208

Source Material:

Native sourced from the extracts of Phleum pratense pollen

Other Names :

Grass pollen allergens group 4; previous name: Phl p IV

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 (1). Timothy grass pollen induces allergic rhinitis (AR), allergic rhinoconjunctivitis (ARC), and exacerbates asthma in sensitized individuals (1). There is a high degree of cross-reactivity between timothy grass and other grass pollens(2).

Native Phl p 4 was identified as a major allergen of timothy grass pollen, binding IgE from 75%-82% of grass-allergic patients (3, 4). In grass allergic Brazilian subjects, the prevalence of sensitization to microarrayed Phl p 4 was 64% (5). Recombinant Phl p 4 showed IgE binding with 31 of 32 nPhl p 4-reactive sera (6), but an important part of reactivity might be lost (7). 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 (8). Apparent monosensitization to Phl p 4 during childhood was reported in the Swedish BAMSE birth cohort (8), but not in the German MAS birth cohort (9).

Environmental Characteristics

Source and tissue

Phl p 4 is present in timothy grass pollen in the outer coat of the pollen wall (exine) and in the cytoplasm, in close contact with plant carbohydrate constituents, distributed inside amyloplasts (starch storage organelles) and between polysaccharide particles (3).

Risk factors

Sensitization to Phl p 4 has an early onset in predisposed individuals (7) . In the German 1990 birth cohort MAS (Multicenter Allergy Study), subjects who developed AR during childhood or as teenagers displayed detectable IgE to Phl p 4 as early as 3 years, similarly to sensitization to grass pollen allergens Phl p 1, Phl p 2, and Phl p 5 (9). In this cohort, the annual incidence of Phl p 4 up to 13 years was 8.6%, an intermediate value between Phl p 1 at 11.9% and Phl p 5 at 7.2% (9). In a cross-sectional observational pediatric study in children aged 4-18 years (mean 11) with symptomatic AR, asthma, or both in Rome (Italy), the prevalence of IgE sensitization to recombinant Phl p 4 was 50%, close to that observed for Phl p2 and Phl p 5 but significantly less than Phl p 1 (greater than 90%) (10).

Sensitization to Phl p 4 was not associated with exposure to particulate air pollution (11).

Clinical Relevance

Disease severity and prediction

Complex sensitization profiles, including sensitization to Phl p 4, are associated with a higher risk for symptomatic AR(9), high atopic features(12) and increasing probability of reporting AR symptoms by the age of 16 years(8) . In the Swedish birth cohort BAMSE, early sensitization to native Phl p 4 was identified as an early predictor of grass allergy(8), an epidemiological finding awaiting pathophysiological explanation given the glycosylated nature and hence extended cross-reactivity of Phl p 4 (8, 13, 14).

Cross-reactive molecules

Phl p 4 exhibits sequence identity of 50% or higher with similar proteins from other grass species (15, 16) showing extensive similarity among members but not with other allergen families. (15, 17)

Molecular Aspects

Biochemistry

Phl p 4 has a molecular weight of 55 kDa (16) and is highly basic (2). It is a berberin bridge enzyme-like protein, bearing 34% sequence identity to the berberin bridge enzyme from California poppy (Eschscholzia californica) (18). Thus, it belongs to the flavin adenine dinucleotide (FAD)-dependent family of vanillyl alcohol oxidases (VAO) (alternatively identified as p-cresol methyl hydroxylase, PCMH) structural superfamily (18). Functionally, Phl p 4 is a glucose dehydrogenase, using dioxygen as a hydrogen acceptor

Isoforms, epitopes, antibodies

As of August 1st, 2021, two isoallergens of Phl p 4 i.e., Phl p 4.0101 and Phl p 4.01.02, have been identified and officially published by the World Health Organization (WHO) and International Union of Immunological Societies (IUIS) Allergen Nomenclature (16)

Cross-reactivity due to structural similarity

Cross-reactivity of Phl p 4 is related to both its protein moiety and its glycosylated lateral chains. Protein cross-reactivity is limited to grass allergens group 4, while CCD cross-reactivity extends to virtually any other CCD-bearing pollen, plant food, insect venom molecule or whole allergen (13).

Phl p 4 exhibits sequence identity of 50% or higher with similar proteins from other grass species (15, 16) showing extensive similarity among members but not with other allergen families. (15, 17)

Diagnostic Relevance

Disease Severity

Sensitization to Phl p 4 has been associated with more complex sensitization profiles, hence with a higher risk for AR (9)

Cross-Reactivity

Phl p 4 shows sequence identity with similar proteins from other temperate and subtropical grass species (7). 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 (7, 20).

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 (21)

Exposure

The main route of exposure is through inhalation of timothy grass pollen.

Compiled By

Author: Joana Vitte

Reviewer: Dr. Christian Fischer

Last reviewed: November 2021

References

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