g209 Phl p 6

Summary

Phl p 6 is a major allergen from timothy grass (Phleum pratense) pollen, belonging to group 5/6 of grass pollen allergens that are found only in Pooideae species. It is a non-glycosylated peptide with cross-reactivity restricted to grass pollen allergens of group 5/6. Therefore, Phl p 6 is a marker of genuine sensitization to grass pollen

Epidemiology

Worldwide distribution

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, 2).

Phl p 6 was identified as a major allergen of timothy grass pollen, binding IgE from 75% of 171 grass-allergic patients (3, 4). In grass pollen allergic patients, sensitization to Phl p 6 is less prevalent than to Phl p 1 and Phl p 5, and overall similar to that of Phl p 2 and Phl p 4 (5). Reported prevalence of Phl p 6 sensitization varies from 44% to almost 90% in different cohorts of adult or pediatric grass pollen allergic patients (1, 5, 6). In an unselected population of 23,077 consecutive Italian subjects with a suspicion of airborne or food allergy, the prevalence of IgE sensitization to Phl p 6 was 13.6% (7).

The Swedish birth cohort BAMSE provided data in general population. Sensitization to Phl p 6 was the fourth most frequent among timothy grass allergens, detected in 0.3% of 763 pediatric subjects at the age of 4 years, in 2.8% at age 8, and 10.4% at age 16 (8).

Apparent monosensitization to Phl p 6 is infrequent (1, 5, 7, 8). 

Environmental Characteristics

Source and tissue

In intact pollen grains, Phl p 6 is found predominantly in small cell wall-associated bodies known as P (polysaccharide-containing)-particles (4). P-particles may become aerosolized, contribute to allergen spreading, and penetrate deep into the airways due to their minute size (2.5 µm) (4). 

Clinical Relevance

Detailed information regarding timothy grass pollen is available in the whole allergen section. Timothy grass pollen induces allergic rhinitis (AR), allergic rhinoconjunctivitis, and exacerbates asthma in sensitized individuals (2). There is a high degree of cross-reactivity between timothy grass and other grass pollens (3). 

Disease severity and prediction

Detectable IgE sensitization to Phl p 6 is usually found in grass allergic patients, in association with other major allergens, but seldom in sensitized subjects without a history of grass pollinosis (1, 8, 9). In the birth cohort BAMSE, Phl p 6 sensitization at age 8 in subjects without grass allergy symptoms conferred an adjusted odds ratio of 5.1 for developing grass pollen AR by the age of 16 (8). However, due to the rare occurrence of Phl p 6 sensitization at age 8, this odds ratio did not reach statistical significance. Finally, apparent monosensitization to Phl p 6, reported in the same cohort, was found in a subject without a history of grass pollinosis and without skin reactivity to timothy grass pollen extract of whole allergen (8).

In an Italian multicenter cohort of children with seasonal allergy, 93% of whom were sensitized to timothy grass at baseline, follow-up data after 6 years did not evidence a predictive value of Phl p 6 sensitization by itself for the type, severity, remission, or persistence of allergic symptoms (10), in line with previous literature (8, 9).

Phl p 6 sensitization in the context of the grass pollen molecular allergen profile is a frequent finding, reported in 72% of grass pollen allergic children (5), but its diagnostic and prognostic relevance has not been established yet (11).

Cross-reactive molecules

Clinically significant cross-reactivity of Phl p 6 is observed only with related grass allergens, namely group 5 (e.g., Phl p 5) and group 6 (1, 9). It was suggested that IgE directed to group 5 allergens from grass pollens devoid of group 6 molecules, such as Lolium multiflorum, efficiently binds Phl p 6 in vitro (12)

Prevention and Therapy

Experimental trials

Phl p 6 induces skin reactivity, in vitro histamine degranulation, and was identified as a relevant molecule for allergen immunotherapy of grass pollinosis (4, 5, 8).

Molecular Aspects

Biochemistry

Phl p 6 is an acidic peptide with a molecular weight of 11 kDa and an alpha-helical folding (4). Its biological function remains elusive (1).

Isoforms, epitopes, antibodies

As of August 15th, 2021, two isoallergens of Phl p 6 i.e., Phl p 6.0101 and Phl p 6.0201, have been officially published by the World Health Organization (WHO) and International Union of Immunological Societies (IUIS) Allergen Nomenclature (13).

Cross-reactivity due to structural similarity

Phl p 6 displays 60% sequence identity to the C-terminal domain of Phl p 5 (1, 3, 4). The N-terminal domain of Phl p 6 is distinct from that of group 5 grass allergens (4). 

Molecular spreading

Upon exposure of predisposed individuals to grass pollen, sensitization to Phl p 6 is infrequent during the preclinical phase of grass pollen allergy, and usually occurs at a later phase, once the individual has become sensitized to Phl p 1, Phl p 4 and Phl p 5, and has developed symptoms of grass pollinosis (1, 9). 

Diagnostic Relevance

Disease Severity

Sensitization to Phl p 6 has been associated with more complex sensitization profiles, hence with a later phase of the natural history of sensitization to grass pollen allergens and a higher risk for symptomatic grass pollinosis (1, 8, 9). 

Cross-Reactivity

Phl p 6 cross-reacts with similar proteins from other temperate and subtropical grass species (1, 3), making it a suitable biomarker of sensitization to grass allergens group 6. In grass allergic Brazilian subjects, who are exposed predominantly to Lolium multiflorum and Cynodon dactylon but not to Phleum pratense, the prevalence of sensitization to microarrayed Phl p 6 was 45% (12).

AIT Prescription

Phl p 1 and Phl p 5, but not Phl p 6, which is cross-reactive with Phl p 5, are usually employed as biomarkers when grass pollen allergen immunotherapy is considered (14). Phl p 6 is a relevant allergen for grass AIT in association with Phl p 1, Phl p 5, and Phl p 2 (5, 8), and was included in peptide-based grass allergy preparations for AIT, demonstrating clinical safety and efficacity (5, 14, 15). 

Exposure

The main route of exposure is through inhalation of timothy grass pollen, and P-particles released from the surface of pollen grass pollen (1, 3, 4)

Compiled By

Author: Joana Vitte

Reviewer: Dr. Christian Fischer

Last reviewed: November  2021