Genetic and structural basis of the human anti-α-galactosyl antibody response.

Humans lack the capacity to produce the Galα1-3Galß1-4GlcNAc (α-gal) glycan, and produce anti-α-gal antibodies upon exposure to the carbohydrate on a diverse set of immunogens, including commensal gut bacteria, malaria parasites, cetuximab, and tick proteins. Here we use X-ray crystallographic analysis of antibodies from α-gal knockout mice and humans in complex with the glycan to reveal a common binding motif, centered on a germline-encoded tryptophan residue at Kabat position 33 (W33) of the complementarity-determining region of the variable heavy chain (CDRH1). Immunoglobulin sequencing of anti-α-gal B cells in healthy humans and tick-induced mammalian meat anaphylaxis patients revealed preferential use of heavy chain germline IGHV3-7, encoding W33, among an otherwise highly polyclonal antibody response. Antigen binding was critically dependent on the presence of the germline-encoded W33 residue for all of the analyzed antibodies; moreover, introduction of the W33 motif into naive IGHV3-23 antibody phage libraries enabled the rapid selection of α-gal binders. Our results outline structural and genetic factors that shape the human anti-α-galactosyl antibody response, and provide a framework for future therapeutics development.

5-grass-pollen SLIT effectiveness in seasonal allergic rhinitis: Impact of sensitization to subtropical grass pollen.

Background: Temperate grass (eg, ryegrass) pollen is a major driver of seasonal allergic rhinitis (SAR) and asthma risks, including thunderstorm asthma. Data for the effectiveness of temperate grass pollen allergen immunotherapy (AIT) in SAR patients from the southern hemisphere, who are frequently polysensitized to subtropical grass pollens, are limited. The 300 IR 5-grass pollen sublingual immunotherapy tablet (300 IR 5-grass SLIT) is known to be effective in polysensitized SAR patients with primary allergy to temperate grasses, however, the influence of polysensitization to subtropical grass pollen on treatment responses has yet to be specifically addressed. Key aims of this study were to measure patient treatment satisfaction during 300 IR 5-grass SLIT treatment and evaluate how polysensitization to subtropical grass pollens affects treatment responses. Methods: A prospective observational study was conducted in 63 patients (aged ≥5 years) in several temperate regions of Australia prescribed 300 IR 5-grass SLIT for SAR over 3 consecutive grass pollen seasons. Ambient levels of pollen were measured at representative sites. Patient treatment satisfaction was assessed using a QUARTIS questionnaire. Rhinoconjunctivitis Total Symptom Score (RTSS) and a Hodges-Lehmann Estimator analysis was performed to evaluate if polysensitization to subtropical grass pollen affected SAR symptom intensity changes during SLIT. Results: A diagnosis of ryegrass pollen allergy was nearly universal. There were 74.6% (47/63) polysensitized to subtropical and temperate grass pollens. There were 23.8% (15/63) monosensitized to temperate grass pollens. From the first pollen season, statistically significant improvements occurred in SAR symptoms compared with baseline in both monosensitized and polysensitized patients, particularly in those polysensitized (P = 0.0297). Improvements in SAR symptoms were sustained and similar in both groups in the second and third pollen seasons, reaching 70-85% improvement (P < 0.01). Polysensitized patients from both northerly and southerly temperate regions in Australia showed similar improvements. Grass pollen counts in both regions were consistently highest during springtime. Conclusions: 300 IR 5-grass SLIT is effective in a real-life setting in SAR patients in the southern hemisphere with primary allergy to temperate grass pollen and predominantly springtime grass pollen exposures. Importantly, SLIT treatment effectiveness was irrespective of the patient's polysensitization status to subtropical grass pollens.