The human natural anti‐αGal antibody targets common pathogens by broad‐spectrum polyreactivity

Abstract

Summary Naturally occurring antibodies are abundant in human plasma, but their importance in the defence against bacterial pathogens is unclear. We studied the role of the most abundant of such antibodies, the antibody against terminal galactose‐α‐1,3‐galactose (anti‐αGal), in the protection against pneumococcal infections (Streptococcus pneumonia). All known pneumococcal capsular polysaccharides lack terminal galactose‐α‐1,3‐galactose, yet highly purified human anti‐αGal antibody of the IgG class reacted with 48 of 91 pneumococcal serotypes. Anti‐αGal was found to contain multiple antibody subsets that possess distinct specificities beyond their general reactivity with terminal galactose‐α‐1,3‐galactose. These subsets in concert targeted a wide range of microbial polysaccharides. We found that anti‐αGal constituted up to 40% of the total antibody reactivity to pneumococci in normal human plasma, that anti‐αGal drives phagocytosis of pneumococci by human neutrophils and that the anti‐αGal level was twofold lower in patients prone to pneumococcal infections compared with controls. Moreover, during a 48‐year period in Denmark, the 48 anti‐αGal‐reactive serotypes caused fewer invasive pneumococcal infections (n = 10 927) than the 43 non‐reactive serotypes (n = 18 107), supporting protection on the population level. Our findings explain the broad‐spectrum pathogen reactivity of anti‐αGal and support that these naturally occurring polyreactive antibodies contribute significantly to human protective immunity.

Diagnostic Vaccination in Clinical Practice

“…This information was not systematically available for the present study. The patients represented the majority of the patients with idiopathic infections in a recent study ( 17 ). Figure 3 shows a flow chart of the establishment of the final cohort.…”

“…A typical symptom of antibody deficiency is recurrent airway infections, although additional infectious disease susceptibilities and comorbidities can be present (5,6). Assessment of antibody competence is therefore a general recommendation for patients with suspected primary immunodeficiency diseases (7). Although diagnostic vaccination is widely used, the details of the procedure vary (8)(9)(10)(11).…”

“…Unconjugated 23-valent pneumococcal capsular-polysaccharide vaccines (PPV) are often used for this purpose. Detailed guidelines for the use of PPV in diagnostic vaccination were proposed in 2012 by the American Academy of Allergy, Asthma & Immunology (AAAAI) (7). These guidelines are based on several key concepts (1,7,12).…”

“…Detailed guidelines for the use of PPV in diagnostic vaccination were proposed in 2012 by the American Academy of Allergy, Asthma & Immunology (AAAAI) (7). These guidelines are based on several key concepts (1,7,12). First, serum levels of individual serotypespecific antibodies should be quantified before vaccination and four to eight weeks after vaccination.…”

“…First, serum levels of individual serotypespecific antibodies should be quantified before vaccination and four to eight weeks after vaccination. Second, dichotomous principles are recommended for data interpretation: i) antibody levels of 1.3 mg/L or higher are considered 'protective' against a given serotype and ii) adequate antibody immunity in adults requires 'protective' levels for at least 70% of the tested serotypespecific antibodies (7). Crucially, the exact number of serotypespecific antibodies for assessment and their serotype specificities are not defined.…”