The importance of polyreactive antibodies in protection against pneumococcal infection

Antibodies are a key element of the immune response. They can bind their molecular targets with exquisite sensitivity and specificity, providing protection against a multitude of pathogens. They have long been understood to be markers of a successful response to vaccination, and are now widely manufactured as highly specific and robust immunotherapeutic agents. Less well understood are the polyreactive antibodies, found in serum, which are able to bind more than one target molecule. Here, we highlight new research into these naturally occurring polyreactive antibodies, which demonstrates their importance for protection against Streptococcus pneumoniae, a common cause of airway infection.

Antibodies against the xeno‐carbohydrate terminal galactose‐a‐1‐3‐galactose (anti‐αGal) are found in human plasma. These antibodies are common, constituting approximately 1% of immunoglobulins, and are found as IgG, IgM and IgA [¹]. They may be generated in response to the carbohydrates expressed by intestinal bacteria [²]. The levels of these anti‐αGal antibodies, which can be of any isotype, are highly variable between individuals but may comprise up to 1% of total IgG and >1% of total IgM. The role of anti‐αGal antibodies in protecting against bacterial pathogens is unclear. While IgG antibodies are known to be particularly important in protective responses in the airways, the contribution of anti‐αGal antibodies to this protection has not previously been explored.Here, we present work [³] that reveals the importance of anti‐αGal antibodies in the protective immune response against Streptococcus pneumoniae, a leading cause of pneumonia, which results in millions of worldwide deaths annually. Antibodies recognizing the highly diverse structural components of the bacterial capsule are important for protection against disease, and the authors had previously reported evidence that anti‐αGal antibodies could react with pneumococci that did not contain the terminal Galα3Gal moiety for which the anti‐αGal antibodies are specific. This indicated that polyclonal human anti‐αGal antibodies could recognize a broader spectrum of bacterial antigens. Such ‘polyreactive’ antibodies have previously been proposed to be important in antibacterial immune responses [⁴]. Bernth Jensen et al. therefore aimed to understand the mechanisms by which anti‐αGal antibodies can display broad reactivity, and whether these antibodies contribute to protection against pneumococcal infection.Initial comparisons between healthy controls and patients with airway infections revealed decreased anti‐αGal levels in individuals with recurrent lower airway infections, even when corrected for age and blood group antigen—which are known confounders. Analysis of data from candidates for lung transplantation, who frequently experience lower airway infections, revealed that this group had increased anti‐αGal levels. Therefore, reduced anti‐αGal appears not to be a consequence of repeated lower airway infections, but may contribute to allowing such infections.To understand the specificity of anti‐αGal IgG, the authors examined reactivity against 91 S. pneumoniae serotypes, identifying positive reactions in at least 48. Of these, 37 are known not to contain the terminal Galα3Gal for which anti‐αGal displays its primary specificity. Carefully controlled follow‐up experiments confirmed that the anti‐αGal IgG contains reactivity to a range of bacterial polysaccharides, and is inhibited by the addition of soluble Galα3Gal; anti‐αGal can therefore be defined as polyreactive. Anti‐αGal antibodies provide an important contribution to the total antipneumococcal reactivity in individual samples, but this contribution is highly variable between individuals, and individuals’ anti‐αGal IgG is variable in the pneumococcal strains it binds. Furthermore, each individual''s anti‐αGal pool contains a wide range of specificities and should therefore be described as the plural ‘anti‐αGals’ or ‘anti‐αGal antibodies’.But do these polyreactive antibodies play an important contribution in protecting humans from pneumococcal disease? These authors had previously demonstrated that anti‐αGal antibodies were able to activate complement as is normal for IgG antibodies [⁵]. Here, they showed, in vitro, that anti‐αGal antibodies dramatically increased the phagocytic activity of primary human blood leucocytes, again by a complement‐dependent pathway. To understand whether they might also protect the population from disease, they analysed data from 29 034 reported cases of this notifiable infection in Denmark, between 1966 and 2014. From these data, they identified that frequently pathogenic subtypes reacted poorly with anti‐αGal, while the most anti‐αGal reactive pneumococcal subtypes caused invasive disease more rarely. Thus, these polyclonal anti‐αGal antibodies may protect the human population from invasive pneumococcal infections.This is an important study, revealing protective functions for polyreactive antibodies in the human population. Polyreactivity is often deemed an unsuitable quality during the development of antibodies for therapeutic purposes [⁶, ⁷], due to the possibility that off‐target specificities may reduce the therapeutic effect or generate undesirable effects. As this work indicates, a better understanding of how polyreactive antibodies provide protection against antigenically diverse pathogens may lead to improved strategies for preventing infection or limiting damaging autoimmune pathology.