Uncovering the mechanisms of IgM in human immunity against bacteria

The human immune system is highly complex and well-equipped to combat most bacteria. However, in some instances bacteria can cause life-threatening infections and the increase of antibiotic-resistant infections highlights a clear demand for the development of alternative treatment strategies. Activating the body’s own immune system with antibodies to clear infections has been deemed a promising strategy. To effectively employ this, a more in-depth understanding about the mechanisms by which antibodies effectively stimulate bacterial killing by the immune system is needed. A potent way to eradicate bacteria by antibodies, is to activate the human complement system as this leads to potent recognition by immune phagocytic cells, as well as direct killing of Gram-negative bacteria. Of the five human antibody isotypes, only IgG and IgM can activate complement. Although it has been established that IgM is more potent in anti-bacterial immunity than IgG, the mechanisms by which human IgM can achieve this remains elusive. Using monoclonal human IgM targeting several bacteria, we show that: 1) anti-bacterial IgM is generally better at activating the complement system than IgG; 2) although the sequential pathway in which IgG and IgM activate complement is similar, the activation mechanism differs; and 3) IgMs could provide broader protection than IgG against bacteria via their superior cross-reactivity. Altogether, the gained knowledge provides fundamental insights into the mechanisms of IgM in human immunity against bacteria and accelerates the development of antibody therapies against problematic infections.