We have recently shown that in mice the spleen is indispensable for the generation or survival of B-1a B cells (17
). B-1a B cells are the major source of natural antibodies and rapidly produce Igs in response to encapsulated bacteria (15
). Mice lacking B-1a B cells have a low level of natural IgM and do not produce antibodies in response to pneumococcal polysaccharide vaccines.
We now demonstrate that in humans the so-called IgM memory B cells have similar survival requirements and function as murine B-1a B cells. Similarly to B-1a B cells, IgM memory B cells cannot be detected in splenectomized and asplenic individuals and their absence is associated with an increased frequency of pneumococcal infections and impaired response to polysaccharide vaccines.
Memory B cells are classically described as highly specific and long-lived cells, generated in response to infectious agents or vaccines in the germinal centers after somatic mutation, selection, and class switch (18
). They persist in the organism and rapidly produce antibodies upon a second challenge with the same pathogen.
In humans 30–60% of the B cells express CD27 and are considered memory B cells. Half of them are IgM memory and the rest are switched memory B cells. IgM memory B cells have few somatic mutations and switched memory B cells express highly mutated VH
Our data suggest that IgM memory B cells have different origins and functions from switched memory B cells. They are undetectable in splenectomized and asplenic patients. In contrast, switched memory B cells are only transiently depleted after splenectomy and are present at normal frequencies in asplenic patients. Because IgM memory B cells carrying somatic mutations can be detected in patients with X-linked HyperIgM syndrome, it has been suggested that only switched but not IgM memory B cells originate from the germinal centers (19
). IgM memory B cells, therefore, may originate in the spleen, in extrafollicular sites, and independently of T cells. Because switched memory B cells only derive from the germinal centers, they represent the “true” memory pool.
Infections of the respiratory tract by encapsulated bacteria remain localized and might be asymptomatic in normal individuals. They are far more frequent, severe, and invasive in patients with anatomical or functional asplenia. The spleen has the function of entrapping circulating pathogens during systemic infections. Our data suggest that it also plays a fundamental role in preventing the spreading of localized infection by the generation of IgM memory B cells. This is supported by the observation that localized infections are more frequent and often develop into invasive diseases (e.g., pulmonitis, meningitis) in individuals lacking IgM memory B cells but with an intact spleen, such as young children and CVID patients. OPSI never occurs in these cases, underlining that splenic components other than B cells remove circulating bacteria and avoid systemic infections that become overwhelming.
The traditional vaccine against S. pneumoniae
, which contains a mixture of capsular polysaccharides from the 23 most frequent bacterial serotypes, induces antibody production only if administered before splenectomy, but is ineffective if the spleen has been already removed (3
). Similarly, it is not protective in children before 2 yr of age. Thus, IgM memory B cells produce antibodies in response to bacterial polysaccharides.
Based on our data, IgM memory B cells functionally resemble murine B-1a B cells but do not express CD5 and may have a different tissue distribution. The frequency of CD5+
B cells, which varies between donors, does not identify any B cell subset. Paradoxically, CD5+
B cells are particularly frequent in young children (unpublished data), the age group most susceptible to pneumococcal infections. Splenectomy had no effect on the frequency of CD5+
B cells. Although CD5 may also have a relevant function in humans, its expression cannot be used to identify human B-1a B cells. The great majority of B-1a B cells is in the mouse peritoneal cavity. We did not find IgM memory B cells in peritoneal exudates (unpublished data). This could be explained by differences in mouse and human anatomy, B cell recirculation, and pathogen tropism. Accordingly, it has been shown that CD5+
B cells cannot be found in the peritoneal cavity of rats, but rat fetal liver stem cells transplanted in mouse generate CD5+
B cells, which populate the peritoneal cavity (20
We show that circulating IgM memory B cells mirror the presence of functional splenic tissue, albeit ectopic and of small size, associated with a low risk of infection and OPSI. Thus, detection of IgM memory B cells could be used to discriminate between patients with a high or low risk of infection after splenectomy and consequent degree of a patient's invalidism.
In children, polysaccharide protein conjugate vaccines against S. Pneumoniae reduce the risk of systemic infection by 90%. By eliciting a classical T-dependent immune response they bypass the immunological impairment due to the lack of IgM memory B cells. The administration of conjugate vaccines should therefore reduce the risk of systemic disease and most likely OPSI after splenectomy.
We propose a model in which IgM and switched memory B cells have different origins and functions. The spleen is indispensable to ensure the presence of circulating IgM memory B cells. It is not known whether the spleen supports IgM memory survival or is the site where IgM memory B cells are generated. B-1a B cells, which are functionally homologous to IgM memory B cells, derive from fetal liver precursors. IgM memory B cells produce natural antibodies and are necessary for the T-independent response against encapsulated bacteria. Mature B cells are generated in the bone marrow, populate spleen and lymph nodes, and in the germinal centers give rise to switched memory B cells () .
Figure 4. Our model on the origin and function of mature and IgM memory B cells. IgM memory B cells might be able to migrate to sites of inflammation and recognize invading pathogens through the B cell receptor (BCR) and possibly other pathogen-binding coreceptors. (more ...)
Finally, because the first and most important sign of primary and secondary B cell immunodeficiency is a high incidence of infections by encapsulated bacteria, the defense against these pathogens might be the primary function of B cells and we show that this function is performed by IgM memory cells.