Switched and IgM memory B cells execute different and noninterchangeable functions.We studied memory B cells in children of different ages, in peripheral blood and spleen and compared them with those of children born asplenic or unable to build germinal centers. We show that, whereas switched memory B cells are mostly generated in the germinal centers at all ages, IgM memory B cells can be distinct in three types with different developmental history. Innate IgM memory B cells, the largest pool in infants, are generated in the spleen by a germinal center-independent mechanism. With age, if the spleen is present and germinal centers are functional, innate IgM memory B cells are remodelled and accumulate somatic mutations. The third type of IgM memory B cell is a by-product of the germinal center reaction. Our data suggest that the B-cell memory developmental program is implemented during the first 5-6 years of life. Keywords:Antibodies r B cells r B cell development r Immunoglobulins r Innate immunity Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Rita Carsetti e-mail: rita.carsetti@opbg.net * These authors contributed equally to this work.The copyright line for this article was changed on 9th February 2018 after original online publication.C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 328Alaitz Aranburu et al. Eur. J. Immunol. 2017. 47: 327-344 IntroductionImmunological memory is the ability of the immune system to recognize and neutralize a previously encountered pathogen, thereby preventing re-infection and disease. Memory is acquired by the immune system through experience. Infants lack immunological memory and have a high risk of infections. The rate of infection and mortality is highest in infants and declines after the age of 5. The decline of child mortality in the last century has been one of the most significant achievements in medical history and is largely due to the introduction of vaccination and use of antibiotics. The first response to infection or vaccination generates the elements of memory: long-lived plasma cells and memory B cells [1][2][3][4]. Long-lived plasma cells continuously secrete specific antibodies (Abs) that upon re-infection will exert the first protection. Memory B cells rapidly react to the renewed challenge and produce Abs when and where these are most needed, i.e. when the pathogen again tries to invade the organism and at the site of its entry.In the adult, 50% of the B cells in the peripheral blood (PB) are memory B cells [5]. Phenotypically memory B cells can be identified by the expression of the CD27 marker. B cells that express CD27 carry somatic mutations in their immunoglobulin (Ig) genes [6]. These are permanent genetic imprints left by the mechanism of Somatic Hyper Mutation (SHM). Somatic mutations are triggered by activation events and results from the combined action of the activation-induced deaminase AID, the uracil-DNA glycosylase UNG and several DNA...

Splenectomized patients are exposed to an increased risk of septicemia caused by encapsulated bacteria. Defense against infection is ensured by preformed serum antibodies produced by long-lived plasma cells and by memory B cells that secrete immunoglobulin in response to specific antigenic stimuli. Studying a group of asplenic individuals (57 adults and 21 children) without additional immunologic defects, we found that spleen removal does not alter serum anti-pneumococcal polysaccharide (PnPS) IgG concentration, but reduces the number of PnPS-specific memory B cells, of both IgM and IgG isotypes. The number of specific memory B cells was low in splenectomized adults and children that had received the PnPS vaccine either before or after splenectomy. Seven children were given the 13-valent pneumococcal conjugated vaccine after splenectomy. In this group, the number of PnPS-specific IgG memory B cells was similar to that of eusplenic children, suggesting that pneumococcal conjugated vaccine administered after splenectomy is able to restore the pool of anti-PnPS IgG memory B cells. Our data further elucidate the crucial role of the spleen in the immunological response to infections caused by encapsulated bacteria and suggest that glycoconjugated vaccines may be the most suitable choice to generate IgG-mediated protection in these patients. Keywords: Asplenia r Memory B cells r Serum anti-PnPS r Splenectomy r Streptococcus pneumoniaeAdditional supporting information may be found in the online version of this article at the publisher's web-site Eur. J. Immunol. 2013Immunol. . 43: 2659Immunol. -2670 Introduction Asplenic patients have an increased susceptibility to bacterial infections that can evolve into severe and often lethal overwhelming postsplenectomy infection (OPSI) [1,2]. Lifetime risk of developing an OPSI is nearly 1-5% and mortality rates range between 40 and 70% [3]. Streptococcus pneumoniae is the most common pathogen causing bacteremia in splenectomized patients, followed by Haemophilus influenzae, Neisseria meningitidis, Escherichia coli, Salmonella, Pseudomonas, and Klebsiella [3,4]. The red pulp of the spleen represents a very important defense from bacteremia. In the red pulp of the spleen, the blood flows slowly in a large net of sinusoids. Macrophages, located among endothelial cells, have the function of removing and destroying particulate antigens, such as bacteria [5][6][7]. In the absence of the spleen, bacteria can therefore accumulate and replicate in the blood causing septic shock.Over the last few years, the role of the spleen in the maintenance of a pool of memory B cells involved in the protection against encapsulated bacteria has been also demonstrated. In particular, we showed that splenectomized patients lack IgM memory B cells [8]. This cell population, also known as marginal zone B cells or effector memory B cells, is produced by a T-independent mechanism [9] and inhabits the marginal zone of the spleen. IgM memory B cells generate the response to pneumococcal polysaccharide (PnP...

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