Human B‐cell memory is shaped by age‐ and tissue‐specific T‐independent and GC‐dependent events

Abstract

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...

Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals

“…Of note, MZ B cells are heterogeneous due to progressive recruitment into GC responses that induce classical memory traits over time, including antigen-driven selection (Aranburu et al., 2017, Descatoire et al., 2014, Klein et al., 1998, Seifert et al., 2015). Nonetheless, MZ B cells exhibit some properties that make them different from ME-M B cells, including NOTCH-dependent but GC-independent ontogeny in addition to IgD lo phenotype (Aranburu et al., 2017, Berkowska et al., 2011, Descatoire et al., 2014). ME-M B cells were abundant in ileum and colon but rare in blood, spleen, and tonsil (Figures 1H and 1I).…”

Switched Memory B Cells Are Increased in Oligoarticular and Polyarticular Juvenile Idiopathic Arthritis and Their Change Over Time Is Related to Response to Tumor Necrosis Factor Inhibitors

“…However, the absolute number of circulating memory B cells decreases over time due to the reduction in the total number of circulating B cells observed after age 4 years . In order to study the dynamic changes of the memory B cell compartment in children, we determined the relative frequency of IgM memory and switched memory B cells as a function of age (Figure B; also see Supplementary Figure 2, http://onlinelibrary.wiley.com/doi/10.1002/art.40410/abstract). Switched memory B cells were expanded in JIA patients until age 16 years, while no statistically significant differences were observed between adult JIA patients and adult healthy controls (Supplementary Figure 2).…”

Lack of Gut Secretory Immunoglobulin A in Memory B-Cell Dysfunction-Associated Disorders: A Possible Gut-Spleen Axis

“…While switched memory B cells are generated by previous immune responses in the germinal centers (GCs) independently from the presence of the spleen, IgM memory B cells may belong to a separate lineage (16,17). They are found in the spleen (18) and in the peripheral blood, are generated through a T cell-and GCindependent mechanism (19), and respond to polysaccharides of encapsulated bacteria. IgM memory B cells are reduced after splenectomy (20).…”