ReviewWhy do we need IgM memory B cells?
Introduction
The existence of immunological B cell memory is a fact [1], [2]. Infections or vaccination leave a permanent imprint in the immune system, constituted by the products of the past reaction in the germinal center [3]: high-affinity antibodies, long-lived plasma cells [4] and memory B cells [5].
Each of these products has a different function. High-affinity antibodies terminate the primary infection clearing the pathogen. They are present at low-levels in the serum in order to ensure a constant first-line protection against a possible new encounter with the same infectious agent. These protective antibodies are secreted by long-lived plasma cells, migrated at the end of the germinal center reaction to the bone marrow, where they survive in a specialized niche [5], [6], [7], [8]. Plasma cells do not express a surface-bound antigen receptor and for this reason they cannot sense antigen [9]. They are antibody factories releasing their products at a constant rate independently of the changing needs of the organism. In case of re-infection antibodies produced by long-lived plasma cells act as the first-line defence being pre-formed high-affinity tools able to neutralize pathogens or toxins. Differently from plasma cells, memory B cells express a surface specific antigen receptor and antigen is necessary to trigger their recall response. During re-infection memory B cells will rapidly differentiate and add large amounts of high-affinity antibodies to those already present in the serum thus effectively blocking the attack [10]. Therefore, long-lived plasma cells maintain a constant level of selected immunoglobulin [11], but upon re-infection the concentration of useful antibodies specifically increases because memory B cells are called into action. Protective antibodies are mostly of IgG isotype.
Another important consequence of immunological memory is the possibility of its transmission to the offspring with the transplacental passage of IgG antibodies. These will protect the child during the first months of life from all infections already experienced by the mother. The neonate also receives maternal antibodies of IgA isotype through the colostrum and breast milk. IgA antibodies are produced by plasma cells migrated to the lactating breast from the intestine [12], [13], [14] and are the product of the maternal immune response to antigens encountered in the intestine. Milk antibodies will control bacterial colonization of the neonatal gut and prevent enteric infections [15], [16].
In conclusion, the neonate will be protected from those pathogens that are common in the environment where the mother lives and against which she is immunized [17].
Section snippets
Two types of memory B cells
Protection of the adult and the offspring is ensured by antibodies mostly of IgG and IgA isotypes and memory B cells induced by natural infection or vaccination correspond to switched memory B cells. In the peripheral blood another population of memory B cells, called IgM memory [18] has been described with different origin, function and significance (Table 1). IgM memory B cells, also known as natural memory or natural effector memory [19], develop in the absence of germinal centers [20], [21]
The origin of IgM memory
As discussed above several evidences support the idea that IgM memory B cells have a GC-independent origin, in vivo. We have shown that in vitro IgM memory B cells can be generated from cord blood transitional B cells through an antigen-independent mechanism triggered by the TLR9 ligand CpG [24], [56].
Transitional B cells are the most immature B cell stage in the periphery [57], [58]. Upon exposure to CpG they proliferate, up-regulate AID expression, acquire somatic mutations and differentiate
Susceptibility to bacterial infections and memory B cells
IgM memory B cells are absent in the newborn [57], [60], congenitally asplenic and splenectomized individuals [59], [61] and in the majority of patients affected by common variable immunodeficiency (CVID) [62].
These three categories have a common clinical feature: increased susceptibility to bacterial infections, associated to impaired response to polysaccharide vaccines notwithstanding a normal concentration of serum IgG.
Neonates have IgG passively transferred from the mother during pregnancy;
Memory B cells and S. pneumoniae
Streptococcus pneumoniae is an encapsulated respiratory bacterium with very fast pathogenesis. In a matter of hours S. pneumoniae can adhere to the nasopharynx epithelium, enter the blood stream, replicate and seed in the meninges. Infection can be prevented by the presence of functional antibody directed to the polysaccharide capsule, IgA and IgM at mucosal site or specific IgG in body fluids generated upon vaccination with polysaccharide conjugated vaccines [82] or natural exposure by
IgM memory B cells and mucosal immunity
In mouse natural antibodies and antibodies against S. pneumoniae are secreted by B-1a B cells [94].
Human IgM memory B cells share with mouse B-1a B cells several functions and phenotypic characteristics (Table 2). B-1a B cells, similar to human IgM memory, produce natural IgM in the serum [95], respond to T-independent antigens [96], including S. pneumoniae [61] and require the spleen for their origin/maintenance [75]. For this reason we have suggested that the two populations may be
IgM memory B cells in evolution
The first living organisms on Earth were bacteria. Able to survive in the extreme conditions of our primitive planet, they changed the environment producing oxygen and creating the possibility for new organisms to develop. Every new form of life had to be equipped with defence mechanisms in order to survive in the established “world of bacteria”. Several strategies were used against pathogens during evolution, including the primitive elements of the innate immune response and the sophisticated
References (105)
- et al.
Human B cell memory
Curr Opin Immunol
(2009) - et al.
Germinal-center organization and cellular dynamics
Immunity
(2007) - et al.
Plasma cell differentiation and survival
Curr Opin Immunol
(2008) - et al.
An increase in milk IgA correlates with both pIgR expression and IgA plasma cell accumulation in the lactating mammary gland of PRM/Alf mice
J Reprod Immunol
(2012) Mucosal immunity: integration between mother and the breast-fed infant
Vaccine
(2003)- et al.
Evidence for a large compartment of IgM-expressing memory B cells in humans
Blood
(1997) - et al.
A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells
Blood
(2003) - et al.
Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88
J Biol Chem
(2003) - et al.
IgM+ IgD+ CD27+ B cells are markedly reduced in IRAK-4-, MyD88-, and TIRAP- but not UNC-93B-deficient patients
Blood
(2012) - et al.
Peptide-mediated interference of TIR domain dimerization in MyD88 inhibits interleukin-1-dependent activation of NF-{kappa}B
J Biol Chem
(2005)
Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells
J Biol Chem
Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme
Cell
Nuclear and cytoplasmic AID in extrafollicular and germinal center B cells
Blood
Helicobacter pylori-induced activation-induced cytidine deaminase expression and carcinogenesis
Curr Opin Immunol
High-throughput immunoglobulin repertoire analysis distinguishes between human IgM memory and switched memory B-cell populations
Blood
Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting
Blood
The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency
J Allergy Clin Immunol
Human blood IgM “memory” B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire
Blood
The human spleen is a major reservoir for long-lived vaccinia virus-specific memory B cells
Blood
Post-splenectomy and hyposplenic states
Lancet
Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens
Immunity
Complications of splenectomy
Am J Med
From the fetal liver to spleen and gut: the highway to natural antibody
Mucosal Immunol
Perspectives on common variable immune deficiency
Ann N Y Acad Sci
Regulation of the polymeric immunoglobulin receptor and IgA transport: new advances in environmental factors that stimulate pIgR expression and its role in mucosal immunity
Mucosal Immunol
The mucosal immune system and its integration with the mammary glands
J Pediatrics
Molecular programming of B cell memory
Nat Rev
Mechanisms that determine plasma cell lifespan and the duration of humoral immunity
Immunol Rev
Immunological memory and protective immunity: understanding their relation
Science
Plasma-cell homing
Nat Rev
Lifetime of plasma cells in the bone marrow
Nature
Survival of long-lived plasma cells is independent of antigen
Int Immunol
Memory B and memory plasma cells
Immunol Rev
Maintenance of serum antibody levels
Ann Rev Immunol
An indispensable role for the chemokine receptor CCR10 in IgA antibody-secreting cell accumulation
J Immunol
CCL28 controls immunoglobulin (Ig)A plasma cell accumulation in the lactating mammary gland and IgA antibody transfer to the neonate
J Exp Med
The B-cell system of human mucosae and exocrine glands
Immunol Rev
On natural and artificial vaccinations
Ann Rev Immunol
Human marginal zone B cells
Ann Rev Immunol
CD40−CD40L independent Ig gene hypermutation suggests a second B cell diversification pathway in humans
Proc Natl Acad Sci U S A
Somatic diversification in the absence of antigen-driven responses is the hallmark of the IgM+ IgD+ CD27+ B cell repertoire in infants
J Exp Med
Maintenance of serological memory by polyclonal activation of human memory B cells
Science
CpG drives human transitional B cells to terminal differentiation and production of natural antibodies
J Immunol
Toll-like receptor signalling
Nat Rev
Pharmacological inhibition of TLR9 activation blocks autoantibody production in human B cells from SLE patients
Rheumatology
Understanding and making use of human memory B cells
Immunol Rev
Prior infections with seasonal influenza A/H1N1 virus reduced the illness severity and epidemic intensity of pandemic H1N1 influenza in healthy adults
Clin Infect Dis
Immunity to pre-1950 H1N1 influenza viruses confers cross-protection against the pandemic swine-origin 2009 A (H1N1) influenza virus
J Immunol
Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors
Nature
Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells
PLoS ONE
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