Elsevier

Immunology Letters

Volume 152, Issue 2, May 2013, Pages 114-120
Immunology Letters

Review
Why do we need IgM memory B cells?

https://doi.org/10.1016/j.imlet.2013.04.007Get rights and content

Highlights

  • There are two types of memory B cells: IgM and switched memory.

  • Switched memory, generated in the germinal centers, respond to secondary challenge.

  • IgM memory B cells confer first line protection against infections.

  • IgM memory B cells are generated by a T-independent mechanism.

  • The spleen is necessary for the development and function of IgM memory B cells.

Abstract

Immunological memory is our reservoir of ready-to-use antibodies and memory B cells. Because of immunological memory a secondary infection will be very light or not occur at all. Antibodies and cells, generated in the germinal center in response to the first encounter with antigen, are highly specific, remain in the organism virtually forever and are mostly of IgG isotype. Long lived plasma cells homing to the bone marrow ensure the constant production of protective antibodies, whereas switched memory B cells proliferate and differentiate in response to secondary challenge. IgM memory B cells represent our first-line defense against infections. They are generated by a T-cell independent mechanism probably triggered by Toll-like receptor-9. They produce natural antibodies with anti-bacterial specificity and the spleen is indispensable for their maintenance.

We will review the characteristics and functions of IgM memory B cells that explain their importance in the immediate protection from pathogens. IgM memory B cells, similar to mouse B-1a B cells, may be a remnant of a primitive immune system that developed in the spleen of cartilaginous fish and persisted throughout evolution notwithstanding the sophisticated tools of the adaptive immune system.

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

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