Specific In Vivo Deletion of B-Cell Subpopulations Expressing Human Immunoglobulins by the B-Cell Superantigen Protein L

Abstract

Some pathogens have evolved to produce proteins, called B-cell superantigens, that can interact with human immunoglobulin variable regions, independently of the combining site, and activate B lymphocytes that express the target immunoglobulins. However, the in vivo consequences of these interactions on human B-cell numbers and function are largely unknown. Using transgenic mice expressing fully human immunoglobulins, we studied the consequences of in vivo exposure of protein L of Peptostreptococcus magnus with human immunoglobulins. In the mature pool of B cells, protein L exposure resulted in a specific reduction of splenic marginal-zone B cells and peritoneal B-1 cells. Splenic B cells exhibited a skewed light-chain repertoire consistent with the capacity of protein L to bind specific kappa gene products. Remarkably, these two B-cell subsets are implicated in innate B-cell immunity, allowing rapid clearance of pathogens. Thus, the present study reveals a novel mechanism that may be used by some infectious agents to subvert a first line of the host's immune defense.Throughout evolution, the continuous interactions between the mammalian host and infectious agents have produced an array of innate and adaptive immune effectors able to combat insults by pathogens (30). Reciprocally, infectious agents have developed efficient countermeasures to persist in the infected host (63). These pathogens have developed mechanisms to mutate, exchange genetic materials, multiply rapidly, vary their phenotype, and occupy diverse ecological niches (61). One intriguing feature of some infectious agents is to produce proteins able to interact specifically with the immunoglobulin (Ig) heavy (H)-or light (L)-chain variable regions, independently of the conventional binding site. They are referred to as "B-cell superantigens" (SAgs) and include protein A of Staphylococcus aureus (SpA) (22,29,52,57), gp120 of human immunodeficiency virus type 1 (HIV-1) (3, 20, 32, 33, 43, 50), staphylococcal enterotoxins A and D (7, 45), and protein L of Peptostreptococcus magnus (12, 13).Although conventional antigens stimulate a small proportion of B cells, the B lymphocytes responsive to SAgs can be orders of magnitude higher. Because the B-cell SAg interacts primarily with the V H or V L portion of the Ig molecule, it can, in principle, trigger all B cells bearing the appropriate V H or V L , regardless of the other J H , D, J L , and pairing with V H or V L segments (58, 68). Since there are a limited number of V genes, this property results in stimulation of a large proportion of the repertoire. For example, the bacterial cell wall protein SpA has sites that interact with the Fab of many IgM, IgA, IgG, and IgE, and this interaction is restricted to the V H 3 gene family, leading to activation of ca. 40% of human polyclonal IgMs (58,68).The function of these proteins is unclear, but their ability to bind conserved portions of Igs suggests that they help the bacteria to evade the host's immune system. Through direct interaction with host Igs, they ...

Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus

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Pathogenesis of B-Cell Superantigen-Induced Immune Complex-Mediated Inflammation

“…This assumption was based on the finding that V H 3-like genes are expressed on BALB/c peripheral B cells (37). Indeed, recent reports have described in vivo functional consequences of the interaction of B-cell SAgs, including SpA, with the membrane-bound form of IgM on peripheral B cells, i.e., depletion of reactive B1 and marginalzone B cells (12,13,41). However, in our experiments, BALB/c mice did not develop signs of inflammation, reminiscent of our early experience with our rabbit model.…”

Staphylococcal Protein A Deletes B-1a and Marginal Zone B Lymphocytes Expressing Human Immunoglobulins: An Immune Evasion Mechanism

“…Our findings reveal that, by virtue of its SAg activity, SpA deletes B-1a and MZ subpopulations in vivo and cripples innate immunity. It is remarkable that protein L of Peptostreptococcus magnus (47) also exhibits a potential to target B lymphocytes with innate immune functions (48). With the recent demonstration based on a transgenic mouse system that SpA can "co-opt" the self-tolerance pathways of BCR-mediated apoptosis and impact B cells important for defense against systemic infection (22,49,50), our data suggest that elimination of B cell subpopulations with innate immune functions may represent an important immune-evasion function that may potentiate ongoing and recurrent infections.…”