Primary immune thrombocytopenia (ITP) is a disorder caused by autoantibody-mediated platelet destruction and decreased platelet production. Rituximab, a B cell-depleting agent, has become the first-line treatment for ITP; however, patients with refractory disease usually require splenectomy. We identified antibody-secreting cells as the major splenic B cell population that is resistant to rituximab. The phenotype, antibody specificity, and gene expression profile of these cells were characterized and compared to those of antibody-secreting cells from untreated ITP spleens and from healthy tissues. Antiplatelet-specific plasma cells (PC) were detected in the spleens of patients with ITP up to 6 months after rituximab treatment, and the PC population displayed a long-lived program similar to the one of bone marrow PC, thus explaining for most of these patients the absence of response to rituximab and the response to splenectomy. When analyzed by multiplex PCR at the single-cell level, normal splenic PC showed a markedly different gene expression profile, with an intermediate signature, including genes characteristic of both long-lived PC and proliferating plasmablasts. Surprisingly, long-lived PC were not detected in untreated ITP spleens. These results suggest that the milieu generated by B cell depletion promotes the differentiation and settlement of long-lived PC in the spleen.

Identification in humans of a bona fide marginal zone B cell population, which differentiates from a splenic marginal zone precursor through a NOTCH2 signaling pathway.

In a recent issue of The Journal of Experimental Medicine, Thomas Rothstein and colleagues, a group with long-standing expertise in the field of mouse B1 cells, reported the description of a B1 B cell subset in human blood, a population that has thus far eluded identification (Griffin et al., 2011). Mouse B1 cells are the main constituents of the B lymphocyte pool in pleural and peritoneal cavities, and are characterized as CD5 + and/or CD11b + cells (Hardy, 2006; Baumgarth, 2011). However, CD5, which was initially identified on chronic lymphocytic leukemia tumors (Boumsell et al., 1978), is not a B1 marker in humans. Human CD5 marks immature/transitional B cells in bone marrow, blood, and spleen (Sims et al., 2005; Cuss et al., 2006), as well as in T cells. Mouse B1 cells are also described as IgM high IgD low CD43 +. The function of CD43 in B1 cells is unknown, and it is also expressed by T lymphocytes, B cell precursors, and plasma cells. Griffin et al. (2011) described a CD20 + CD27 + CD43 + CD70  subset present in adult and human cord blood with functional characteristics that they describe as typical B1 cell attributes: spontaneous IgM secretion, constitutive BCR signaling, and ability to drive allogeneic T cell proliferation. It should be noted that this last feature has been shown to be displayed by switched memory B cells in humans, likely because of the high expression of CD80 and/or CD86 on these cells (Liu et al., 1995; Good et al., 2009). A striking point of the observations of Griffin et al. (2011) was their quantitative aspect. Despite considerable variations between individual blood donors, the proportion of CD43 + cells among CD27 + B cells averaged 40-50% in adults, with a higher frequency in young individuals, and a lower fre

Humoral memory is maintained by two types of persistent cells, memory B cells and plasma cells, which have different phenotypes and functions. Long-lived plasma cells can survive for a lifespan within a complex niche in the bone marrow and provide continuous protective serum antibody levels. Memory B cells reside in secondary lymphoid organs, where they can be rapidly mobilized upon a new antigenic encounter. Surface IgG has long been taken as a surrogate marker for memory in the mouse. Recently, however, we have brought evidence for a long-lived IgM memory B cell population in the mouse, while we have also argued that, in humans, these same cells are not classical memory B cells but marginal zone (MZ) B cells which, as opposed to their mouse MZ counterpart, recirculate and carry a mutated B cell receptor. In this review, we will discuss these apparently paradoxical results.

Graphical abstract Adaptive immunity can compensate for a defect in the innate immune response, as seen with humans lacking a key TLR adaptor who can mount an antibody response to a bacterial pathogen.

Control of the ongoing SARS-CoV-2 pandemic is endangered by the emergence of viral variants with increased transmission efficiency, resistance to marketed therapeutic antibodies and reduced sensitivity to vaccine-induced immunity. Here, we screen B cells from COVID-19 donors and identify P5C3, a highly potent and broadly neutralizing monoclonal antibody with picomolar neutralizing activity against all SARS-CoV-2 variants of concern (VOC) identified to date. Structural characterization of P5C3 Fab in complex with the Spike demonstrates a neutralizing activity defined by a large buried surface area, highly overlapping with the receptor-binding domain (RBD) surface necessary for ACE2 interaction. We further demonstrate that P5C3 shows complete prophylactic protection in the SARS-CoV-2 infected hamster challenge model. These results indicate that P5C3 opens exciting perspectives either as a prophylactic agent in immunocompromised individuals with poor response to vaccination or as combination therapy in SARS-CoV-2-infected individuals.

Highlights d Highly potent anti-SARS-CoV-2 antibody has broad activity against all VOCs d Binding epitope strongly overlaps with the RBD surface necessary for ACE2 interaction d Complete prophylactic protection in the SARS-CoV-2infected hamster challenge model d The anti-SARS-CoV-2 antibody could be used in a prophylactic setting

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