ÍSince the introduction of new generation pertussis vaccines, resurgence of pertussis has been observed in many developed countries. Former whole-cell pertussis (wP) vaccines are able to protect against disease and transmission but have been replaced in several industrialized countries because of their reactogenicity and adverse effects. Current acellular pertussis (aP) vaccines, made of purified proteins of Bordetella pertussis, are efficient at preventing disease but fail to induce long-term protection from infection. While the systemic and mucosal T cell immunity induced by the 2 types of vaccines has been well described, much less is known concerning B cell responses. Taking advantage of an inducible activation-induced cytidine deaminase fate-mapping mouse model, we compared effector and memory B cells induced by the 2 classes of vaccines and showed that a stronger and broader memory B cell and plasma cell response was achieved by a wP prime. We also observed that homologous or heterologous vaccine combinations that include at least 1 wP administration, even as a booster dose, were sufficient to induce this broad effector response, thus highlighting its dominant imprint on the B cell profile. Finally, we describe the settlement of memory B cell populations in the lung following subcutaneous wP prime vaccination.

Introduction Pertussis vaccines have drastically reduced the disease burden in humans since their implementation. Despite their success, pertussis remains an important global public health challenge. Bordetella pertussis resurgence could be a result of greater surveillance combined with improved diagnosis methods, changes in Bordetella pertussis biology, vaccine schedules, and/or coverage. Additionally, mechanisms of protection conferred by acellular pertussis (aP) and whole-cell pertussis (wP) vaccines differ qualitatively. There are no clear immune correlates of protection for pertussis vaccines. Pertussis antigens can induce toxin neutralizing antibodies, block adherence or engage complement mediated phagocytic/bactericidal killing. Areas covered We reviewed the existing evidence on antibody-mediated serum bactericidal and opsonophagocytic activity and discussed the relevance of these functional antibodies in the development of next-generation pertussis vaccines. Expert opinion Current paradigm proposes that wP vaccines may confer greater herd protection than aP vaccines due to their enhanced clearance of bacteria from the nasopharynx in animal models. Functional antibodies may contribute to the reduction of nasal colonization, which differentiates aP and wP vaccines. Understanding the intrinsic differences in protective immune responses elicited by each class of vaccines will help to identify biomarkers that can be used as immunological end points in clinical trials.

Dogma holds that plasma cells, as opposed to B cells, cannot bind antigen because they have switched from expression of membrane-bound immunoglobulins (Ig) that constitute the B-cell receptor (BCR) to production of the secreted form of immunoglobulins. Here we compare the phenotypical and functional attributes of plasma cells generated by the T-cell-dependent and T-cell-independent forms of the hapten NP. We show that the nature of the secreted Ig isotype, rather than the chemical structure of the immunizing antigen, defines two functionally distinct populations of plasma cells. Fully mature IgM-expressing plasma cells resident in the bone marrow retain expression of a functional BCR, whereas their IgG + counterparts do not. Antigen boost modifies the gene expression profile of IgM + plasma cells and initiates a cytokine production program, characterized by upregulation of CCL5 and IL-10. Our results demonstrate that IgM-expressing plasma cells can sense antigen and acquire competence for cytokine production upon antigenic challenge.

BACKGROUND & AIMS:The liver receives blood from the gastrointestinal tract through the portal vein, and thereby is exposed continuously to dietary antigens and commensal bacteria. Alcoholic liver disease (ALD) is associated with intestinal dysbiosis, increased intestinal permeability, release of microbes into the portal circulation, and increased serum levels and liver deposits of IgA. We characterized B-cell production of IgA in livers of mice at homeostasis, after oral immunization, in a mouse model of ALD and in human liver samples.METHODS:We performed studies with Balb/c and C57BL/6-Ly5.1 mice, as well as transgenic mice (quasimonoclonal, activation-induced [cytidine] deaminase-Cre-tamoxifen-dependent estrogen receptor 2 [ERT2], Blimp-1-green fluorescent protein [GFP]). C57BL/6-Ly5.1 mice were fed chronic plus binge ethanol to create a model of ALD. Some mice also were given repeated injections of FTY720, which prevents egress of IgA-secreting cells from Peyer's patches. We obtained nontumor liver tissues from patients with colorectal carcinoma undergoing surgery for liver metastases or hepatocellular carcinoma. B cells were isolated from mouse and human liver tissues and analyzed by flow cytometry and enzyme-linked ImmunoSpot (ELISpot). In wild-type and transgenic mice, we traced newly generated IgA-secreting cells at steady state and after oral immunization with 4-hydroxy-3-nitrophenylacetyl (NP)-Ficoll or cholera toxin. IgA responses were also evaluated in our model of ALD.RESULTS:Livers of control mice contained proliferative plasmablasts that originated from Peyer's patches and produced IgAs reactive to commensal bacteria. After oral immunization with cholera toxin or a thymus-independent antigen, a substantial number of antigen-specific IgA-secreting cells was found in the liver. Mice fed ethanol had features of hepatitis and increased numbers of IgA-secreting cells in liver, compared with mice given control diets, as well as higher levels of serum IgA and IgA deposits in liver sinusoids. Injection of FTY720 during ethanol feeding reduced liver and serum levels of IgA and IgA deposits in liver and prevented liver injury. Human liver tissues contained a significant proportion of IgA-producing plasma cells that shared phenotypic and functional attributes with those from mouse liver, including reactivity to commensal bacteria.CONCLUSIONS:Based on studies of mice and human liver tissues, we found the liver to be a site of IgA production by B cells, derived from gut-associated lymphoid tissues. These IgAs react with commensal bacteria and oral antigens. Livers from mice with ethanol-induced injury contain increased numbers of IgA-secreting cells and have IgA deposits in sinusoids. IgAs in the liver could mediate clearance of gut-derived antigens that arrive through portal circulation at homeostasis and protect these organs from pathogens.

Intestinal DCs orchestrate gut immune homeostasis by dampening proinflammatory T‐cell responses and inducing anti‐inflammatory IgA responses. Although no specific DC subset has been strictly assigned so far to govern IgA response, some candidate subsets emerge. In particular, plasmacytoid DCs (pDCs), which notoriously promote anti‐viral immunity and T‐cell tolerance to innocuous antigens (Ags), contribute to IgA induction in response to intestinal viral infection and promote T‐cell‐independent IgA responses in vitro. Here, using two transgenic mouse models, we show that neither short‐term nor long‐term pDC depletion alters IgA class switch recombination in Peyer's patches and frequency of IgA plasma cells in intestinal mucosa at steady state, even in the absence of T‐cell help. In addition, pDCs are dispensable for induction of intestinal IgA plasma cells in response to oral immunization with T‐cell‐dependent or T‐cell‐independent Ags, and are not required for proliferation and IgA switch of Ag‐specific B cells in GALT. These results show that pDCs are dispensable for noninfectious IgA responses, and suggest that various DC subsets may play redundant roles in the control of intestinal IgA responses.

Le plasmocyte (PC), stade terminal de la differenciation du lymphocyte B induite par l'antigene, est la cellule effectrice de l'immunite humorale responsable de la production des anticorps. La population plasmocytaire se divise en deux grands sous-types differant par leur duree de vie et par leur localisation anatomique. On distingue ainsi les PC a duree de vie courte ou PC effecteurs (dans les tissus lymphoides secondaires) et les PC a longue duree de vi (LLPC ou PC a memoire) localises principalement dans la moelle osseuse. Ces derniers contribuent a la memoire humorale en continuant a secreter des anticorps protecteurs apres resolution de l'infection. Nos resultats experimentaux montrent que les Ags thymo-dependants (TD) et les Ag thymo-independants (TI) induisent des PC medullaires exprimant des caracteristiques phenotypiques et fonctionnelles differentes. Ainsi, l'expression d'une forme membranaire fonctionnelle du recepteur antigenique (BCR) persiste sur les LLPC TI alors qu'elle est perdue sur les LLPC TD. Cette fonctionnalite nouvelle portee par les PC medullaires TI n'est pas dependante de la sous population lymphocytaire B recrutee ni de la nature de l'Ag, mais de l'isotype IgM. Nos resultats montrent egalement que cette population de PC medullaires a les caracteristiques des LLPC : ces PC sont quiescents, ils demeurent dans la moelle osseuse jusqu'a 180 jours et sont phenotypiquement semblables aux LLPC. Nos travaux ont permis de montrer que les LLPC a IgM sont capables de reconnaitre l'Ag et que l'engagement de leur BCR par l'Ag conduit a la production d'IL10

Adoptive cell therapy represents a promising approach for several chronic diseases. This study describes an innovative strategy for biofunctionalization of nanoparticles, allowing the generation of synthetic particulate antigens (SPAg). SPAg activate polyclonal B cells and vectorize noncognate proteins into their endosomes, generating highly efficient stimulators for ex vivo expansion of antigen-specific CD4+ T cells. This method also allows harnessing the ability of B cells to polarize CD4+ T cells into effectors or regulators.