Obesity promotes a diminished response to vaccinations and infections. Therefore, understanding how obesity targets B cell‐driven humoral immunity, particularly at a mechanistic level, is essential to elucidate. Using a murine model, we report that diet‐induced obesity impairs early B cell development and induces a dysfunctional immune response. B cells from obese mice displayed a two‐fold reduction in the number of CD19 + cells, resulting in decreased frequencies of various B cell subsets in the bone marrow. Early lymphoid commitment markers such as IL7Rα, IL7R, and STAT5 showed significantly decreased expression at the transcript level. In addition, obese mice had reduced mRNA expression of the B cell lymphopoiesis markers, PAX5 and Oct2, compared to controls. Functionally, B cells from obese mice had elevated IgM and IgG levels in the absence of stimulation. When B cells from the obese mice were challenged with anti‐TLR4 or anti‐BCR/TLR9 in vitro, the ability to produce IgM and IgG was diminished. Overall, these findings demonstrate that obesity hinders B cell development and drives a dysregulated immune response, which could contribute to impaired responses to infections and vaccinations. Support or Funding Information Supported by NIH R01AT008375 (SRS)
Obesity is hypothesized to drive an impairment in humoral immunity. However, it is unclear how obesity directly targets B cell responses in humans. This study investigated how obese subjects, relative to lean controls, responded to anti‐B cell receptor (BCR) and toll‐like receptor (TLR) 9 stimulation. Obese individuals with a BMI of >30 had a significant increase in the percentage of B cells in circulation compared to their lean counterparts whereas the percentage of monocytes, helper T cells, and cytotoxic T cells remained unchanged. B cell IL‐6 secretion was lowered upon anti‐BCR/TLR9 stimulation in the obese compared to lean controls. Furthermore, a positive correlation was observed between BMI and IgM, but not IgG, production upon anti‐BCR/TLR9 stimulation. These results demonstrate that B cell function is impaired in obese individuals, which could contribute toward diminished responses to infection and vaccination in obesity. Support or Funding Information Research was supported by NIH R01AT008375
Abstract B cells generate antibodies that are essential for immune protection. Major events driving B cell responses occur in lymphoid tissues, which guide antigen acquisition and support cellular interactions, yet complexities of B cell subsets in human lymphoid tissues are poorly understood. Here we perform undirected, global profiling of B cells in matched human lymphoid tissues from deceased transplant organ donors and tracked dissemination of B cell clones. In addition to identifying unanticipated features of tissue-based B cell differentiation, we resolve two clonally independent subsets of marginal zone B cells that differ in cell surface and transcriptomic profiles, tendency to disseminate, distribution bias within splenic marginal zone microenvironment and immunoglobulin repertoire diversity and hypermutation frequency. Each subset is represented in spleen, gut-associated lymphoid tissue, mesenteric lymph node, and also blood. Thus, we provide clarity and diffuse controversy surrounding human MZB - the ‘elephant in the room’ of human B cell biology.
Obesity is associated with an increased risk of infection and poor response to vaccination, which may be driven by impaired antibody production. Therefore, therapeutic strategies are needed to enhance the humoral response. We previously demonstrated that n‐3 polyunsaturated fatty acids (PUFA) can enhance antibody production to a T‐independent antigen. Therefore, we tested the possibility that the n‐3 PUFA docosahexaenoic acid (DHA) could improve antibody production upon influenza infection in obese mice. To investigate the effect of DHA on humoral immunity, we fed mice for 15 weeks with a control or a high fat diet with or without DHA supplementation followed by infection with influenza A/Puerto Rico/8/34. Our findings reveal that DHA supplementation improved the decrement in hemagglutination inhibition (HAI) titers of obese mice after influenza infection. Mechanistically, DHA did not target B‐cell PPARγ (peroxisome proliferator‐activated receptors) or the DHA‐sensing G‐protein coupled receptor 120 to boost antibody levels. Instead, DHA increased the levels of downstream D‐series specialized pro‐resolving lipid mediators (SPMs), which are known to increase antibody production through the generation of CD138 + antibody secreting cells. Specifically, we identified 14‐HDHA to be elevated upon DHA intervention, which elevated HAI titers upon influenza infection and increased the frequency of CD138 + cells. Overall, the results suggest that DHA may have potential therapeutic applications for improving humoral immunity. Support or Funding Information Supported by NIH R01AT008375 (SRS).
Cryptosporidium parvum causes diarrhea in infants under 5 years, in immunosuppressed individuals or in young ruminants. This parasite infects the apical side of ileal epithelial cells where it develops itself and induces inflammation. Antimicrobial peptides (AMPs) are part of the innate immune response, playing a major role in the control of the acute phase of C. parvum infection in neonates. Intestinal AMP production in neonates is characterized by high expressions of Cathelicidin Related Antimicrobial Peptide (CRAMP), the unique cathelicidin in mice known to fight bacterial infections. In this study, we investigated the role of CRAMP during cryptosporidiosis in neonates. We demonstrated that sporozoites are sensitive to CRAMP antimicrobial activity. However, during C. parvum infection the intestinal expression of CRAMP was significantly and selectively reduced, while other AMPs were upregulated. Moreover, despite high CRAMP expression in the intestine of neonates at homeostasis, the depletion of CRAMP did not worsen C. parvum infection. This result might be explained by the rapid downregulation of CRAMP induced by infection. However, the exogenous administration of CRAMP dampened the parasite burden in neonates. Taken together these results suggest that C. parvum impairs the production of CRAMP to subvert the host response, and highlight exogenous cathelicidin supplements as a potential treatment strategy.
Due to the immaturity of their immune system, neonates are highly sensitive to intestinal infections.During the neonatal period, antimicrobial peptide (AMP) expression differs substantially from that of adults as this is the case for the cathelicidin-related antimicrobial peptide CRAMP expressed preferentially in the neonatal period while conversely other AMPs such as Reg3c are expressed later in life.Among enteric neonatal diseases, Cryptosporidiosis is a zoonotic disease and is highly prevalent in in young infant less than 5 years old in underdeveloped country and in neonatal ruminants worldwide.Cryptosporidium parvum is the etiological agent of this diarrheal disease and infects exclusively epithelial cells.Innate immunity is important to control the acute phase of infection in neonates with dendritic cells and IFNc playing a major role.Antimicrobial peptides are important contributors of innate immunity, but the role of CRAMP, which is elevated in the intestine of neonates has never been investigated during Cryptosporidiosis so far.In this work, we used the neonatal murine model of cryptosporidiosis and unlike all the other antimicrobial peptides analyzed CRAMP expression in the intestinal epithelial cells was significantly reduced during infection.This reduced CRAMP expression is independent of IFNg, a cytokine strongly produced during infection but also Myd88 and gut flora independent.When C. parvum infected neonatal mice orally received exogenous CRAMP to compensate the reduced expression of this AMP, the parasitic load of neonates was significantly decreased.In addition, when free parasites were in direct contact with CRAMP, this AMP affects the viability of sporozoites, the first free infectious form of this parasite.All together, these data suggest that C. parvum induces the reduction of CRAMP expression to escape the anti-parasiticidal effect of CRAMP.The molecular mechanism by which the parasite subverts epithelialderived CRAMP production is currently under investigation.
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