ABSTRACT
B cells represent a critical component of the adaptive immune response whose development and differentiation are determined by antigen-dependent and antigen-independent interactions. In this study, we explored the effects of IL-4 and pattern-recognition receptor (PRR) ligands on B cell development and differentiation by investigating their capacity to drive the in vitro maturation of human transitional B cells. In the presence of IL-4, ligands for TLR7/8, TLR9, and NOD1 were effective in driving the in vitro maturation of cord blood transitional B cells into mature, naïve B cells as measured by CD23 expression, ABCB1 transporter activation and upregulation of sIgM and sIgD. In addition, several stimulation conditions, including TLR9 ligand alone, favored an expansion of CD27+ IgM memory B cells. Transitional B cells stimulated with TLR7/8 ligand + IL-4 or TLR9 ligand, with or without IL-4, induced a significant subpopulation of CD23+CD27+ B cells expressing high levels of sIgM and sIgD, a minor B cell subpopulation found in human peripheral blood. These studies illustrate the heterogeneity of the B cell populations induced by cytokine and PRR ligand stimulation. A comparison of transitional and mature, naïve B cells transcriptomes to identify novel genes involved in B cell maturation revealed that mature, naïve B cells were less transcriptionally active than transitional B cells. Nevertheless, a subset of differentially expressed genes in mature, naïve B cells was identified including genes associated with the IL-4 signaling pathway, PI3K signaling in B lymphocytes, the NF-κB signaling pathway, and the TNFR superfamily. When transitional B cells were stimulated in vitro with IL-4 and PRR ligands, gene expression was found to be dependent on the nature of the stimulants, suggesting that exposure to these stimulants may alter the developmental fate of transitional B cells. The influence of IL-4 and PRR signaling on transitional B cell maturation illustrates the potential synergy that may be achieved when certain PRR ligands are incorporated as adjuvants in vaccine formulations and presented to developing B cells in the context of an inflammatory cytokine environment. These studies demonstrate the potential of the PRR ligands to drive transitional B cell differentiation in the periphery during infection or vaccination independently of antigen mediated BCR signaling.
Subject(s)
Precursor Cells, B-Lymphoid , Toll-Like Receptor 7 , Cell Differentiation , Cytokines/metabolism , Humans , Interleukin-4/pharmacology , Ligands , Lymphocyte Activation , Phosphatidylinositol 3-Kinases , Precursor Cells, B-Lymphoid/metabolism , Receptors, Pattern Recognition , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 9/metabolismABSTRACT
A subcommittee of the Hawaii Governor's Joint Task Force on Rat Lungworm Disease developed preliminary guidelines for the diagnosis and treatment of neuroangiostrongyliasis (NAS) in 2018 (Guidelines, 2018). This paper reviews the main points of those guidelines and provides updates in areas where our understanding of the disease has increased. The diagnosis of NAS is described, including confirmation of infection by real-time polymerase chain reaction (RTi-PCR) to detect parasite DNA in the central nervous system (CNS). The treatment literature is reviewed with recommendations for the use of corticosteroids and the anthelminthic drug albendazole. Long-term sequelae of NAS are discussed and recommendations for future research are proposed.
Subject(s)
Angiostrongylus cantonensis/physiology , Strongylida Infections , Adrenal Cortex Hormones/administration & dosage , Albendazole/administration & dosage , Animals , Anthelmintics/administration & dosage , Hawaii , Humans , Strongylida Infections/diagnosis , Strongylida Infections/drug therapyABSTRACT
Angiostrongylus cantonensis is a metastrongylid lungworm of rats with a global distribution and the cause of neuroangiostrongyliasis in humans. In Hawai'i, neuroangiostrongyliasis cases have occurred sporadically since 1960; however, in 2001, the number of cases on Maui and Hawai'i Island began to increase significantly. Since most human treatment trials have been conducted in Thailand, where the disease is usually mild, there is a need to develop treatment protocols for Hawai'i, where there is a broader disease spectrum. In 2018, preliminary guidelines for the diagnosis and treatment of neuroangiostrongyliasis were developed for Hawai'i's physicians. This article summarizes those guidelines and provides additional recommendations for individuals who recently ingested an infected intermediate host.
