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Diets high in cholesterol alter intestinal immunity. Here, we examined how the cholesterol metabolite 25-hydroxycholesterol (25-HC) impacts the intestinal B cell response. Mice lacking cholesterol 25-hydroxylase (CH25H), the enzyme generating 25-HC, had higher frequencies of IgA-secreting antigen-specific B cells upon immunization or infection. 25-HC did not affect class switch recombination, but rather restrained plasma cell (PC) differentiation. 25-HC was produced by follicular dendritic cells and increased in response to dietary cholesterol. Mechanistically, 25-HC restricted activation of the sterol sensing transcription factor SREBP2, thereby regulating B cell cholesterol biosynthesis. Ectopic expression of SREBP2 in germinal center B cells induced rapid PC differentiation, whereas SREBP2 deficiency reduced PC output in vitro and in vivo. High cholesterol diet impaired, whereas Ch25h deficiency enhanced, the IgA response against Salmonella and the resulting protection from systemic bacterial dissemination. Thus, a 25-HC-SREBP2 axis shapes the humoral response at the intestinal barrier, providing insight into the impact of high dietary cholesterol in intestinal immunity.

B cells are well known as critical mediators of humoral immune responses via the production of antibodies. However, numerous studies have also identified populations of B cells that are characterized by their anti-inflammatory properties. These "regulatory B cells" restrain excessive inflammatory responses in a wide range of health conditions. A significant knowledge gap remains concerning the nature of the signals that determine whether a B cell exerts a pro-inflammatory or anti-inflammatory function. In this perspective, we explore the concept that in addition to the cytokine microenvironment, intracellular and extracellular metabolic signals play a pivotal role in controlling the balance between regulatory and antibody-producing B cell subsets. Determining the metabolites and tissue-specific signals that influence B cell fate could establish novel therapeutic targets for the treatment of diseases where abnormal B cell responses contribute to pathogenesis.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease where a loss of tolerance to nuclear antigens leads to inflammation in multiple organ systems. The cause of SLE remains ill defined, although it is known that a complex interplay between genes and environment is necessary for disease development. In recent years, case studies have reported that the incidence of SLE in the USA, for example, has increased by approximately 3 fold. Although the reason for this is likely to be multifactorial, it has been hypothesized that the increasing incidence of autoimmune disease is due to considerable shifts in the bacterial communities resident the gut, collectively known as the gut microbiota, following a change in diet and the widespread introduction of antibiotics. Furthermore, a growing body of evidence suggests that the gut microbiota plays a role in the development of a range of autoimmune diseases including inflammatory bowel disease, multiple sclerosis, type one diabetes and rheumatoid arthritis. In this review, we summarize how advances in DNA-based sequencing technologies have been critical in providing baseline information concerning the gut microbiota in health and how variation amongst individuals in controlled by multiples factors including age, genetics, environment and the diet. We also discuss the importance of the gut microbiota in the development of a healthy immune system and how changes in particular bacterial phyla have been associated with immune abnormalities in animal models of autoimmune disease. Finally, in order to place the data in a clinical context, we highlight recent findings showing that abnormalities in the gut microbiota can be detected in patients with SLE, which provides the rationale for greater investigation into whether microbiota-targeted therapies could be used for the treatment/prevention of disease.

Summary B cells perform many immunological functions, including presenting lipid antigen to CD1d-restricted invariant natural killer T (iNKT) cells, known to contribute to maintaining tolerance in autoimmunity. Patients with systemic lupus erythematous (SLE) display dysregulated B cell responses and reduced peripheral iNKT cell frequencies. The significance of these defects and how they relate to SLE pathogenesis remain elusive. We report that B cells are essential for iNKT cell expansion and activation in healthy donors but fail to exert a similar effect in SLE patients. Defective B cell-mediated stimulation of iNKT cells in SLE patients was associated with altered CD1d recycling, a defect recapitulated in B cells from healthy donors after stimulation with interferon-α (IFN-α) and anti-immunoglobulin (Ig). iNKT cell number and function were restored in SLE patients responding to anti-CD20 treatment upon normalization of CD1d expression exclusively in repopulated immature B cells. We propose that healthy B cells are pivotal for iNKT cell homeostasis., Highlights ► B cells sustain iNKT cell homeostasis and activation in healthy individuals ► SLE B cells fail to sustain iNKT cell homeostasis and activation ► SLE B cells were characterized by a profound decrease in surface CD1d expression ► Correct trafficking of CD1d is important for the maintenance of iNKT cell homeostasis

Regulatory B cells have largely been reported as B cells at a developmental stage before plasma cell differentiation. Matsumoto et al. (2014) report that IL-10(+) plasmablasts restrain autoimmune inflammation and suggest an ontological connection between immature B cells and regulatory plasmablasts.

Compelling evidence has demonstrated that IL-10-producing regulatory B cells (B(regs)) are specialized to suppress immune responses and control various immunopathologies. Several reports have provided information on the phenotype, generation, and mechanism of action of B(regs). Recent work has also identified B(regs) in humans and has begun to unravel their phenotype and mode of suppression. A complete analysis of their function in immune-mediated diseases is required for possible future use of B(regs) as a part of new clinical strategies for treating autoimmune diseases and in the induction of transplant tolerance.

Recent advances have demonstrated the existence of an IL-10-producing B cell subset with regulatory capacity named (Bregs). In mice, Bregs have been shown to restrain the severity of autoimmune disorders and contribute to the development of infection and cancer. In humans, CD19 + CD24 hi CD38 hi C D1d hi B cells have been ascribed with regulatory function. We have shown that this B cell subset inhibits the activation of T helper (Th)1 and Th17 responses whilst supporting the differentiation of FoxP3 + Tregs. We have shown that, in addition to regulating the differentiation of CD4 + T cells, Bregs are essential for the maintenance of CD1d-restricted invariant natural killer T ( i NKT) cells in healthy individuals but fail to exert the same effect in SLE patients. i NKT cells play a potent immune-regulatory role functioning in both innate and adaptive immunity. Defective B cell-mediated stimulation of i NKT cells in SLE was associated with rapid CD1d recycling leading to reduced CD1d surface expression on B cells from SLE patients, a defect that could be recapitulated in B cells from healthy individuals after simultaneous stimulation with interferon-a (IFN-a) and anti-immunoglobulin (Ig). i NKT cell homeostasis was restored in SLE patients responding to B cell depletion therapy, upon normalization of CD1d levels in repopulated CD19 + CD24 hi CD38 hi C D1d hi Bregs.