Keeping a delicate balance in the immune system by eliminating invading pathogens, while still maintaining self-tolerance to avoid autoimmunity, is critical for the body's health. The gut microbiota that resides in the gastrointestinal tract provides essential health benefits to its host, particularly by regulating immune homeostasis. Moreover, it has recently become obvious that alterations of these gut microbial communities can cause immune dysregulation, leading to autoimmune disorders. Here we review the advances in our understanding of how the gut microbiota regulates innate and adaptive immune homeostasis, which in turn can affect the development of not only intestinal but also systemic autoimmune diseases. Exploring the interaction of gut microbes and the host immune system will not only allow us to understand the pathogenesis of autoimmune diseases but will also provide us new foundations for the design of novel immuno-or microbebased therapies.
SUMMARY
Gut microbiota profoundly affect gut and systemic diseases, but the mechanism whereby microbiota affect systemic diseases is unclear. It is not known whether specific microbiota regulate T follicular helper (Tfh) cells, whose excessive responses can inflict antibody-mediated autoimmunity. Using the K/BxN autoimmune arthritis model, we demonstrated that Peyer’s patch (PP) Tfh cells were essential for gut commensal segmented filamentous bacteria (SFB)-induced systemic arthritis despite the production of auto-antibodies predominantly occurring in systemic lymphoid tissues, not PPs. We determined that SFB, by driving differentiation and egress of PP Tfh cells into systemic sites, boosted systemic Tfh cell and auto-antibody responses that exacerbated arthritis. SFB induced PP Tfh cell differentiation by limiting the access of interleukin 2 to CD4+ T cells, thereby enhancing Tfh cell master regulator Bcl-6 in a dendritic cell-dependent manner. These findings showed that gut microbiota remotely regulated a systemic disease by driving the induction and egress of gut Tfh cells.
Membrane permeabilizing
peptides (MPPs) are as ubiquitous as the
lipid bilayer membranes they act upon. Produced by all forms of life,
most membrane permeabilizing peptides are used offensively or defensively
against the membranes of other organisms. Just as nature has found
many uses for them, translational scientists have worked for decades
to design or optimize membrane permeabilizing peptides for applications
in the laboratory and in the clinic ranging from antibacterial and
antiviral therapy and prophylaxis to anticancer therapeutics and drug
delivery. Here, we review the field of membrane permeabilizing peptides.
We discuss the diversity of their sources and structures, the systems
and methods used to measure their activities, and the behaviors that
are observed. We discuss the fact that “mechanism” is
not a discrete or a static entity for an MPP but rather the result
of a heterogeneous and dynamic ensemble of structural states that
vary in response to many different experimental conditions. This has
led to an almost complete lack of discrete three-dimensional active
structures among the thousands of known MPPs and a lack of useful
or predictive sequence-structure–function relationship rules.
Ultimately, we discuss how it may be more useful to think of membrane
permeabilizing peptides mechanisms as broad regions of a mechanistic
landscape rather than discrete molecular processes.
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