Cytokines play crucial roles in coordinating the activities of innate and adaptive immune systems. In response to pathogen recognition, innate immune cells secrete cytokines that inform the adaptive immune system about the nature of the pathogen and instruct naïve T cells to differentiate into the appropriate T cell subtypes required to clear the infection. These include Interleukins, Interferons and other immune-regulatory cytokines that exhibit remarkable functional redundancy and pleiotropic effects. The focus of this review, however, is on the enigmatic Interleukin 12 (IL-12) family of cytokines. This family of cytokines plays crucial roles in shaping immune responses during antigen presentation and influence cell-fate decisions of differentiating naïve T cells. They also play essential roles in regulating functions of a variety of effector cells, making IL-12 family cytokines important therapeutic targets or agents in a number of inflammatory diseases, such as the CNS autoimmune diseases, uveitis and multiple sclerosis.

Much of the mammalian genome is transcribed, generating long non-coding RNAs (lncRNAs) that can undergo post-transcriptional surveillance whereby only a subset of the non-coding transcripts is allowed to attain sufficient stability to persist in the cellular milieu and control various cellular functions. Paralleling protein turnover by the proteasome complex, lncRNAs are also likely to exist in a dynamic equilibrium that is maintained through constant monitoring by the RNA surveillance machinery. In this Review, we describe the RNA surveillance factors and discuss the vital role of lncRNA surveillance in orchestrating various biological processes, including the protection of genome integrity, maintenance of pluripotency of embryonic stem cells, antibodygene diversification, coordination of immune cell activation and regulation of heterochromatin formation. We also discuss examples of human diseases and developmental defects associated with the failure of RNA surveillance mechanisms, further highlighting the importance of lncRNA surveillance in maintaining cell and organism functions and health.Non-coding RNAs (ncRNAs) are a type of RNA that are not translated into protein and include small ncRNAs (such as microRNAs) in the range of 15-30 nucleotides 1-3 and long ncRNAs (lncRNAs), which are generally considered as longer than 200 nucleotides 4 . LncRNAs include a variety of transcripts, all of which can modulate gene expression in specific ways based on cell type, developmental stage and function 5-7 (Box 1). As only a fraction of lncRNAs may be biologically relevant to a given process, cells use RNA surveillance pathways to identify and degrade most lncRNAs.RNA surveillance is necessary for genome stability and gene expression [8][9][10] . Whereas mechanisms of mRNA surveillance have been extensively reviewed 11,12 , less is known about the surveillance of the diverse types of lncRNA. Although the various components of the RNA surveillance pathways are still being characterized, it is known that endoribonucleases, 5′-exoribonucleases and 3′-exoribonucleases can degrade nascent lncRNAs, often with the

Summary The relationship between commensal microbes and their hosts has been studied for many years. Commensal microorganisms are known to have a significant role in regulating the physiology of their hosts and preventing pathogenic infections while the hosts’ immune system is important in determining the composition of the microbiota. More recently, specific effects of the intestinal microbiota on the local and distal immune systems have been uncovered with important consequences for health and disease, and alterations in intestinal microbial composition has been associated with various disease states. Here, we will review the current understanding of the microbiota/immune system crosstalk, highlight the clinical consequences of changes in the microbiota and consider how to harness this symbiotic relationship to improve public health.

B cells undergo two types of genomic alterations to increase antibody diversity: introduction of point mutations into immunoglobulin heavy- and light-chain (IgH and IgL) variable regions by somatic hypermutation (SHM) and alteration of antibody effector functions by changing the expressed IgH constant region exons through IgH class switch recombination (CSR). SHM and CSR require the B cell–specific activation-induced cytidine deaminase (AID) protein, the transcription of germline noncoding RNAs, and the activity of the 3′ regulatory region (3′RR) super-enhancer. Although many transcription regulatory elements (e.g., promoters and enhancers) reside inside the IgH and IgL sequences, the question remains whether clusters of regulatory elements outside IgH control CSR. Using RNA exosome–deficient mouse B cells where long noncoding RNAs (lncRNAs) are easily detected, we identified a cluster of three RNA-expressing elements that includes lncCSRIgA (that expresses lncRNA-CSRIgA). B cells isolated from a mouse model lacking lncRNA-CSRIgA transcription fail to undergo normal levels of CSR to IgA both in B cells of the Peyer’s patches and grown in ex vivo culture conditions. lncRNA-CSRIgA is expressed from an enhancer site (lncCSRIgA) to facilitate the recruitment of regulatory proteins to a nearby CTCF site (CTCFlncCSR) that alters the chromosomal interactions inside the TADlncCSRIgA and long-range interactions with the 3′RR super-enhancer. Humans with IgA deficiency show polymorphisms in the lncCSRIgA locus compared with the normal population. Thus, we provide evidence for an evolutionarily conserved topologically associated domain (TADlncCSRIgA) that coordinates IgA CSR in Peyer’s patch B cells through an lncRNA (lncRNA-CSRIgA) transcription-dependent mechanism.

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Papillary carcinoma is the most common thyroid malignancy. Usual sites of metastasis include lungs and bone, but renal metastasis is very rare. Here we present a case of a follicular variant of papillary carcinoma with renal and lung metastasis at presentation.