Scurvy and Tinea Corporis Simulating Leukocytoclastic Vasculitis.

ABSTRACT: Leukocytoclastic vasculitis (LCV) is a small vessel inflammatory condition considered to be caused by circulating immune complexes and often occurs after an acute infection or exposure to a new medication, although it may be associated with an underlying systemic disease or be idiopathic in nature. It is important to determine the etiology, identify the extent of the disease for early intervention and appropriate management, and treat and/or eliminate the underlying cause. Here, we report cases of scurvy and tinea corporis that presented with histopathologic features of LCV and had significant clinical improvement with treatment of the underlying etiologies. These cases emphasize that histopathologic features of early evolving LCV may be seen in other settings including scurvy and tinea corporis. Appropriate treatment of the underlying condition is important for optimized patient management.

A rare cause of melena.

Melanoma presenting in the gastrointestinal tract is commonly due to metastasis from a primary cutaneous or ocular lesion. There have been a few case reports of primary GI melanoma which is commonly seen in the rectum and anus. We report a case of a 77-year-old man who presented with GI bleeding and was found to have a primary small bowel melanoma. This case highlights how to approach the workup of a melanoma lesion found in the GI tract.

Nucleoporin Seh1 Interacts with Olig2/Brd7 to Promote Oligodendrocyte Differentiation and Myelination.

Nucleoporins (Nups) are involved in neural development, and alterations in Nup genes are linked to human neurological diseases. However, physiological functions of specific Nups and the underlying mechanisms involved in these processes remain elusive. Here, we show that tissue-specific depletion of the nucleoporin Seh1 causes dramatic myelination defects in the CNS. Although proliferation is not altered in Seh1-deficient oligodendrocyte progenitor cells (OPCs), they fail to differentiate into mature oligodendrocytes, which impairs myelin production and remyelination after demyelinating injury. Genome-wide analyses show that Seh1 regulates a core myelinogenic regulatory network and establishes an accessible chromatin landscape. Mechanistically, Seh1 regulates OPCs differentiation by assembling Olig2 and Brd7 into a transcription complex at nuclear periphery. Together, our results reveal that Seh1 is required for oligodendrocyte differentiation and myelination by promoting assembly of an Olig2-dependent transcription complex and define a nucleoporin as a key player in the CNS.

Sec13 Regulates Expression of Specific Immune Factors Involved in Inflammation In Vivo.

The Sec13 protein functions in various intracellular compartments including the nuclear pore complex, COPII-coated vesicles, and inside the nucleus as a transcription regulator. Here we developed a mouse model that expresses low levels of Sec13 (Sec13(H/-)) to assess its functions in vivo, as Sec13 knockout is lethal. These Sec13 mutant mice did not present gross defects in anatomy and physiology. However, the reduced levels of Sec13 in vivo yielded specific immunological defects. In particular, these Sec13 mutant mice showed low levels of MHC I and II expressed by macrophages, low levels of INF-γ and IL-6 expressed by stimulated T cells, and low frequencies of splenic IFN-γ+CD8+ T cells. In contrast, the levels of soluble and membrane-bound TGF-ß as well as serum immunoglobulin production are high in these mice. Furthermore, frequencies of CD19+CD5-CD95+ and CD19+CD5-IL-4+ B cells were diminished in Sec13(H/-) mice. Upon stimulation or immunization, some of the defects observed in the naïve mutant mice were compensated. However, TGF-ß expression remained high suggesting that Sec13 is a negative modulator of TGF-ß expression and of its immunosuppressive functions on certain immune cells. In sum, Sec13 regulates specific expression of immune factors with key functions in inflammation.

Vesicular stomatitis virus inhibits mitotic progression and triggers cell death.

Vesicular stomatitis virus (VSV) infects and kills a wide range of cell types; however, the mechanisms involved in VSV-mediated cell death are not fully understood. Here we show that VSV infection interferes with mitotic progression, resulting in cell death. This effect requires the interaction of VSV matrix (M) protein with the Rae1-Nup98 complex in mitosis, which is associated with a subset of ribonucleoproteins (RNPs). VSV displaced Rae1 from spindle poles, caused spindle abnormalities and triggered substantial cell death during metaphase. These effects were attenuated in cells infected with VSV expressing a mutant M protein that does not bind efficiently to the Rae1-Nup98-RNP complex. In cells that progressed to late mitosis, M protein prevented proper nuclear formation and chromatin decondensation. VSV is an oncolytic (anti-tumour) agent as it preferentially replicates and kills tumour cells. As tumour cells have a high mitotic index, VSV-mediated mitotic cell death probably contributes to its oncolytic activity.

NFAR-1 and -2 modulate translation and are required for efficient host defense.

We report here that the alternatively spliced nuclear factors associated with double-stranded RNA, NFAR-1 (90 kDa) and -2 (110 kDa), are involved in retaining cellular transcripts in intranuclear foci and can regulate the export of mRNA to the cytoplasm. Furthermore, the NFAR proteins were found to remain associated with exported ribonucleoprotein complexes. Loss of NFAR function, which was embryonic-lethal, caused an increase in protein synthesis rates, an effect augmented by the presence of the mRNA export factors TAP, p15, or Rae1. Significantly, NFAR depletion in normal murine fibroblasts rendered these cells dramatically susceptible to vesicular stomatitis virus replication. Collectively, our data demonstrate that the NFARs exert influence on mRNA trafficking and the modulation of translation rates and may constitute an innate immune translational surveillance mechanism important in host defense countermeasures against virus infection.

Influenza virus targets the mRNA export machinery and the nuclear pore complex.

The NS1 protein of influenza A virus is a major virulence factor that is essential for pathogenesis. NS1 functions to impair innate and adaptive immunity by inhibiting host signal transduction and gene expression, but its mechanisms of action remain to be fully elucidated. We show here that NS1 forms an inhibitory complex with NXF1/TAP, p15/NXT, Rae1/mrnp41, and E1B-AP5, which are key constituents of the mRNA export machinery that interact with both mRNAs and nucleoporins to direct mRNAs through the nuclear pore complex. Increased levels of NXF1, p15, or Rae1 revert the mRNA export blockage induced by NS1. Furthermore, influenza virus down-regulates Nup98, a nucleoporin that is a docking site for mRNA export factors. Reduced expression of these mRNA export factors renders cells highly permissive to influenza virus replication, demonstrating that proper levels of key constituents of the mRNA export machinery protect against influenza virus replication. Because Nup98 and Rae1 are induced by interferons, down-regulation of this pathway is likely a viral strategy to promote viral replication. These findings demonstrate previously undescribed influenza-mediated viral-host interactions and provide insights into potential molecular therapies that may interfere with influenza infection.

The nucleoporin Nup96 is required for proper expression of interferon-regulated proteins and functions.

Nup98 and Nup96 are components of the nuclear transport machinery and are induced by interferons (IFN). Nup98 is a constituent of an mRNA export pathway that is targeted by viruses and regulated by IFN. However, the role of Nup96 in IFN-related mechanisms has not been established. To investigate the function of Nup96 in vivo, we generated Nup96(+/-) mice that express low levels of Nup96, as Nup96(-/-) mice are lethal. The Nup96(+/-) mice presented selective alterations of the immune system, which resulted in downregulation and impaired IFN alpha- and gamma-mediated induction of MHC I and IFNgamma induction of MHC II, ICAM-1, and other proteins. Frequency of TCRalphabeta+ and CD4+ T cells, which depends on MHC function, is reduced in NUP96(+/-) mice. Upon immunization, Nup96(+/-) mice showed impaired antigen presentation and T cell proliferation. Nup96(+/-) cells and mice were highly susceptible to viral infection, demonstrating a role for Nup96 in innate and adaptive immunity.

Viral interactions with the nuclear transport machinery: discovering and disrupting pathways.

Viruses have been invaluable tools for discovering key pathways of nucleocytoplasmic transport. Conversely, disruption of specific nuclear transport pathways, are crucial for the productive life cycle of some viruses. The major cellular mRNA export pathway, which uses TAP (NXF1)/p15(NXT) as receptor, was discovered as a result of TAP interaction with CTE-containing RNAs from Mason-Pfizer Monkey Virus. In addition, CRM1 or exportin 1, which is a transport receptor that mediates nuclear export of proteins, snRNAs, rRNAs and a small subset of mRNAs, was discovered as an interacting partner of the Rev protein of HIV1. Viruses may disrupt the nuclear transport machinery to prevent host antiviral response. VSV Matrix (M) protein inhibits mRNA export by forming a complex with the mRNA export factor Rae1 whereas poliovirus inhibits nuclear import of proteins by probably degrading Nup62 and Nup153. Hence, this review focuses on viruses as tools and as disruptors of nucleocytoplasmic trafficking.