The Tumour Suppressor TMEM127 Is a Nedd4-Family E3 Ligase Adaptor Required by Salmonella SteD to Ubiquitinate and Degrade MHC Class II Molecules.

The Salmonella enterica effector SteD depletes mature MHC class II (mMHCII) molecules from the surface of infected antigen-presenting cells through ubiquitination of the cytoplasmic tail of the mMHCII ß chain. Here, through a genome-wide mutant screen of human antigen-presenting cells, we show that the NEDD4 family HECT E3 ubiquitin ligase WWP2 and a tumor-suppressing transmembrane protein of unknown biochemical function, TMEM127, are required for SteD-dependent ubiquitination of mMHCII. Although evidently not involved in normal regulation of mMHCII, TMEM127 was essential for SteD to suppress both mMHCII antigen presentation in mouse dendritic cells and MHCII-dependent CD4+ T cell activation. We found that TMEM127 contains a canonical PPxY motif, which was required for binding to WWP2. SteD bound to TMEM127 and enabled TMEM127 to interact with and induce ubiquitination of mature MHCII. Furthermore, SteD also underwent TMEM127- and WWP2-dependent ubiquitination, which both contributed to its degradation and augmented its activity on mMHCII.

Can gut microbiota of men who have sex with men influence HIV transmission?

Gaining a complete understanding of transmission risk factors will assist in efforts to reduce new HIV infections, especially within the disproportionally affected population of men who have sex with men (MSM). We recently reported that the fecal microbiota of MSM elevates immune activation in gnotobiotic mice and enhances HIV infection in vitro over that of fecal microbiota from men who have sex with women. We also demonstrated elevation of the gut homing marker CD103 (integrin αE) on CD4+ T cells by MSM-microbiota. Here we provide additional evidence that the gut microbiota is a risk factor for HIV transmission in MSM by showing elevated frequencies of the HIV co-receptor CCR5 on CD4+ T cells in human rectosigmoid colon biopsies. We discuss our interest in specific MSM-associated bacteria and propose the influx of CD103+ and CCR5+ CD4+ T cells into the colon as a potential link between the MSM microbiota and HIV transmission.

Difficulty diagnosing chronic cryptococcal meningitis in idiopathic CD4+ lymphocytopenia.

A 64-year-old man with idiopathic CD4(+) lymphocytopenia developed cognitive impairment and gait ataxia with isolated obstructive hydrocephalus, which was fatal. Cerebrospinal fluid showed mild pleocytosis, but the etiology was not revealed by extensive analysis. At autopsy, inflammatory cells, CD8(+) lymphocytes and abundant macrophages but not CD4(+) lymphocytes were infiltrating the meninges at the base of the brain. Electron microscopy demonstrated that inflammation was caused by Cryptococcus neoformans, which was localized exclusively within macrophages, where it grew with budding. Our study suggests that, in idiopathic CD4(+) lymphocytopenia, macrophages can efficiently phagocytize but inefficiently digest C. neoformans, thus representing a vehicle of chronic intracellular infection.

Idiopathic Cd4+T-lymphocytopenia--two unusual patients with cryptococcal meningitis.

Idiopathic CD4+T-lymphocytopenia (ICL) is a syndrome characterised by the depletion in the CD4+T-cells but without evidence of HIV infection. Aside from low CD4+lymphocyte counts, the immunologic findings in these patients are distinct from the abnormalities found in HIV infection. There are numerous reports of ICL associated with different diseases and clinical conditions. Opportunistic infections, mostly seen in HIV patients are the most common among them. We describe two patients without risk factors for human immunodeficiency virus (HIV) infection, each of whom presented with cryptococcal meningitis and was found to have idiopathic CD4+T-lymphocytopenia. One of them also acquired EBV and CMV coinfection of the central nervous system.

Primary aspergillosis of the larynx associated with CD4+ T lymphocytopenia.

The purpose of this study was to report the first case (to our knowlege) of primary laryngeal aspergillosis in a patient with underlying CD4(+) T lymphocytopenia. Laryngeal involvement of Aspergillus is more commonly seen as a part of a wider infection involving the respiratory system in an immunocompromised host. However, primary infection of the larynx is extremely rare. Although there were 12 cases of primary laryngeal aspergillosis previously reported in healthy subjects, there is no known study describing immunological findings in detail. We report a case of primary laryngeal aspergillosis in a healthy 79-year-old male. The examination of his immunity subsequently revealed that there was a marked decline in the number of CD4(+) T lymphocytes and a decrease in the ratio of CD4(+) to CD8(+). It is suggested that it is essential to examine the defence mechanisms, specifically cell-mediated immunity in a patient showing primary laryngeal aspergillosis.

Pulmonary Mycobacterium avium disease in a young patient with idiopathic CD4+ T lymphocytopenia.

A case of pulmonary Mycobacterium avium (M. avium) disease associated with idiopathic CD4+ T lymphocytopenia is reported. A rapidly growing pulmonary nodule was detected on a chest roentgenogram in a young man. Bronchoscopic examination revealed M. avium infection. Hematological studies showed a low CD4+ cell count in the absence of any identifiable immunodeficiency, including human immunodeficiency virus (HIV) infection. With the combination of chemotherapy and surgery, he had a good clinical outcome. Idiopathic CD4+ T lymphocytopenia should be considered in patients with unexplained opportunistic infection.