Fc Receptor-Like Proteins in Pathophysiology of B-cell Disorder.

Members of the family of Fc receptor-like (FcRL) proteins, homologous to FcγRI, have been identified by multiple research groups. Consequently, they have been described using multiple nomenclatures including Fc receptor homologs (FcRH), immunoglobulin superfamily receptor translocation-associated genes (IRTA), immunoglobulin-Fc-gp42-related genes (IFGP), Src homology 2 domain-containing phosphatase anchor proteins (SPAP), and B cell cross-linked by anti-immunoglobulin M-activating sequences (BXMAS). They are now referred to under a unified nomenclature as FCRL. Eight different human FCRL genes have been identified, all of which appear to be related to the genes of the immunoglobulin superfamily (IgSF) of cellular adhesion molecules. These type 1 transmembrane glycoproteins are composed of different combinations of 5 types of immunoglobulin-like domains, with each protein consisting of 3 to 9 domains, and no individual domain type conserved throughout all of the FCRL proteins. Ligands for the majority of the FCRLs remain unknown. In general, FCRL expression is restricted to lymphocytes and is primarily expressed in B-lymphocytes, supporting FCRL's involvement in a variety of immune disorders. Most FCRLs functionally repress B-cell activation; however, they might have dual roles in lymphocyte functions as these proteins often possess immunoreceptor tyrosine activation (ITAM) and inhibitory (ITIM) motif elements. The biological functions of these newly recognized FCRL proteins are just beginning to emerge, and might provide the insight necessary for understanding pathophysiology of lymphocyte disorders and treating different immune diseases.

Human papillomavirus status and gene expression profiles of oropharyngeal and oral cancers from European American and African American patients.

BACKGROUND: Disparities in prevalence, human papillomavirus (HPV) status, and mortality rates for head and neck cancer have been described between African American and European American patients. METHODS: We studied the HPV status and gene expression profiles in 56 oropharyngeal/oral cavity tumors and 9 normal tissue samples from European American and African American patients treated in South Carolina between 2010 and 2012. RESULTS: Overall, 59% of tumors were HPV DNA-positive, but only 48% of those expressed E7 mRNA (HPV-active). The prevalence of HPV-active tumors was 10% in African American patients and 39% in European American patients. Tumors positive for HPV DNA but negative for HPV mRNA exhibited gene expression profiles distinct from those of both HPV-active and HPV-negative cancers, suggesting that HPV DNA-positive/RNA-negative tumors may constitute a unique group. CONCLUSION: This study provides a direct assessment of differential expression patterns in HPV-related oropharyngeal cancer arising from African American and European American patients, for which there is a paucity of data. © 2015 Wiley Periodicals, Inc. Head Neck 00: 000-000, 2015.

Predicting HPV status in head and neck cancer: the predictive value of sociodemographic and disease characteristics.

OBJECTIVE: To determine whether the human papillomavirus (HPV) status of head and neck squamous cell carcinomas (HNSCCs) can be reliably predicted based on sociodemographic and disease characteristics alone. DESIGN A retrospective medical chart review of clinical and pathologic features. SETTING: Tertiary academic medical center. PATIENTS: We studied patients treated for HNSCC who were tested for markers of HPV or had tissue available for testing between 2006 and 2010. MAIN OUTCOME MEASURES: Four otolaryngology-head and neck surgery trainees were given the database of patient clinical and pathologic features and asked to predict the HPV status for each patient. The trainees' responses were scored for accuracy, positive and negative predictive value, and interrater agreement. Multiple linear regression analyses were performed to determine predictors of HPV positivity. RESULTS: A total of 174 patients meeting inclusion criteria were identified, 95 of whom were determined to have HPV-positive tumor tissue. Residents were able to accurately predict HPV status in 110 to 125 patients (63%-72%), with positive predictive values of 76% to 84% and negative predictive values of 61% to 69%. The only variables significantly related to HPV status were male sex (P = .01) and oropharyngeal subsite (P = .02). Only 4 patients had a "typical" HPV-positive profile. CONCLUSIONS: Knowledge of cancer stage, primary site, basaloid features, tumor differentiation, and presence of cystic neck disease and patient age, race, and smoking status did not allow accurate predictions of HPV status in many patients. Clinical testing of tumor tissue remains essential for a diagnosis of HPV-positive disease.

Human papillomavirus and oropharyngeal cancer: what you need to know in 2009.

OPINION STATEMENT: Oropharyngeal cancer has demonstrated a steady increase in incidence over the past 20 years in contrast to declining numbers of head and neck squamous cell carcinoma (HNSCC) overall. Recent evidence has found that high-risk strains of human papillomavirus (HPV) are the likely cause of the changing epidemiology of oropharyngeal cancer. HPV-associated oropharyngeal cancer has a molecular, epidemiological, and clinical profile that is distinct from non-HPV HNSCC. Clinicians managing oropharyngeal HNSCC need to be aware of differences in the HPV HNSCC population which may impact treatment outcomes. Testing of HNSCC tumor tissue for HPV using validated and precise techniques should be performed when feasible.

EBV LMP-2A employs a novel mechanism to transactivate the HERV-K18 superantigen through its ITAM.

EBV encodes latent membrane protein (LMP)-2A that functions as a homologue of the activated BCR. We have previously shown that LMP-2A transactivates a human endogenous retrovirus, HERV-K18, in infected B-lymphocytes. The Env protein of HERV-K18 encodes a superantigen that strongly stimulates a large number of T cells. To delineate the mechanism through which LMP-2A transactivates HERV-K18 env, we tested a panel of tyrosine mutants of LMP-2A in a murine B lymphoma that stably harbors HERV-K18. Our analysis revealed that the immunoreceptor tyrosine-based activation motif (ITAM) of LMP-2A is important for HERV-K18 env transactivation. ITAM contains 2 tyrosines that initiate signaling cascades when both residues are phosphorylated. However, in our study, single-tyrosine mutants of ITAM still retained full induction of HERV-K18 env. After truncating 25 kb of genomic sequence downstream of HERV-K18, LMP-2A failed to transactivate HERV-K18 env. Thus, an LMP-2A-inducible element is located downstream of HERV-K18.

Human papillomavirus and head and neck cancer: a growing concern.

Head and neck cancer is increasing in incidence in patients without the usual risk factors for the disease. Practitioners need to be aware that young, non-smoking patients are also at risk for certain types of head and neck cancer. Head and neck cancer in this patient group is likely due to infection of the tonsil and tongue with high-risk strains of human papillomavirus (HPV). There is strong epidemiological and laboratory evidence that HPV is a cause of head and neck cancer. Therefore, any patient with persistent lesions, ulcers, swallowing difficulty, change in voice, or neck mass needs prompt referral to an otolaryngologist- head and neck surgeon.

Murine Vbeta3+ and Vbeta7+ T cell subsets are specific targets for the HERV-K18 Env superantigen.

Superantigens are a class of proteins that are derived from microorganisms and have the unique characteristic of stimulating T cells in a TCR Vbeta-specific manner, causing massive T cell proliferation and immune deregulation. For this reason, superantigens have been implicated in the development of multiple diseases. We have previously identified and cloned an EBV-associated superantigen, human endogenous retrovirus (HERV)-K18 envelope protein (Env). This superantigen is transactivated upon IFN-alpha treatment and EBV infection and stimulates human Vbeta13+ T cells. Due to the limited scope of work that can be conducted with human samples and the complexity of HERVs in general, we set out to study the physiological effects of HERV-K18 Env in a murine model. In this report, we demonstrate the superantigen activity of HERV-K18 Env in mice and describe the generation of HERV-K18 transgenics, using a bacterial artificial chromosome as transgenes that allow the faithful reproduction of the expression pattern of this human provirus. From our in vitro and in vivo results we conclude that HERV-K18 Env stimulates Vbeta3+ and Vbeta7+ T cells in mice. The definition of the murine Vbeta specificity and the establishment of a transgenic model will permit the investigation of the role of this superantigen in the life cycle of EBV and its implicated diseases.

Expression of human endogenous retrovirus HERV-K18 superantigen is elevated in juvenile rheumatoid arthritis.

OBJECTIVE: To investigate the presence of a host-encoded superantigen as possible etiologic factor in pediatric rheumatic disease. We measured the expression and the ability of interferon-alpha (IFN-alpha) to induce the human endogenous retrovirus HERV-K18 superantigen in juvenile rheumatoid arthritis (JRA) and pediatric systemic lupus erythematosus (SLE). METHODS: Expression levels of HERV-K18 were measured in peripheral blood or synovial fluid mononuclear cells (SFMC) from 13 patients with JRA, 11 pediatric SLE patients, and 24 healthy controls, by semiquantitative reverse transcription-polymerase chain reaction, comparing 18S ribosomal transcripts as endogenous standard. IFN-alpha induction was tested by pretreatment of samples with 2000 U/ml. RESULTS: HERV-K18 expression was significantly elevated in peripheral blood from patients with JRA (mean ratio of HERV-K18 to 18S ribosomal transcripts 2.456, SD 2.122; p = 0.014), but not patients with SLE (mean 0.997, SD 0.579; p = 0.258), compared to controls (mean 0.749, SD 0.598). HERV-K18 transcripts were detected in SFMC of 7/7 JRA patients. IFN-alpha induced HERV-K18 strongly in JRA (mean fold induction = 8.934, SD 15.556) and controls (mean 8.270, SD 6.609), but weakly in SLE (mean 2.432, SD 2.219; p = 0.009). HERV-K18 levels were found to be independent of previously determined modifiers of expression, including Epstein-Barr virus infection, IFN-alpha levels, or the percentage of B cells in peripheral blood. CONCLUSION: HERV-K18 superantigen levels were elevated in JRA patients, but not pediatric patients with SLE, suggesting a possible mechanism for autoimmunity in the former group by superantigen stimulation of autoreactive T cells.

Epstein-Barr virus latent membrane protein LMP-2A is sufficient for transactivation of the human endogenous retrovirus HERV-K18 superantigen.

Superantigens are microbial proteins that strongly stimulate T cells. We described previously that the Epstein-Barr virus (EBV) transactivates a superantigen encoded by the human endogenous retrovirus, HERV-K18. We now report that the transactivation is dependent upon the EBV latent cycle proteins. Moreover, LMP-2A is sufficient for induction of HERV-K18 superantigen activity.