Linking Susceptibility to Infectious Diseases to Immune System Abnormalities among HIV-Exposed Uninfected Infants.

HIV-exposed uninfected (HEU) infants experience increased overall mortality from infectious causes when compared to HIV-unexposed uninfected (HU) infants. This is the case in both the resource-rich and resource-limited settings. Here, we explore the concept that specific types of infectious diseases that are more common among HEU infants could provide clues as to the potential underlying immunological abnormalities. The most commonly reported infections in HEU vs. HU infants are caused by encapsulated bacteria, suggesting the existence of a less effective humoral (antibody, complement) immune response. Decreased transplacental transfer of protective maternal antibodies has consistently been observed among HEU newborns, suggesting that this may indeed be one of the key drivers of their susceptibility to infections with encapsulated bacteria. Reassuringly, HEU humoral response to vaccination appears to be well conserved. While there appears to be an increase in overall incidence of acute viral infections, no specific pattern of acute viral infections has emerged; and although there is evidence of increased chronic viral infection from perinatal transmission of hepatitis C and cytomegalovirus, no data exist to suggest an increase in adverse outcomes. Thus, no firm conclusions about antiviral effector mechanisms can be drawn. However, the most unusual of reported infections among the HEU have been opportunistic infections, suggesting the possibility of underlying defects in CD4 helper T cells and overall immune regulatory function. This may relate to the observation that the immunological profile of HEUs indicates a more activated T cell profile as well as a more inflammatory innate immune response. However, both of these observations appear transient, marked in early infancy, but no longer evident later in life. The causes of these early-life changes in immune profiles are likely multifactorial and may be related to in utero exposure to HIV, but also to increased environmental exposure to pathogens from sicker household contacts, in utero and postnatal antiretroviral drug exposure, and, in certain circumstances, differences in mode of feeding. The relative importance of each of these factors will be important to delineate in an attempt to identify those HEU at highest risk of adverse outcomes for targeted interventions.

Mixed epithelial-stromal tumor (MEST) of seminal vesicle: a proposal for unified nomenclature.

In contrast to the common tumors of the prostate, seminal vesicle demonstrates low potential for neoplastic proliferation. Of the rare primary seminal vesicle tumors, adenocarcinoma is the most common, but there are also rare seminal vesicle neoplasms which demonstrate epithelial and stromal components. These neoplasms have been described in the literature under various names, including "epithelial-stromal tumor," "cystic epithelial-stromal tumor," "cystadenoma," "cystomyoma," "mesenchymoma," "Müllerian adenosarcoma-like tumor," "phyllodes tumor," and "cystosarcoma phyllodes." The spectrum of reported mixed epithelial-stromal tumors (MEST) of seminal vesicle encompasses low, intermediate and high-grade tumors, but the precise distinction and nomenclature for these tumors remain unsettled. We propose a common nomenclature for these tumors, based on the review of published cases and 2 index cases from our practice, which represent the low-grade category. The first patient was 46 years old and presented with seminal vesicle neoplasm detected on routine rectal examination. The neoplasm measured 4 cm in greatest dimension, and completely replaced the left seminal vesicle. The tumor was circumscribed and consisted of multiple cysts separated by spindle-cell stroma. The second patient was a 60-year-old man, who had an incidental seminal vesicle neoplasm, which was discovered when he underwent a radical prostatectomy for a prostatic adenocarcinoma, (Gleason score 3+4, stage 3a). Both neoplasms contained hypercellular stroma, which was composed of uniform spindle cells, arranged in fascicles and interspersed between the glands. Both tumors lacked worrisome morphology, such as infiltrative borders, cell atypia, increased mitotic activity, hemorrhage, and necrosis. The stromal cells were reactive for estrogen and progesterone receptors, and desmin. The cysts and dilated glands were lined by epithelial cells, which were positive for cytokeratin 7 and were negative for prostate-specific antigen and prostate-specific acid phosphatase. The first patient underwent prostatectomy and was alive and without evidence of disease recurrence or progression after 11 years of follow-up. Similarly, the second patient had no evidence of disease recurrence or progression after 8 months of follow-up. We propose that term seminal vesicle "mixed epithelial-stromal tumor" be used to designate the tumors of the seminal vesicle containing epithelial and stromal components, with a distinction of grade based on the histologic features and the biological behavior. Histologic features to be evaluated for grade separation include stromal atypia, mitotic activity, nuclear pleomorphism, and tumor necrosis. Designations "low-grade MEST," "intermediate-grade MEST (uncertain malignant potential)," and "high-grade MEST" of seminal vesicle can be applied to these tumors to better characterize and study them in the future.

Altered innate immune development in HIV-exposed uninfected infants.

BACKGROUND: Early in life, HIV-exposed uninfected (HEU) infants are at an increased risk of morbidity and mortality from infectious disease compared with HIV-unexposed (UE) infants. To improve our understanding of the mechanisms underlying their increased risk, we contrasted innate immune development between HEU and UE infants in a developing world setting, where early life infectious disease risk is exceptionally high. METHODS: A prospective longitudinal cohort of HEU and UE newborns was established, and the most detailed characterization to date of HEU infant immune development was performed. Single-cell cytokine production was analyzed by flow cytometry after stimulation of whole blood with pathogen-associated molecular patterns (PAMPs). RESULTS: Monocyte, classical dendritic cell, and plasmacytoid dendritic cell composition was similar between HEU and UE infants throughout the first year of life. However, HEU mononuclear cells mounted an enhanced pro-inflammatory response to PAMP stimulation, both in quantity of cytokine produced per cell and in proportion of responder cells. Significant differences in cytokine production were detected on the single-cell level in a PAMP-specific pattern, but only at 2 and 6 weeks of age; all differences normalized by 12 months of age. CONCLUSIONS: This time course of innate immune deviation early in life corresponds to the clinical window of vulnerability to infections in HEU infants and may be at least partially responsible for their increased morbidity and mortality from infectious disease.

Long-term clinical outcome of inverted urothelial papilloma including cases with focal papillary pattern: is continuous surveillance necessary?

OBJECTIVE: To investigate the necessity for continuous cystoscopic surveillance of inverted papilloma (IP), including tumors exhibiting mixed morphology (IP with focal papillary architecture). METHODS: We retrieved all cases of de novo ("primary") IP, diagnosed in our institution during 10 years (from January 2000 to December 2009), from the information database. Patients with a history of urothelial carcinoma or concurrent urothelial carcinoma were excluded. Surveillance was performed by routine cystoscopy, and follow-up was obtained from our institutional and regional clinical and pathology databases. RESULTS: We identified 35 patients with IP, including 3 with focal papillary architecture. Mean patient age was 60 years (range, 26-88) with male-to-female ratio of 1.9:1. Most common tumor location was urinary bladder (86%), followed by urethra (14%). Focal papillary architecture was identified in 3 patients (aged 51, 52, and 78 years). Mean follow-up was 66 months (median 68; range, 11-132). Only 1 male patient (age 81) had a subsequent diagnosis of IP on follow-up cystoscopy at 9 months; no recurrence or progression was documented in the other patients diagnosed with IP. CONCLUSION: The absence of progression of IP on long-term follow-up in this study strongly argues against the need of continuous surveillance for patients in whom (1) strict diagnostic criteria are followed, (2) a complete resection can be ascertained, and (3) no previous or concurrent urothelial malignancies are documented. In this study, the 3 patients with IP showing focal papillary architecture had a benign course, similar to the previously documented cases.

Antibody responses to vaccination among South African HIV-exposed and unexposed uninfected infants during the first 2 years of life.

HIV-exposed but uninfected (HEU) infants born to HIV-infected mothers from areas in the world with a high burden of infectious disease suffer higher infectious morbidity and mortality than their HIV unexposed uninfected (HUU) peers. Vaccination provides protection from infection. The possibility exists that altered response to vaccination contributes to the higher rate of infection in HEU than in HUU infants. While short-term, cross-sectional studies support this notion, it is unclear whether or not HEU infants develop long-term protective immune responses following the WHO extended program on immunization (EPI). Vaccine-specific antibody responses were compared between HEU and HUU infants from 2 weeks until 2 years of age in a longitudinal South African cohort. Total IgG and antibodies specific for Bordetella pertussis, Haemophilus influenzae type b (Hib), tetanus toxoid, hepatitis B virus (HepB), and measles virus were measured at multiple time points throughout the first 2 years of life. Prevaccine antibodies (maternal antibodies passively acquired) specific for tetanus were lower in HEU than in HUU infants, while prevaccine antibodies to HepB were higher in HEU than in HUU infants. Both groups responded similarly to tetanus, Hib, and HepB vaccination. HEU demonstrated stronger pertussis vaccine responses, developing protective titers 1 year earlier than HUU patients, and maintained higher anti-tetanus titers at 24 months of age. Vaccine-induced antibodies to measles virus were similar in both groups at all time points. Our results suggest that the current EPI vaccination program as practiced in South Africa leads to the development of vaccine-specific antibody responses that are equivalent in HEU and HUU infants. However, our data also suggest that a large fraction of both HEU and HUU South African infants have antibody titers for several infectious threats that remain below the level of protection for much of their first 2 years of life.

Ontogeny of Toll-like receptor mediated cytokine responses of South African infants throughout the first year of life.

The first year of life represents a time of marked susceptibility to infections; this is particularly true for regions in sub-Saharan Africa. As innate immunity directs the adaptive immune response, the observed increased risk for infection as well as a suboptimal response to vaccination in early life may be due to less effective innate immune function. In this study, we followed a longitudinal cohort of infants born and raised in South Africa over the first year of life, employing the most comprehensive analysis of innate immune response to stimulation published to date. Our findings reveal rapid changes in innate immune development over the first year of life. This is the first report depicting dramatic differences in innate immune ontogeny between different populations in the world, with important implications for global vaccination strategies.

A single immunization near birth elicits immediate and lifelong protective immunity.

Most existing vaccines do not induce protective immunity immediately following birth, nor do they retain protective efficacy in the latter years of life without booster doses. Using a mouse model, we present evidence that a live-replicating vaccine administered only once shortly after birth was able to induce both immediate and lifelong protection. Newborn mice immunized with a safe, highly attenuated strain of Listeria monocytogenes (Lm) were already protected by day 7 post-vaccination when challenged with a virulent strain of Lm. Furthermore, all mice remained fully protected for 2 years after only a single immunization. Vaccine-specific T cell immune responses were still detectable 2 years later, indicating long-lived immune memory even in neonatal vaccine recipients. Analysis of memory precursor subsets, specific for antigens homologous to Lm or a model vaccine (Ova), demonstrated remarkable similarity between adult and neonatal vaccine recipient effector and central memory CD8 T cell development. The magnitude of expansion of antigen specific memory T cells post-infectious challenge correlated with protection in both groups. This is the first direct evidence that vaccination--even in the absence of a booster dose--is capable of inducing immediate and lifelong protective immune memory regardless of age at the time of initial vaccination.

Neonatal immunization with Listeria monocytogenes induces T cells with an adult-like avidity, sensitivity, and TCR-Vbeta repertoire, and does not adversely impact the response to boosting.

Listeria monocytogenes (Lm) holds promise as a neonatal vaccine vehicle. Here we show that Lm immunized neonatal mice reached maximal Ag-specific CD8(+) T cell expansion after only a single immunization, while adults required two doses. Ag-specific CD4(+) T cell expansion in both age groups required a boost to reach its peak. Neither functional avidity, sensitivity, nor the TCR-Vbeta repertoire of the Ag-specific T cells differed between mice immunized as neonates or adults. Lastly, neonatal immunization did not decrease protection or preclude a booster response. Overall, our data provide further evidence in support of immunization at birth as a feasible public health strategy to combat early life infections.