The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants.

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αß T cell counts at birth persisted over time, with normal memory αß and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αß T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αß T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αß T cells, autoimmune conditions were more frequent in these patients compared with the general population.

Vaccination with prefusion-stabilized respiratory syncytial virus fusion protein induces genetically and antigenically diverse antibody responses.

An effective vaccine for respiratory syncytial virus (RSV) is an unrealized public health goal. A single dose of the prefusion-stabilized fusion (F) glycoprotein subunit vaccine (DS-Cav1) substantially increases serum-neutralizing activity in healthy adults. We sought to determine whether DS-Cav1 vaccination induces a repertoire mirroring the pre-existing diversity from natural infection or whether antibody lineages targeting specific epitopes predominate. We evaluated RSV F-specific B cell responses before and after vaccination in six participants using complementary B cell sequencing methodologies and identified 555 clonal lineages. DS-Cav1-induced lineages recognized the prefusion conformation of F (pre-F) and were genetically diverse. Expressed antibodies recognized all six antigenic sites on the pre-F trimer. We identified 34 public clonotypes, and structural analysis of two antibodies from a predominant clonotype revealed a common mode of recognition. Thus, vaccination with DS-Cav1 generates a diverse polyclonal response targeting the antigenic sites on pre-F, supporting the development and advanced testing of pre-F-based vaccines against RSV.

The Identity of Human Tissue-Emigrant CD8+ T Cells.

Lymphocyte migration is essential for adaptive immune surveillance. However, our current understanding of this process is rudimentary, because most human studies have been restricted to immunological analyses of blood and various tissues. To address this knowledge gap, we used an integrated approach to characterize tissue-emigrant lineages in thoracic duct lymph (TDL). The most prevalent immune cells in human and non-human primate efferent lymph were T cells. Cytolytic CD8+ T cell subsets with effector-like epigenetic and transcriptional signatures were clonotypically skewed and selectively confined to the intravascular circulation, whereas non-cytolytic CD8+ T cell subsets with stem-like epigenetic and transcriptional signatures predominated in tissues and TDL. Moreover, these anatomically distinct gene expression profiles were recapitulated within individual clonotypes, suggesting parallel differentiation programs independent of the expressed antigen receptor. Our collective dataset provides an atlas of the migratory immune system and defines the nature of tissue-emigrant CD8+ T cells that recirculate via TDL.

Three monthly doses of 60 mg/kg praziquantel for Schistosoma haematobium infection is a safe and effective treatment regimen.

BACKGROUND: Praziquantel (PZQ) is the standard treatment for Schistosomiasis in sub-Saharan Africa. However, there is evidence suggesting praziquantel treatment failure in Schistosome infections with associated potential renal impairment. The objective of this study was to determine the effect of three monthly doses of 60 mg/kg/day PZQ on schistosome egg count, liver and renal function during the treatment of urinary schistosomiasis in Ghana. METHODS: A nested case-control study was designed from a cohort screened for schistosomiasis; 28 schistosomiasis positive cases by microscopy matched with 53 healthy controls by age and gender. The study population was urban dwellers from the Asokwa sub-metropolitan area, Kumasi in Ghana. Participants were within the age range of 6 to 30 years. We assessed Schistosoma haematobium egg counts in urine and its associated impact on liver and renal function at baseline, treatment and post-treatment phases using serum. RESULTS: Of the 28 cases and 53 controls, 78.6% and 81.1% were males respectively. Globulin levels before treatment was higher in cases [36.7 (32.8, 40.1) vrs 30.5 (22.4, 33.8), p = 0.005] at pre-treatment but not at post-treatment [35.8 (31.2, 39.1) vrs 37.4 (29.7, 43.0), p = 0.767]. Estimated cure rate was 42.9, 46.4 and 96.4% after first, second and third dose respectively. Schistosome egg counts dropped significantly (p = 0.001) from before second dose to post-treatment. Similarly, levels of alanine aminotransferase (p = 0.001), aspartate aminotransferase (p = 0.028) and gamma glutamyl transferase (p = 0.001) significantly declined towards post-treatment. Estimated glomerular filtration rate significantly improved from before second dose to post-treatment using both the Chronic Kidney Disease Epidemiology Program (p = 0.001) and 4-variable Modification of Diet in Renal Disease (p = 0.002) equations. CONCLUSION: Treatment of urinary Schistosoma hematobium infections with a repeated high monthly dose of 60 mg/kg of praziquantel for 3 months is safe and effective.

Genotypic characterisation of human papillomavirus infections among persons living with HIV infection; a case-control study in Kumasi, Ghana.

OBJECTIVES: The objective of this study is to describe the burden of human papillomavirus (HPV) infection among women living with HIV and non-infected women in Ghana. METHODS: A case-control study was conducted involving 107 women living with HIV aged between 18 and 59 years (cases) and 100 non-HIV-infected apparently healthy women (controls) who were recruited from the Kumasi South Hospital, from July to December, 2014. Cervicovaginal swabs were taken from study participants to characterise 28 high- and low-risk HPV genotypes using a multiplex real-time PCR. RESULTS: The overall mean age for the participants was 40.10 ± 9.76 years. The prevalence of high-risk (hr)-HPV genotypes was significantly higher among the cases than the controls (77.4% vs. 41.6%, P < 0.0001). Overall, HPV 58 and 54 were the most predominant high-risk (18.8%) and low-risk (15.0%) genotypes detected. The two most common hr-HPV genotype isolates were 58 (18.8%) and 35 (15.9%) with 58 being the most prevalent among age group 35-44 years compared with hr-HPV 16, 18, 35 and 45, found predominantly among 18-34 age group. CONCLUSIONS: Significant variations exist in HPV genotypes among HIV-infected and uninfected women.

Variations in levels of IL-6 and TNF-α in type 2 diabetes mellitus between rural and urban Ashanti Region of Ghana.

BACKGROUND: A surge in pro-inflammatory markers, Il-6 and TNF-α, has been associated with type 2 diabetes mellitus (T2DM). However, there is no data on the dynamics of these markers in T2DM Ghanaian populations. The aim of this study was to determine variations in the levels of IL-6 and TNF-α in T2DM patients. This study also examined the associations of IL-6 and TNF-α with anthropometric measurement and the effect of co-morbidity with hypertension using rural and urban dwellers in the Ashanti region, Ghana. METHODS: A nested case-control design using participants aged 25-70 years consisting of 77 T2DM ± hypertension patients and 112 controls were selected from a larger study on Research on Obesity and Diabetes among African Migrants (RODAM). Anthropometric measurements, blood pressure and body fat percentage were measured. Fasting blood samples were analyzed for glucose, IL-6 and TNF-α levels. RESULTS: The median level of IL-6 was significantly higher (p < 0.0001) among rural dwellers compared to urban dwellers. Inversely, urban dwellers had significantly higher (p = 0.0424) median level of TNF-α compared to rural cases. No significant differences were observed in IL-6 (p = 0.3571) and TNF-α (p = 0.2581) among T2DM patients compared with T2DM ± hypertension patients. A weak negative correlation was found between IL-6 and BMI in urban T2DM. DISCUSSION: The average level of IL-6 was higher in rural T2DM participants compared with those in urban setting. However, higher levels of TNF-α was observed among the study participants with T2DM in urban settings compared to those of rural. In this study, we observed that co-morbidity of hypertension had no significant effect on the levels of IL-6 and TNF-α. We are of the opinion that higher physical activity levels among rural particpants and high obesity levels in urabn participants explain the observation but needs more numbers to validate. CONCLUSION: This study revealed that IL-6 levels were higher among rural dwellers than urban while TNF-α levels were higher in urban dwellers than rural in patients with T2DM. There was no association of body fat percentage and body mass index with IL-6 and TNF-α levels. Co-morbidity of hypertension with T2DM had no effect on IL-6 and TNF-α levels.

Discovery and verification of amyotrophic lateral sclerosis biomarkers by proteomics.

Recent studies using mass spectrometry have discovered candidate biomarkers for amyotrophic lateral sclerosis (ALS). However, those studies utilized small numbers of ALS and control subjects. Additional studies using larger subject cohorts are required to verify these candidate biomarkers. Cerebrospinal fluid (CSF) samples from 100 patients with ALS, 100 disease control, and 41 healthy control subjects were examined by mass spectrometry. Sixty-one mass spectral peaks exhibited altered levels between ALS and controls. Mass peaks for cystatin C and transthyretin were reduced in ALS, whereas mass peaks for posttranslational modified transthyretin and C-reactive protein (CRP) were increased. CRP levels were 5.84 +/- 1.01 ng/ml for controls and 11.24 +/- 1.52 ng/ml for ALS subjects, as determined by enzyme-linked immunoassay. This study verified prior mass spectrometry results for cystatin C and transthyretin in ALS. CRP levels were increased in the CSF of ALS patients, and cystatin C level correlated with survival in patients with limb-onset disease. Our biomarker panel predicted ALS with an overall accuracy of 82%.