HIV Immunogens: Affinity Is Key.

Generation of broadly neutralizing antibodies is a key aim of HIV vaccine design, but the precursor B cells are rare. Abbott et al. (2018) report that high affinity and avidity immunogens are required to promote maturation of low frequency B cells in germinal centers.

Reticuloendothelial activation and phenotypic alteration of peripheral monocytes with enhanced liver recruitment drive liver injury secondary to yellow phosphorus.

BACKGROUND AND AIM: Monocytes and macrophages play a crucial role in the pathogenesis of acute liver failure (ALF). We aimed to study reticuloendothelial activation and its correlation with disease severity in commonly encountered yellow phosphorus (rodenticide)-induced hepatotoxicity patients. We also studied peripheral monocyte phenotype in a subset of patients. METHODS: Reticuloendothelial activation markers were analyzed and correlated with disease severity score in a prospectively collected database of yellow phosphorus-related hepatoxicity patients between 2018 and 2021. In a prospective cohort of these patients and age-matched healthy controls, peripheral blood monocyte phenotyping was performed. RESULTS: Reticuloendothelial activation markers were analyzed in 67 patients [Age: 23(12-64) years; median (range), men: 25, acute liver injury (ALI): 38, ALF: 29, model for end-stage liver disease (MELD) score: 28 (7-40)] of yellow phosphorus-induced hepatotoxicity. Serum ferritin (927; 10.3-34 807 ng/mL), sCD163 (4.59; 0.11-12.7 µg/mL), sCD25 (3050; 5.6-17 300 pg/mL) and plasma von Willebrand factor (423.5, 103-1106 IU/dL) were increased and showed significant correlation with liver disease severity assessed by MELD score (ρ = 0.29, ρ = 0.6, ρ = 0.56 and ρ = 0.46 respectively). Phenotyping and serum immune markers were performed in seven patients (M: 4; age: 27, 15-37 years; median, range; MELD score: 36, 21-40) and compared with eight healthy controls. Increase in classical monocytes and decrease in patrolling and intermediate monocyte subsets were observed in ALF cohort. HLA-DRlow CD163hi (immune exhaustion), CD64hi (immune complex-mediated response), and CCR2hi (liver homing) monocyte phenotype was noted. CONCLUSION: Altered peripheral monocyte phenotype with enhanced liver homing and macrophage activation, suggests important role of innate immune activation, and provides a potential therapeutic target, in yellow phosphorus-induced hepatotoxicity.

Functionally significant metabolic differences between B and T lymphocyte lineages.

Activation of B and T lymphocytes leads to major remodelling of the metabolic landscape of the cells enabling their post-activation functions. However, naive B and T lymphocytes also show metabolic differences, and the genesis, nature and functional significance of these differences are not yet well understood. Here we show that resting B-cells appeared to have lower energy demands than resting T-cells as they consumed lower levels of glucose and fatty acids and produced less ATP. Resting B-cells are more dependent on OXPHOS, while T-cells show more dependence on aerobic glycolysis. However, despite an apparently higher energy demand, T lineage cells showed lower rates of protein synthesis than equivalent B lineage stages. These metabolic differences between the two lineages were established early during lineage differentiation, and were functionally significant. Higher levels of protein synthesis in B-cells were associated with increased synthesis of MHC class II molecules and other proteins associated with antigen internalization, transport and presentation. The combination of higher energy demand and lower protein synthesis in T-cells was consistent with their higher ATP-dependent motility. Our data provide an integrated perspective of the metabolic differences and their functional implications between the B and T lymphocyte lineages.

Altered Peripheral Blood Leucocyte Phenotype and Responses in Healthy Individuals with Homozygous Deletion of FHR1 and FHR3 Genes.

A homozygous 83-kb deletion encompassing the genes for complement factor-H-related proteins 1 and 3 (FHR 1, FHR3) is known as a risk factor for some immune inflammatory disorders. However, the functional relevance of this FHR1/3 deletion is relatively unexplored. Globally, healthy populations of all ethnic groups tested show an 8-10% prevalence of homozygosity for this deletion polymorphism. We have begun to compare the peripheral leucocyte phenotype and functionality between FHR1/3-/- and FHR1/3+/+ healthy adult individuals. We report that the two groups show significant differences in their peripheral blood innate leucocyte subset composition, although the adaptive immune subsets are similar between them. Specifically, FHR1/3-/- individuals show higher frequencies of patrolling monocytes and lower frequencies of classical monocytes than FHR1/3+/+ individuals. Similarly, FHR1/3-/- individuals show higher frequencies of plasmacytoid dendritic cells (pDCs) and lower frequencies of myeloid DCs (mDCs) than FHR1/3+/+ individuals. Notably, classical monocytes specifically showed cell-surface-associated factor H (FH), and cells from the FHR1/3-/- group had somewhat higher surface-associated FH levels than those from FHR1/3+/+ individuals. FHR1/3-/- monocytes also showed elevated secretion of TNF-α, IL-1ß, and IL-10 in response to TLR7/8 or TLR4 ligands. Similarly, FHR1/3-/- mDCs and pDCs showed modest but evident hyper-responsiveness to TLR ligands. Our findings, that the FHR1/3-/- genotype is associated with significant alterations of both the relative prominence and the functioning of monocyte and DC subsets, may be relevant in understanding the mechanism underlying the association of the genotype with immune inflammatory disorders.

Characterization of genetic predisposition and autoantibody profile in atypical haemolytic-uraemic syndrome.

We previously reported that Indian paediatric patients with atypical haemolytic-uraemic syndrome (aHUS) showed high frequencies of anti-complement factor H (FH) autoantibodies that are correlated with homozygous deletion of the genes for FH-related proteins 1 and 3 (FHR1 and FHR3) (FHR1/3-/- ). We now report that Indian paediatric aHUS patients without anti-FH autoantibodies also showed modestly higher frequencies of the FHR1/3-/- genotype. Further, when we characterized epitope specificities and binding avidities of anti-FH autoantibodies in aHUS patients, most anti-FH autoantibodies were directed towards the FH cell-surface anchoring polyanionic binding site-containing C-terminal short conservative regions (SCRs) 17-20 with higher binding avidities than for native FH. FH SCR17-20-binding anti-FH autoantibodies also bound the other cell-surface anchoring polyanionic binding site-containing region FH SCR5-8, at lower binding avidities. Anti-FH autoantibody avidities correlated with antibody titres. These anti-FH autoantibody characteristics did not differ between aHUS patients with or without the FHR1/3-/- genotype. Our data suggest a complex matrix of interactions between FHR1-FHR3 deletion, immunomodulation and anti-FH autoantibodies in the aetiopathogenesis of aHUS.

Peripheral residence of naïve CD4 T cells induces MHC class II-dependent alterations in phenotype and function.

BACKGROUND: As individual naïve CD4 T lymphocytes circulate in the body after emerging from the thymus, they are likely to have individually varying microenvironmental interactions even in the absence of stimulation via specific target recognition. It is not clear if these interactions result in alterations in their activation, survival and effector programming. Naïve CD4 T cells show unimodal distribution for many phenotypic properties, suggesting that the variation is caused by intrinsic stochasticity, although underlying variation due to subsets created by different histories of microenvironmental interactions remains possible. To explore this possibility, we began examining the phenotype and functionality of naïve CD4 T cells differing in a basic unimodally distributed property, the CD4 levels, as well as the causal origin of these differences. RESULTS: We examined separated CD4hi and CD4lo subsets of mouse naïve CD4 cells. CD4lo cells were smaller with higher CD5 levels and lower levels of the dual-specific phosphatase (DUSP)6-suppressing micro-RNA miR181a, and responded poorly with more Th2-skewed outcomes. Human naïve CD4lo and CD4hi cells showed similar differences. Naïve CD4lo and CD4hi subsets of thymic single-positive CD4 T cells did not show differences whereas peripheral naïve CD4lo and CD4hi subsets of T cell receptor (TCR)-transgenic T cells did. Adoptive transfer-mediated parking of naïve CD4 cells in vivo lowered CD4 levels, increased CD5 and reactive oxygen species (ROS) levels and induced hyporesponsiveness in them, dependent, at least in part, on availability of major histocompatibility complex class II (MHCII) molecules. ROS scavenging or DUSP inhibition ameliorated hyporesponsiveness. Naïve CD4 cells from aged mice showed lower CD4 levels and cell sizes, higher CD5 levels, and hyporesponsiveness and Th2-skewing reversed by DUSP inhibition. CONCLUSIONS: Our data show that, underlying a unimodally distributed property, the CD4 level, there are subsets of naïve CD4 cells that vary in the time spent in the periphery receiving MHCII-mediated signals and show resultant alteration of phenotype and functionality via ROS and DUSP activity. Our findings also suggest the feasibility of potential pharmacological interventions for improved CD4 T cell responses during vaccination of older people via either anti-oxidant or DUSP inhibitor small molecules.

Utility of peripheral blood monocyte subsets, circulating immune complexes and serum cytokines in assessment of SLE activity: an observational, cross-sectional study.

INTRODUCTION: SLE disease measurements by current standards are less than perfect. Monocytes and their subsets are part of innate immunity, and one of our objectives was to look at their role in SLE disease activity. We also looked at the common serum cytokines and the role of circulating immune complex (CIC) estimation in the assessment of disease activity. METHODS: We conducted a single-centre observational cross-sectional study of SLE patients with active and inactive disease as the comparison arms. Blood samples were collected for (a) peripheral blood monocyte separation and flowcytometric analysis of monocyte subsets based on CD14 and CD16 surface markers, and (b) ELISA for serum cytokines and CIC estimation. Results were analysed in terms of the difference in medians between the active and inactive disease groups using the Mann-Whitney U test (non-normally distributed data). RESULTS: The absolute monocyte count was lower in the active group than the inactive group (median (IQR) of 329 (228.5) vs. 628 (257)/microliter, p = 0.001). The frequency (%) of the intermediate monocyte subset showed a trend towards an increase in active disease (median (IQR) of 15.10% (9.65) vs. 11.85% (8.00), p = 0.09). It also had a significant positive correlation to the SLEDAI scores (r = 0.33, p = 0.046). The mean fluorescence intensity (MFI) of CD163, expressed primarily by intermediate subsets, was increased, and CD11c MFI was reduced in active disease. Serum TNF-a level was elevated in active disease (median (IQR) of 38 (48.5) pg/ml vs. 9 (48.5) pg/ml, p = 0.042). CIC ELISA at an optimal cut-off of 10 meq/ml provided an area under the curve (AUC) of 0.85 for detecting active SLE. CONCLUSION: Peripheral blood monocytes are depleted in active disease. The intermediate monocyte subset may have a role in disease activity. TNF-alpha correlated modestly with disease activity. CIC estimation by ELISA may be used in addition to or as an alternative to current standards of laboratory tests for the serological assessment of activity.

Study of pathogenic T-helper cell subsets in Asian Indian patients with Takayasu arteritis.

The relapses and refractory disease are a challenge in the management of patients with Takayasu arteritis (TAK). We quantified pathogenic CD4 + memory T helper cells bearing surface markers CD161 and/or p-glycoprotein (MDR1) in patients with TAK. Peripheral blood mononuclear cells of 21 patients with TAK and 16 age-matched controls were stained with anti-CD3, anti-CD4, anti-CD45RA, anti-CD161 and anti-p-glycoprotein antibodies and subjected to flow cytometry by FACS ARIAIII. Eighteen patients underwent follow-up immunophenotyping. Intracellular staining for interleukin-17 and interferon-γ was performed for 18 patients and 11 controls. Surgical arterial biopsies of 6 TAK and 5 non-inflammatory controls were subjected to immunohistochemistry with anti-CD161 and anti-p-glycoprotein. At baseline the frequency of MDR1 + CD4 + and CD161 + MDR1 + CD4 + memory T cells was higher in TAK than controls (p = 0.002 and 0.01, respectively). After stimulation, the frequency of IFN-y + CD161 + cells was higher in TAK than controls (p = 0.028). Modal fluorescence intensity of CD161 + MDR1 + CD45RA - CD4 + cells was higher in active as compared with stable disease (p = 0.041). At 6 months, MDR1 + and CD161 + MDR1 + memory CD4 + T cells decreased significantly only in patients who had complete/partial response to treatment (p = 0.047 and 0.02, respectively). To conclude, MDR1 + and MDR1 + CD161 + CD4 + memory T-helper cells are increased in patients with TAK. These cells decreased only in patients with response to treatment during subsequent follow-up.

Role of apoptosis-inducing factor (Aif) in the T cell lineage.

Multiple checkpoints regulating finely balanced death-versus-survival decisions characterize both thymic development and peripheral homeostasis of T lymphocytes. While exploring the mechanisms of T cell death involved at various stages during the life of a T cell, we have observed and reported a variety of non-redundant roles for apoptosis inducing factor (Aif), a mitochondrial flavoprotein. Aif is ubiquitously expressed in all cell lineages and functions as an NADH oxidase in its mitochondrial location. It is released following the mitochondrial death signals, whereupon it translocates to the nucleus, binds to DNA and causes large-scale DNA fragmentation. During T cell development, Aif is important for developing thymocytes to navigate the double negative (DN)3 to DN4 transition (beta-selection), via its oxidoreductase property which protects the rapidly proliferating cells from death due to reactive oxygen species (ROS). In peripheral mature T cells, Aif deficiency leads to an increased susceptibility of T cell blasts to activation induced cell death (AICD), possibly mediated by its antioxidant function, and decreased sensitivity to neglect-induced death (NID). Thus, Aif seems to have pro-apoptotic and anti-apoptotic roles in the same lineage in different contexts and at different stages. Surprisingly, in the closely related B lymphocyte lineage, Aif deficiency does not result in any abnormality. These findings generate the possibility of specific T cell dysfunction in human disease caused by Aif deficiency, as well as in mitochondriopathies due to other causes. Also, these data raise questions regarding the basis of lineage-specific consequences of the dysfunction/deficiency of apparently ubiquitous molecules.

T cell ageing: effects of age on development, survival & function.

Age associated decline of the immune system continues to be a major health concern. All components of innate and adaptive immunity are adversely affected to lesser or greater extent by ageing resulting in an overall decline of immunocompetence. As a result in the aged population, there is increased susceptibility to infection, poor responses to vaccination, and increased incidence of autoreactivity. There is an increasing focus on the role of T cells during ageing because of their impact on the overall immune responses. A steady decline in the production of fresh naïve T cells, more restricted T cell receptor (TCR) repertoire and weak activation of T cells are some of the effects of ageing. In this review we summarize our present understanding of the effects of ageing on naïve CD4 T cells and potential approaches for therapeutic interventions to restore protective immunity in the aged population.

Usefulness of urinary calprotectin as a novel marker differentiating functional from structural acute kidney injury in the critical care setting.

BACKGROUND: Biomarkers are fundamental tools for differentiating between types of acute kidney injury (AKI) and may thus be crucial in management and prognosis. We report on a recently described biomarker, calprotectin, that appears to be a promising candidate in differentiating hypovolemic/functional AKI from intrinsic/structural AKI, whose acknowledgement may play a role in improving outcomes. We aimed to study the efficacy of urinary calprotectin in differentiating these two forms of AKI. The effect of fluid administration on the subsequent clinical course of AKI, its severity and the outcomes were also studied. METHODOLOGY: Children who presented with conditions predisposing to AKI or with diagnosis of AKI were included. Urine samples for calprotectin analysis were collected and stored at - 20 ºC for analysis at the end of the study. Fluids were administered as per clinical conditions, followed by intravenous furosemide 1 mg/kg, and patients were observed closely for at least 72 h. Children with serum creatinine normalization and clinical improvement were classified as with functional AKI, while those with no response were classified as with structural AKI. Urine calprotectin levels between these two groups were compared. Statistical analysis was performed with SPSS 21.0 software. RESULTS: Of the 56 children enrolled, 26 were classified as with functional AKI and 30 as with structural AKI. Stage 3 AKI was observed in 48.2% of patients and stage 2 AKI in 33.8%. Mean urine output, creatinine and stage of AKI improved with fluid and furosemide or furosemide alone (OR 6.08, 95% CI 1.65-27.23) (p < 0.01). A positive response to fluid challenge was in favor of functional AKI (OR 6.08, 95% CI 1.65-27.23) (p = 0.008). Presence of edema, sepsis and need for dialysis were hallmarks of structural AKI (p < 0.05). Urine calprotectin/creatinine values were 6 times higher in structural AKI compared to functional AKI. Urine calprotectin/creatinine ratio showed the best sensitivity (63.3%) and specificity (80.7%) at a cut-off value of 1 mcg/mL in differentiating the two types of AKI. CONCLUSION: Urinary calprotectin is a promising biomarker that may help differentiating structural from functional AKI in children.

Risk of COVID-19 re-infection and its predictors (CORES): protocol for a community-based longitudinal cohort study in Vellore, India.

INTRODUCTION: The incidence of SARS-CoV-2 re-infection has not been widely evaluated in low-income and middle-income countries. Understanding immune responses elicited by SARS-CoV-2 natural infection and factors that lead to re-infection in a community setting is important for public health policy. We aim to investigate the risk of primary infection and re-infection among those without and with evidence of prior infection as defined by the presence of antibodies to SARS-CoV-2 spike protein. METHODS AND ANALYSIS: A baseline seroprevalence survey will test for SARS-CoV-2 antibodies among healthy adults in Vellore, India. Based on an expected seropositivity rate of 50% in the general population, with annual attack rates of 12%, 6%, 4.8% and 4% among those unvaccinated and seronegative, vaccinated and seronegative, unvaccinated and seropositive, and vaccinated and seropositive, respectively, we will recruit 1200 adults who will be followed up for a total of 24 months. Weekly self-collected saliva samples will be tested by reverse transcription-PCR (RT-PCR) to detect SARS-CoV-2 infections, for a period of 1 year. For any person testing RT-PCR positive, blood samples will be collected within 2 days of RT-PCR positivity and on days 30 and 90 to assess the kinetics and longevity of the antibody responses, B cell memory and T cell memory post-infection. The data will be analysed to estimate seroprevalence at baseline and over time, the risk factors for infection, rates of primary infection and re-infection, and provide a comparison of the rates across groups based on infection and vaccination status. ETHICS AND DISSEMINATION: The study has been approved by the Institutional Review Board (IRB No: 13585) of Christian Medical College and Hospital, Vellore. The results of the study will be made available through journal publications and conference presentations. TRIAL REGISTRATION NUMBER: Central Trial Registry of India: CTRI/2020/11/029438.

Plasma Von Willebrand Factor Levels Predict Survival in COVID-19 Patients Across the Entire Spectrum of Disease Severity.

BACKGROUND: Characterization of reticulo-endothelial activation in COVID-19 may guide treatment. OBJECTIVES: To assess reticulo-endothelial activation and its correlation with disease severity and death in patients across the entire spectrum of COVID-19 severity. METHODS: Consecutive hospitalized COVID-19 patients were studied, with similar number of patients in each disease severity category. Baseline serum ferritin, sCD163 (macrophage activation markers) and plasma von Willebrand factor (VWF) antigen (endothelial activation marker) levels were studied. Clinical parameters and plasma D-dimer levels were also studied. The study parameters were correlated with COVID-19 severity and survival. RESULTS: The 143 patients (104 males [80%], age 54 [42 - 65] years, median [inter-quartile range]) presented 4 (3-7) days after symptom onset. Thirty-four patients had mild disease, 36 had moderate disease, 36 had severe disease and 37 had critical disease at baseline. With increasing COVID-19 severity, ferritin, sCD163, VWF and D-dimer levels significantly increased at baseline, however, 139 patients had normal sCD163 levels. Of the reticulo-endothelial markers, VWF level independently correlated with COVID-19 severity and with survival. VWF level > 332.6 units/dl correlated with COVID-19 severity (odds ratio [OR]: 2.77 [95% confidence interval (C.I): 1.1 - 6.99], p value: 0.031) and in-hospital death (OR [95% CI]: 29.28 [5.2 - 165], p value < 0.001). CONCLUSIONS: Reticulo-endothelial activation markers increased incrementally with worsening COVID-19 severity. Baseline endothelial activation marker (VWF), and not macrophage activation markers, independently correlated with COVID-19 severity and death.

Reticuloendothelial activation correlates with disease severity and predicts mortality in severe alcoholic hepatitis.

BACKGROUND: Overactivation of reticuloendothelial cells lining liver sinusoids - Kupffer cells (macrophages) and sinusoidal endothelial cells - may narrow the sinusoidal lumen, impair perfusion in liver microcirculation and contribute to disease severity in alcoholic hepatitis. AIM: The aim of the article was to assess reticuloendothelial activation in patients with severe alcoholic hepatitis (SAH). METHODS: In SAH patients, we prospectively studied baseline reticuloendothelial activation markers [serum ferritin, sCD163 and plasma von Willebrand factor (VWF) antigen] and Macrophage Activation Syndrome (MAS) criteria, correlated them with disease severity scores [model for end-stage liver disease (MELD) and Sequential Organ Failure Assessment (SOFA) scores] and analyzed their ability to predict survival over a 90-day follow-up period. RESULTS: A total of 50 SAH patients [45 (37-49) years, median (interquartile range), 49 males, discriminant function, 76.2 (54.5-106.6); MELD score, 30 (26.2-36)] were studied. 41 SAH patients (82%) had ferritin >500 ng/mL, and all (100%) had markedly raised sCD163 and VWF levels. The median sCD163 level was 10-fold higher than healthy controls and the median VWF level was 5-fold above the upper limit of normal. In total, 37 SAH patients (74%) met MAS criteria. Reticuloendothelial activation markers correlated with MELD and SOFA scores (P < 0.05). VWF was an independent marker to predict mortality in SAH [adjusted hazard ratio, 1.002 (1.000-1.004)]. CONCLUSIONS: The reticuloendothelial system was markedly activated and correlated with disease severity scores in SAH patients.VWF predicted short-term mortality independent of MELD and sCD163. Further larger multicentric studies are needed to validate these findings.

Juvenile myelomonocytic leukemia presenting with coexistent cytomegalovirus infection--a case report.

SUMMARY: We report a case of juvenile myelomonocytic leukemia (JMML) with coexistent cytomegalovirus (CMV) infection in a 10-month-old child that caused initial diagnostic dilemma. The patient presented with fever, anemia, lymphadenopathy, and hepatosplenomegaly. The peripheral blood smear and bone marrow aspirate examination showed monocytosis, leukoerythroblastosis, myeloid hyperplasia, and increased blasts. Serologic test for CMV was positive and thus the hematologic picture was attributed to CMV infection and gancyclovir was started. The patient, however, did not improve clinically. A repeat peripheral smear and marrow showed persistence of the above picture and a diagnosis of JMML was made. Viral infections in young children may present with hematologic features overlapping with JMML and simultaneous occurrence of both may cause diagnostic dilemma.

Characterization of biological variation of peripheral blood immune cytome in an Indian cohort.

Immune parameters show characteristic normal baseline levels and variance in the population. We characterised the degree of inter-individual and within-individual variation over one-year time period in 33 immune cell subsets by flow cytometry in peripheral blood mononuclear cells from 43 healthy young adult volunteers. Our analysis revealed that immune subsets that showed low variability between individuals also showed low short-term fluctuations within-individuals, as well as concordance in siblings. However, when baseline levels and degree of fluctuation were considered together, individuals failed to cluster into discreet groups. Together, the data reveal complex inter-relationships between immune subsets in individuals, and provide insights into the observed heterogeneity between individuals and between multiple immune subsets.

Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus.

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.

Cell-intrinsic regulation of peripheral memory-phenotype T cell frequencies.

Memory T and B lymphocyte numbers are thought to be regulated by recent and cumulative microbial exposures. We report here that memory-phenotype lymphocyte frequencies in B, CD4 and CD8 T-cells in 3-monthly serial bleeds from healthy young adult humans were relatively stable over a 1-year period, while Plasmablast frequencies were not, suggesting that recent environmental exposures affected steady state levels of recently activated but not of memory lymphocyte subsets. Frequencies of memory B and CD4 T cells were not correlated, suggesting that variation in them was unlikely to be determined by cumulative antigenic exposures. Immunophenotyping of adult siblings showed high concordance in memory, but not of recently activated lymphocyte subsets. To explore the possibility of cell-intrinsic regulation of T cell memory, we screened effector memory-phenotype T cell (TEM) frequencies in common independent inbred mice strains. Using two pairs from these strains that differed predominantly in either CD4 TEM and/or CD8 TEM frequencies, we constructed bi-parental bone marrow chimeras in F1 recipient mice, and found that memory T cell frequencies in recipient mice were determined by donor genotypes. Together, these data suggest cell-autonomous determination of memory T niche size, and suggest mechanisms maintaining immune variability.

Comparison of Human Neonatal and Adult Blood Leukocyte Subset Composition Phenotypes.

The human peripheral leukocyte subset composition depends on genotype variation and pre-natal and post-natal environmental influence diversity. We quantified this composition in adults and neonates, and compared the median values and dispersal ranges of various subsets in them. We confirmed higher frequencies of monocytes and regulatory T cells (Tregs), similar frequencies of neutrophils, and lower frequencies of CD8 T cells, NKT cells, B1 B cells and gamma-delta T cells in neonatal umbilical cord blood. Unlike previous reports, we found higher frequencies of eosinophils and B cells, higher CD4:CD8 ratios, lower frequencies of T cells and iNKT cells, and similar frequencies of CD4 T cells and NK cells in neonates. We characterized monocyte subsets and dendritic cell (DC) subsets in far greater detail than previously reported, using recently described surface markers and gating strategies and observed that neonates had lower frequencies of patrolling monocytes and lower myeloid dendritic cell (mDC):plasmacytoid DC (pDC) ratios. Our data contribute to South Asian reference values for these parameters. We found that dispersal ranges differ between different leukocyte subsets, suggesting differential determination of variation. Further, some subsets were more dispersed in adults than in neonates suggesting influences of postnatal sources of variation, while some show the opposite pattern suggesting influences of developmental process variation. Together, these data and analyses provide interesting biological possibilities for future exploration.

Potter syndrome with an unusual cardiac anomaly.

Potter syndrome is a congenital anomaly characterised by bilateral renal agenesis, pulmonary hypoplasia, cardiac, skeletal abnormalities and maternal oligohydramnios. Here we report a case of Potter syndrome with bilateral renal agenesis, pulmonary hypoplasia and complete transposition of the great vessels, which had been identified during a post-mortem examination. Although cardiac anomalies are known to exist with Potter syndrome, complete transposition of the great vessels has not been reported in the literature.