Meanwhile, between July 2009

and March 2010, only 6 (8%) of 75 viruses isolated in Nagasaki, in the southern part of Japan, possessed both S203T and A197T (12). Through surveillance in several click here areas in Japan between May 2009 and January 2010, Morlighem et al. also demonstrated that less than 20% (47 or 48/253 isolates) had both these substitutions (13). BLAST analysis showed that, out of the 563 A(H1N1)pdm09 with S203T isolated by May 2010, only 123 (22%) had both the S203T and A197T substitutions. These findings indicate that the ratio of the epidemic strains in the university students is different from those in other areas. In addition to the Q293H, S203T, and A197T mutations, we observed several unique and fixed amino acid changes in

the HA1 region of the isolates examined in this study. Substitutions of S69L, P137L, A186T and D187N occurred in the antigenic sites Cb, Ca, Sb and Sb, respectively (10). We postulate that these substitutions affect antigenicity and that Sapporo- and Texas-like viruses may therefore vary in antigenicity. We found https://www.selleckchem.com/products/Gemcitabine-Hydrochloride(Gemzar).html substitution of A134T in Sapporo-like T38 and T44, and of D187N in Sapporo-like T52. Since these amino acid positions are located in the receptor-binding site (14), these substitutions may affect the binding of virus to host calls. The substitutions of D187E and D222G could shift receptor specificity from α2,6- to α2,3-linked sialic acid (15). Substitutions of D222G/N possibly also alter the virulence of the virus; isolates possessing this substitution have been detected in fatal cases in several countries (16–18). We observed none of these substitutions among the isolates in this study. The A(H1N1)pdm09 genome has been DOK2 found to have an extremely

high evolutionary rate (19). Based on the ratio of dN/dS, Karoline et al. demonstrated that the seasonal H3N2 and H1N1 virus genes show stochastic variation (dN/dS < 1) (Table 1). On the other hand, the A(H1N1)pdm 09 of the 70 isolates demonstrated positive evolution (dN/dS > 1). In particular, Texas-like viruses showed the highest dN/dS value of the three groups and had significantly higher rates of missense mutation than Sapporo-like viruses. The high proportion of Texas-like viruses in this study possibly reflects these higher values, which denote more positive evolution. These findings may indicate that A(H1N1)pdm09 is more influenced than the other viruses by immune selection pressure. Although elderly people exposed to the 1918 “Spanish flu” had antibodies that cross-neutralized A(H1N1)pdm09 (21, 22), they may be also have been affected by A(H1N1)pdm09 due to antigenic drift. In conclusion, our phylogenetic analysis of the HA genes of the isolates shows that different virus populations, which might also vary in antigenicity, were responsible for the two student epidemics.

40 This is also true when populations from Taiwan (TW), OCE, and NAM and SAM, which exhibit a very high degree of diversification probably because of rapid genetic drift, are excluded. Significant correlations Small molecule library with geography are also obtained at the global scale when genetic distances

are estimated by weighting them by the molecular distances (i.e. the nucleotide differences) among the alleles.51 This result is therefore robust and leads to the conclusion that human migrations were a primary force in the evolution of HLA variation worldwide, in addition to demographic expansions (contributing to allelic diversification) and contractions (contributing to population diversification). Genetic signatures of the history

of modern humans are even more detectable when one focuses on the HLA genetic patterns within specific continental areas. The following examples are illustrative. In Africa, linguistic differentiations among populations speaking languages of each of the four main African linguistic phyla – Niger-Congo (NC), Nilo-Saharan (NS), Afro-Asiatic (AA) and Khoisan (KH) – are excellent predictors of HLA genetic differentiations: according to a recent analysis of HLA-DRB1 variation in Africa,63 AA populations from Ethiopia (i.e. Amhara and Oromo, which exhibit a very high frequency of DRB1*13:02, but also elevated *07:01 and *03:01 frequencies) cluster with AA populations from North Africa, whereas the Nyangatom, a NS population, also from Ethiopia, show a peculiar genetic profile and share some similarities

(high frequencies of *11:01) with NC, the buy Y-27632 latter being further differentiated into West Africans (high frequencies of *13:04) and Central-South Africans (high frequencies of *15:03). Therefore, although the HLA genetic patterns of African populations appear to be geographically structured according to South, West, East and North differentiations,64 a close relationship is also found for the DRB1 locus between genetic and linguistic variation in Africa. This confirms the conclusions drawn from the study of other genetic markers like GM (as described in an earlier section), RH and the Y chromosome:13,14,65 at least for these polymorphisms, present oxyclozanide African genetic patterns are mostly explained by recent migrations (i.e. within the last ∼ 15 000 years) corresponding to the expansion of the main linguistic families in this continent. At loci HLA-C and -DRB1 (and this is also the case for GM, as stated above), the HLA genetic structure of Europeans reveals marked variation between West-Central and North populations, on one hand, and Southeast populations, on the other (with elevated frequencies of DRB1*11:04, DRB1*11:01 and C*04:01 compared with the other regions), a sharp genetic boundary being detected approximately at the level of the Alps.

Consequently, the finding needs to be confirmed in a larger sample that includes more patients with thymic alteration. Our result confirmed the correlation between the frequency of periphery Th17 cells and the selleck products concentration of AChR antibodies of patients with MG. However, the AChR concentration has no relationship with the subtype of MG. But the number of Th17 cells with MG patients may be associated with certain thymic pathology changes or pathological subtype. Moreover, we further detected the evolution of Th17 cells (%) in the peripheral blood after thymectomy in 10 MG patients with TM. There was a trend towards decreased population of

Th17 cells (%), although this did not reach statistical significance (data not shown). IL-17A is the hallmark cytokine of Th17 cells and has been shown to SAHA HDAC ic50 function as a proinflammatory cytokine that upregulates a number of chemokines and matrix metalloproteases, leading to the recruitment of neutrophils into sites of inflammation [24]. We found that the expression of IL17 and serum IL-17 levels were markedly higher in patients with TM than those of the HC. But there were no significant differences between HC and TH or NT. Thus, the observed increase in Th17 cells in our patients with MG may represent a thymoma-specific phenomenon.

Taken together, these results indicate that Th17 cells are closely associated with the immune injury induced by TM. Development of Th17 phenotypes requires the presence of TGF-β in addition to the presence of IL-6. However, we failed to find significant difference in the level of TGF-β and IL-6 between patients with MG and HC. It has been demonstrated that IL-23 bridging the IL-17 cytokine family leads to the identification of the Th17 lineage [25]. Others also recently characterized that IL-23 is considered currently to play a role in maintaining Th17 cell survival [19,

26]. Kobayashi [27] found that IL-17 production was significantly increased by IL-23 in lamina propria CD4+ cells from ulcerative colitis (UC), and upregulated IL-23p19 mRNA expression was correlated with IL-17 in UC. In humans, IL-1β has been implicated as an essential Protirelin cytokine for the Th17 differentiation, as IL-1β in naïve CD4 cells induced retinoic acid–related orphan nuclear hormone receptor c (RORc) expression and Th17 differentiation, which was enhanced by IL-6 and IL-23 [28, 29]. Sutton [30] demonstrated that IL-17A could be induced from γδT cells directly by IL-1 and IL-23 derived from activated DCs. A more recent study indicated that prostaglandin E2 (PGE2) and IL-23 plus IL-1β induce the Th17 immune response preferentially in CD161+ CD4+ memory T cells in inflammatory bowel disease (IBD) [31]. We also found that the expression of two Th17 relative cytokines, IL-1β and IL-23, was upregulated statistically in TM group.

Studies were conducted over a wide range of geographical settings, including subjects with African, Asian, European and Indian descent. The characteristics of the individual studies (Table 1) and the absolute numbers of allele frequencies in the cases and controls (Table 2) were also summarized. Some studies used PCR to amplify restriction fragment length polymorphisms (RFLP) of the 1513 locus used to define genotypes (Li et al., 2002; Niño-Moreno et al.,

2007; Mokrousov et al., 2008; Xiao et Selleckchem Tanespimycin al., 2009; Sambasivan et al., 2010) and allele-specific PCR assays to determine the −762 locus genotype (Niño-Moreno et al., 2007; Mokrousov et al., 2008; Xiao et al., 2009). Li et al. (2002) and Sambasivan et al. (2010) used PCR-ligation detection reactions and PCR-RFLP to define the −762 locus genotype, respectively, and Fernando et al. (2007) used amplification assays using a Sequence Detection System to define the 1513 locus genotype. It was shown that the −762TC SNP in the promoter region was associated with tuberculosis susceptibility in an Asian Indian population (Sambasivan et al., 2010), but with significant protection

against tuberculosis in a Gambian population (Li et al., 2002), and no association was identified between the 1513AC SNP and tuberculosis susceptibility in both of them. While a significant association was identified between the P2X7 1513AC variant Dabrafenib research buy and pulmonary tuberculosis, no association was found between the −762TC polymorphism and tuberculosis susceptibility in Mexican Mestizos (Niño-Moreno et al., 2007) or Russian Caucasians (Mokrousov et al., 2008). Researchers from Australia, however, observed an association between the 1513 C allele ADAM7 and extrapulmonary (compared with pulmonary) tuberculosis in an Australian Vietnamese population (Fernando et al., 2007). Xiao et al. (2009) found that neither the 1513AC nor the −762TC P2X7 variants were significantly associated with tuberculosis in a Chinese Han

population. The pooled OR using a fixed effects model for the six studies examined for the 1513 C allele was 1.44 (95% CI 1.23–1.68; P<0.00001, Fig. 1), including a total of 1044 cases and 1286 control subjects (Li et al., 2002; Fernando et al., 2007; Niño-Moreno et al., 2007; Mokrousov et al., 2008; Xiao et al., 2009; Sambasivan et al., 2010). Intrastudy heterogeneity was not observed between the six studies examined (χ2=4.58, P=0.60). A total of 857 cases and 1068 control subjects from five studies were used to carry out the metaanalysis for the −762 C allele (Li et al., 2002; Niño-Moreno et al., 2007; Mokrousov et al., 2008; Xiao et al., 2009; Sambasivan et al., 2010). Because intrastudy heterogeneity was found between the five studies (χ2=22.18, P=0.0002), the random effects model was used. The pooled OR using the random effects model was 1.01 (95% CI 0.70–1.44; P=0.97, Fig. 2).

In this sequential digest, neither CatL nor CatB could further digest the 15- and 18-kDa fragments (Data S1), although these enzymes were active as reflected in their ability to degrade MBP. Similarly, we were unable to detect further proteolysis of CatG-treated HLA-DR using CatS, D, X, H, or AEP (data not shown). In order to examine whether endogenous CatG might contribute to MHC II proteolysis in living APCs, we first looked for inverse correlations between changes in MHC II levels and CatG levels in human primary APCs following in vitro stimulation. Indeed, CatG, which is expressed by mDC1s,19 was down-regulated upon

lipopolysaccharide (LPS) stimulation (Data S2), a manipulation known to increase surface MHC II levels and shut down MHC II turnover.4 Similarly, decreased levels of

CatG correlated with increased MHC II levels in primary human B cells after stimulation with interleukin 3-MA mw (IL)-4 (Data S2). Next, to test whether CatG is causally involved in MHC II turnover, we examined whether addition of CatG to APCs modulates DR expression. Previously, we demonstrated that B-LCLs do not express CatG, but can acquire CatG added to culture media and target it to endocytic compartments.38 To evaluate the impact of CatG on the steady-state levels of HLA-DR molecules, we incubated B-LCLs with or without CatG for 4·5 hr. The cells were harvested, Linsitinib ic50 and HLA-DR levels were compared by immunoblotting. Levels of both alpha and beta chains of HLA-DR were unchanged when incubated with purified CatG or with CatG and the CatG inhibitor (Data S3). Furthermore, CatG added exogenously to a B-LCL did not alter surface levels of HLA-DR molecules, as quantified by flow cytometry with L243 (Data S4) and the anti-DR antibody Tü36 (data not shown). Importantly, the B-LCL used in these experiments, 9.5.3, is DM-deficient; thus, these negative results were not explained by DM-mediated protection Farnesyltransferase from CatG. In order to examine whether endogenous CatG expression in certain primary human APC types, such as mDC1 and

B cells,19 contributes to MHC II turnover, we tested whether the CatG inhibitor,29 which inhibits intracellular CatG in intact cells,21 causes accumulation of DR in such APCs. No increase in total DR levels in primary B cells was seen by western blot, however, after 4·5, 24 and 72 hr of CatG inhibition (Fig. 6a–c). Similarly, total DR levels were unchanged in mDC1s when CatG was subjected to prolonged inhibition (24 and 72 hr; data not shown). Moreover, analysis of cell surface levels of HLA-DR by flow cytometry demonstrated that the CatG inhibitor did not affect expression of surface HLA-DR in either B cells or mDC1s (Data S5). These results argued against a causal relationship between the inversely correlated levels of endogenous CatG and MHC II expression.

Indeed, treatment with rhIL-10 significantly reduced both CD8+ and CD4+ T-cell proliferation (Fig. 7C), thus proving a central role of IL-10 in the regulation of the T-cell response to allogenic monocytes. In this study, we demonstrated the role of the IRAK4 kinase as a differential switch between TLR-induced pro-inflammatory and anti-inflammatory cytokine production. This observation is of interest as to date IRAK4 is mainly being viewed as a central executor of the MyD88 pathway that unselectively transduces all signals downstream of MyD88. As previously described in IRAK4-deficient mice [26], stimulation of IRAK4 knockdown monocytes with TLR4 and TLR2 ligands resulted in markedly reduced pro-inflammatory cytokine

secretion such as TNF and IL-12 (Fig. 2A–C) and Daporinad ic50 concomitant reduction of the NF-κB subunits p50 and p65 responsible for the transcription of these cytokines (Fig. 2D). The results obtained are further in accordance Selleckchem Selumetinib with observations made in cells of IRAK4- and MyD88-deficient patients. There, TLR stimulation fails to activate the NF-κB pathway and cells display an impaired cytokine response after stimulation with agonists for TLR-1, TLR-2, TLR-4, TLR-5, TLR-7, and TLR-8 [17-20]. Similarly, siRNA-mediated silencing of MyD88 caused a significant reduction in TNF and IL-12 cytokine production in human monocytes (Fig. 4C,D), highlighting the cooperative interaction

of MyD88 and IRAK4 in TLR-induced synthesis of pro-inflammatory cytokines such as TNF and IL-12. IRAK4-deficient patients are more susceptible to infections with pyogenic bacteria, especially Gram-positive species such as S. pneumoniae and/or S. aureus [18]. Consistently, the predisposition to S. aureus infections was also reported in IRAK4-deficient mice [26]. Until now, little is known about the role of monocytes in response to these pathogens albeit these cells belong to those first to encounter bacterial pathogens in blood stream infections.

In this study, we tested the role of IRAK4 in the TLR-mediated response of human monocytes to bacterial infections. In particular, our results showed diminished IL-12 Amisulpride secretion and elevated TNF and IL-10 levels after treatment with live S. aureus and S. pneumoniae (Fig. 1C). To further assess these findings we conducted MyD88 knockdown experiments, obtaining concomitantly reduced IL-12 and IL-10 secretion. However, TNF levels were only slightly diminished (Fig. 4E). This strongly suggests that IL-12 and IL-10 secretion evoked by bacterial infections is MyD88-dependent, whereas TNF production is also regulated in a MyD88-independent fashion, possibly triggered via TRIF or cytosolic PRR-induced IFN-I [27]. In general, bacteria represent complexes of multiple ligands that can be sensed by membrane-bound as well as cytosolic PRR. The most prominent difference between stimulation with bacteria and single TLR ligands was an increase in TNF release under IRAK4-silencing conditions (Fig. 1C) and under rapamycin treatment (Fig. 5B).

Genetic information for receptor chains is carried by a germline pool of variable (V), joining (J), and diversity (D) genes that undergo somatic DNA rearrangements

to generate receptors with diverse-binding specificity selleck monoclonal antibody [2]. The “innate-like” γδ T cells have unique features when compared with the more abundant αβ T cells, e.g. a preferential distribution in both epithelial and mucosal sites, an immunoglobulin (IG)-like antigen recognition mechanism in addition to the MHC-restricted one. Moreover, their percentage in peripheral blood cells, depending on age and species, differs strikingly from that of αβ T cells [3]. Artiodactyls are referred to as “γδ-high species” since they exhibit a higher frequency and a wider physiological distribution of γδ T cells with respect to other mammalian species, including humans and

mice which are referred to as “γδ-low species” [4]. The locus organization and expression of TCRG and TCRD genes have been characterized in ruminants; these species have been shown to possess a large TCRG [5, 6] and TCRD [7] germline repertoire. Camelus dromedarius (often referred to as the Arabian or one-humped camel) RG7422 ic50 is arguably the most famous member of the Camelidae family for its historical and economic importance. Despite this, the dromedary literature is far less extensive than that on other domestic animals. Even the relative phylogenetic placement of Camelidae within Cetartiodactyla remains uncertain [8]. Indeed, it should be noted that the immune system of the camelids has so far been considered unique: in addition to the conventional tetrameric IgGs, camelids have special smaller heavy chain-only antibodies [9]. Here, we report an extensive analysis of the locus organization and expression of the TCRG genes in dromedary. The germline locus is composed

of only a few genes: two TCRGVs, four TCRGJs, and two TCRGCs. Indeed our gene expression data suggest that in this organism, γ chain diversity is likely to be generated not only by V-J rearrangement but also by somatic hypermutation (SHM) in the variable domain. It is generally accepted that SHM occurs primarily in germinal center B cells and is Methocarbamol the driving force for antibody affinity maturation. It introduces mainly point mutations into the variable domains of IG genes, at a rate of 10−5 to 10−3 per base per generation [10]. G-C and A-T base pairs are mutated at roughly equal frequencies with certain “”hotspot”" DNA motifs ((A/G/T)G(C/T)(A/T) motif (or DGYW) and (A/T)A (or WA), as well as their reverse complements) being preferentially targeted by the enzyme activation-induced cytidine deaminase (AID) [10-12]. Recently, it has been reported that SHM occurs also in the TCRGV region of the sandbar shark [13]. In our opinion, our findings support the important conclusion that, as for TCRDV genes [14], the C. dromedarius TCRG gene repertoire is also likely to have been shaped by SHM.

Management of a patient with an elevated troponin requires an appreciation that this patient has a worse prognosis Palbociclib price than someone with normal troponin followed by a clinical judgement about what further investigation is appropriate to this patient. A major difficulty for nephrologists is that the lack of evidence for specific cardiovascular therapies in patients undergoing dialysis100 makes it difficult to select a therapy that may offer a survival or other benefit. In addition, the elevated

troponin does not help determine the underlying pathology to target and some therapies such as revascularization with coronary artery bypass graft surgery carry a considerable mortality risk in patients undergoing dialysis.101 This is a major issue if troponin Volasertib price is used to screen asymptomatic patients. In patients with symptoms of acute coronary syndromes, the need to investigate further is more straightforward, although evidence is still lacking. High levels of BNP suggest a myocardium under stress due to chronic volume overload, a poorly functioning ventricle or both. BNP levels can be reduced by treatment with beta-blocking

drugs in patients receiving dialysis,102,103 but the use of beta-blocking drugs is yet to be tested in an adequately powered study with clinical outcomes. Treatment with losartan reduced BNP levels in one study.104 However, results of randomized studies of renin-angiotensin system antagonists conflict in dialysis patients with some studies suggesting

benefit,105,106 and others demonstrating no benefit in the primary outcome.107 Finally, one uncontrolled study used the level of BNP to guide ultrafiltration in patients undergoing dialysis Rutecarpine with volume overload,108 and demonstrated that BNP and extracellular fluid volume could be lowered. However, larger controlled studies of ‘BNP-guided therapy’ are needed to determine whether this approach can reduce clinically important end-points, bearing in mind that interventions targeting an improvement in other laboratory markers in patients undergoing dialysis have not proved beneficial in randomized controlled trials.109,110 Cardiac troponin and BNP offer promise for future clinical application in patients undergoing dialysis. Although reduced kidney function may have a role in their frequent abnormal levels, their strong associations with adverse clinical outcomes in this population and the potential pathological pathways they represent provide opportunities for treatment strategies to be guided by biomarker levels. However, much remains to be done before this promise is realized, including a better understanding of day to day variability of BNP and determining a ‘reference range’ of this marker for dialysis patients with minimal cardiac pathology.

We investigated the association of SOCS with disease progression in patients with pulmonary TB. For this purpose, we studied peripheral

blood mononuclear cells (PBMCs) and T cells from patients with pulmonary TB (TB, n = 33) and healthy endemic controls (EC, n = 15). Cases were stratified into those with moderately advanced (Mod-PTB) or far advanced disease (Adv-PTB). Interferon-gamma (IFN-γ), SOCS1 and SOCS3 gene expression was determined by RT-PCR. Statistical analysis was performed using the Mann–Whitney test. Levels of IL6 (P = 0.018) and IL10 (P = 0.013) were found to be elevated in PBMC supernatants from patients with TB as compared with EC. SOCS1 mRNA gene expression in T cells from patients with TB was increased as compared with that of EC (P = 0.02). In addition, levels of SOCS1 mRNA transcripts were found to be Ridaforolimus elevated in PBMCs of Adv-PTB as compared with Mod-PTB Nutlin-3a (P = 0.008) cases. Our data show that raised SOCS1 levels are associated with increased disease severity in TB. As SOCS1 regulates IFN-γ-driven immunity and SOCS1 can be further upregulated by IL6 levels, the increase in SOCS1 in severe disease indicates a mechanism by which mycobacteria impede disease control in TB. One-third of the world’s population has been estimated to be infected with Mycobacterium tuberculosis, which causes 1.8 million deaths annually [1, 2]. The interplay between host T cell and macrophages by appropriate

activation of cytokines such as IFN-γ and TNFα results in restriction of mycobacterial infection by appropriate granuloma formation [3]. CD4+ T cells play a central role in containment of M. tuberculosis infection by secreting interferon-gamma (IFN-γ) [4]. The enhanced susceptibility to mycobacterial infection of IFN-γ knockout mice [5, 6], and of patients with genetic defects in IL12/IFN-γ pathway [7] and the lowered antigen-stimulated T-cells IFN-γ responses in patients with active tuberculosis (TB) [8–11] all provide strong evidence that IFN-γ plays a significant role in defence against M. tuberculosis. Interferon-gamma activates Sulfite dehydrogenase transcriptional expression of IFN-γ response

genes mediated by the signal transducer and activator of transcription (STAT)-1 molecule [12]. An essential component of cytokine regulation is the timely termination of signals. Suppressor of cytokine signalling (SOCS) are a family of molecules that act as negative regulators of cytokine signalling by inhibiting Janus-activated kinase (JAK)/STAT activation [13] and thus affect immune responses to infection in the host. SOCS1 inhibits STAT1 activation and thereby the expression of IFN-γ-mediated genes [14, 15]. M. tuberculosis-induced IL6 has been shown to upregulate SOCS1 expression in activated CD4+ T cells, thereby interfering with STAT1 phosphorylation induced by IFN-γ [16]. SOCS1−/− mice die within three weeks after birth because of uncontrolled IFN-γ signalling [17].

The bone marrow has been known to be a source of

IL-7 in vivo.36 We therefore examined the possibility that there was preferential accumulation of CD45RA+ CD27− CD4+ U0126 T cells of a particular specificity in this lymphoid compartment. First we compared the distribution of CD4+ CD45RA/CD27 subsets in paired blood and bone marrow samples from healthy donors and observed a significant increase in the percentage of CD45RA− CD27− and CD45RA+ CD27− CD4+ T cells in the bone marrow compared with the blood of the same individuals (Fig. 7a). We investigated next whether the specificity of T cells in the bone marrow was similar to that found in the blood of the same individuals (Fig. 7b). We found that the increased proportion of CMV-specific CD4+ T

cells relative to other populations was also observed in bone marrow see more samples, indicating that the inflation of CMV-specific T cells occurs in more than one lymphoid compartment in vivo (Fig. 7b). In addition, the proportion of CMV-, VZV- and EBV-specific CD4+ T cells was not significantly different between the two compartments. However, there were significantly more PPD-specific CD4+ T cells in the bone marrow compared with the peripheral blood from the same donors, although the significance of this is not clear at present. We next investigated whether there was preferential accumulation of CD45RA− CD27− and CD45RA+ CD27− CD4+ T cells of a particular specificity in the bone marrow. We found that the proportion of CMV-, VZV-, EBV- and PPD-specific populations in the bone marrow that were CD45RA− CD27− and CD45RA+ CD27− was not different to that in the blood of the same individuals

(Fig. 7c). Therefore it appears that CD45RA− CD27− and CD45RA+ CD27− T cells of all specificities have equal propensity to accumulate in the bone marrow and that it is not a unique site for the generation of CMV-specific effector/memory CD4+ T cells. In this study we show that whereas persistent CMV infection is mainly responsible for the increase of CD45RA− CD27− and CD45RA+ CD27− CD4+ click here T cells in older subjects, both ageing as well as CMV infection contribute to the decrease of CD45RA+ CD27+ CD4+ T cells. This latter observation may reflect the impact of thymic involution compounded with persistent CMV infection during ageing.1 The majority of CD45RA− CD27− and CD45RA+ CD27− populations in CMV-infected subjects are CMV-specific but there are also increased numbers of these effector CD4+ cells that are specific for other viruses, i.e. EBV, HSV and VZV. This suggests that CMV infection may drive a global increase in CD4+ T-cell differentiation suggesting a bystander phenomenon. However, we cannot rule out the possibility that some people are particularly susceptible to the reactivation of latent viruses in general, CMV included.