Positive selection in dNTPase SAMHD1 throughout mammalian evolution.

The vertebrate protein SAMHD1 is highly unusual in having roles in cellular metabolic regulation, antiviral restriction, and regulation of innate immunity. Its deoxynucleoside triphosphohydrolase activity regulates cellular dNTP concentration, reducing levels below those required by lentiviruses and other viruses to replicate. To counter this threat, some primate lentiviruses encode accessory proteins that bind SAMHD1 and induce its degradation; in turn, positive diversifying selection has been observed in regions bound by these lentiviral proteins, suggesting that primate SAMHD1 has coevolved to evade these countermeasures. Moreover, deleterious polymorphisms in human SAMHD1 are associated with autoimmune disease linked to uncontrolled DNA synthesis of endogenous retroelements. Little is known about how evolutionary pressures affect these different SAMHD1 functions. Here, we examine the deeper history of these interactions by testing whether evolutionary signatures in SAMHD1 extend to other mammalian groups and exploring the molecular basis of this coevolution. Using codon-based likelihood models, we find positive selection in SAMHD1 within each mammal lineage for which sequence data are available. We observe positive selection at sites clustered around T592, a residue that is phosphorylated to regulate SAMHD1 activity. We verify experimentally that mutations within this cluster affect catalytic rate and lentiviral restriction, suggesting that virus-host coevolution has required adaptations of enzymatic function. Thus, persistent positive selection may have involved the adaptation of SAMHD1 regulation to balance antiviral, metabolic, and innate immunity functions.

The low frequency of recessive disease: insights from ENU mutagenesis, severity of disease phenotype, GWAS associations, and demography: an analytical review.

A survey of a select panel of 14 genetic diseases with mixed inheritance confirms that, while autosomal recessive (AR) disease genes are more numerous than autosomal dominant (AD) or X-linked (XL) ones, they make a smaller average contribution to disease. Data collected from N-ethyl-N-nitrosourea (ENU) mutagenesis studies show a similar excess of AR mutations. The smaller AR contribution may partially reflect disease severity, but only in the comparison of AR with AD mutations. On the contrary, XL mutations for the 14 diseases are generally more severe. Genome-wide associations studies (GWAS) data provide fresh insight into the shortage, with a limited negative selection effect mediated by the pleiotropic expression of recessive disease genes in other deleterious phenotypes. Genomic data provide further evidence of purging selection in a past European population bottleneck followed by a dramatic population explosion, now more clearly associated with past climate change. We consider these likely to be the main factors responsible for the low AR to AD/XL inheritance ratio.

Immune privilege as an intrinsic CNS property: astrocytes protect the CNS against T-cell-mediated neuroinflammation.

Astrocytes have many functions in the central nervous system (CNS). They support differentiation and homeostasis of neurons and influence synaptic activity. They are responsible for formation of the blood-brain barrier (BBB) and make up the glia limitans. Here, we review their contribution to neuroimmune interactions and in particular to those induced by the invasion of activated T cells. We discuss the mechanisms by which astrocytes regulate pro- and anti-inflammatory aspects of T-cell responses within the CNS. Depending on the microenvironment, they may become potent antigen-presenting cells for T cells and they may contribute to inflammatory processes. They are also able to abrogate or reprogram T-cell responses by inducing apoptosis or secreting inhibitory mediators. We consider apparently contradictory functions of astrocytes in health and disease, particularly in their interaction with lymphocytes, which may either aggravate or suppress neuroinflammation.

Human congenital diseases with mixed modes of inheritance have a shortage of recessive disease. A demographic scenario?

An archive of congenital human diseases is presented, aiming to contain all those where recessive (biallelic) can be compared with X-linked and/or dominant (monoallelic) inheritance. A significant deficit of recessive inheritance is evident, both in disease inheritance and in contribution to inheritance per known disease gene. The deficit contrasts with expectation derived from the cell biology of mutation, and from the importance of recessive mutation in evolution and its preponderance in N-ethyl-N-nitrosourea (ENU) mutagenesis. The deficit fits well with the standard model of demographic change since the neolithic era, and may also reflect natural selection acting on heterozygotes.

Epistasis: the key to understanding immunological disease?

Epistasis is fast becoming central to the understanding of the complex relationship between genotype and phenotype observed in autoimmune disease. A study in this issue of the European Journal of Immunology uses in-depth analysis of genome-wide mapping by polymorphic microsatellite markers to shed light on the genomic control of autoimmunity and self-tolerance.

Ten years of progress in vaccination against cancer: the need to counteract cancer evasion by dual targeting in future therapies.

Although cancer immunology has made vigorous progress over the last decade, its future remains uncertain. Tumors have clearly proved subject to immune surveillance, leading to antigenic editing, and means of activating both T and B arms of the immune system have been devised. Therapeutic vaccination and monoclonal antibody therapy have so far proved disappointing, because tumors prove adept at evasion from immune control. Dual targeting could well counteract evasion, provided that the two targets are independent and are attacked simultaneously. This stage has nearly but not quite been reached in several forms of immunotherapy, particularly of B-cell cancers, although such treatment also carries hazards.

Testing the theory of immune selection in cancers that break the rules of transplantation.

Modification of cancer cells likely to reduce their immunogenicity, including loss or down-regulation of MHC molecules, is now well documented and has become the main support for the concept of immune surveillance. The evidence that these modifications, in fact, result from selection by the immune system is less clear, since the possibility that they may result from reorganized metabolism associated with proliferation or from cell de-differentiation remains. Here, we (a) survey old and new transplantation experiments that test the possibility of selection and (b) survey how transmissible tumours of dogs and Tasmanian devils provide naturally evolved tests of immune surveillance.

The role of HLA promoters in autoimmunity.

Population studies reveal HLA class I and class II gene polymorphisms associated with all the common chronic autoimmune diseases, notably spondylarthropathies, rheumatoid arthritis, multiple sclerosis and type I diabetes. We here discuss the exceptionally high levels of nucleotide diversity in the MHC region likely to reflect not only balancing selection acting on the epitope binding sites but also natural selection operating on the promoter region. The latter possibility is supported by functional studies with promoters, higher levels of diversity in the promoters of class II than class I genes and the relatively high frequency of single nucleotide polymorphisms around transcription factor binding sites. This, we argue, reflects the need for an appropriate level of signalling at the immunological synapse. We here summarise our knowledge of HLA promoter polymorphisms and how these translate into differential expression, T cell polarisation and inflammation. We discuss current strategies for pharmaceutical intervention in HLA expression.

Fundamental immunology and what it can teach us about HIV vaccine development.

This survey covers the immunological background to development of an HIV vaccine, starting from an overview of present understanding of the mechanisms of immunoregulation. It follows the uptake, processing and presentation of an antigen, from its initial uptake by a dendritic cell and its deposit on the dendrites of follicular dendritic cells. It pursues the antigen through uptake by B cells, presentation of epitopes to helper T cells and the eventual production of antibody. In the second arm of the immune response it follows synapse formation between dendritic cell and CD4/CD8 cells leading to production of CTL. It identifies epitope linkage as a key element in directing these pathways. It identifies the principal functions of the various types of cell cooperation. Continuing, it focuses on topics relevant to vaccine development: Th1/Th2 balance: new adjuvants based on ligands of TLRs and other activators of innate immunity, as well as new forms of intervention in antigen processing. We urge that the new vaccine fusion constructs be evaluated against a fusion gold standard rather than against antigen alone. These considerations open new strategies of HIV vaccine development. . Finally we urge that vaccine trials should include storage of individual DNA samples, in order to gain better understanding of the genetic parameters of vaccine efficacy.

T helper cells and efficacy of Haemophilus influenzae type b conjugate vaccination.

A small number of fully vaccinated children in the UK have experienced invasive Haemophilus influenzae type b (Hib) infection. A rise in disease in recent years has been associated with lower vaccine-induced antibody levels over the first 5 years of life, forcing greater dependence on immunological memory for protection. This has necessitated the introduction of a catch-up campaign, designed to boost immunity in children aged 6 months to 4 years of age. We suggest that the conjugate vaccine's inability to induce pathogen specific helper T cells, combined with a loss of natural boosting due to reduced circulation of Hib, may have contributed to the rising incidence of invasive disease 10 years after introduction of the conjugate vaccine. If so, the changing epidemiology of Hib infection in the UK may in part reflect the failure of a subunit vaccine to activate adequately all the necessary components of the immune system. This observation has implications for optimal scheduling of more recently licensed meningococcal and pneumococcal conjugate vaccines.

Instruction of naive CD4+ T cells by polarized CD4+ T cells within dendritic cell clusters.

Cooperation between CD4(+) T cells can enhance the response and modulate the cytokine profile, and defining these parameters has become a major issue for multivalent-vaccine strategies. We explored cooperation using adoptive transfer of two populations of TCR transgenic T cells of different specificity. One was transferred without prior activation, whereas the second was activated for five days by antigen stimulation under polarizing culture conditions. Both populations were transferred into a single adoptive host and then primed by particle-mediated DNA delivery. Polarized Th1 cells (inducers) raised the frequency of IFN-gamma(+) cells within a naive (target) population, whereas Th2 inducers raised the frequency of IL-4(+) and reduced that of IL-2(+) cells. These effects were obtained when the genes for both antigens were on the same particle, favoring presentation by the same dendritic cell, but not when on different particles delivered to different dendritic cells. Autonomy of DC clusters allows linked sets of antigens (e.g. from a single pathogen) to maintain cytokine bias, but allows other independent responses, each with their own set of autonomous clusters.

Patterned variation in murine MHC promoters.

To compare variation in regulatory and coding DNA, promoter sequences have been obtained from wild-derived mice and laboratory rats. The sequences are from the proximal promoter of the H2Aa, H2Ab, H2Eb, and H2K genes of 24 wild-derived inbred strains and a sample of the corresponding exon 2 sequences and of the RT1.Ba gene of six strains of laboratory rat. They reveal a high level of variation in the mouse MHC class II promoters (H2A and H2E), a low level in MHC class I (H2K), and none in the rat. The variation is pronounced in and around the cAMP response element, a major binding site for modulating promoter activity in response to external stimulation. This finding, together with the different levels of variation in MHC classes I and II, is suggestive of natural selection. However, selection operating via the MHC coding sequences must also contribute, as indicated by the minimal variation in both the MHC class II promoter and coding sequences of the rat. Furthermore CIITA (trans-activator of class II) of the mouse has been reported to have minimal variation in its promoter and none in its coding sequence. Taken together these data suggest that the regulatory and coding sequences undergo coselection. Each of the mouse class II promoters has a pattern of variation that appears to be basically dimorphic, with further variation added by recombination/mutation. The dimorphic allelic lineages are in marginally detectable linkage disequilibrium with the exon 2 sequences, particularly in H2Aa, thus lending further support to the coevolution hypothesis.