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.

Genetic disease in India and the West compared: provisional analysis of population dynamics.

The Indian Genetic Disease Database (IGDD) and Online Mendelian Inheritance in Man (OMIM) survey human populations that have different climate histories. Comparison of the two shows an outstanding difference in the relative frequency of recessive disease genes. Several of the diseases mediated at least in part by recessive gene mutations in India are not so mediated in the Western populations covered by OMIM, or are so mediated to a lesser extent.

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.

The interplay between pathogen-associated and danger-associated molecular patterns: an inflammatory code in cancer?

There is increasing evidence of a close link between inflammation and cancer, and at the core of inflammation there are both pathogen-associated molecular patterns (PAMPs) and danger (or damage)-associated molecular patterns (DAMPs). Microorganisms harbor molecules structurally conserved within groups called PAMPs that are recognized by specific receptors present on immune cells, such as monocytes and dendritic cells (DCs); these are the pattern recognition receptors (PRRs). Activation through different PRRs leads to production of pro-inflammatory cytokines.

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.

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.

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.

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.

Inflammation at the interface of innate and acquired immunity.

This is the short summary of the presentation at the 2nd Belgrade Meeting on Immunoregulation entitled "Inflammation at the interface of Innate and Acquired Immunity" held recently under the auspice of European Federation of Immunological Societies and organized by Medical School, University of Kragujevac.

Aqueous humor alloreactive cell phenotypes, cytokines and chemokines in corneal allograft rejection.

As biopsies are not taken at the time of human corneal allograft rejection, most information on the early cellular changes in rejection is from animal models. We examined the phenotype of alloreactive cells present in the human anterior chamber during corneal graft rejection by flow cytometry and quantified aqueous humor levels of cytokines and chemokines using cytometric bead array. Aqueous and peripheral blood samples were taken from patients with graft endothelial rejection (n = 11) and from control patients undergoing cataract surgery (n = 8).

Mitigating selection in HLA-B27 not confirmed.

The existence of a small, discrete group of HLA-B27 promoters, potentially able to mitigate the deleterious effect of this allele, has not been confirmed.

Reflections on the clonal-selection theory.

How do we account for the immune system's ability to produce antibodies in response to new antigens? It has been 50 years since F. Macfarlane Burnet published his answer to this question: the clonal-selection theory of antibody diversity. The idea that specificity for diverse antigens exists before these antigens are encountered was a radical notion at the time, but one that became widely accepted.

A survey of H2 gene sequences, including new wild-derived genes.

A comprehensive collection of mouse major histocompatibility complex (MHC) promoter and exon 2 sequences is here presented and analysed. It covers the three best known class II genes and one class I gene, and includes new wild mouse sequences from the 'w' back-cross strains and from the Jackson collection. All sequences are in GenBank, and the new exon sequences largely confirm previous typing by serology and immune function.

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.

Can unresolved infection precipitate autoimmune disease?

Autoimmune diseases are frequently postulated to arise as post-infectious phenomena. Here we survey the evidence supporting these theories, with particular emphasis on Crohn's disease and ankylosing spondylitis. Direct proof that infection establishes persistent autoimmunity remains lacking, although it may provoke a prolonged inflammatory response when occurring on a susceptible immunological background.

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.