Figure 6. Synergy of HLA-KIR (human leucocyte antigen-killer immunoglobulin receptor) compound genotypes and duality between autoimmunity and infection. The general paradigm for HLA-KIR epistasis based on current disease association studies. Different HLA- KIR combinations provide different levels of activation and inhibition of NK (natural killer) and T cells resulting in differing susceptibility and protection against infection and autoimmunity. limited understanding of KIR gene expression control. Despite these complications, several points emerge from the data. In general, KIR-HLA combinations with a tendency towards stronger NK cell activation or lower levels of inhibition are associated with increased risk of autoimmune diseases but tend to be protective against infectious diseases. On the other hand, stronger inhibitory combinations are associated with protection against inﬂammatory diseases and disorders in pregnancy (Fig. 6). The data are consistent with the idea that disease sus- ceptibility is modiﬁed by speciﬁc KIR-HLA ligand interactions. For this reason several studies have examined KIR and HLA class I combinations in disease association studies. Such studies will need to be large, with well-controlled populations, in order to be adequately powered. In order to rule out false positives, risk variants will likely have to undergo replication tests of validity because of the many semi-independent tests that will have to be considered. A recent study describing the speciﬁc combinations of KIR3DL1 and HLA-B alleles that inﬂuence HIV disease progression exempliﬁes the signiﬁ- cance of KIR-HLA epistasis in disease-resistance and the importance of distinguishing between alleles. The data also afﬁrm a key role for NK cells in limiting HIV infec- tion (Martin et al., 2007). Epigenetics Epigenetic changes refer to chemical modiﬁcations of chromatin without alteration to the underlying DNA sequence itself. Combinations of these changes modulate the accessibility of regulatory DNA sequences to tran- scriptional activators and repressors. In this way, collec- tive gene activation and local control of gene-speciﬁc transcription is controlled by the ‘epigenetic code’ (Bern- stein et al., 2007). This complex regulation and interplay are believed to have an essential role in cellular differenti- ation, allowing cells to stably maintain different charac- teristics despite containing the same genomic material. It is also invoked in diverse cellular phenomena such as chromosomal stability, gene silencing and parental imprinting. Modiﬁcations of chromatin components include methylation of DNA cytosine residues and post- translational alterations to histone proteins, including MHC architecture, evolution and disease 187 acetylation, phosphorylation and ubiquination. Such changes are maintained when cells divide, and although most of these features are considered dynamic through development, some epigenetic features may display trans-generational inheritance (Crews et al., 2007; Jirtle & Skinner, 2007). However, since these modiﬁcations can be inﬂuenced by endogenous and exogenous factors, the epigenome is essentially the interface between genetics and the environment, where the hardwired primary genetic code is modulated by the plasticity of epigenetic code. To date, genetic studies of MHC-linked disease have almost exclusively concentrated on DNA sequence dif- ferences. However, given that a full explanation for most MHC correlations with disease has not yet been reached, it seems rational to consider the involvement of epigenet- ics. Interest is heightened by several inferences; ﬁrst, the association of epigenetic dysfunction in other parts of the genome with human diseases (Feinberg, 2007). Second, the fact that some MHC genes, including HLA genes, are already known to be regulated by epigenetic events (Wright & Ting, 2006). Also several epigenetic phenom- ena, such as imprinting, violate Mendelian principles. One area of focus is epigenetic modulations on HLA and their effects on tumours. Inactivation of classical HLA genes through DNA hypermethylation may be one of the mechanisms through which cells create an immune privilege and through which neoplastic cells escape immune recognition. Conversely, transcription activation of non-classical HLA-G through demethylation, and resultant HLA-G protein expression, may facilitate tumour cells to evade immunosurveillance. In accordance, glioma cell lines expressing HLA-G are resistant to allo-reactive lysis (Wiendl et al., 2002), and HLA-G- positive melanoma cell lines are protected from NK cell cytolysis (Cabestre et al., 1999). Correlation between promoter methylation and HLA-G repression, and the observation that a demethylating treatment reverses promoter activity in vitro, lend credence to this hypothesis (Mouillot et al., 2005). As opposed to genetic alterations, epigenetic events can be modiﬁed by pharmacological agents that induce DNA hypomethylation or inhibit deacetlylation. Consequently, there is interest to manipulate this system therapeutically, for example to generate anticancer immune responses or to dampen-down autoimmune reactions (Yoo & Jones, 2006). For example, methylation inhibitors might provide beneﬁts in certain inﬂammatory diseases where HLA-G is suspected to function as an inhibitory feedback signal. However, current epigenetic treatments lack speciﬁcity. For instance, epigenetic cancer therapies using DNA methylation inhibitors to prevent inactivation of classical HLA may in turn activate expression of HLA-G and thus could favour tumour immune escape. Systematic efforts are underway to measure speciﬁc forms of epigenetic information throughout the genome. The Human Epigenome Consortium is a public-private collaboration that has initiated the Human Epigenome Project (HEP) in order to identify and catalogue methylation variable © 2008 The Author Journal compilation © 2008 Blackwell Publishing Ltd, International Journal of Immunogenetics 35, 179–192