**5. Conclusions**

Gene expression in the immune system is tightly regulated by epigenetic processes, including DNA methylation, chromatin remodeling and histone modifications, that orchestrate development, maturation and cell lineage commitment. In line with this, specific DNA methylation signatures and histone modification patterns can be detected for each cell population.

Next-generation sequencing technologies have enabled the identification of several new forms of IEI, surprisingly changing the scenario and expanding the knowledge of their molecular basis. Nonetheless, a genetic etiology still needs to be elucidated for many of them; hence, it is reasonable that alterations to the epigenetic mechanisms that control the transcription of genes involved in immune response may contribute to the pathogenesis of at least some of these disorders.

In addition, although most genetic IEIs are paradigmatic examples of monogenic disorders, a broad spectrum of severity and clinical phenotypes is widely recognized. Therefore, epigenetic signatures may be implicated in the regulation of disease expressivity and penetrance, possibly expanding the phenotype.

**Author Contributions:** R.R., G.G, A.R., N.B.-P. and C.P. conceived and designed the review; R.R., G.G., F.C., C.M., L.P., C.N., E.T., E.C. (Emma Coppola), A.D.R. and E.C. (Emilia Cirillo) wrote the paper; R.R. and F.C. created the figure; A.R. and C.P. supervised the Review. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by the Ministero della Salute (RF 2016-02364303).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

