Clinical Trial Summary
Inborn Errors of Immunity (IEI) include clinically heterogeneous rare genetic diseases
depending on mutations in about 300 different genes. Clinically, this group of diseases is
characterized by the presence of infectious, inflammatory, autoimmune, and
lymphoproliferative symptoms. Understanding the pathogenesis of these diseases can guide the
implementation of targeted therapies and improve prognosis.
In recent years, IEI have been described that do not necessarily present with repeated
infectious symptoms but rather with autoimmune, lymphoproliferative, and autoinflammatory
manifestations, or with forms of immunodeficiency with a spectrum of susceptibility to one or
few infectious agents. In this case, simple laboratory tests are not sufficient to
characterize the disease since no particular immunophenotypic changes are evident. To correct
classify the patients and to improve knowledge on the pathogenesis of the diseases, complex
immunologic-functional studies are required. These studies should be started prior to genetic
analysis, with the aim of targeting and narrowing it down. Although the ever-decreasing costs
of Next Generation Sequencing (NGS) methods make it convenient to analyse many genes or even
the entire exome simultaneously, the analysis of the data resulting from NGS can be complex
and provide results of uncertain interpretation. In these cases, immunologic-functional
studies can clarify the real causal role of the identified genetic variants.
The identification of genotype-phenotype correlation is crucial to establish new therapeutic
targets for diseases orphan of specific etiological treatments. In vitro and in vivo disease
models are key tools to test drugs repositioning, as was the case for Lapaquistat in the
treatment of periodic fevers caused by de-regulation of the cholesterol metabolic pathway.
