Dear Colleagues, 

The scope of this Special Issue is to highlight the unique role of autoimmune or autoinflammatory phenotypes with a hereditary inheritance, in uncovering the role of different pathways in the pathogenesis of these disorders.

Autoimmunity and autoinflammatory diseases are conditions involving different aspects of the immune system. While autoimmunity involves the adaptive response, mediated by B and T lymphocytes and autoantibodies, autoinflammatory diseases are caused by the dysregulation of natural immunity, through the inflammasome, with all its players. However, this classical definition is challenged by conditions like Behcet’s syndrome, where the involvement of both arms of the immune system is present. The complexity of all those conditions is increased by the close relationship of the immune system with the environment. In all autoimmune and autoinflammatory disorders, environmental triggers give an important contribution along with genetic factors, suggesting that a complex architecture is responsible for the final phenotype. Most of the common autoimmune diseases, such as Systemic Lupus Erythematous, Rheumatoid Arthritis, Multiple Sclerosis, and Sjogren’s syndrome, usually do not show a classical Mendelian inheritance. In these cases, given the probable complex multifactorial origin, genome-wide association studies (GWAS) have been applied to uncover common gene variants responsible for the increased risk. However, the genetic variants discovered by GWAS contributed to a small fraction of the overall risk and many times was not possible to identify the mechanism of a variant in determining the pathogenesis of the disease. On the other side, for many autoinflammatory conditions, such as Familial Mediterranean Fever, Cryopyrinopathies, and TRAPS, there is a major gene responsible for the disease, and it is possible to confirm the clinical diagnosis with a molecular test. However, even for autoinflammatory disorders 70-80% of the cases do not show a Mendelian inheritance, and they are sometimes defined as SURF (Syndrome of Undifferentiated Recurrent Fever), indicating that those patients have a clinical diagnosis of autoinflammatory disease, characterized just by recurrent fever, but the underlying cause or mechanism is still unknown.

In approximately 5 to 10% of all autoimmune/autoinflammatory disorders, it is possible to suspect monogenic or familial segregation of the disease, more often dominant or in some cases recessive, suggesting that a major variant in a gene represents a strong predisposing factor for the development of the disease. In these cases, the new technologies of sequencing, exome and whole genome sequencing, along with classical linkage analysis, allowed the identification of new genes making it possible to further extend our knowledge.

The discovery of genes responsible for monogenic forms of common diseases already helped to have better diagnoses, supported by a molecular mechanism and it will help to identify new molecular targets for newer and more effective treatments.

Dr. Eugenio Sangiorgi
Guest Editor

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