**2. Definition, pathophysiology, and etiology of autoimmune diseases**

ADs are a cluster of heterogenous pathological events with an increasing number of registered cases worldwide and a prevalence of around 10% in the western populations, according to thorough epidemiological studies [8]. The hallmark of AD is the tissue injury and consequent malfunction resulting from a system or organ-specific inflammatory reaction due to the failure of self-antigen tolerance [9, 10]. Shaping the classification of AD advanced and these diseases were re-defined over the years: autoimmune inflammatory diseases used to be typically divided into autoimmune diseases and autoinflammatory diseases [11]; this separation is based on the involvement of either the innate or the adaptive immune systems and the detection of increased titer of autoantibodies [11]. So according to this definition set, ADs are distinguished by the involvement of the adaptive immune system represented by T and B lymphocytes and the presence of autoantibodies [11]. Over a decade ago, McGonagle and McDermott suggested the "continuum model" in immunology, in which a spectrum of diseases is established including the autoinflammatory and AD in both extremities of the created spectrum [12]. Moreover, the authors suggested criteria to set the boundaries for diseases to be considered clinically autoinflammatory or autoimmune, based on the genetic mutations that occur in each type of disease [12]. Thus, margins of ADs are set by mutations linked to monogenic autoimmune diseases which exhibit predisposed to the adaptive immune system and the existence of autoantibodies. On the contrary, the margins are set for autoinflammatory diseases by mutations in elements that take place in the innate immune system mutations specifically in tissues that are prone to pathological events onset, where no evidence of the involvement of autoimmune mechanisms [12–14]. In the last few years, the concept of autoinflammation and autoimmune diseases kept being refined as several monogenic and polygenic common and novel disorders have been recognized, feeding into the updating of
