*3.1.1 Innate immunity*

The innate immune system constitutes the first line of defense in an individual's immune system. As a result, it detects pathogens as well as other harmful triggers that may cause inflammation and trigger adaptive immunity [22]. Among the effector cells of innate immunity are macrophages, dendritic cells, and antigen-presenting cells (APCs) [23]. Innate immunity identifies and recognizes the molecular patterns expressed by pathogens (pathogen associated molecular patterns, PAMPs) or by damaged cells (damage associated molecular patterns, DAMPs) [24]. There are three types of pattern recognition receptors (PRR): TLRs (Toll-like receptors), RLRs (RIG-I-like receptors), and NLRs (nucleotide-binding oligomerization domain-like receptors) [25]. It is thought that upon recognition of foreign molecules, intracellular signal transduction pathways are induced, which induces the expression of interferon alpha (IFN) sequences, IFN-α sequences, TNF sequences, and interleukin 1 (IL-1)

sequences. Both autoinflammatory and autoimmune diseases can be caused by the dysregulation of these receptors, which mostly involves excessive or prolonged activation [11, 26]. The activation of the inflammasome is crucial to host defense against pathogens. Several inflammasomes are implicated in the immunological process of diseases, including NALP1 and NALP3, or cryopyrin inflammasomes. By activating pro-caspase-1, the inflammasome mediates the conversion of pro-IL-1ß and IL-18 into the active forms. Genetic mutations in either pyrin, cryopyrin, or TNF receptor super-family genes have been associated with autoinflammatory diseases [27]. It is unclear how inflammasomes contribute to autoimmunity. Nevertheless, its role is still yet to be discovered as NLRI and IL-1ß as a primary suspect to look at. The upregulation of IL-2 receptor that leads to B cell proliferation and enhanced antibody production is caused by the crucial role of IL-1ß, which affects both B and T cells, thereby prolonging T cell survival [28]. Furthermore, they drive differentiation of the Th17 cells as well. Therefore, IL-1ß stimulates T and B cells and may play a crucial role in linking the NLR activation with adaptive immunity response [20].

### *3.1.2 Adaptive immunity*

For adaptive immunity to mature, it requires between three and five days. B cells, T cells, and cytotoxic T cells are involved in adaptive immunity [19]. Antigens are recognized by specific antigen receptors, primarily B and T cell receptors (BCR and TCR), which are highly specific. As such, innate immunity provides a first line of defense against damage and infection. Adaptive immunity, however, provides a more effective but slower resistance.

A significant role is played by adaptive immunity in the development and maintenance of autoimmune diseases. Despite this, different mechanisms contribute to the disease by the innate immune system. The autoimmune process is divided into two phases: During the initiation phase (phase 1), self-nucleic acids released by apoptotic cells are recognized and internalized by dendritic cells (DC) through TLR, causing IFN-α, production. The IFN- α stimulates the maturation of dendritic cells, the presentation of autoantigens, the recruitment of B and T cells, and the production of autoantibodies. After entering a second phase, (self-sustaining amplification) plasmocytoid dendritic cells internalize autoantibodies and nucleic acids through Fcy-receptors (FcyRs). DC and T cells are stimulated and activated by IFN- α, resulting in self-perpetuation of antibody production and inflammation [6, 29].

### **3.2 The immunological disease continuum**

IL-1 1β and type I interferon (IFN) are also polarized cytokines that are related to innate immunity, with IFN being more associated with autoimmune diseases, specifically Systemic Lupus Erythematosus (SLE), while IL-1β is associated with pure innate immunity. The importance of recognizing Type I IFN dysregulation driving autoimmunity, as well as NLR dysfunction driving classical autoinflammatory diseases without autoantibody formation, has led to a polarization in the classification of immune diseases. From the original recognition of autoinflammatory diseases being linked to NLR cytoplasmic resident innate immune receptors (NLRP3 in particular). There have been several reports linking innate immune-mediated pathologies to inflammasomes, including NLRC4. It is remarkable that NLR family members show consistent association with both monogenic and polygenic autoinflammatory disease, whereas TLRs do not, possibly attributable to functional redundancy in TLRs.
