Targets for Periodic Fever Syndrome

Understanding the molecular targets implicated in Periodic Fever Syndrome (PFS) is fundamental for unraveling the disease's pathogenic mechanisms, identifying actionable therapeutic interventions, and supporting rational drug discovery. PFS encompasses a group of autoinflammatory disorders characterized by recurrent fevers and systemic inflammation, typically in the absence of infectious or autoimmune triggers. The pathogenesis centers on dysregulation of innate immune pathways, notably those governing the production and release of pro-inflammatory cytokines such as interleukin 1 beta (IL1B) and tumor necrosis factor (TNF). These cytokines are well-established mediators of fever and systemic inflammation, and their aberrant activity is a hallmark of PFS. Additional genetic contributors, such as altered antigen processing by endoplasmic reticulum aminopeptidase 2 (ERAP2) and transcriptional regulation by IKAROS family zinc finger 1 (IKZF1), have been implicated in autoinflammatory phenotypes and immune dysregulation, providing further mechanistic insight. By focusing on these directly relevant targets, researchers can elucidate the molecular cascades leading to periodic fever episodes and chronic inflammation, enabling the development of targeted therapies—such as cytokine inhibitors or small molecules modulating immune signaling. Moreover, these targets serve as valuable biomarkers for diagnosis, disease monitoring, and stratification of therapeutic response, thereby advancing precision medicine approaches in PFS.

Pro-Inflammatory Cytokines And Mediators

This category encompasses molecular targets that are central to the inflammatory cascade and directly implicated in the pathogenesis of Periodic Fever Syndrome. It includes interleukin 1 beta (IL1B) and tumor necrosis factor (TNF), both of which are potent pro-inflammatory cytokines whose dysregulated production or signaling is a core feature of PFS. These mediators drive fever, systemic inflammation, and tissue damage, and their inhibition has demonstrated clinical benefit in autoinflammatory syndromes.

Interleukin 1 Beta (IL1B)

Interleukin 1 Beta (IL1B) is a key pro-inflammatory cytokine encoded by the IL1B gene (Entrez: 3553, KEGG: 3553, UniProt: P01584). Structurally, IL1B is produced as an inactive pro-protein that is cleaved by caspase-1 within the inflammasome complex to yield the active 17 kDa cytokine. Its secretion is tightly regulated by pattern recognition receptor (PRR) signaling and inflammasome activation. IL1B exerts its effects by binding to the IL-1 receptor, activating NF-κB and MAPK pathways, and promoting the expression of adhesion molecules, chemokines, and additional cytokines. In PFS, gain-of-function mutations or dysregulation of inflammasome components (e.g., NLRP3) lead to excessive IL1B production, resulting in recurrent fever episodes and systemic inflammatory symptoms. Clinical and genetic studies have established a causal link between IL1B pathway hyperactivation and several PFS subtypes, including familial Mediterranean fever and cryopyrin-associated periodic syndromes. Therapeutically, IL1B blockade (e.g., with anakinra or canakinumab) is highly effective in reducing fever frequency and severity, underscoring its central pathogenic role and utility as a therapeutic target and biomarker.

Tumor Necrosis Factor (TNF)

Tumor Necrosis Factor (TNF) is a master regulator of inflammation encoded by the TNF gene (Entrez: 7124, KEGG: 7124, UniProt: P01375). TNF is synthesized as a transmembrane precursor and cleaved by TNF-alpha converting enzyme (TACE/ADAM17) to release the soluble 17 kDa cytokine. TNF acts via TNFR1 and TNFR2 receptors, activating downstream NF-κB, JNK, and caspase pathways, leading to the transcription of pro-inflammatory genes, apoptosis, and further cytokine release. In PFS, TNF overproduction has been documented in patients with TNF receptor-associated periodic syndrome (TRAPS), where mutations in TNFRSF1A impair receptor shedding and prolong TNF signaling. This results in persistent inflammation, fever, and tissue damage. TNF inhibitors (e.g., etanercept, infliximab) have shown efficacy in TRAPS and other autoinflammatory syndromes, validating TNF as a direct therapeutic target and a biomarker for disease activity.

Antigen Processing And Immune Regulation

This category includes targets involved in antigen processing and transcriptional regulation of immune cell development, which may contribute to the pathogenesis of Periodic Fever Syndrome by modulating immune responses and susceptibility to autoinflammatory episodes. Key targets are endoplasmic reticulum aminopeptidase 2 (ERAP2) and IKAROS family zinc finger 1 (IKZF1), both of which have emerging evidence linking them to immune dysregulation and autoinflammatory disease phenotypes.

Endoplasmic Reticulum Aminopeptidase 2 (ERAP2)

Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) is encoded by the ERAP2 gene (Entrez: 64167, KEGG: 64167, UniProt: Q6P179) and is an M1 zinc metallopeptidase localized to the endoplasmic reticulum. ERAP2 trims antigenic peptides for loading onto MHC class I molecules, influencing the repertoire of peptides presented to cytotoxic T cells and NK cells. Structurally, ERAP2 contains a catalytic domain with a zinc-binding motif essential for its aminopeptidase activity. Regulatory mechanisms include cytokine-induced expression and post-translational modifications. Recent genetic studies have associated ERAP2 polymorphisms with increased susceptibility to autoinflammatory diseases, possibly by altering antigen presentation and modulating innate immune activation. In PFS, altered ERAP2 function may contribute to aberrant immune activation and perpetuation of inflammatory episodes, although the precise mechanisms remain under investigation. ERAP2 is a potential biomarker for disease susceptibility and a candidate for small molecule modulation in immune-mediated diseases.

IKAROS Family Zinc Finger 1 (IKZF1)

IKAROS Family Zinc Finger 1 (IKZF1) is a transcription factor encoded by the IKZF1 gene (Entrez: 10320, KEGG: 10320, UniProt: Q13422). It contains multiple zinc finger domains mediating DNA binding and dimerization, and regulates the development and function of lymphoid cells, including T and B cells. IKZF1 modulates the expression of genes involved in immune tolerance and cytokine signaling. Mutations or dysregulation of IKZF1 have been linked to immune dysregulation syndromes and increased risk of autoinflammatory diseases. In the context of PFS, altered IKZF1 activity may disrupt immune homeostasis and contribute to inappropriate activation of inflammatory pathways, although direct mechanistic links are still being elucidated. IKZF1 is a potential biomarker for immune dysregulation and may represent a novel therapeutic target in autoinflammatory disorders.