AUTOINFLAMMATORY DISEASES IN HEMATOLOGY FROM DIAGNOSIS TO TREATMENT

AUTOINFLAMMATORY_DISEASES_IN_HEMATOLOGY_FROM_DIAGNOSIS_TO_TREATMENTkapak

DYSREGULATIONOF INFLAMMATION-AUTOINFLAMMATION-MGCS

Hülya Yılmaz Tekinhatun

Diyarbakır Gazi Yaşargil Training and Research Hospital, Department of Hematology, Diyarbakır, Türkiye

Yılmaz Tekinhatun H. Dysregulation of Inflammation-AutoinflammationMGCS. In: Kurt Yüksel M, editor. Autoinflammatory Diseases in Hematology from Diagnosis to Treatment. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.15-23.

ABSTRACT

The immune system is a complex defense mechanism that protects the body against infections and injuries. While inflammation is essential for tissue repair and host defense, uncontrolled inflammatory responses can lead to chronic diseases, organ damage, and even death. The inflammatory process consists of two main phases: the initiation phase, where pro-inflammatory mediators and polymorphonuclear leukocytes (PMNs) become activated, and the resolution phase, which involves specialized pro-resolving mediators (SPMs) such as resolvins, protectins, and maresins. These lipid-derived molecules play a critical role in terminating inflammation and promoting tissue repair. Dysregulation in these mechanisms leads to prolonged inflammation, contributing to various chronic diseases. Key signaling pathways, including NF-kB and STING, regulate inflammatory responses. NF-kB is a transcription factor responsible for producing pro-inflammatory cytokines and chemokines. While its activation is necessary for immune defense, excessive activation results in immune dysregulation, seen in conditions like sepsis and chronic inflammatory diseases. Similarly, the STING pathway, which responds to cytosolic nucleic acids, plays a vital role in the immune response against infections. However, its overactivation contributes to autoimmune diseases and hyperinflammatory conditions. Pharmacological modulation of these pathways offers promising therapeutic interventions. Autoinflammatory diseases arise from dysregulated innate immune responses, often involving genetic mutations that disrupt normal immune regulation. Mutations in TNFR1 lead to excessive TNF signaling, causing sustained inflammation. Additionally, inflammasomes like NLRP3 and pyrin play crucial roles in autoinflammation, triggering the release of IL-1b and contributing to conditions such as Familial Mediterranean Fever (FMF) and Cryopyrin-Associated Periodic Syndromes (CAPS). The chapter also discusses monoclonal gammopathy of clinical significance (MGCS)-associated inflammatory hematological disorders. MGCS results from the production of monoclonal immunoglobulins that cause significant organ damage despite the absence of malignancy. Diseases such as systemic capillary leak syndrome, TEMPI syndrome, scleromyxedema, and Schnitzler syndrome are linked to MGCS. Their pathophysiology involves endothelial dysfunction, cytokine dysregulation, and excessive immune activation. Overall, understanding the molecular mechanisms of inflammation and immune dysregulation provides insights into developing targeted therapies for inflammatory and autoinflammatory diseases.

Keywords: Inflammation; Paraproteinemias; Schnitzler syndrome; Scleromyxedema; Capillary leak syndrome

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