Autoimmunity and Clonal Hematopoiesis: Two Faces of Immune Dysregulation

Autoimmune diseases and hematological neoplasms have traditionally been considered distinct clinical entities. However, accumulating evidence indicates that they may represent interconnected manifestations of a broader process of immune dysregulation. On the one hand, loss of self-tolerance may promote autoimmune disease; on the other hand, clonal expansion may lead to hematological malignancy. These processes are not mutually exclusive. Somatic mutations may enhance inflammatory pathways, while chronic inflammation may favour the expansion of mutated hematopoietic clones. The aim of this thesis was to explore this relationship through two complementary disease models. Sjögren’s disease was investigated as a systemic autoimmune disorder characterized by chronic exocrine gland inflammation and increased lymphoproliferative risk. Myeloid neoplasms were examined as clonal hematological disorders in which autoimmune manifestations may reflect specific molecular and biological backgrounds. By integrating imaging, histopathology, serology, and molecular profiling, this work sought to identify biomarkers able to capture the transition between immune activation, tissue damage, and clonal evolution. The first part of the thesis focused on Sjögren’s disease as a model of autoimmune lymphoproliferation. In this context, ultra-high frequency ultrasound (UHFUS) was explored not merely as a diagnostic technique, but as a tool capable of visualizing tissue-level manifestations of immune dysregulation. The observation that very hypoechoic areas in labial salivary glands corresponded to severe and atypical lymphoid infiltration provided the initial rationale for considering these lesions as candidate imaging biomarkers of lymphoid organization. This proof of concept was then expanded in a larger cohort of patients evaluated for suspected Sjögren’s disease, where labial salivary gland UHFUS showed diagnostic value and, more importantly for the scope of the thesis, helped distinguish different patterns of glandular involvement. Within this framework, very hypoechoic areas emerged as the most relevant ultrasound finding. Unlike more general abnormalities, such as inhomogeneity or hyperechoic bands, these lesions were observed only in patients with Sjögren’s disease and appeared to identify a more specific pattern of glandular immune involvement. Their relevance was further supported by the extension of UHFUS assessment to the lacrimal glands, where very hypoechoic areas were again detected only in Sjögren’s disease. This cross-organ recurrence suggests that these lesions may not be an isolated salivary gland finding, but rather a shared exocrine gland imaging phenotype potentially linked to severe lymphoid organization and lymphoproliferation-prone tissue changes. The second part of the thesis addressed the opposite perspective: whether clonal hematological disease may be associated with autoimmune manifestations. Myeloid neoplasms were considered as a model in which somatic mutations can shape inflammatory and immune pathways. The review of Philadelphia chromosome-negative myeloproliferative neoplasms provided the biological background for this concept, highlighting how clonal hematopoiesis and driver mutations may contribute not only to myeloid proliferation, but also to systemic inflammation, thrombosis, endothelial dysfunction, and autoimmune phenomena. Thus, clonal hematopoiesis was interpreted not only as a premalignant or malignant process, but also as a potential driver of immune-mediated clinical manifestations. The original study on myeloid neoplasms further supported this view. Autoimmune manifestations were not randomly distributed across patients but were associated with specific somatic mutational profiles. In particular, mutations involving genes such as ASXL1, RUNX1, PTPN11, DNMT3A, and TET2 appeared to define molecular backgrounds more frequently linked to autoimmunity. Although autoimmune disease itself did not significantly affect survival, some of the mutation profiles associated with autoimmunity were also linked to poorer outcome. This suggests that autoimmune manifestations in myeloid neoplasms may not simply represent coincidental comorbidities but may instead act as clinical indicators of distinct clonal architectures with potential prognostic relevance. Taken together, the findings of this thesis support a unified view of immune dysregulation. In Sjögren’s disease, chronic autoimmune inflammation may promote lymphoid organization within exocrine glands and create a microenvironment favourable to lymphoproliferative evolution. In myeloid neoplasms, somatic mutations may influence immune and inflammatory pathways, contributing to the development of autoimmune manifestations. Although these two models differ in their clinical expression, they converge on the same biological principle: immune dysregulation can manifest as autoimmunity, clonality, or both. From a translational perspective, this thesis identifies two complementary biomarker strategies. In Sjögren’s disease, UHFUS provides an imaging biomarker that may identify glandular lymphoproliferative involvement and support the diagnosis of SjD. In myeloid neoplasms, NGS provides a molecular biomarker associated with autoimmune manifestations and may contribute to hematological prognostic stratification. ogether, these findings suggest that imaging and molecular biomarkers can capture different but interconnected expressions of immune dysregulation, supporting a more integrated model of patient stratification at the interface between rheumatology and hematology. Future studies should validate these findings in larger, prospective, and multicentre cohorts in which molecular variables, imaging variables, including UHFUS of paired salivary and lacrimal glands and conventional SGUS, and environmental variables are comprehensively collected. In Sjögren’s disease, comparative imaging–histology studies will be essential to definitively demonstrate whether very hypoechoic areas correspond to lymphoproliferative tissue changes and to clarify their diagnostic and prognostic significance. In myeloid neoplasms, functional studies will be needed to determine whether specific molecular mutations directly contribute to the development of autoimmune manifestations, moving beyond association towards causality.