Cellular dysregulation in autoimmune and autoinflammatory diseases: Emerging mechanisms and therapeutic opportunities

Autoimmune and autoinflammatory diseases have traditionally been interpreted as disorders arising from dysregulation of adaptive or innate immune responses, respectively. However, growing evidence suggests that these conditions are more broadly rooted in alterations of cellular homeostasis across multiple cell types, including both immune and non-immune compartments.

Disrupted cell-intrinsic processes—such as aberrant stress-adaptive responses, defective protein homeostasis, metabolic imbalance, epigenetic remodeling, persistent inflammasome activation and pro-inflammatory cytokine production, impaired resolution of inflammation, dysregulated senescence programs, and maladaptive trained immunity—are increasingly recognized as key contributors to disease pathogenesis.

Furthermore, intercellular communication within complex tissue microenvironments—mediated by paracrine signaling and extracellular vesicles—plays a critical role in amplifying and sustaining immune dysregulation and inflammatory responses. This evolving perspective calls for a more integrated understanding of disease mechanisms, centered on cell-intrinsic and extrinsic alterations as unifying frameworks across autoimmune and autoinflammatory conditions.

Despite important advances in the understanding of immune-mediated pathways and diseases, many mechanistic aspects underlying autoimmune and autoinflammatory disorders remain poorly defined, limiting the development of effective and targeted therapies. This Research Topic aims to address the need for a comprehensive framework that integrates cell-intrinsic and extrinsic mechanisms driving disease pathogenesis across both immune and non-immune compartments. In particular, we seek to explore how alterations in cellular programs—such as proteostasis, stress responses, inflammasome activation, metabolic rewiring, senescence, and epigenetic changes—interact with microenvironmental signals to shape disease progression.

Recent technological advances, including single-cell omics, spatial omics, and systems biology approaches, offer unprecedented opportunities to dissect these processes at high resolution. By bringing together fundamental and translational research, this Research Topic aims to identify novel pathogenic pathways and uncover innovative therapeutic strategies targeting not only immune responses but also broader cellular dysfunctions, ultimately fostering more precise and effective interventions.

This Research Topic welcomes Original Research Articles, Reviews, and Perspectives on cellular dysregulation in autoimmune and autoinflammatory diseases, spanning basic, translational, and clinical research. We aim to understand how disrupted cellular homeostasis, together with altered cell-extrinsic mechanisms, drives disease across immune and non-immune compartments.

We particularly encourage submissions addressing:

- Dysregulation of non-immune and immune cells contributing to disease pathogenesis

- Cell-intrinsic pathogenic mechanisms, including aberrant stress-adaptive responses, defective protein homeostasis, metabolic imbalance, epigenetic remodeling, persistent inflammasome activation and pro-inflammatory cytokine production, impaired resolution of inflammation, dysregulated senescence programs, and maladaptive trained immunity

- Role of the tissue microenvironment and cell-extrinsic mechanisms in disease pathogenesis, including paracrine networks and extracellular vesicle-mediated intercellular communication

- Single-cell and spatial omics, and systems biology approaches to dissect cellular heterogeneity and disease networks

- Mechanisms linking chronic inflammation to tissue damage, dysfunction, and impaired repair

- Mechanisms underlying the onset and progression of autoimmunity, including pathways linking immune dysregulation to tissue damage, dysfunction, and defective repair

- Identification of novel biomarkers of cellular dysfunction and therapeutic targets

- Emerging, regenerative, and resolution-based therapeutic strategies beyond classical immune modulation

We particularly encourage studies that bridge mechanistic insights with translational relevance and therapeutic innovation.

This Research Topic accepts submissions in the following formats: Brief Research Report, Case Report, Classification, Clinical Trial, Editorial, FAIR² Data, General Commentary, Hypothesis and Theory, Methods, Mini Review, Opinion, Original Research, Perspective, Review, Study Protocol, Systematic Review, and Technology and Code. All published articles will undergo rigorous external peer review and may be subject to publication fees.


Please note that manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this Research Topic. Manuscripts focusing solely on cost-effectiveness studies are also not considered for publication in this journal.


Topic Editor Raffaella Molteni declares having created the following patent with number PCT/IB2024/060412 "MEANS AND METHODS FOR GENETIC MODIFICATION OF UBA1" filed on 23 Oct 2024 (Status: pending; Inventors: S.Ferrari, M. Fiumara, L. Naldini, R. Molteni, G. Cavalli)

This Research Topic accepts submissions in the following formats: Brief Research Report, Case Report, Classification, Clinical Trial, Editorial, FAIR² Data, General Commentary, Hypothesis and Theory, Methods, Mini Review, Opinion, Original Research, Perspective, Review, Study Protocol, Systematic Review, and Technology and Code. All published articles will undergo rigorous external peer review and may be subject to publication fees.

Please note that manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this Research Topic. Manuscripts focusing solely on cost-effectiveness studies are also not considered for publication in this journal.