When leaders fail: Exploring the role of dysfunctional leader cells in autoimmune disease pathogenesis

Leader cell dysfunction, disrupting tissue repair and immune communication, presents a novel and potentially crucial mechanism contributing to autoimmune disease pathogenesis. Elucidating the specific roles and dysfunctions of leader cells in various autoimmune conditions could unveil new therapeutic targets, although significant challenges in research and therapeutic implementation remain. 

The concept of 'leader cells'—specialised cells orchestrating collective cell behaviours during development, tissue repair, and cancer progression—offers a compelling, yet relatively unexplored lens for examining  the pathogenesis of autoimmune diseases [1]. These cells are crucial for maintaining tissue homeostasis and integrity, coordinating complex processes through mechanical force generation, signaling molecule secretion, and intercellular communication [1, 2]. Dysfunction within these critical leader cells, potentially arising from genetic predispositions, environmental insults, or pathogen interactions, can profoundly disrupt tissue equilibrium [2]. We hypothesise that such leader cell dysfunction represents a significant factor in the breakdown of self-tolerance and the subsequent development of autoimmune pathology, potentially linking tissue-level dysregulation to immune system activation, a concept often explored through mechanisms like molecular mimicry [3].

The precise mechanisms by which dysfunctional leader cells could trigger or perpetuate autoimmunity are likely multifaceted. Aberrant tissue repair responses represent a key pathway; failure of leader cells to properly orchestrate repair can lead to chronic inflammation, excessive release of damage-associated molecular patterns (DAMPs), and inappropriate exposure of self-antigens, providing triggers for autoreactive immune responses [4, 5]. Furthermore, dysfunctional leader cells might alter the local immune microenvironment through dysregulated production of cytokines, chemokines, or extracellular vesicles, shifting the balance towards a pro-inflammatory state and impairing regulatory immune cell function [6, 7]. Specific leader cell populations have been implicated in tissues prone to autoimmune attack. For instance, in the pancreas, specialized 'hub' or 'leader' beta cells that normally coordinate islet responses could, if dysfunctional, contribute to the inflammatory milieu and beta cell destruction seen in Type 1 Diabetes [8, 9]. Similarly, compromised leader cell function during repair in epithelial tissues like the gut or skin could impair barrier integrity, potentially driving conditions like inflammatory bowel diseases or psoriasis [7, 10].

This leader cell perspective complements established autoimmune mechanisms like genetic susceptibility and environmental triggers [3]. However, significant challenges remain. Distinguishing whether leader cell dysfunction is a primary cause or a secondary consequence of the autoimmune process (cause or effect) is crucial. Experimental hurdles include the precise identification and specific manipulation of leader cells in vivo within complex tissue environments. Furthermore, the potential overlap in mechanisms between leader cells in repair and cancer necessitates caution when considering therapeutic interventions [1].

I do not have any conflict of interest.