Interplay between fungal infections and autoimmunity: mechanisms and therapeutic perspectives

Abstract

Fungal infections and autoimmunity share a complex, bidirectional relationship that significantly impacts patient outcomes. Emerging evidence highlights how fungal pathogens contribute to autoimmune processes by triggering immune dysregulation. Conversely, autoimmunity and its immunomodulatory treatments increase susceptibility to fungal infections. These interactions manifest through altered immune responses, including changes in inflammatory signaling, antigen recognition, and mycobiome composition. The resulting interplay complicates disease management, necessitating careful balancing of antifungal defenses with immune modulation. This review synthesizes current knowledge on the role of fungal infections in the progression of autoimmune conditions and explores how autoimmune diseases predispose individuals to fungal infections. Key insights emphasize the need for integrative treatment approaches, addressing both infection risks and immune system imbalances.

Keywords: Antifungal Therapeutics; Autoimmunity; Fungal Infections; Mycobiome.

Figure 1. Mechanisms that may link fungal infections to autoimmunity.

(A) Fungal dysbiosis impacting adaptive immunity. Recognition of fungi by host cells influences epithelial integrity and immune homeostasis. Myeloid cells, primarily CX3CR1⁺ MNPs, integrate fungal microbe-associated molecular patterns (MAMPs) and microenvironmental cues to coordinate immunity. Although commensal fungi can prevent inflammation, excessive Th17 responses contribute to autoimmunity. Candidalysin and proinflammatory cytokines, such as IL-1β, from myeloid cells are involved in Th17 polarization. Involvement of ASCAs is considered a possible candidate involved in pathogenicity. (B) Molecular and cellular mechanisms that may link fungal infections to autoimmunity. Although these links have yet to be fully established, the involvement of molecular mimicry, epitope spreading, and other immunomodulatory effects—such as trained immunity and innate tolerance—has been speculated. MNPs mononuclear phagocytes, ASCA anti-S. cerevisiae antibodies, DC dendritic cell, MS multiple sclerosis, RA rheumatoid arthritis, SLE systemic lupus erythematosus, APCs antigen-presenting cells, TCR T-cell receptor, MHC II major histocompatibility complex II. Graphics were created with BioRender.com.

Figure 2. Autoimmune conditions associated with fungal infections.

Various autoimmune and inflammatory conditions are impacted by fungal infections through fungal gut dysbiosis, antifungal antibodies and antigens, and immunomodulatory treatment. We summarized cases on RA, SLE, MS, T1D, and IBD (which is not an autoimmune disease). Graphics were created with BioRender.com.

Figure 3. Antifungal therapeutics, immune modulation, and autoimmunity.

(A) Antifungal therapies may impact autoimmune processes by modulating immune responses. Standard antifungal drugs—including polyenes, azoles, pyrimidine analogs, and echinocandins—not only target fungal components but can also activate innate immune receptors or allow host DAMP release, potentially triggering off-target immune activation. (B) As new strategies emerge, immunomodulatory treatments like colony-stimulating factors, IFNγ, and immune checkpoint inhibitors show promise in enhancing fungal clearance but may carry risks of promoting or exacerbating autoimmunity. Likewise, biologics and vaccines are advancing but require further investigation to assess long-term immune effects. Cell-based therapies, including granulocyte transfusions and fungal antigen-specific CAR-T cells, offer novel antifungal approaches but raise concerns about T-cell dysregulation. Graphics were created with BioRender.com.