A cross-species review traces how iodine influences immune defenses and why the boundary between benefit and harm remains difficult to define.
Paper: Iodine and Its Impact on the Immune System of Humans and Domesticated Mammals: A Narrative Review
In a recent narrative review published in the journal Nutrients, researchers at the University of Guelph and ImmunoCeutica Inc., Canada, mapped the direct and indirect immunomodulatory mechanisms of iodine across humans and domesticated mammals. The review suggested that iodine status follows a narrow U-shaped relationship, with an adequate intake range supporting leukocyte metabolism, tissue antioxidant capacity, and thyroid-hormone-driven immune responses, although the precise intake and tissue-level thresholds for immune function remain uncertain.
Crucially, both chronic iodine deficiency and sustained dietary excess may disrupt immune homeostasis. Deficiency may weaken host microbial clearance, while sustained excess may promote oxidative stress, altered cytokine profiles, and autoimmune thyroiditis in genetically and epigenetically susceptible individuals.
Background
Iodine is an essential micronutrient traditionally best recognized for its role in thyroid hormone (TH; thyroxine [T4] and triiodothyronine [T3]) biosynthesis. More recent evidence, however, indicates that, beyond the thyroid gland, active iodide (I−) transport occurs in tissues expressing transporters such as the sodium iodide symporter (NIS) or pendrin. Within thyroid follicular cells specifically, NIS is located on the basolateral membrane and pendrin on the apical membrane.
These sites include the salivary glands, lactating mammary tissue, gastric mucosa, and immune structures such as the bone marrow, thymus, and spleen, while iodine also accumulates in circulating leukocytes.
Studies have shown that while population dietary guidelines, including those established by the Institute of Medicine, Health Canada, and the World Health Organization (WHO), define recommended daily intakes to prevent classical goiter and neurodevelopmental deficits, these frameworks rely largely on thyroid-centric parameters.
Unfortunately, the impacts of iodine intake on leukocyte signaling cascades, reactive iodine species (RIS) generation, and multisystem immune competence across mammalian species remain poorly characterized and inconsistently integrated into nutritional guidance.
*Iodine exerts immunomodulatory, antimicrobial, and antioxidative effects that depend on iodine intake and tissue context. Under sufficient iodine intake, thyroid hormone (TH) production supports balanced natural killer (NK) cell and T and B cell responses, iodophor (povidone-iodine, PVP-I) use promotes effective myeloperoxidase (MPO)-mediated microbial killing via controlled reactive iodine/oxygen species (RIS/ROS), and dietary iodide enhances nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant capacity in the blood, mammary gland, and milk, including induction of superoxide dismutase (SOD) and glutathione peroxidase (GPx). In contrast, iodine imbalance (insufficient or excess) skews T helper (Th)1/Th17 and regulatory T cell (Treg) populations with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, predisposing to autoimmune thyroiditis, impairing MPO-derived RIS/ROS-mediated host defence at low iodine, and amplifying ROS-driven oxidative stress, inflammation, and tissue injury at excess iodine. *
About the study
The present review aimed to address this knowledge gap by evaluating the nutrikinetics, direct leukocyte interactions, and thyroid-mediated immunomodulatory pathways of iodine across humans, livestock (cattle, sheep, goats, and swine), and companion animals (dogs, cats). The authors used targeted PubMed searches and manual screening of reference lists, making this a narrative synthesis rather than a systematic review or meta-analysis.
The narrative review examined several mechanisms, including NIS- and pendrin-mediated cellular uptake, type 1 iodothyronine deiodinase (DIO1) conversion of T4 to bioactive T3, myeloperoxidase (MPO)-dependent antimicrobial halogenation, and nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant signaling.
Furthermore, the review analyzed the immunological outcomes of the acute Wolff-Chaikoff effect versus the Jod-Basedow phenomenon, alongside underlying genetic risk loci (HLA-DR, CTLA4, PTPN22) and epigenetic DNA methylation patterns (CCL5, CXCL8, CXCR5, YWHAG) associated with iodine-induced autoimmunity.
Study findings
One cited human cell-culture study found that direct leukocyte exposure to iodide at low to sub-millimolar concentrations (10-1000 µM in vitro) increased peripheral blood mononuclear cell (PBMC) secretion of interleukin (IL)-6, interferon-gamma (IFN-γ), and IL-10. The authors cautioned that these concentrations likely exceed typical free iodide levels in lymphoid tissues and should not be interpreted as physiological exposure thresholds.
However, other in vitro studies indicated that complex formulations or higher concentrations shifted cytokine balances toward pro-inflammatory chemokines, such as IL-8 and monocyte chemoattractant protein-1 (MCP-1). Because these findings came from controlled PBMC experiments, their relevance to whole organisms remains uncertain. Under iodine deficiency, experimental and clinical evidence suggests that reduced TH signaling may impair neutrophil and macrophage chemotaxis and reduce T cell proliferation and activation markers (CD25, CD69), while reduced iodide availability may limit MPO-driven production of reactive iodine species (RIS) and reactive oxygen species (ROS), weakening pathogen killing.
B cell-mediated adaptive immunity may also be compromised, with studies reporting attenuated antibody titers, smaller germinal centers, and delayed immunoglobulin class switching from IgM to IgG.
Conversely, experimental and animal studies suggest that chronic iodine excess can promote excessive intrathyroidal iodination, thereby generating ROS that cause cell injury or death and the release of alarmins.
Downstream, alarmin ligation of pattern recognition receptors can activate nuclear factor-kappa B (NF-κB), driving local expression of IL-1β, IL-6, and TNF-α. In healthy individuals, acute high-dose iodide exposure was observed to trigger the self-limiting Wolff-Chaikoff effect, transiently blocking TH synthesis for 24-50 hours before "escape" via NIS downregulation usually restores homeostasis.
In contrast, susceptible individuals, including those with previously iodine-deficient or structurally abnormal thyroids and autonomous nodules, may develop the Jod-Basedow phenomenon, in which affected thyroid tissue fails to suppress iodide transport and can produce sustained thyrotoxicosis. Evidence for this phenomenon comes mainly from case reports and small series in high-risk individuals and does not establish precise dose thresholds or population-wide incidence.
In genetically susceptible hosts carrying HLA-DR susceptibility alleles, heavily iodinated thyroglobulin and thyroid peroxidase (TPO) peptides may be presented more efficiently to autoreactive CD4+ T cells. Variants affecting CTLA4 and PTPN22, two regulators of immune activation, may further reduce control over autoreactive T- and B-cell responses.
Epigenetic analyses from mostly cross-sectional studies associated iodine exposure and autoimmune thyroiditis with altered methylation of genes involved in chemokine signaling (CCL5, CXCL8, and CXCR5) and cellular stress responses (YWHAG and BRSK2). These patterns may modulate chemokine expression, lymphocyte recruitment, and thyroid cell stress signaling, but their causal mechanisms and temporal stability remain uncertain.
Finally, comparative veterinary data identified species-specific outcomes. In dairy cattle, one study found that iodine supplementation improved udder health, reduced milk somatic cell counts, and enhanced Fc-γ receptor-mediated phagocytosis. In pregnant ewes, iodine intake several-fold above requirements was accompanied by lower lamb plasma IgG after colostrum consumption, suggesting impaired passive transfer and less efficient neonatal intestinal absorption despite adequate colostral IgG.
Similarly, in companion animals, iodine excess produced thyroid changes consistent with goiter and potentially primary hypothyroidism in canine puppies, while long-term excess has been identified as a potential contributor to nodular thyroid hyperplasia and hyperthyroidism in aging cats, although feline hyperthyroidism is multifactorial.
Conclusions
The present narrative review emphasizes that iodine operates within a narrow physiological window essential for balancing endocrine output, cellular redox status, and immunocompetence, although exact immune-specific boundaries have not been defined.
The authors caution that existing dietary guidelines focus primarily on classical thyroid deficiency outcomes and rarely incorporate immune-function endpoints, extrathyroidal iodine targets, or tissue-specific toxicity thresholds.
The review emphasizes that future research should prioritize longitudinal human cohorts and intervention studies, together with controlled animal studies, that integrate precise exposure biomarkers with detailed immunological endpoints to refine species- and life-stage-specific intake guidelines.
Journal reference:
- Simpson, R. A., Shandilya, U. K., Wagter-Lesperance, L. C., Bridle, B. W., Mallard, B. A., & Karrow, N. A. (2026). Iodine and Its Impact on the Immune System of Humans and Domesticated Mammals: A Narrative Review. Nutrients, 18(15), 2432. DOI: 10.3390/nu18152432. https://www.mdpi.com/2072-6643/18/15/2432