Does severe vitamin D deficiency impair immune regulation and raise infection and autoimmune risk?

Severe vitamin D deficiency, typically defined as serum 25-hydroxyvitamin D (25(OH)D) levels falling below 10–12 ng/mL (25–30 nmol/L), significantly compromises immune system homeostasis. For older adults, maintaining adequate immunomodulation is particularly critical due to age-related immunosenescence.

Clinical and effectiveness evidence

• Infection susceptibility: Clinical and epidemiological data reveal that severe deficiency correlates with a significantly increased risk, severity, and mortality of acute respiratory tract infections, sepsis, and severe COVID-19.
• Autoimmune activity: Observational studies consistently demonstrate an inverse relationship between serum 25(OH)D levels and autoimmune markers, particularly thyroid autoantibodies such as anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG). Clinical trials show that correcting severe deficiency through targeted vitamin D supplementation successfully reduces these autoantibody titers.

Mechanistic pathways

• Innate immunity compromise: Severe deficiency impairs vitamin D receptor (VDR)-mediated transcription of the CAMP gene. This directly reduces production of the essential antimicrobial peptide cathelicidin (LL-37), weakening first-line mucosal barrier defenses against pathogens.
• Adaptive immune dysregulation: Active vitamin D regulates the T-helper 17 (Th17) and regulatory T (Treg) cell balance. A severe lack of 25(OH)D disrupts this immunoregulatory axis, leading to a pro-inflammatory state characterized by reduced FoxP3+ Treg numbers—which compromises immunological tolerance—and unchecked Th17 activity that promotes B-cell autoantibody production.

Bottom line

• Severe vitamin D deficiency is robustly linked to impaired immune regulation and increased susceptibility to infections and autoimmune activity, mediated by compromised cathelicidin production and a disrupted Treg/Th17 immunoregulatory balance. For older adults, targeted repletion to maintain adequate 25(OH)D levels is a clinically important strategy to support mucosal defense and systemic immune tolerance.