Association of vitamin D status with immune markers in a cohort of healthy adults

Authors: Riazati, Niknaz; ENGLE-STONE, REINA - University Of California, Davis; STEPHENSEN, CHARLES - US Department Of Agriculture (USDA)

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/13/2024
Publication Date: 12/21/2024
Citation: Riazati, N., Engle-Stone, R., Stephensen, C.B. 2024. Association of vitamin D status with immune markers in a cohort of healthy adults. Journal of Nutrition. 155(2):621-633. https://doi.org/10.1016/j.tjnut.2024.12.010.
DOI: https://doi.org/10.1016/j.tjnut.2024.12.010

Interpretive Summary: Adequate vitamin D status is currently defined as a serum 25-hydroxy vitamin D (25(OH)D) threshold of 50 nmol/L because this level is needed for maintenance of calcium balance and bone health.  However, in the past 20 years research has shown that vitamin D affects many aspects of immune function independent of its role in calcium biology.  Efforts have thus begun to determine if the 50 nmol/L threshold also allows for adequate immune function.  To address this question, ARS scientists from the Davis Location conducted an observational study in 361 healthy adults to identify linear or curvilinear associations between 25(OH)D and 79 markers of immune function with the goal of finding inflection points suggestive of a vitamin D status threshold for specific immune markers. Inflection points were found at or below approximately 50 nmol/L for three immune markers, two of which relate to higher inflammatory immunity below this level. Five other inflection points were found at approximately 70 nmol/L, all of which suggest a threshold for dampening of inflammatory immunity peaking at this level, perhaps driven by regulatory T cell activity and dampening production of the T-cell chemokine IP-10.  These results suggest that two thresholds may exist for immune activity.  Serum 25(OH)D concentrations below 50 nmol/L may represent a deficient level resulting in signs of systemic immune activation (e.g., elevated blood platelets), while levels between 50 and 70 nmol/L show increasing regulatory T-cell activity plateauing at 70 nmol/L, suggesting this higher level as a threshold for adequate immune regulation.  These proposed thresholds should be useful for designing future intervention studies to help define recommendations for vitamin D intake to optimize immune health.

Technical Abstract: Background: Immune function is affected by vitamin D status, but the optimal serum 25-hydroxy vitamin D [25(OH)D] concentration for immune function is not known. Objectives: We hypothesized that 25(OH)D would be associated with markers of inflammation and immune activation. Methods: We identified associations between 25(OH)D and immune markers from 361 healthy adults using polynomial regression. Linear regression was used to define the slope (ß) of significant linear associations, and piecewise regression identified inflection points (IPs) for curvilinear associations with P < 0.05. IPs with a slope difference (SD) P < 0.05 before and after were significant. Results: 25(OH)D had linear, negative associations with interleukin (IL)-6 (ß: 0.126; P ¼ 0.009) and macrophage-derived chemokine (MDC) (ß: 0.108; P ¼ 0.04) and a linear, positive association with matrix metalloproteinase (MMP)-1 (ß: 0.108; P ¼ 0.04). Among the significant curvilinear associations, 2 showed negative associations below but positive associations above an IP with nearly significant SD P values, including percentage of effector-memory CD8 T cells (IP: 56.2 nmol/L; SD P ¼ 0.067) and platelet concentration (IP: 38.9 nmol/L; SD P ¼ 0.058). The opposite associations, positive below and negative above an IP, were seen for eotaxin (IP: 49.5 nmol/L; SD P ¼ 0.049); interferon (IFN)-'-induced protein-10 (IP-10) (IP: 71.8 nmol/L; SD P ¼ 0.02); percentage of CD4 T cells expressing programmed cell death protein (PD)-1 (IP: 71.2 nmol/L; SD P ¼ 0.01); percentage of Tregs expressing human leukocyte antigen, DR isotype (HLA-DR) (IP: 67.5 nmol/L; SD P < 0.0001); percentage of memory Tregs (IP: 68.8 nmol/L; SD P ¼ 0.002); and percentage of memory Tregs expressing HLA-DR (IP: 68.8 nmol/L; SD P ¼ 0.0008). Conclusions: These findings are consistent with low vitamin D status allowing and higher vitamin D status dampening inflammation and immune activation. IP analysis identified possible thresholds for vitamin D effects on immune function. Two of 3 IPs at ~50 nmol/L show higher inflammation below this concentration, suggesting 50 nmol/L as a minimum target for dampening inflammation. IPs at ~70 nmol/L identify a threshold for CD4 T-cell activity, including Treg activation and IFN-'-driven production of the T-cell chemokine IP-10, suggesting an optimal concentration for regulating adaptive immunity. This study was registered at clinicaltrials.gov as NCT02367287.