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Severe Vitamin D Deficiency Elevates HSP70 Antibodies Indicating Ovarian Pathology
*Corresponding author: Kaushiki M. Kadam, Gamete Immunobiology Lab, National Institute for Research in Reproductive and Child Health, ICMR, Mumbai, India. kaushikikadam@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Ahire S, Choudhary KG, Kadam KM. Severe Vitamin D Deficiency Elevates HSP70 Antibodies Indicating Ovarian Pathology. Fertil Sci Res. 2025;12:16. doi: 10.25259/FSR_12_2025
Abstract
Objectives
The vitamin D endocrine system has a systemic role in regulating the immune and reproductive systems. New research shows that both calcium and vitamin D are important for female fertility. Vitamin D deficiency (VDD) is associated with polycystic ovarian syndrome (PCOS) and premature ovarian insufficiency (POI). However, VDD is asymptotic, especially in adolescents and young adults. Further, vitamin D regulates Tregulatory lymphocytes, whose deficiency mediates TH1 response, causing POI in women. Our lab has earlier reported that women with idiopathic POI and failed in vitro fertilization-embryo transfer harbour autoantibodies to heat shock proteins HSP70 and HSP90. Given the important role of Treg cells in immune tolerance and ovulation, we sought to assess whether severe VDD can compromise ovarian function and concomitantly elevate antibodies to HSP70.
Material and Methods
Immature Balb/c mice were weaned onto either a control or VDD diet and maintained for 150 days. Ovarian histology and serum anti-HSP70 levels were assessed at VDD60, 90 and 150 time points.
Results
Ovarian histology was unchanged at VDD60 and deteriorated by VDD90. Elevated anti-HSP70 titre was noted by VDD60, which was slightly increased by VDD90.
Conclusion
Our study shows that severe VDD can compromise ovarian function and concomitantly elevate antibodies to HSP70. This can be a potential early biomarker of severe VDD-induced underlying ovarian pathology.
Keywords
Autoantibodies
HSP70
Ovary
Premature ovarian insufficiency
Vitamin D
INTRODUCTION
Vitamin D deficiency (VDD) is asymptomatic and still prevalent globally, especially in adolescents and young adults. [1–3]
Vitamin D-FGF23-Parathyroid hormone (PTH)-prolactin feedback loop regulates calcium absorption and phosphorus reabsorption. Fluctuations in the vitamin D endocrine axis disrupt the immune system, intestine, liver, kidney and ovary function.[4]
Recent studies show that vitamin D and/or calcium have important roles in female fertility. [5,6] In women, VDD is associated with polycystic ovarian syndrome (PCOS) and premature ovarian insufficiency (POI) as well as autoimmune diseases. [7–9]
Thirty percent of cases of POI have an autoimmune origin. These women have increased autoantibody-producing B cells and altered Treg/effector T cell ratios, including autoantibodies to ovarian and thyroid antigens, which are indicative of disease pathology.[10,11] Recent studies with cyclophosphamide-induced POI mouse models show that regulatory T-cell (Treg) deficiency mediates TH1 response, leading to increased apoptosis of granulosa cells and impaired steroidogenesis.[12] Notably, VDD perturbs B cell, Treg cell, and dendritic cell populations crucial for tissue homeostasis and is known to cause POI in mice.[8,9,13]
Under steady-state conditions, Treg cells stimulate follicular B2 cells to secrete IgM and IgG subtype natural antibodies to self-proteins such as heat shock proteins (HSPs).[14] Natural antibodies are more likely in females. Their levels remain stable over time, potentially associated with debris clearance. However, they can increase with age. It is likely that changes in IgG autoantibodies against specific proteins could be indicative of disease pathology.[15] IgG and IgM autoantibodies to HSPA5, HSP90β, actin and alpha-actinin are reported with increased atretic follicles in women with idiopathic POI and failed in vitro fertilisation (IVF)-embryo transfers.[16,17]
Severe VDD leads to secondary hyperparathyroidism. In humans, long-term VDD is identified only through tools such as questionnaire-based studies.[18,19] Threshold values for VDD and the clarity in the inflection point of PTH are unclear in the adolescent population, making it difficult to identify[20–23] thus highlighting the need for another reliable marker.
The present exploratory study tests the hypothesis that VDD at a younger age would compromise thymic function, affecting peripheral tolerance, thereby elevating anti-HSP70 antibodies. A dietary intervention model with normal calcium and phosphorus would aid in mimicking the human condition. Ovarian histology and serum anti-HSP70 levels were assessed at VDD60, 90 and 150 time points to include at least two folliculogenesis cycles. The primary outcome was VDD-induced elevation in anti-HSPA5 Abs, while the secondary outcome was the change in Ab levels correlated to changes in ovarian pathology. The findings are discussed in correlation with our previous mouse model and human studies.
MATERIAL AND METHODS
Method
The study was approved by the Institutional Animal Ethics Committee (NIRRCH-IAEC Study No. 03/13). Female Balb/c Day 21 pups from each litter were weaned and randomly assigned to two groups: Control and VDD, each further subdivided into three groups: Day 60, 90 and 150 (N = 18). VDD was induced with a commercial diet having normal calcium and phosphate contents and no lactate (Cat No. 0296007410, MP Biomedicals, CA, USA). The control group was fed normal chow, while the VDD group was fed vitamin D-deficient chow.[24] Oestrus was monitored from Day 42. Blood was collected fortnightly from the retro-orbital vein. Mice were sacrificed in the diestrus phase closest to the treatment day of interest, and ovaries were harvested for histology. Ovaries were assessed as reported earlier.[25] Serum was separated for enzyme-linked immunosorbent assay (ELISA) and hormone assays. VDD onset was confirmed (total 25-OH Vitamin D, Cat No. 90340, Crystal Chem, IL, USA). Based on histology results, serum samples were pooled per group and tested for reactivity against immunodominant peptides of HSPA5, as reported earlier.[26] All peptides were coated at 1 μg/well. Serum (1:10) reactivity was tested by immunosorbent assay against immunodominant epitopes from HSPA5 [P1: EKFAEEKLK; aa546-556; signature peptide and P2: VVDSDELPLK, aa355-363 (peptide2.0, USA; 42% identity with mouse HSP90ß). Rat sperm tail ODF2 [LCLKVPECARQHRPGRERQEDCQ, in-house synthesised (Kadam et al., unpublished results) and blocking peptide (sc-365874 P)] and anti-ODF2 (sc-393881, Santa Cruz Biotechnology, USA) served as a negative control, while bovine serum albumin (BSA) fraction V (Sigma, USA) served as an internal control and anti-HSP70 (H5147, Sigma Aldrich, USA) as a positive control. Secondary antibody (1:6000 rabbit anti-mouse, Cat no. P0161, Dako, USA) was used to detect binding. 3,3',5,5'-Tetramethylbenzidine substrate (Cat no. T0440, Sigma Aldrich, USA) was used for detection. Reactivity was calculated after correcting for albumin autoreactivity.[27] Animals were excluded from the study due to death. Standardised effect size was calculated as reported.[28] Histology results (N = 6) were analysed by Student’s t-test and two-way ANOVA with Tukey’s post hoc test, while HSPA5 titres were analysed by t-test and principal component analysis with Jamovi.[29]
RESULTS
Histology
Ovarian histology [Figure 1-(I)] analysis showed alterations in follicles across time in the t-test (Suppl data): primary (p = 0.009, df = 32, effect size = 0.957), secondary (p = 0.313, df = 32, effect size = 0.352), tertiary (p = 0.004, df = 32, effect size = 1.076), Graafian (p = 0.041, df = 32, effect size = 0.733) and atretic (p = 0.029, effect size = −0.784), with no difference in corpora lutea (CL, p = 0.511, effect size = −0.229). The post hoc Shapiro-Wilk test showed significance for all follicle types except CL across time. Overall, antral follicle count was decreased in VDD90 vs. Control and had persistent CL [Figure 1 (II)-(a-e)]. Two-way ANOVA shows both diet and duration don’t have a significant effect on primary follicles [F(2,28) = 1.34, p = 0.278, effect size = 0.057]; however, diet alone has a significant effect {[F(2,28) = 3.57, p = 0.041, effect size = 0.152]. The overall model shows a significant effect [F(5,28) = 3.91, p = 0.008]}. There is a significant effect of diet and duration on secondary follicles {[F(2,28) = 7.25, p = 0.003, effect size = 0.268] overall model [F(5,28) = 4.97, p = 0.002]}. Both diet and duration don’t have a significant effect on tertiary follicles {[F(2,28) = 2.13, p = 0.138, effect size = 0.064], overall model [F(5,28) = 8.05, p < 0.001]}; however, Tukey’s post hoc test shows there is a significant effect of duration between groups (CTL60 vs. VDD60, p = 0.038, d = 1.921; CTL90 vs. VDD90, p = 0.034, d = 1.859; CTL60 vs. VDD150, p = 0.001, d = 2.851; CTL90 vs. VDD150, p = 0.003, d = 2.541). While diet [F(1,28) = 6.19, p = 0.019, effect size = 0.128] and duration [F(2,28) = 4.64, p = 0.018, effect size = 0.193] alone have significant effects on Graafian follicles in a small number of mice. The overall model shows both have significant effects on Graafian follicles [F(5,28) = 4.3,p = 0.005], while post hoc Tukey’s test shows both diet and duration [F(2,28) = 2.37] have significant effects (CTL60 vs. VDD90, p = 0.042, d = 1.807; CTL60 vs. VDD150, p = 0.022, d = 2.068) on Graafian follicles. Principal Component Analysis revealed that three factors account for 67.80% of the cause for ovarian dysfunction: type of follicle and duration of VDD (34.30%), atretic follicles (18.30%) and corpora lutea (15.30%) [[Figure 1-(II)-(g)]. Mature follicle numbers are being majorly affected, while persistent CL may contribute to elevated autoantibodies.
Suppl data
Suppl dataFSR_12_2025_SM_704295473.
- (I): Ovarian histology across days 60, 90 & 150 of VDD. (A) Control 150 shown for comparison against VDD60, 90 and 150. All analyses were done with age matched controls for VDD changes across time, (B-D) VDD60-150. Significant changes seen VDD90 onwards. Decreased primary, tertiary and Graafian follicles, persistent CL (*), decreased corpus albicans (star), several cysts (arrowheads), empty follicles (arrows). Note even at Control 150 all follicle types can be seen. There is no disruption of hilum observed which is evident in all VDD ovaries (N = 6). Magnification 40X. Histological staining with eosin-hematoxylin. (II): Changes in ovarian follicles with diet across time. Quantitative changes in ovarian follicles from Control (CTL) vs vitamin D deficient (VDD) groups at 60, 90 and 150 days: (a) primary, (b) secondary follicle, (c) tertiary follicle, (d) Graafian follicle, (e ) corpora lutea, (f) atretic follicles and (g) Principal Component analysis indicating factors contributing to ovarian pathology. Mean ± SD, N = 6.
Spontaneous Autoreactivity to Immunodominant Epitopes of HSPA5 and HSP90β
Serum immunoreactivity using two immunodominant epitopes of HSPA5 was assessed by immunosorbent assay [Figure 2a–b]. Reactivity was seen to both epitopes as early as VDD60; the titres were slightly elevated at VDD90 and then remarkably dropped by VDD150 when ovaries appeared afollicular on histology (data not shown) [CV: 4.21% and 3.11% intra-assay; 3.66% inter-assay variation]. Data have a non-normal distribution. Student’s t-test showed reactivity to P1 was significant [F(1,4) = 8.988, p = 0.04] with a moderate effect (0.556) vs. P2 [F(1,4) = 0.787, p = 0.573, effect size = 0.778] between groups across time.
- Spontaneous autoreactivity by ELISA. Immunodominant epitopes (a) P1, Peptide 1 & (b) P2, Peptide 2 from heat shock proteins HSPA5 and HSP90β were reacted with pooled sera (N = 6; 1:10) obtained at 60, 90 and 150 days of vitamin D deficiency (VDD) vs Control (CTL). Note changes in antibody titres across time between groups.
DISCUSSION
The study explored VDD-induced elevation in HSPA5 antibodies and correlative changes in ovarian histology. A dietary interventional model was used to induce VDD in immature Day 21 female mice to mimic human conditions. This model for VDD with a diet normal in calcium and phosphate, while lacking lactose, has been compared in Balb/c and C57Bl/6 strains. Of these, Balb/c mice showed 17-fold lower Cyp27b1 mRNA (1alpha-hydroxylase, converts vitamin D into its active form) levels with concomitant reduction in circulating vitamin D levels.[24] as well as elevated PTH and prolactin (PRL) levels by VDD60 onwards.[30,31]Further, this strain shows a greater number of Treg cells and tight regulation of autoantibodies to HSP70.[32–34] These factors favoured the use of the Balb/c strain to test our hypothesis of a VDD-mediated drop in Treg numbers manifesting in elevated HSPA5 autoantibodies.
Correlating with human age (post-weaning as per Dutta and Sengupta[35]) the mice at Day 21 (6 years—comparable age in humans) weaned onto a VDD diet were maintained for 150 days.[35] Mice were sacrificed at VDD60 (16.4 years), VDD90 (24.65 years) and VDD150 (43 years). Gifondorwa and group report that Balb/c mice weaned onto VDD diets with normal calcium have a ~30% drop in serum calcium levels with no hypophosphatemia by VDD56 (15.3 human years), while hyperparathyroidism sets in by VDD63 (17.22 human years).[33] Thus, findings indicate a combined systemic effect of VDD and elevated PRL.
The ovaries were not significantly different between the groups by VDD60 (16.4 years). However, oestrus cycle irregularities were apparent VDD60 onwards and escalated with the onset of severe VDD by day 90 (data not shown). This led to a protracted diestrus phase in the VDD90 group (data not shown). Persistent CL in the VDD group could be a source of unresolved inflammation. The first signs of autoantibodies were at VDD60 (16.4 human years) before the hyperparathyroidism onset and agree with the literature.[33] The Ab titre increased along with ovarian dysfunction by VDD90 (24.65 human years). Reactivity to P1 was seen across time, while that for P2 was seen only at VDD90 when the titres were high. This could be due to elevated PRL, which is elevated further by VDD90 and then plateaus.[33] Overall, this agrees with 8–9 years for autoimmune initiation in humans.
In silico stochastic modelling suggests that vitamin D insufficiency alters the Treg/Teff ratio, thereby leading to autoantibody generation.[36] Thus, in our study, severe VDD seems to have altered the Treg/Teff ratio, as seen from reactivity to immunodominant epitopes (P1 and P2) of HSPA5.
Previous studies from our lab found reactivity to these epitopes at a mean age of 27.7 ± 6.0 years in women with idiopathic POI.[16] At the time, we did not investigate PTH and PRL status since PRL is not a reliable marker.[37] Nonetheless, 43.48% of these women showed reactivity to HSPA5 and/or HSP90β in combination with other antigens. Of these women, only 2.7% with reactivity to HSPA5 alone could conceive through IVF, while 5.4% who had reactivity to both HSPA5 and HSP90β did not. The reactivity was seen in both oocyte and CL in human and mouse models.[25,38] The age of detection for either HSPA5 and/or HSP90β was late twenties to early thirties, while for HSP90β alone, it was early twenties in humans. Reactivity to both HSPs could be due to higher anti-HSPA5 Ab titres as well as the number of follicles. In our mouse study, immunosuppression could rescue fertility when reactivity to P2 and hence HSP90β was lost with a reduction in Ab titres.[39] Correlating these with our present study, it is likely that undetected vitamin D insufficiency in peri-pubertal years may lead to raised HSPA5 Abs. Further escalation to severe VDD-induced secondary hyperparathyroidism in late teen years is potentially detrimental to female fertility.
Severe VDD-induced secondary hyperparathyroidism elevates PRL, which, through its receptor, acts on the ovary and immune cells. In the ovary, it induces POI via receptors in the antral follicles and cumulus-oocyte complexes.[40] It increases HSP70 expression in granulosa cells (GCs) and induces apoptosis by downregulating its receptors and triggering oxidative stress autophagic pathways in ovarian GCs.[41–43] Both GCs and HSP70 act as antigen-presenting entities for the innate immune system during ovulation.[44–46] Under steady-state conditions, ovulation is an inflammatory condition stemmed by resident immune cells as well as those recruited from the gut to prevent autoimmunity. However, high PRL promotes proinflammatory cytokine-mediated alteration of Treg and dendritic cell populations.[47,48] In POI induced with immunodominant HSPA5, actin and actinin peptides, there was no immune infiltration of the ovary. However, increased atretic follicles were noted.[25] Thus, it is likely that HSP70 Abs may be anti-inflammatory and counter the escalation of CL regression into an autoimmune disease. This agrees with our present findings wherein ovarian failure appears to manifest by VDD90 from the onset of elevated circulating anti-HSPA5 (VDD60). IgG levels are reported to increase due to insufficient vitamin D in school-age children.[36,49] In our study, anti-HSPA5 Ab titres peaked from VDD60 (deficient) to VDD90 (severely deficient) with a sharp reduction at VDD150, with a change in histology and loss/reduction of the inciting antigen (data not shown). Thus, it appears that HSPA5 Abs is the earliest sign of underlying ovarian pathology.
In adolescents, growth hormone (GH) can mitigate calcium deficiency via the PRL receptor.[50] However, when GH pulsatility becomes irregular in girls in their late teens, this protective effect may be lost. Thus, this may affect calcium levels in vitamin D insufficient/deficient girls, further affecting Treg cell populations. Likely, the age of onset, calcium intake and VDD severity-mediated PRL elevation will determine ovarian function in these girls. Nevertheless, depending on the ovarian reserve, these women can get pregnant. The presence of elevated anti-HSPA5 Abs could be a differentiating factor.
A limitation of this study is the exploratory nature, small sample size and pooled sera, limiting statistical analyses. Further, we did not explore other antigens reported in POI. It will be worthwhile to investigate if the persistent CL leads to reactivity to other antigens over time. Anti-HSPA5 Abs can be predictors of pregnancy outcomes and immunosuppressant regimen.[16,25,26] Further, they can be developed as a useful biomarker for early diagnosis of VDD-induced underlying ovarian pathology and POI risk.
Acknowledgements
Mr. Devidas Gaikwad and Mr. Mahadeo Marchande from the GIB lab, with Mr. Tawade and Mr. More (Animal House Facility, NIRRCH), are gratefully acknowledged for their technical assistance. The study was completed with financial aid from the Indian Council of Medical Research.
Authors’ contributions
KK: Formulated the study; KK, SA, KC: Did the experiments and collected data; KK: Analysed the data and wrote the manuscript.
Ethical approval
The research/study was approved by the Institutional Review Board at the National Institute for Research in Reproductive and Child Health, number 03/13, dated 5th March 2013.
Declaration of patient consent
Patient consent is not required as there are no patients in this study.
Financial support and sponsorship
Indian Council of Medical Research.
Conflicts of interest
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
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