Vitamin D and estrogen steroid hormones and their immunogenetic roles in Infectious respiratory (TB and COVID-19) diseases

Borborema, Maria Eduarda de Albuquerque; Lucena, Thays Maria Costa de; Silva, Jaqueline de Azevêdo

doi:10.1590/1415-4757-GMB-2022-0158

person Maria Eduarda de Albuquerque Borborema

schoolUniversidade Federal de Pernambuco, Departamento de Genética, Laboratório de Genética e Biologia Molecular Humana (LGBMH), Recife, PE, Brazil.schoolUniversidade Federal de Pernambuco, Laboratório de Imunopatologia Keizo Asami (LIKA), Recife, PE, Brazil.

person Thays Maria Costa de Lucena

schoolUniversidade Federal de Pernambuco, Departamento de Genética, Laboratório de Genética e Biologia Molecular Humana (LGBMH), Recife, PE, Brazil.schoolUniversidade Federal de Pernambuco, Laboratório de Imunopatologia Keizo Asami (LIKA), Recife, PE, Brazil.

person Jaqueline de Azevêdo Silva

schoolUniversidade Federal de Pernambuco, Departamento de Genética, Laboratório de Genética e Biologia Molecular Humana (LGBMH), Recife, PE, Brazil.schoolUniversidade Federal de Pernambuco, Laboratório de Imunopatologia Keizo Asami (LIKA), Recife, PE, Brazil.

0000-0003-1660-7299

Associate Editor:

Carlos F. M. Menck

Send correspondence to Jaqueline de Azevêdo Silva. Universidade Federal de Pernambuco, Departamento de Genética, Laboratório de Genética e Biologia Molecular Humana (LGBMH), Av. Prof. Moraes Rego, 1235, 50760-901, Recife, PE, Brazil. E-mail: Jaqueline.azevedo@ufpe.br.

Conflict of Interest

The authors declare that there is no conflict of interest that could be perceived as prejudicial to the impartiality of the reported research.

groupsAuthor Contributions

MEBA wrote, discussed, conceived, and prepared all figures of the manuscript; TMCL wrote the COVID-19 related sessions, participated in all figures concept, design, and discussion; JAS conceived, discussed the sessions and figures, reviewed, and proof read the manuscript. All authors read and approved the final version.

Figures (5)
Tables (2)

Thumbnail

Figure 1 - Metabolic and genetic aspects of VD₃. A) Metabolism of VD₃. In epidermal cells is found the molecule 7-dehydrocholesterol, which is broken down by UVB radiation from the sun, forming pre-VD₃. This undergoes first hydroxylation process in liver through CYP2R1 enzyme, having as a product of the reaction to 25-hydroxyvitamin D₂. This is converted into 1,25α-dihydroxyvitamin D₃ through the second hydroxylation process through CYP27B1 enzyme. B) Chromosomal localization of the VDR gene. VD₃ performs its functions by connecting to the VDR, forming VD₃/VDR. C) Transcriptional complex of VD₃/VDR. Gene regulation by genomic site (red arrow) occurs when VD₃ binds to VDBP transporter. The VD₃/VDR interaction is recruited to nucleus that heterodimerizes with RXRα and RXRβ. These act as transcription factors and bind to the VDREs present in the promoter region of target genes. Gene regulation by means of the alternative site (blue arrow) is a rapid response that occurs when VDR interacts with caveolae and through signal transduction activates the PI3K enzyme that induces intracellular conduction through secondary messages in the promoter region of target genes.

Thumbnail

Figure 2 - Genetic effect of VDR on different cells of the immune system. In macrophages VDR inhibits activation of NF-kB. In monocytes, the production of IL-6, TNF-α and MCP-1 is inhibited. The VD₃/VDR/RXR complex promotes IFN-γ gene silencing. Blockade of AP-1 and NFAT formation by VD₃/VDR/RXR complex promotes suppressive effect on transcription of IL-2, IL-9 and IL-17. The immunomodulatory action of VD₃ inhibits the immune response of Th1 cells and modulates the activities of Th2 and Treg cells, through the production of IL-4, and IL-10 and TGF-β, respectively. VD₃ inhibits the production of antibodies.

Thumbnail

Figure 3 - Mechanism of action of the Mtb in front of VD₃. The Mtb is phagocytized by the alveolar macrophages, is internalized in phagosome, fuses with lysosome and forms the phagolysosome via IFN-γ. Bacilli remain in the cytoplasmic vacuole and recruit immune cells to maintain the innate response. Mtb can be recognized through TLRs and induces several cascades of intracellular signaling. The presence of VD₃ affects Mtb infection through two mechanisms: recruitment of the VD₃/VDR/RXR complex to the VDRE present in promoter region of the hCAP-18 gene and consequent production of LL-37, antimicrobial peptide, and formation of IFN-γ independent phagolysosome with activation of PI3K signal transduction.

Thumbnail

Figure 4 - Immunogenetic activity of VD₃ in COVID-19. VD₃ induces the production of Treg cells. The VD₃/VDR complex induces expression of anti-inflammatory cytokines. VD₃ inhibits the differentiation and maturation of DCs, preventing migration to lymph nodes and activation of T cells of pro-inflammatory profile. VD₃ regulates expression of PD-L1. The increase in the activity of the alternative axis of RAS induces greater expression of ACE2, VD₃ may decrease viral replication.

Thumbnail

Figure 5 - Genomic and non-genomic mechanisms of E₂. In genomic signaling, E₂ binds to ERα and ERβ receptors in the cytoplasm, which undergo a conformational change, dimerize, and are translocated to nucleus. ERα e ERβ act as transcription factors, and E₂/ER complex binds to ERE sequences near promoter region inducing transcription. In non-genomic signaling, plasma membrane receptors activate PI3K/AKT. The ERα subunit binds to Cys447 and also binds to caveolae through Ser522, inducing transcriptional activity due to histone modification. E₂ also has a link with GPCRs that interacts with E₂/ER complex and induces transcriptional activation.

Thumbnail

Table 1 - VDR SNPs.

Thumbnail

Table 2 - Lifetime immune profile.

VDR SNP	Function
rs2228570 (FokI)	Location: exon 2; Change: C > T. Generates a non-synonymous polymorphism resulting in a change of threonine to methionine. The presence of the restriction site FokI C allele, generates a new start codon (ATG) 9 bp after the common starting site, which translates to a shorter truncated VDR protein of 424 amino acids with more transactivation capacity as a transcription factor than the wild type full-length VDR A isoform (VDRA) with 427 amino acids (Luo et al., 2011; Carvalho et al., 2015; Salimi et al., 2019).
rs11568820 (Cdx2)	Location: VDR promoter region; Change: A > G. Potentiates the binding strength between VDR and its transcriptional complex (Ralston and Rossant, 2008; Savory et al., 2009).
rs7975232 (ApaI)	Location: intron 8; Change: A > C. Does not change the amino acid sequence of the VDR protein, therefore could affect mRNA stability and the gene expression of VDR (Salimi et al., 2019).
rs1544410 (BsmI)	Location: intron 8; Change: A > G. Could affect mRNA stability and VDR gene expression. Could generate an alteration in the splice sites for mRNA transcription or a change in the intron regulatory elements of VDR (Ozaki et al., 2000; Huang et al., 2002; Luo et al., 2012).
rs731236 (TaqI)	Location: exon 9; Change: C > T. Generates a synonymous change of the isoleucine amino acid in the coding sequence, therefore it does not change the encoded protein, but it could influence the stability of the mRNA (Carvalho et al., 2015; Salimi et al., 2019).

Age	Differences
Intrauterine life	Woman: -Increased adaptability to stress (Klein and Flanagan, 2016); -Less inflammation of the placenta; -Lower production of cytokines; -Greater cardiovascular stability. Man: - Increased inflammatory response due to exacerbated activation of the innate immune response by androgen hormones (Carr et al., 1983; Klein and Flanagan, 2016).
0-13 months	Man: - High monocyte count when in high pathogenic load environments (Bellamy et al., 2000).
5-12 years	Woman: -Low levels of immunoglobulin A (IgA), but equivalent levels of IgG and IgM (Klein and Flanagan, 2016; Xiaoxia Lu et al., 2020). Man: -Increased NK cell count; -Enhanced innate immune response (Lee et al., 1996).
Puberty	Woman: - More active inflammation. - Higher CD4⁺ T cell count; - Higher proportion of CD4⁺/CD8⁺ T cells. Man: -Higher number of Treg (Afshan et al., 2012).
Adult life/Childbearing age	Woman: -Higher expression of inflammatory markers; -Less susceptibility to infections (Kovats, 2015; Trenti et al., 2018).
Pregnancy	- Unique immune system (Mor and Cardenas, 2010); - Immune cells are regulated by E₂, inhibiting TNF, IL-1β, and IL-6 (Pierdominici et al., 2010).
Elderly/menopause	Woman: - Suppression of the immune system (Castelo-Branco and Soveral, 2014); - Increased release of pro-inflammatory cytokines (IL-1, IL-6, TNF) and inhibition of IFN-γ release and B and T cells recruitment. Man: - Increased expression of IL-6R (Maggio et al., 2006); - Decreased activation of the immune system and inflammatory cytokines (Kumru et al., 2004).