HLA-G Expression and Immune Regulation in Human Diseases

Human leukocyte antigen G (HLA-G) is a non-classical major histocompatibility complex class I molecule with potent immunomodulatory properties. Under physiological conditions, its expression is tightly restricted to the maternal–fetal interface and certain immune-privileged tissues, where it contributes to tolerance by engaging inhibitory receptors on natural killer cells, T lymphocytes and antigen-presenting cells. Deleterious or aberrant upregulation of HLA-G has been documented in a spectrum of pathological states, notably solid tumours, haematological malignancies, chronic infections and transplantation settings, facilitating immune escape and chronicity. Conversely, deficient or dysregulated HLA-G expression is implicated in autoimmune and inflammatory diseases, reflecting its essential role in curtailing excessive effector responses. Regulation of HLA-G occurs at multiple levels: genetic polymorphisms in the 5′ upstream regulatory region and the 3′ untranslated region influence transcriptional activity and mRNA stability; microenvironmental cues such as hypoxia, cytokines and hormones modulate promoter responsiveness; and post-transcriptional mechanisms including microRNA binding further refine expression. Soluble isoforms and extracellular vesicle–associated HLA-G expand its functional repertoire as both a local and systemic tolerance inducer. The global significance of HLA-G research spans prognostic biomarker development, design of immune-checkpoint therapies and understanding of host–pathogen interactions, offering tangible avenues for personalised medicine and immunotherapeutic innovation.

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HLA-G Expression and Immune Regulation in Human Diseases publication trend

The graph below shows the total number of articles in hla-g expression and immune regulation in human diseases across all publications each year (not limited to Nature Index journals).

Technical terms

HLA-G: A non-classical MHC class I molecule with limited polymorphism, specialised in immune tolerance.

Immune checkpoint: Regulatory pathways in the immune system that maintain self-tolerance and modulate the duration and amplitude of immune responses.

Soluble HLA-G (sHLA-G): Circulating isoforms of HLA-G generated by alternative splicing or proteolytic shedding, capable of exerting systemic immunosuppressive effects.

3′ untranslated region (3′UTR): The mRNA segment downstream of the coding sequence that contains regulatory motifs influencing transcript stability and microRNA binding.

Epistatic interaction: A genetic phenomenon where variants at two or more loci interact to influence a phenotype, often modulating disease risk or progression.

References

1. Harnessing the potential of HLA-G in cancer therapy: advances, challenges, and prospects. Journal of Translational Medicine (2024).
2. HLA‐G as a Tolerogenic Molecule in Transplantation and Pregnancy. Journal of Immunology Research (2014).
3. Recent Advances in Our Understanding of HLA‐G Biology: Lessons from a Wide Spectrum of Human Diseases. Journal of Immunology Research (2016).
4. Transcriptional and Posttranscriptional Regulations of the HLA-G Gene. Journal of Immunology Research (2014).
5. MiRNA-Mediated Control of HLA-G Expression and Function. PLOS ONE (2012).
6. HLA-G Molecules in Autoimmune Diseases and Infections. Frontiers in Immunology (2014).
7. HLA-G high-expressor 3’UTR markers are linked to gastric cancer development and survival. Cancer Immunology, Immunotherapy (2024).
8. Evidence for Epistatic Interaction between HLA-G and LILRB1 in the Pathogenesis of Nonsegmental Vitiligo. Cells (2023).