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The Antigen-Processing Pathway via Major Histocompatibility Complex I as a New Perspective in the Diagnosis and Treatment of Endometriosis

Izabela Nowak
Izabela Nowak
 oraz 
Patrycja Bochen
Patrycja Bochen
   | 13 mar 2024
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Article Category: Review
Data publikacji: 13 mar 2024
Zakres stron: -
Otrzymano: 02 lis 2023
Przyjęty: 30 sty 2024
DOI: https://doi.org/10.2478/aite-2024-0008
Słowa kluczowe
© 2024 Izabela Nowak et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Fig 1.

The antigen-processing pathway via MHC-I. De novo synthesized MHC-I heavy chain associates with the BIP and calnexin and then binds to β2m. Calnexin is replaced by its soluble counterpart, calreticulin, and this complex is linked by the disulfide isomerase ERp57. Tapasin bridges this MHC-I complex to TAP (Thomas and Tampé 2017). During the immune response, new subunits with increased activity of LMP2, LMP7, and LMP10 are formed under the influence of cytokines (Ferrington and Gregerson 2012; Leone et al. 2013). After protein degradation by the immunoproteasome in the cytosol, peptide fragments are transferred to the lumen of the ER (ER-Lumen) by transporters TAP1 and TAP2 (Thomas and Tampé 2017), where they are trimmed by heterodimeric aminopeptidases ERAP1 and ERAP2 (Lankat-Buttgereit and Tampé 2002; Evnouchidou et al. 2014; López de Castro 2018; Evnouchidou and van Endert 2019). Peptides can also be trimmed by the LNPEP aminopeptidase in the cytosol (Saveanu et al. 2009; Segura et al. 2009; Weimershaus et al. 2012; Agrawal and Brown 2014). Peptide/MHC-I complexes can leave the multicomponent PLC with the assistance of TAPBPR (McShan et al. 2022) and finally are transferred via the Golgi-Network to the cell surface. Their antigenic cargo is inspected by cytotoxic T cells (Scholz and Tampé 2005; Trowitzsch and Tampé 2020) and NK cells (Lee 2017; Compagnone et al. 2019) (created by Adobe Illustrator). β2m, β2-microglobulin; BIP, binding immunoglobulin protein; CD8; ER, endoplasmic reticulum; ERAP, endoplasmic reticulum aminopeptidases; ERp57; LMP, low molecular weight protein; LNPEP, leucyl and cystinyl aminopeptidase; MHC-I, major histocompatibility complex I; NK, natural killer; PLC, peptide-loading complex; TAP, transporters associated with antigen processing; TAPBPR, TAP-binding protein-related; TCR, T cell receptor.
The antigen-processing pathway via MHC-I. De novo synthesized MHC-I heavy chain associates with the BIP and calnexin and then binds to β2m. Calnexin is replaced by its soluble counterpart, calreticulin, and this complex is linked by the disulfide isomerase ERp57. Tapasin bridges this MHC-I complex to TAP (Thomas and Tampé 2017). During the immune response, new subunits with increased activity of LMP2, LMP7, and LMP10 are formed under the influence of cytokines (Ferrington and Gregerson 2012; Leone et al. 2013). After protein degradation by the immunoproteasome in the cytosol, peptide fragments are transferred to the lumen of the ER (ER-Lumen) by transporters TAP1 and TAP2 (Thomas and Tampé 2017), where they are trimmed by heterodimeric aminopeptidases ERAP1 and ERAP2 (Lankat-Buttgereit and Tampé 2002; Evnouchidou et al. 2014; López de Castro 2018; Evnouchidou and van Endert 2019). Peptides can also be trimmed by the LNPEP aminopeptidase in the cytosol (Saveanu et al. 2009; Segura et al. 2009; Weimershaus et al. 2012; Agrawal and Brown 2014). Peptide/MHC-I complexes can leave the multicomponent PLC with the assistance of TAPBPR (McShan et al. 2022) and finally are transferred via the Golgi-Network to the cell surface. Their antigenic cargo is inspected by cytotoxic T cells (Scholz and Tampé 2005; Trowitzsch and Tampé 2020) and NK cells (Lee 2017; Compagnone et al. 2019) (created by Adobe Illustrator). β2m, β2-microglobulin; BIP, binding immunoglobulin protein; CD8; ER, endoplasmic reticulum; ERAP, endoplasmic reticulum aminopeptidases; ERp57; LMP, low molecular weight protein; LNPEP, leucyl and cystinyl aminopeptidase; MHC-I, major histocompatibility complex I; NK, natural killer; PLC, peptide-loading complex; TAP, transporters associated with antigen processing; TAPBPR, TAP-binding protein-related; TCR, T cell receptor.

Elements of antigen processing machinery in the context of MHC I (in alphabetical order)

Component Full name Function References
1 ERAP1 and ERAP2

Endoplasmic

Reticulum Aminopeptidase 1 and 2

 Trimming the antigenic peptides in the endoplasmic reticulum Evnouchidou et al. (2014) and Evnouchidou and van Endert (2019)
2 LMP2, LMP7 and LMP10 Immunoproteasome Low Molecular Weight Proteins 2, 7, and 10 Processing of proteins to peptides in the cytosol Ferrington and Gregerson (2012) and Leone et al. (2013)
3 LNPEP Leucyl and Cystinyl Aminopeptidase Trimming peptides in the cytosol Agrawal and Brown (2014) and Segura et al. (2009)
4 MHC I Major Histocompatibility Complex I Presenting antigens to immune cells on the cell surface Trowitzsch and Tampé (2020)
5 Tsn Tapasin Bridging the MHC I complex to transporters associated with antigen processing (TAP) Thomas and Tampé (2017)
6 TAPBPR TAP-Binding Protein-Related Facilitating high-affinity epitope selection and peptide loading in the antigen presentation pathway McShan et al. (2022) and Teng et al. (2002)
7 TAP1 and TAP2 Transporter associated with Antigen Processing 1 and 2 Transporting peptide precursors into the endoplasmic reticulum Evnouchidou et al. (2014) and Evnouchidou and van Endert (2019)

Experimental evidence of the relationship between HLA class I and endometriosis

Objective Methods Results References
1 To investigate whether HLA-G polymorphisms may influence susceptibility to endometriosis and its progression

- PCR-RFLP

- Allelic discrimination methods with TaqMan SNP Genotyping Assays

- The HLA-G rs1632947:GG genotype was associated with protection against the disease and its severe stages

- HLA-G rs1233334:CT protected against progression

 Bylińska et al. (2018)
2 To investigate an association between HLA-C genotype and the occurrence of endometriosis - Sequence-based typing method - The occurrence of HLA-C*03:03*01 was increased in endometriosis than in control groups Chou et al. (2020)
3 To study the association between HLA genotypes and endometriosis - PCR-MPH method - Significant positive association with endometriosis was observed for HLA-B7 Kitawaki et al. (2002)
4 To evaluate the sHLA-G levels in the blood sera of women with deep endometriosis and ovarian endometrioma throughout the menstrual cycle and to compare with the levels of sHLA-G in the blood sera of women with ovarian cancer - ELISA test - The level of sHLA-G concentration in the blood serum of patients with deep endometriosis fluctuates throughout the menstrual cycle, and during the proliferative and secretory phases, it remains at a high level comparable to that found in patients with ovarian cancer Mach et al. (2010)
5 To assess whether the HLA-G is involved in the pathophysiology of endometriosis or disease progression

- ELISA test

- Immunohistochemistry assays

- Higher concentrations of sHLA-G in the serum but not in the peritoneal fluid were observed in women with advanced endometriosis compared to the control group

- In situ, expression of HLA-G protein was also higher in ectopic but not in eutopic endometrium of women with advanced endometriosis compared to the control group

 Rached et al. (2019)
6 To assess whether HLA class I expression on eutopic and ectopic endometrial cells modifies susceptibility to lymphocyte-mediated lysis

- Immunofluorescence

- Flow cytometry

 - The HLA-B7 allele inhibits the cytotoxic activity, suggesting that the growth of ectopic endometrial cells might be under a genetic control Semino et al. (1995)
7 To compare the expression of HLA class I in endometrial samples from patients with and without endometriosis - Immunohistochemical assays - A significantly higher expression of HLA I in the endometriosis group than in controls, both in the glandular cells and in the stromal cells, was observed Vernet-Tomás et al. (2006)
8 To explore the role of DNA methylation in endometriosis

- Direct bisulfite sequencing

- qRT-PCR

- DNA hypermethylation in the intron VII of the HLA-C*07 gene appears to regulate the expression of HLA-C*07

- The aberrant DNA methylation in this region was positively correlated with the occurrence of endometriosis

 Zhao et al. (2023)
eISSN:
1661-4917
Język:
Angielski
Częstotliwość wydawania:
Volume Open
Dziedziny czasopisma:
Medicine, Basic Medical Science, Biochemistry, Immunology, Clinical Medicine, other, Clinical Chemistry
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