Boston Center for Endometriosis, Brigham and Women’s Hospital, Boston Children’s Hospi-tal, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USAUnited States
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The Major Histocompatibility Complex (MHC), the genetic region that encodes the proteins responsible for tissue graft rejection,1 encodes MHC Class I (MHC-I) and MHC Class II (MHC-II) glycoproteins. There are two subclasses of MHC-I proteins. Classical MHC-I (MHC-Ia) proteins are membrane-bound isoforms that are expressed in all nucleated cells of the body and present intracellular pathogen-derived peptides or the animal’s own peptides on the cell surface for immune recognition by CD8 T cells.
Opinion Interactions of Immunomodulatory HLA-G * *Corresponding author with Immune Cells during Pregnancy and Parveen Parasar, DVM, PhD Boston Center for Endometriosis Brigham and Women’s Hospital Endometriosis Boston Children’s Hospital Harvard Medical School * 300 Longwood Avenue Parveen Parasar* Boston, MA 02115, USA E-mail: suprovet@gmail.com Boston Center for Endometriosis, Brigham and Women’s Hospital, Boston Children’s Hospi- tal, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA Volume 2 : Issue 4 Article Ref. #: 1000GOROJ2121 The Major Histocompatibility Complex (MHC), the genetic region that encodes the proteins responsible for tissue graft rejection,1 encodes MHC Class I (MHC-I) and MHC Class Article History th II (MHC-II) glycoproteins. There are two subclasses of MHC-I proteins. Classical MHC-I Received: November 14 , 2015 th (MHC-Ia) proteins are membrane-bound isoforms that are expressed in all nucleated cells of Accepted: November 30 , 2015 st the body and present intracellular pathogen-derived peptides or the animal’s own peptides on Published: December 1 , 2015 the cell surface for immune recognition by CD8 T cells. Contrary to MHC-Ia proteins, non- classical MHC-I (MHC-Ib) molecules are less polymorphic, possess specific molecular mo- Citation tifs in their transmembrane domains and contain premature stop codons. MHC-II proteins are Parasar P. Interactions of immu- expressed only by professional Antigen Presenting Cells (APC), which present extracellular nomodulatory HLA-G with im- pathogen-derived or self-peptides bound to MHC-II proteins on their cell surface for recogni- mune cells during pregnancy and tion by CD4 T cells. Immunological recognition of pathogens involves proteolysis of foreign endometriosis. Gynecol Obstet Res Open J. 2015; 2(4): 93-95. pathogen into peptides which are assembled on MHC-I and -II glycoproteins. Interaction of doi: 10.17140/GOROJ-2-121 MHC-I and MHC-II-peptide complexes with CD8 and CD4 T Cell Receptors (TCR), respec- tively, leads to effector functions including removal of infected cells to clear the infection. The fetal allograft must remain unharmed by the mother’s potentially hostile immune system throughout the term. Several mechanisms have been reported which contribute to immune tol- erance to the fetus including the production of Transforming Growth Factor beta 1 (TGF)-β1 and Interleukin-10 (IL-10) by T-regulatory cells (Tregs), secretion of prolactin, progesterone and gonadotropin by both fetal and endometrial cells, secretion of immunosuppressive cyto- kines, chemokines, and prostaglandins which dampen T lymphocyte proliferation.2 An appropriate regulation of MHC class I genes at the maternal fetal interface is criti- cal for immunological acceptance of allogeneic conceptus.3 Trophoblast cells do not express MHC-II antigens that are expressed mainly on antigen presenting cells (APCs). However, tro- phoblast cells express immunomodulatory non-classical HLA-I antigens (HLA-Ib) molecules. Contrary to ubiquitous and highly polymorphic classical class I glycoproteins (HLA-Ia), HLA- Ib proteins are oligomorphic, undergo alternative splicing to produce membrane and soluble isoforms in specific cell/tissue types. Examples of class Ib proteins are Human Leukocyte An- 4-6 7 8 tigens HLA-E, -F and -G, Qa-2 in mice, Mamu-AG in Rhesus Macaques, and Paan-AG in Olive baboons.9 HLA-G has been studied most and is a potent immunomodulatory during pregnancy. This protein is alternatively spliced to produce seven messenger RNA (mRNA) isoforms, four membrane-bound isoforms (HLA-G1, -G2, -G3, and -G4) and three soluble isoforms (HLA- G5, -G6 and -G7).10 Expression of membrane and soluble HLA-G isoforms is critically im- Copyright portant phenomenon which renders maternal immune cells inactive by serving as a ligand ©2015 Parasar P. This is an open for leukocyte receptors during pregnancy. HLA-G is expressed, in the first trimester and at access article distributed under the Creative Commons Attribution 4.0 term, by extravillous and placental villous syncytiotrophoblast cells; latter only expressing 10 + International License (CC BY 4.0), non-membrane forms.10 Membrane HLA-G isoforms induce suppression of CD4+ T cells and which permits unrestricted use, 11 Natural Killer (NK) cells. Soluble HLA-G is primarily shed or released by trophoblast cells. distribution, and reproduction in A minute quantity is also produced by regulatory T cells and antigen presenting cells (APCs) any medium, provided the original 12,13 work is properly cited. such as monocytes and dendritic cells. Soluble HLA-G in non-pregnant individuals reflects the quantity expressed by monocytes. Soluble HLA-G1 isoform 3. Davies CJ. Why is the fetal allograft not rejected? J Anim Sci.
14,15 induces apoptosis of activated CD8 T cells, down regulates 2007; 85(13 Suppl): E32-E35.
+ CD4+ T cell proliferation and inhibits NK-cell mediated cytotox- 16-19 icity. HLA-G interacts with Immunoglobulin-like transcript 4. Ellis SA, Sargent IL, Redman CW, McMichael AJ. Evidence 2 (ILT2), Immunoglobulin-like transcript 4 (ILT4), killer cell for a novel HLA antigen found on human extravillous tropho- immunoglobulin-like receptor KIR2DL4, and CD94/NKG2A blast and a choriocarcinoma cell line. Immunology. 1986; 59: receptors expressed by maternal NK-cells and inhibits their cell 595-601.
lysis properties. The ILT receptors are expressed by NK cells, monocytes and macrophage cells; ILT2 by B-lymphocytes, and 5. Redman CW, McMichael AJ, Stirrat GM, Sunderland CA, + + some CD4+ and CD8+ T-lymphocytes. HLA-G, therefore, is an Ting A. Class 1 major histocompatibility complex antigens on important immunomodulatory protein during pregnancy circum- human extra-villous tro-phoblast. Immunology. 1984; 52(3): venting the maternal immune system during pregnancy and pro- 457-468.
6. Geraghty DE, Koller BH, Orr HT. A human major histocom- Interactions of HLA-G with immune cells on one hand patibility complex class I gene that encodes a protein with a modulates the climate favorably within uterus but on the other shortened cytoplasmic segment. Proc Natl Acad Sci USA. 1987; is associated with gynecologic diseases such as preeclampsia.10 84(24): 9145-9149.
Endometriosis is an estrogen dependent disease that is character- ized by the presence of endometrial glands and stroma in ectopic 7. Warner CM, Gollnick SO, Flaherty L, Goldbard SB. Analysis locations, mainly the pelvic peritoneum, ovaries and rectovagi- of Qa-2 antigen expression by preimplantation mouse embryos: nal septum. Studies suggest that eutopic endometrium expressed possible relationship to the preimplantation-embryo-develop- HLA-G only in menstrual phase and not in secretory or prolifer- ment (Ped) gene product. Biol Reprod. 1987; 36(3): 611-616.
ative phase. They also identified HLA-G expressing cells in the doi: 10.1095/biolreprod36.3.611 peritoneal cavity.20 In contrast, another study revealed expres- sion of HLA-G by glandular epithelium of peritoneal endome- 8. Boyson JE, Iwanaga KK, Golos TG, Watkins DI. Identifica- triotic lesions and not eutopic epithelium of the subjects.21 The tion of the rhesus monkey HLA-G ortholog. Mamu-G is a pseu- HLA-G expressing endometrial cells may dampen peritoneal dogene. J Immunol. 1996; 157: 5428-5437.
NK cell-cytotoxicity via HLA-G-leukocyte receptor interaction thus letting endometrial implants survive and establish onto the 9. Langat DK, Morales PJ, Fazleabas AT, Mwenda JM, Hunt JS.
peritoneal sites and consequently develop into endometriotic Baboon placentas express soluble and membrane-bound Paan- tissue implants. Eutopic endometrium of women with endome- AG proteins encoded by alternatively spliced transcripts of the triosis is more resistant to NK cell lysis compared to eutopic en- class Ib major histocompatibility complex gene, Paan-AG. Im- dometrium from women without the disease. Impaired NK cell munogenetics. 2002; 54: 164-173. doi: 10.1007/s00251-002- function can favor endometrial cells evade immune system and 0454-8 thus develop lesions in the peritoneum.22 10. Djurisic S, Hviid TV. HLA Class Ib molecules and immune Endometriosis is an enigmatic and multifactorial dis- cells in pregnancy and preeclampsia. Front Immunol. 2014; 5: ease. An intriguing factor in the onset of endometriosis is that 652. doi: 10.3389/fimmu.2014.00652 refluxed endometrial implants that are cleared off normally by immune cells evade the maternal immune system and establish 11. LeMaoult J, Krawice-Radanne I, Dausset J, Carosella ED.
during progression of the disease. Immunomodulatory interac- HLA-G1-expressing antigen-presenting cells induce immu- tions of HLA-G and other class Ib molecules with immune cells nosuppressive CD4+ T cells. Proc Natl Acad Sci USA. 2004; which protect fetal allograft may play a role in pathophysiology 101(18): 7064-7069. doi: 10.1073/pnas.0401922101 of endometriosis and therefore need to be addressed and consid- ered during development of research platform and therapeutic 12. Feger U, Tolosa E, Huang YH, et al. HLA-G expression de- strategies for this disease.
fines a novel regulatory T-cell subset present in human periph- eral blood and sites of inflammation. Blood. 2007; 110(2): 568-