Wikipedia

HLA-F

HLA class I histocompatibility antigen, alpha chain F is a protein that in humans is encoded by the HLA-F gene.[4][5] It is an empty intracellular molecule that encodes a non-classical heavy chain anchored to the membrane and forming a heterodimer with a β-2 microglobulin light chain. It belongs to the HLA class I heavy chain paralogues that separate from most of the HLA heavy chains. HLA-F is localized in the endoplasmic reticulum and Golgi apparatus, and is also unique in the sense that it exhibits few polymorphisms in the human population relative to the other HLA genes; however, there have been found different isoforms from numerous transcript variants found for the HLA-F gene. Its pathways include IFN-gamma signaling and CDK-mediated phosphorylation (cyclin-dependent kinase) and removal of the Saccharomyces cerevisiae Cdc6 protein, which is crucial for functional DNA replication.[6]

HLA-F
Identifiers
AliasesHLA-F, CDA12, HLA-5.4, HLA-CDA12, major histocompatibility complex, class I, F
External IDsOMIM: 143110; MGI: 3647514; HomoloGene: 133121; GeneCards: HLA-F; OMA:HLA-F - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3134

630294

Ensembl

n/a

UniProt

P30511

Q0WXH6

RefSeq (mRNA)

NM_001098478
NM_001098479
NM_018950

NM_001177467

RefSeq (protein)

NP_001091948
NP_001091949
NP_061823

NP_001170938

Location (UCSC)Chr 6: 29.72 – 29.74 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

HLA-F

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The Major Histocompatibility Complex (MHC) is a group of cell surface proteins that in humans is also called the Human Leukocyte Antigen (HLA) complex. These proteins are encoded by a cluster of genes known as the HLA locus. The HLA locus occupies a ~ 3Mbp stretch that is located on the short arm of chromosome 6, specifically on 6p21.1-21.3.[7] The MHC proteins are classified into three main categories, namely class I, II, and III. There are over 140 genes within the HLA locus and they are often called HLA genes.[8][9] HLA-A, B, and C are the classical class I genes and HLA-E, F and G are the nonclassical class I genes.[10][4] The protein encoded from the gene HLA-F was originally isolated from the human lymphoblastoid cell line 721.[11]

Gene

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The HLA-F gene is located on the short arm of chromosome 6, telomeric to the HLA-A locus.[10] HLA-F has little allelic polymorphism[8] and is highly conserved in other primates.[12] HLA-F appears to be a recombinant between two multigene families, one that comprises conserved sequences found in all class I proteins (single transmembrane span) and another distinct family of genes with a conserved 3’ UTR. Many of these genes are highly transcribed and differentially expressed.[4] The heavy chain gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domains, the putative peptide binding sites, exon 4 encodes the alpha3 domain, exon 5 and 6 encode the transmembrane region and exons 7 and 8 the cytoplasmic tail. However, exons 7 and 8 (the cytoplasmic tail) are not translated due to an in-frame translation termination codon in exon 6.[5]

Protein

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The HLA-F protein is a ~40-41 kDa molecule with conserved domains.[13] Exon 7 is absent from the mRNA of HLA-F.[4][14] The absence of this exon produces a modification in the cytoplasmic tail of the protein making it shorter relative to classical HLA class-I proteins.[4] The cytoplasmic tail helps HLA-F exit the endoplasmic reticulum,[15] and that function is primarily done by the amino acid valine found at the C-terminal end of the tail.[15][16]

Structure

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The structure of HLA-F is similar to that of the other HLA class I genes, which consist of eight exons.  Of the key residues likely to form from the floor of the groove, position 97 is a glycine whose residue is a single proton, whereas in most class Ia structures it is a charged residue and in HLA-E, it is a bulky hydrophobic tryptophan. If the HLA-F groove binds to a peptide, then the glycine residue will create space in the mid-portion of the groove which might allow larger side chains to fit and be accommodated . This nonclassical class I gene also has two histidine residues (His 114-His116) close together in the C-terminal groove floor, mirroring His-9-His99 in HLA-E. Tyr 7, Tyr 59, Tyr 159 and Tyr 171, which are typically involved in the hydrogen-bonding network to the peptide N-terminal residues, are conserved.[17]

The possible pocket regions of HLA-F include a situation where the A pocket is hydrophobic and similar to that of HLA-E, and pocket B retains Met 45 and Ala 67, which also characterize the HLA-E pocket and are likely to be hydrophobic and large. The C-pocket, however, differs significantly from that of the HLA-E with similarities to the C pocket of HLA-B8. In the D pocket region of this protein, the Asn 99 may favor a charged residue, but the other residues in this pocket, including phenylalanine make predictions hard to make. However, the F-pocket of HLA-F appears well conserved with HLA-E and the other class Ia molecules and likely favors an aliphatic group, such as leucine.[17][18]

Expression

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Classic HLA class I molecules interact with HLA-F through their heavy chain.[16] However, HLA class I molecules only interact with HLA-F when they are in the form of an open conformer (free of peptide). Thus, HLA-F is expressed independently of bound peptide.[16][19]

Intracellular expression

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HLA-F is expressed intracellularly in peripheral blood lymphocytes (PBL), resting lymphocyte cells (B, T, NK, and monocytes), tonsils, spleen, thymus, bladder, brain, colon, kidney, liver, lymphoblast, T cell leukemia, choriocarcinoma, and carcinoma.[13][20][21]

Extracellular expression

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HLA-F is expressed on the cell surface of activated lymphocytes, HeLa cells, EBV-transformed lymphoblastoid cells, and in some activated monocyte cell lines.[15][20] The surface expression of HLA-F coincides with the activated immune response since HLA-F is mostly found on the surface of stimulated T memory cells but not on circulating regulatory T cells.[22]

Expression during pregnancy

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In the first trimester, HLA-F is weakly expressed in the trophoblastic elements residing outside the villi (extravillous trophoblast cells). Its expression increases and translocated onto the cell surface during the second trimester, coinciding with fetal growth which, in context, suggests it plays a role in development.[23]

Interaction with NK cells

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HLA-F can be expressed in two ways on the cell surface: with  β2m and a peptide as a complex of HLA-F heavy chain  or without the peptide and  β2m as an open conformer with just the heavy chain. It can transport from the endoplasmic reticulum partially with the aid of tapasin, independent from the TAP protein complex, typically associated with antigen processing and transportation. Open conformer (OC) HLA-Fs can form homodimers and heterodimers with distinct HLA class I OCs, which may suggest they are involved in cross-presentation of extracellular antigens.[24]

 HLA OCs are able to bind to other receptors than the HLA complex with the β2m and peptide, most relevant to the diverse function of HLA-F. These receptors include binding inhibitory and activating immune receptors primarily expressed in natural killer (NK) cells, but also includes other immune cells. To do this, HLA OCs bind to the activating receptor KIR3DS1 and inhibitory receptor killer receptors 3DL1 and 3dL2.[18]

 Recent studies further suggest that HLA-F also presents long peptides (7 to more than 30 amino acids) to T cell receptors. They are able to do this because of an amino acid substitution in position 62 that forms an open-ended groove with N-terminal extensions. It is still not known if there may be consequences for this in the immune regulation at the feto-maternal contact zone.[24]

Transcriptional regulation of HLA-F

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In the promoter of HLA-F, both studied regulatory modules display homology to the classical MHC class I genes. HLA-F has a conserved κB1 site enhancer bound by NF- κB, but the HLA-F gene is not induced by NF- κB without flanking regulatory sequences (such as IRSE) that provide a helper function. The IRSE in HLA-F is homologous to other classical MHC class I genes.  INF- γ also induces HLA-F with its IRSE (IFN-stimulated response element). Further, it is also induced by CIITA, a transcriptional coactivator that regulates the transcription of MHC class II genes.[25]

Function

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HLA-F belongs to the non-classical HLA class I heavy chain paralogues. Compared to classical HLA class I molecules, it exhibits very few polymorphisms. This class I molecule mainly exists as a heterodimer associated with the invariant light chain β-2 microglobulin.

HLA-F is currently the most enigmatic of the HLA molecules. Hence, its precise functions still remain to be resolved. Though, in contrast to other HLA molecules, it mainly resides intracellularly and rarely reaches the cell surface, e.g. upon activation of NK, B and T cells. Unlike classical HLA class I molecules, which possess ten highly conserved amino acids responsible for antigen recognition, HLA-F only has 5, suggesting a biological function different from peptide presentation. Upon immune cell activation, HLA-F binds free forms of HLA class I molecules and reaches the cell surface as heterodimer. In this way HLA-F stabilizes HLA class I molecules that haven't yet bound peptides, thereby acting as a chaperone and transporting the free HLA class I to, on, and from the cell surface.[26]

Association with specialized ligands

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HLA-F has been observed only in a subset of cell membranes, mostly B cells and activated lymphocytes.[23] As a result, it has been suggested that its role involves association with specialized ligands that become available in the cell membrane of activated cells.[13] For example, HLA-F can act as a peptide binding of ILT2 and ILT4.[21][6] HLA-F can associate with TAP (transporter associated with antigen processing) and with the multimeric complex involved in peptide loading.[13][21][20][22]

Maternal immunity tolerance

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It has been observed that all three non-classical HLA class I proteins are expressed in placental trophoblasts in contact with maternal immune cells.[8] This suggests that these proteins collaborate in the immune response and that HLA-F plays a fundamental role in both normal and maternal immune response.[8] HLA-F is also expressed in decidual extravillous trophoblasts.[23] During pregnancy, HLA-F interacts with T reg cells and extravillous trophoblasts mediating maternal tolerance to the fetus.[22]

Intermolecular communication

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During the interaction between HLA-F and the heavy chain (HC) of HLA class I molecules in activated lymphocytes, HLA-F plays a role as a chaperone, escorting HLA class I HC to the cell surface and stabilizing its expression in the absence of peptide.[16] HLA-F binds most allelic forms of HLA class I open conformers, but it does not bind peptide complexes.[19]

The expression patterns of HLA-F in T cells suggest that HLA-F is involved in the communication pathway between T reg and activated T cells, where HLA-F signals that the immune response has been activated. During this communication, either HLA-F invokes secretion of inhibitory cytokines by the regulatory T cells or it provides a simple inhibitory signal to the regulatory T cells, allowing a normal immune response to proceed.[22]

Exogenous antigen cross-presentation

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Viral proteins and other exogenous antigens decrease surface HLA-F expression because the exogenous proteins interact with HLA class I molecules at the same sites where HLA-F interacts, producing crosslinking. The exogenous proteins trigger an internal co-localization of both HLA-F and HLA class I molecules.[19] Exogenous proteins with higher affinity will interact more readily with HLA class I molecules triggering a dissociation of HLA class I/HLA-F, thereby reducing the surface levels of HLA-F.[19] HLA-F interacts with the open conformer (OC) of HLA class I and they function together in cross-presentation of exogenous antigen. Exogenous antigen binds to a structure on the surface of activated cells; this structure is composed of HLA class I open conformer and HLA-F; the peptide-binding point of contact is a specific HLA class I epitope on the exogenous antigen.[19]

Ligand during inflammatory response

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The complex HLA-F/HLA class I OC has two distinct roles that are central to the inflammatory response: first, it is a ligand for KIR receptors and can both activate and inhibit KIR; second, it is involved in cross-presentation of exogenous antigen.[27][28][18]

The complex HLA-F/HLA class-I OC is a ligand for a subset of KIR (Killer-cell immunoglobulin-like receptor) receptors.[27] Specifically, it was demonstrated that HLA-F interacts physically and functionally with three KIR receptors: KIR3DL2, KIR2DS4, and KIR3DS1, particularly during the inflammatory response.[27][28][18] KIR directly interacts with both HLA-F and HLA class-I individually (i.e. no dimerization between HLA-F and HLA class-I is necessary).

Disease association

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HLA-F has been linked to several diseases (Table). For cancer and tumors, HLA-F expression has been found to be enhanced in gastric adenocarcinoma,[29] breast cancer,[30] esophageal carcinoma,[31] lung cancer,[32] hepatocellular carcinoma,[33] and neuroblastoma.[34] HLA-F has also been associated with susceptibility to several diseases: hepatitis B,[35] Systemic Lupus Erythematosus,[36] and Type 1 diabetes (T1D).[37]

Disease associations
disease reference
gastric adenocarcinoma [29]
breast cancer [30]
esophageal carcinoma [31]
lung cancer [32]
hepatocellular carcinoma [33]
neuroblastoma [34]
hepatitis B [35]
Systemic Lupus Erythematosus [36]
Type 1 Diabetes [37]

References

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  1. ^ a b c ENSG00000237508, ENSG00000234487, ENSG00000206509, ENSG00000137403, ENSG00000235220, ENSG00000204642 GRCh38: Ensembl release 89: ENSG00000229698, ENSG00000237508, ENSG00000234487, ENSG00000206509, ENSG00000137403, ENSG00000235220, ENSG00000204642 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ a b c d e Geraghty DE, Wei XH, Orr HT, Koller BH (January 1990). "Human leukocyte antigen F (HLA-F). An expressed HLA gene composed of a class I coding sequence linked to a novel transcribed repetitive element". The Journal of Experimental Medicine. 171 (1): 1–18. doi:10.1084/jem.171.1.1. PMC 2187653. PMID 1688605.
  5. ^ a b "Entrez Gene: HLA-F major histocompatibility complex, class I, F".
  6. ^ a b Allan DS, Lepin EJ, Braud VM, O'Callaghan CA, McMichael AJ (October 2002). "Tetrameric complexes of HLA-E, HLA-F, and HLA-G". Journal of Immunological Methods. 268 (1): 43–50. doi:10.1016/s0022-1759(02)00199-0. PMID 12213342.
  7. ^ Krebs J, Goldstein E, Kilpatrick S (2014). "Chapter 18: Somatic recombination and hypermutation in the immune system". Lewin's GENES XI. USA: Jones & Bartlett Learning. pp. 459–99. ISBN 978-1-4496-5985-1.
  8. ^ a b c d Pyo CW, Williams LM, Moore Y, Hyodo H, Li SS, Zhao LP, et al. (May 2006). "HLA-E, HLA-F, and HLA-G polymorphism: genomic sequence defines haplotype structure and variation spanning the nonclassical class I genes". Immunogenetics. 58 (4): 241–251. doi:10.1007/s00251-005-0076-z. PMID 16570139. S2CID 22308414.
  9. ^ Smith WP, Vu Q, Li SS, Hansen JA, Zhao LP, Geraghty DE (May 2006). "Toward understanding MHC disease associations: partial resequencing of 46 distinct HLA haplotypes". Genomics. 87 (5): 561–571. doi:10.1016/j.ygeno.2005.11.020. PMID 16434165.
  10. ^ a b Koller BH, Geraghty DE, DeMars R, Duvick L, Rich SS, Orr HT (February 1989). "Chromosomal organization of the human major histocompatibility complex class I gene family". The Journal of Experimental Medicine. 169 (2): 469–480. doi:10.1084/jem.169.2.469. PMC 2189218. PMID 2562983.
  11. ^ Geraghty DE, Koller BH, Orr HT (December 1987). "A human major histocompatibility complex class I gene that encodes a protein with a shortened cytoplasmic segment". Proceedings of the National Academy of Sciences of the United States of America. 84 (24): 9145–9149. Bibcode:1987PNAS...84.9145G. doi:10.1073/pnas.84.24.9145. PMC 299709. PMID 3480534.
  12. ^ Daza-Vamenta R, Glusman G, Rowen L, Guthrie B, Geraghty DE (August 2004). "Genetic divergence of the rhesus macaque major histocompatibility complex". Genome Research. 14 (8): 1501–1515. doi:10.1101/gr.2134504. PMC 509259. PMID 15289473.
  13. ^ a b c d Wainwright SD, Biro PA, Holmes CH (January 2000). "HLA-F is a predominantly empty, intracellular, TAP-associated MHC class Ib protein with a restricted expression pattern". Journal of Immunology. 164 (1): 319–328. doi:10.4049/jimmunol.164.1.319. PMID 10605026.
  14. ^ O'Callaghan CA, Bell JI (June 1998). "Structure and function of the human MHC class Ib molecules HLA-E, HLA-F and HLA-G". Immunological Reviews. 163: 129–138. doi:10.1111/j.1600-065x.1998.tb01192.x. PMID 9700506. S2CID 6160579.
  15. ^ a b c Boyle LH, Gillingham AK, Munro S, Trowsdale J (June 2006). "Selective export of HLA-F by its cytoplasmic tail". Journal of Immunology. 176 (11): 6464–6472. doi:10.4049/jimmunol.176.11.6464. PMID 16709803.
  16. ^ a b c d Goodridge JP, Burian A, Lee N, Geraghty DE (June 2010). "HLA-F complex without peptide binds to MHC class I protein in the open conformer form". Journal of Immunology. 184 (11): 6199–6208. doi:10.4049/jimmunol.1000078. PMC 3777411. PMID 20483783.
  17. ^ a b Sim MJ, Sun PD (June 2017). "HLA-F: A New Kid Licensed for Peptide Presentation". Immunity. 46 (6): 972–974. doi:10.1016/j.immuni.2017.06.004. PMID 28636965.
  18. ^ a b c d Garcia-Beltran WF, Hölzemer A, Martrus G, Chung AW, Pacheco Y, Simoneau CR, et al. (September 2016). "Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1". Nature Immunology. 17 (9): 1067–1074. doi:10.1038/ni.3513. PMC 4992421. PMID 27455421.
  19. ^ a b c d e Goodridge JP, Lee N, Burian A, Pyo CW, Tykodi SS, Warren EH, et al. (August 2013). "HLA-F and MHC-I open conformers cooperate in a MHC-I antigen cross-presentation pathway". Journal of Immunology. 191 (4): 1567–1577. doi:10.4049/jimmunol.1300080. PMC 3732835. PMID 23851683.
  20. ^ a b c Lee N, Geraghty DE (November 2003). "HLA-F surface expression on B cell and monocyte cell lines is partially independent from tapasin and completely independent from TAP". Journal of Immunology. 171 (10): 5264–5271. doi:10.4049/jimmunol.171.10.5264. PMID 14607927.
  21. ^ a b c Lepin EJ, Bastin JM, Allan DS, Roncador G, Braud VM, Mason DY, et al. (December 2000). "Functional characterization of HLA-F and binding of HLA-F tetramers to ILT2 and ILT4 receptors". European Journal of Immunology. 30 (12): 3552–3561. doi:10.1002/1521-4141(200012)30:12<3552::AID-IMMU3552>3.0.CO;2-L. PMID 11169396. S2CID 42462661.
  22. ^ a b c d Lee N, Ishitani A, Geraghty DE (August 2010). "HLA-F is a surface marker on activated lymphocytes". European Journal of Immunology. 40 (8): 2308–2318. doi:10.1002/eji.201040348. PMC 3867582. PMID 20865824.
  23. ^ a b c Ishitani A, Sageshima N, Lee N, Dorofeeva N, Hatake K, Marquardt H, Geraghty DE (August 2003). "Protein expression and peptide binding suggest unique and interacting functional roles for HLA-E, F, and G in maternal-placental immune recognition". Journal of Immunology. 171 (3): 1376–1384. doi:10.4049/jimmunol.171.3.1376. PMID 12874228.
  24. ^ a b Burian A, Wang KL, Finton KA, Lee N, Ishitani A, Strong RK, Geraghty DE (2016-09-20). Allen RL (ed.). "HLA-F and MHC-I Open Conformers Bind Natural Killer Cell Ig-Like Receptor KIR3DS1". PLOS ONE. 11 (9): e0163297. Bibcode:2016PLoSO..1163297B. doi:10.1371/journal.pone.0163297. PMC 5029895. PMID 27649529.
  25. ^ Jordier F, Gras D, De Grandis M, D'Journo XB, Thomas PA, Chanez P, et al. (2020). "HLA-H: Transcriptional Activity and HLA-E Mobilization". Frontiers in Immunology. 10: 2986. doi:10.3389/fimmu.2019.02986. PMC 6978722. PMID 32010122.
  26. ^ Persson G, Jørgensen N, Nilsson LL, Andersen LH, Hviid TV (April 2020). "A role for both HLA-F and HLA-G in reproduction and during pregnancy?". Human Immunology. HLA-G Special Issue. 81 (4): 127–133. doi:10.1016/j.humimm.2019.09.006. PMID 31558330. S2CID 203568247.
  27. ^ a b c Goodridge JP, Burian A, Lee N, Geraghty DE (October 2013). "HLA-F and MHC class I open conformers are ligands for NK cell Ig-like receptors". Journal of Immunology. 191 (7): 3553–3562. doi:10.4049/jimmunol.1300081. PMC 3780715. PMID 24018270.
  28. ^ a b Burian A, Wang KL, Finton KA, Lee N, Ishitani A, Strong RK, Geraghty DE (2016-09-20). "HLA-F and MHC-I Open Conformers Bind Natural Killer Cell Ig-Like Receptor KIR3DS1". PLOS ONE. 11 (9): e0163297. Bibcode:2016PLoSO..1163297B. doi:10.1371/journal.pone.0163297. PMC 5029895. PMID 27649529.
  29. ^ a b Ishigami S, Arigami T, Okumura H, Uchikado Y, Kita Y, Kurahara H, et al. (April 2015). "Human leukocyte antigen (HLA)-E and HLA-F expression in gastric cancer". Anticancer Research. 35 (4): 2279–2285. PMID 25862890.
  30. ^ a b Harada A, Ishigami S, Kijima Y, Nakajo A, Arigami T, Kurahara H, et al. (November 2015). "Clinical implication of human leukocyte antigen (HLA)-F expression in breast cancer". Pathology International. 65 (11): 569–574. doi:10.1111/pin.12343. PMID 26332651.
  31. ^ a b Zhang X, Lin A, Zhang JG, Bao WG, Xu DP, Ruan YY, Yan WH (January 2013). "Alteration of HLA-F and HLA I antigen expression in the tumor is associated with survival in patients with esophageal squamous cell carcinoma". International Journal of Cancer. 132 (1): 82–89. doi:10.1002/ijc.27621. PMID 22544725. S2CID 23526646.
  32. ^ a b Lin A, Zhang X, Ruan YY, Wang Q, Zhou WJ, Yan WH (December 2011). "HLA-F expression is a prognostic factor in patients with non-small-cell lung cancer". Lung Cancer. 74 (3): 504–509. doi:10.1016/j.lungcan.2011.04.006. PMID 21561677.
  33. ^ a b Xu Y, Han H, Zhang F, Lv S, Li Z, Fang Z (January 2015). "Lesion human leukocyte antigen-F expression is associated with a poor prognosis in patients with hepatocellular carcinoma". Oncology Letters. 9 (1): 300–304. doi:10.3892/ol.2014.2686. PMC 4246689. PMID 25435979.
  34. ^ a b Morandi F, Cangemi G, Barco S, Amoroso L, Giuliano M, Gigliotti AR, et al. (2013-11-21). "Plasma levels of soluble HLA-E and HLA-F at diagnosis may predict overall survival of neuroblastoma patients". BioMed Research International. 2013: 956878. doi:10.1155/2013/956878. PMC 3856218. PMID 24350297.
  35. ^ a b Zhang J, Pan L, Chen L, Feng X, Zhou L, Zheng S (March 2012). "Non-classical MHC-Ι genes in chronic hepatitis B and hepatocellular carcinoma". Immunogenetics. 64 (3): 251–258. doi:10.1007/s00251-011-0580-2. PMID 22015712. S2CID 14765632.
  36. ^ a b Jucaud V, Ravindranath MH, Terasaki PI, Morales-Buenrostro LE, Hiepe F, Rose T, Biesen R (March 2016). "Serum antibodies to human leucocyte antigen (HLA)-E, HLA-F and HLA-G in patients with systemic lupus erythematosus (SLE) during disease flares: Clinical relevance of HLA-F autoantibodies". Clinical and Experimental Immunology. 183 (3): 326–340. doi:10.1111/cei.12724. PMC 4750595. PMID 26440212.
  37. ^ a b Richardson SJ, Rodriguez-Calvo T, Gerling IC, Mathews CE, Kaddis JS, Russell MA, et al. (November 2016). "Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes". Diabetologia. 59 (11): 2448–2458. doi:10.1007/s00125-016-4067-4. PMC 5042874. PMID 27506584.

Further reading

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