It has recently come to light that nucleated red blood cells (RBCs) of fish, amphibians, reptiles and birds are multifunctional cells, because in addition to being involved in gas exchange and transport, it has also been reported that they respond to pathogens by means of (i) phagocytosis, (ii) antigen presentation, (iii) production of cytokines and antimicrobial peptides, (iv) regulation of complement system, and (v) exerting paracrine molecular communication with other immune cells and modulating their functions. Similarly, human cord blood nucleated RBCs have been shown to exert a regulatory function in the innate immune response, by means of the suppression of the production of inflammatory cytokines. This chapter comprises the study of the implications of nucleated RBCs as mediators of both branches of immune system (innate and adaptive immune responses).
- nucleated red blood cells
- immune response
- antimicrobial peptides
- antigen presentation
Red blood cells (RBCs) are the most abundant cell type in the bloodstream, and their life span has been estimated to be 120 and 50 days in human and murine species, respectively . In mammals, mature RBCs are biconcave disks that lack cell nucleus, organelles, and ribosomes , and their best known function is gas exchange and respiration. However, the most characteristic feature of nonmammalian RBCs is the presence of a nucleus which allows them to transcribe and translate proteins and therefore intervene in additional functions different from delivery of oxygen to tissues (Figure 1) . The nucleated RBCs are able to respond against pathogens by employing various mechanisms. This chapter review encompasses the up-to-date studies about the involvement of nucleated red blood cells (RBCs) as immune response cell mediators against microbes.
2. The role of nucleated RBCs in innate immune system
The innate immune system is an evolutionarily older defense strategy found in many organisms such as animals, plants, fungi, insects, and primitive multicellular organisms. This system is the first line of defense against pathogen infections. It is known as non-specific immune system and does not provide long-lasting immunity to the host [4, 5]. The innate immune system includes many types of molecules (receptors and effectors) to sense and eliminate pathogens. Moreover, nucleated RBCs release signaling molecules that trigger the activation of adaptive immune system. The implication of these cells in the innate immune response described to date is shown in Figures 1 and 2.
2.1 Nucleated RBCs trigger IFN type I response
It has been reported that nucleated RBCs do express pattern recognition receptors (PRRs) for pathogen-associated molecular patterns (PAMPs) . PAMPs are small molecular motifs conserved in evolution and characteristic from pathogens. There are a vast variety of PAMPs, for example, bacterial lipopolysaccharides (LPS), bacterial flagellin, lipoteichoic acid from Gram-positive bacteria, peptidoglycan, and nucleic acid variants from viruses—such as double-stranded RNA (dsRNA) or nonmethylated viral 5’-C-phosphate-G-3′ (CpG)-containing DNA [7, 8]. PAMPs are recognized by the host cells through their PRRs such as Toll-like receptors (TLRs), retinoid acid-inducible gene I (RIG-I)-like receptors (RLRs), AIM2-like receptors (ALRs), and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) [8, 9].
Among these receptors, a wide repertoire of TLRs have been described in nucleated RBCs, which allow them to respond to both bacterial and viral pathogens . Chicken RBCs constitutively express gene transcripts of
Among RLRs, a family of receptors which interact intracellularly with viral dsRNA [3, 11, 12], RIG-I has also been reported in salmon RBCs. However, the expression of other members of RLR family, such as melanoma differentiation-associated protein 5 (MDA5) or probable ATP-dependent RNA helicase DExH-box helicase 58 (LGP2), in nucleated RBCs is still unknown .
Activation of these receptors with their corresponding PAMPs triggers the signaling networks that induce the transcription of a set of genes characteristic of the innate immune response such as the expression of interferon type I (IFN1) [17, 18]. The IFN1 is reportedly known to play a similar role in mammalian and nonmammalian species . The binding of IFN1 to their cellular receptors induces different cell signaling pathways leading to the transcription of interferon-stimulated genes (ISGs), including important mediators of antiviral response such as myxovirus resistance protein (Mx), 2′–5′oligoadenylate synthetase (OAS), protein kinase RNA-activated (PKR), viperin, interferon-stimulated gene 15 (ISG15), IFN-induced protein with tetratricopeptide repeats (IFIT), and tripartite motif (TRIM) family, tetherin, among others .
In this regard, chicken and rainbow trout RBCs treated with polyI:C have been reported to induce upregulation of type I IFNs [3, 10] and also interferon-inducible genes Mx  and OAS , a protein responsible for initiating the RNAse L pathway in order to cleave viral RNA . In addition, it has been described that nucleated RBCs when infected with a virus increase the expression of IFN1 and their ISGs. A study of Atlantic salmon-infected individuals with salmon anemia virus (ISAV) first demonstrated the ability of RBCs to induce
Nevertheless, the involvement of IFN 1 response in nucleated RBCs and how does this response influence the global defense against viral infections remain to be demonstrated.
2.2 Nucleated RBCs induce interleukin response
TLR signaling culminates in cellular activation and production of cytokines . Cytokines are secreted proteins involved in cell recruitment and regulation of both innate and adaptive immune responses. They are essential for an effective host immune response to pathogens . The nucleated RBCs apart from type I IFN expression have been reported to produce other cytokines, at gene or protein level, in response to several PAMPs.
Chicken RBCs stimulated with polyI:C have shown an increase in interleukin 8 (
Rainbow trout RBCs exposed to VHSV have shown augmented IL-8 (Figure 3) and interleukin 1β (IL-1β) protein levels . IL-8 acts as a chemotactic factor for heterophils and other leukocytes such as monocytes . Further studies are needed to consider the chemotactic properties of nucleated RBCs, however. On the other hand, rainbow trout RBCs exposed to IPNV showed a downregulation trend of IL-8, IL-1β, and tumor necrosis factor-α (TNF-α) protein expression . Similarly, human cord blood nucleated RBCs have been shown to exert a regulatory function in the innate immune response, by means of the suppression of the production of inflammatory cytokines such as TNF-α and IL-1β from monocytes in lipopolysaccharide (LPS)-mimicked system to suppress a vigorous innate immune reaction, which can be harmful to fetuses .
Interferon gamma (IFNγ), a highly pleiotropic pro-inflammatory and antiviral cytokine exclusively produced in immune-related cells, has been detected in murine nucleated erythroid cells and may exert a regulatory influence on development and functionality of cells pertaining to monocyte/ macrophage lineage . In addition, it has been shown that chicken RBCs stimulated with fungal species
Taken altogether, these evidences indicate that nucleated RBCs exert paracrine molecular communication with other cells by means of cytokine production. Therefore, nucleated RBCs could play an important role in the recruitment and/or activation of immune cells.
2.3 Nucleated RBCs produce antimicrobial peptide and protein expression
Antimicrobial peptides (AMPs) exist in all living creatures in nature and present the first line of host defense against infectious pathogens  by means of molecular mechanisms of cellular disruption  and multifaceted immunomodulatory functions . Fish nucleated RBCs have been reported to produce antimicrobial peptides in response to the viral infection.
Rainbow trout RBCs expose to VHSV induced an upregulation of β-defensin 1 (BD1) protein levels (Figure 3). Defensins belong to a family of small cysteine-rich peptides that have amphiphilic and cationic properties . BD is produced and stored in epithelial cells, neutrophils, and phagocytes . During infection by pathogens, BD stored in granular bodies is released into the phagosomes or the extracellular system . Additionally, they are known as chemotactic attractants for immune cells and participate in immune regulation .
Another AMP recently found in fish RBCs is Nk-lysin (Nkl) . Nkl is orthologous to human cytolytic protein granulysin, produced by natural killer cells and cytotoxic T lymphocytes [41, 42], and involved in the destruction of bacteria, fungi, and parasites . Nkl is stored in cytolytic granules together with perforin and granzymes [41, 42]. However, Nkl in turbot RBCs was found in autophagolysosomes. This is reportedly known to link mechanism to VHSV defense in turbot RBCs .
Hepcidins, another family of cysteine-rich antimicrobial peptides, have also been found to be produced by fish RBCs . They were first identified in the human liver  and also in some fish species . But these peptides have also been reported to be expressed in other organs such as cardiac stomach, esophagus , heart, gill, spleen, kidney, and peripheral blood leucocytes  dependent upon the species. They have been shown to respond to bacterial and viral infections . Regarding RBCs, Nombela and colleagues found that rainbow trout RBCs exposed to VHSV did not vary hepcidin protein levels . Therefore, the possible role of hepcidin in nucleated RBCs against infectious pathogens is not known yet.
Histone proteins share all of the essential traits of cationic AMPs (CAMPs); they are hydrophobic and cationic and can form amphipathic alpha-helical structures . Recently, it has been demonstrated that a histone mixture (H1, H2A, H2B, H3, H4, and H5) extracted and purified from chicken RBCs had antimicrobial activity against a variety of Gram-negative and Gram-positive planktonic bacteria , as well as eradication activity against Gram-positive bacterial biofilms . It has also been reported that histone H5 from chicken RBCs has a broad-spectrum antimicrobial activity .
In addition to AMPs, another protein with antimicrobial activity found in RBCs is hemoglobin , which is the most abundant protein of RBCs. It has been described that hemoglobin can elicit antimicrobial activity through reactive oxygen species production under pathogen attack . The pathogen clearance from the bloodstream is also carried out by the hemoglobin oxygen .
In brief, nucleated RBCs can produce antimicrobial molecules in response to pathogens. It therefore supports the important contribution of RBCs in the regulation of host defense against pathogens.
2.4 Complement regulation on RBCs
The complement system is a component of the innate immune system which is involved in the clearance of pathogens, dying cells and immune complexes through opsonization, induction of an inflammatory response, and formation of a lytic pore. This system is composed by a group of 30 different plasma and membrane proteins, which are involved in three distinct pathways of complement activation: the classical, lectin, and alternative pathway. The classical pathway is activated by immune complexes, by pattern recognition molecules such as C-reactive protein (CRP), or directly by apoptotic cells and microbial surfaces. The lectin pathway is triggered by carbohydrate structures from pathogen, and the alternative pathway is activated by the spontaneous hydrolysis of the protein C3 (reviewed in ).
Autologous cells are protected from complement activation and posterior lysis by regulatory proteins . RBCs are continuously in contact with complement proteins in the blood plasma; therefore, they have complement regulatory proteins on their cell membrane to prevent this activation . It has been reported that human and rainbow trout RBCs highly express the regulatory protein complement receptor 1 (CR1) or CD35 [56, 57]. An important function of RBC CR1 is to eliminate complement-opsonized immune complexes from the circulation. A failure in this receptor can end up in inflammation and damage to healthy tissues . In addition, it has been described that human RBCs can sequester typ. 5 adenovirus (Ad5) through CR1 and Coxsackie virus-adenovirus receptor (CAR), in the presence and absence of anti-Ad5 antibodies and complement, respectively. In this context, human RBCs may act as circulating viral traps or clarifiers and prevent systemic virus infection . The studies of immune complex clearance in rainbow trout showed a similar complement-dependent way to eliminate immune complex as found in humans, suggesting that rainbow trout CR1 has a similar function to human CR1 .
3. The role of nucleated RBCs in adaptive immune response activation
The adaptive immune system consists of a specialized group of cells responsible of a specific immune response which eliminates and prevents reoccurrence of pathogens by immunological memory . The cells that carry out adaptive immune response are B and T lymphocytes . All nucleated cells are capable of presenting an antigen, through major histocompatibility complex (MHC) molecules . MHCI plays a key role in antigen presentation of intracellular pathogens. Nucleated RBCs can express MHCI, and this molecule has been found on the surface of RBCs from rainbow trout , African clawed frogs , and chickens . In addition, it has been reported that PRV infection induces genes involved in antigen presentation via MHCI in salmon RBCs , and incubation with polyI:C upregulates gene ontology (GO) categories related to antigen processing, antigen presentation, and MHCI receptor activity in rainbow trout RBCs . Unlike MHCI, MHCII molecules are generally restricted to some endothelial cells and a subset of antigen-presenting cells (APCs), such as macrophages, dendritic cells, and B cells . However, MHCII transcripts have been detected in chicken  and rainbow trout RBCs . Moreover, in rainbow trout RBCs, a combination of transcriptome- and proteome-sequencing data identified functional pathways related to antigen presentation via major histocompatibility complex class II. The set of genes/proteins identified were ARP1 actin-related protein 1 homolog B (ACTR1B), adaptor-related protein complex 1 beta 1 subunit (AP1B1), adaptor-related protein complex 2 alpha 1 subunit (AP2A1), adaptor-related protein complex 2 alpha 2 subunit (AP2A2), ADP ribosylation factor 1 (ARF1), calnexin (CANX), capping actin protein of muscle Z-line alpha subunit 1 (CAPZA1), clathrin light chain A (CLTA), clathrin heavy chain (CLTC), cathepsin D (CTSD), dynamin 2 (DNM2), dynein cytoplasmic 1 heavy chain 1 (DYNC1H1), dynein light chain LC8 typ. 2 (DYNLL2), and member RAS oncogene family (RAB7A) (Figure 4) .
Taking the above-said observations into account, these facts indicate that nucleated RBCs might participate in antigen presentation through MHCI and MHCII and suggest that RBCs may be participants in the immunological synapse with T and NK cells. Besides, it has been published that human RBCs could play a biological role in the modulation of T-cell differentiation and survival in the active cell division . Also, natural killer enhancing factor (NKEF) protein in human RBC cytosol mediates enhancement of NK cell activity . In addition, in rainbow trout RBCs, functional pathways related to regulation of leukocyte activation were identified by a combination of transcriptome- and proteome-sequencing data . Separately, rainbow trout RBCs have been reported to use phagocytosis to bind and engulf
Separately, other molecules related to adaptive immune response have been identified in nucleated RBCs. An example of these molecules is the immunoreceptor tyrosine-based activation motif (ITAM) which is contained in certain transmembrane proteins of the immune system and is important for the signal transduction in immune cells . ITAM-bearing molecules are expressed on rainbow trout RBCs . Another molecule, Epstein–Barr virus G-protein-coupled receptor 2 (EBI2), which plays a critical role in the regulation of T-cell-dependent antibody responses and provides a mechanism to balance short- versus long-term antibody responses , has also been reported to be highly expressed in rainbow trout young RBCs . Based on these facts, a role for RBCs in the adaptive immune response may be established. However, the function of these molecules and their effect on the antiviral adaptive immune response of nucleated RBCs remain to be studied.
Nucleated red blood cells (RBCs) of fish, amphibians, reptiles, and birds contain the transcriptional and translational machinery necessary to produce characteristic molecules of the immune system to respond against pathogen attacks. The mechanisms by which nucleated RBCs may contribute to the clearance of the pathogens are (i) phagocytosis, (ii) antigen presentation, (iii) producing cytokines and antimicrobial peptides, (iv) regulation of complement system, and (v) exerting paracrine molecular communication with other immune cells and modulate their functions. The nucleated RBCs seem to be involved in regulation of both innate and adaptive immune responses, and these findings highlight the important contribution of RBCs in the host defense against pathogens. However, more studies are needed to elucidate the role of RBCs in the immune response and the molecular mechanisms involved in these processes. And, the RBCs could be considered as potential targets for new prophylactic or therapeutic strategies against viral infections.
This work was supported by the European Research Council (ERC Starting Grant GA639249). The authors would like to thank Remedios Torres and Efren Lucas for their technical assistance.
Conflict of interest
The authors declare no conflict of interest.
Khandelwal S, Saxena RK. A role of phosphatidylserine externalization in clearance of erythrocytes exposed to stress but not in eliminating aging populations of erythrocyte in mice. Experimental Gerontology. 2008; 43(8):764-770
Moras M, Lefevre SD, Ostuni MA. From erythroblasts to mature red blood cells: Organelle clearance in mammals. Frontiers in Physiology. 2017; 8:1076
Morera D et al. RNA-Seq reveals an integrated immune response in nucleated erythrocytes. PLoS One. 2011; 6(10):e26998
Grasso P, Gangolli S, Gaunt I. Essentials of Pathology for Toxicologists. Florida, USA: CRC Press Inc; 2002
Alberts B et al. Molecular Biology of the Cell. Fourth ed. Garland Science: New York and London; 2002
Morera D, Mackenzie SA. Is there a direct role for erythrocytes in the immune response? Veterinary Research. 2011; 42(1):89
Janeway CA Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harbor Symposia on Quantitative Biology. 1989; 54(Pt 1):1-13
Janeway CA, Medzhitov R. Innate immune recognition. Annual Review of Immunology. 2002; 20(1):197-216
Creagh EM, O'Neill LA. TLRs, NLRs and RLRs: A trinity of pathogen sensors that co-operate in innate immunity. Trends in Immunology. 2006; 27(8):352-357
St Paul M et al. Chicken erythrocytes respond to toll-like receptor ligands by up-regulating cytokine transcripts. Research in Veterinary Science. 2013; 95(1):87-91
Rodriguez MF et al. Characterization of toll-like receptor 3 gene in rainbow trout ( Oncorhynchus mykiss). Immunogenetics. 2005; 57(7):510-519
Wessel O et al. Piscine orthoreovirus (PRV) replicates in Atlantic salmon ( Salmo salar L.) erythrocytes ex vivo. Veterinary Research. 2015; 46:26
Shen Y et al. Fish red blood cells express immune genes and responses. Aquaculture and Fisheries. 2018; 3(1):14-21
Iqbal M, Philbin VJ, Smith AL. Expression patterns of chicken toll-like receptor mRNA in tissues, immune cell subsets and cell lines. Veterinary Immunology and Immunopathology. 2005; 104(1–2):117-127
Cormier F. Avian pluripotent haemopoietic progenitor cells: Detection and enrichment from the para-aortic region of the early embryo. Journal of Cell Science. 1993; 105(Pt 3):661-666
Nombela I, Ortega-Villaizan MDM. Nucleated red blood cells: Immune cell mediators of the antiviral response. PLoS Pathogens. 2018; 14(4):e1006910
Robertsen B. The interferon system of teleost fish. Fish & Shellfish Immunology. 2006; 20(2):172-191
Zou J, Bird S, Secombes C. Antiviral sensing in teleost fish. Current Pharmaceutical Design. 2010; 16(38):4185-4193
Schultz U, Kaspers B, Staeheli P. The interferon system of non-mammalian vertebrates. Developmental and Comparative Immunology. 2004; 28(5):499-508
Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: A complex web of host defenses. Annual Review of Immunology. 2014; 32:513-545
Liang SL, Quirk D, Zhou A. RNase L: Its biological roles and regulation. IUBMB Life. 2006; 58(9):508-514
Workenhe ST et al. Infectious salmon anaemia virus replication and induction of alpha interferon in Atlantic salmon erythrocytes. Virology Journal. 2008; 5:36
Dahle MK et al. Transcriptome analyses of Atlantic salmon ( Salmo salar L.) erythrocytes infected with piscine orthoreovirus (PRV). Fish & Shellfish Immunology. 2015; 45(2):780-790
Haatveit HM et al. Viral protein kinetics of piscine orthoreovirus infection in atlantic Salmon blood cells. Viruses. 2017; 9(3):49
Nombela I et al. Infectious pancreatic necrosis virus triggers antiviral immune response in rainbow trout red blood cells, despite not being infective. F1000Research. 2017; 6:1968
Nombela I et al. Identification of diverse defense mechanisms in rainbow trout red blood cells in response to halted replication of VHS virus. F1000Research. 2017; 6:1958
Medzhitov R. Toll-like receptors and innate immunity. Nature Reviews. Immunology. 2001; 1(2):135-145
Kaiser MG et al. Cytokine expression in chicken peripheral blood mononuclear cells after in vitro exposure to Salmonella enterica serovar Enteritidis. Poultry Science. 2006; 85(11):1907-1911
Bystry RS et al. B cells and professional APCs recruit regulatory T cells via CCL4. Nature Immunology. 2001; 2(12):1126-1132
Kogut MH. Dynamics of a protective avian inflammatory response: The role of an IL-8-like cytokine in the recruitment of heterophils to the site of organ invasion by Salmonella enteritidis. Comparative Immunology, Microbiology and Infectious Diseases. 2002; 25(3):159-172
Cui L et al. Immunoregulatory function of neonatal nucleated red blood cells in humans. Immunobiology. 2016; 221(8):853-861
Seledtsova GV et al. A role for interferon-gamma and transforming growth factor-beta in erythroid cell-mediated regulation of nitric oxide production in macrophages. Immunology. 1997; 91(1):109-113
Passantino L et al. Antigenically activated avian erythrocytes release cytokine-like factors: A conserved phylogenetic function discovered in fish. Immunopharmacology and Immunotoxicology. 2007; 29(1):141-152
Chico V et al. Shape-shifted red blood cells: A novel red blood cell stage? Cell. 2018; 7(4):E31
Yi Y et al. High-throughput identification of antimicrobial peptides from amphibious mudskippers. Marine Drugs. 2017; 15(11):E364
Smith VJ, Desbois AP, Dyrynda EA. Conventional and unconventional antimicrobials from fish, marine invertebrates and micro-algae. Marine Drugs. 2010; 8(4):1213-1262
Peschel A, Sahl HG. The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nature Reviews. Microbiology. 2006; 4(7):529-536
Casadei E et al. Characterization of three novel beta-defensin antimicrobial peptides in rainbow trout ( Oncorhynchus mykiss). Molecular Immunology. 2009; 46(16):3358-3366
Ellis AE. Innate host defense mechanisms of fish against viruses and bacteria. Developmental and Comparative Immunology. 2001; 25(8–9):827-839
Pereiro P et al. Nucleated teleost erythrocytes play an Nk-Lysin- and autophagy-dependent role in antiviral immunity. Frontiers in Immunology. 2017; 8:1458
Andersson M et al. NK-lysin, a novel effector peptide of cytotoxic T and NK cells. Structure and cDNA cloning of the porcine form, induction by interleukin 2, antibacterial and antitumour activity. The EMBO Journal. 1995; 14(8):1615-1625
Pena SV, Krensky AM. Granulysin, a new human cytolytic granule-associated protein with possible involvement in cell-mediated cytotoxicity. Seminars in Immunology. 1997; 9(2):117-125
Clayberger C et al. 15 kDa granulysin causes differentiation of monocytes to dendritic cells but lacks cytotoxic activity. Journal of Immunology. 2012; 188(12):6119-6126
Krause A et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Letters. 2000; 480(2–3):147-150
Wang KJ et al. Cloning and expression of a hepcidin gene from a marine fish ( Pseudosciaena crocea) and the antimicrobial activity of its synthetic peptide. Peptides. 2009; 30(4):638-646
Douglas SE et al. Identification and expression analysis of hepcidin-like antimicrobial peptides in bony fish. Developmental and Comparative Immunology. 2003; 27(6–7):589-601
Hirono I et al. Two different types of hepcidins from the Japanese flounder Paralichthys olivaceus. The FEBS Journal. 2005; 272(20):5257-5264
Gui L et al. Two hepcidins from spotted scat ( Scatophagus argus) possess antibacterial and antiviral functions in vitro. Fish & Shellfish Immunology. 2016; 50:191-199
Kawasaki H, Iwamuro S. Potential roles of histones in host defense as antimicrobial agents. Infectious Disorders Drug Targets. 2008; 8(3):195-205
Rose-Martel M, Hincke MT. Antimicrobial histones from chicken erythrocytes bind bacterial cell wall lipopolysaccharides and lipoteichoic acids. International Journal of Antimicrobial Agents. 2014; 44(5):470-472
Rose-Martel M et al. Histones from avian erythrocytes exhibit antibiofilm activity against methicillin-sensitive and methicillin-resistant Staphylococcus aureus. Scientific Reports. 2017; 7:45980
Jodoin J, Hincke MT. Histone H5 is a potent antimicrobial agent and a template for novel antimicrobial peptides. Scientific Reports. 2018; 8(1):2411
Jiang N et al. Respiratory protein-generated reactive oxygen species as an antimicrobial strategy. Nature Immunology. 2007; 8(10):1114-1122
Minasyan HA. Erythrocyte and leukocyte: Two partners in bacteria killing. International Reviews of Immunology. 2014; 33(6):490-497
Thielen AJF, Zeerleder S, Wouters D. Consequences of dysregulated complement regulators on red blood cells. Blood Reviews. 2018; 32:280-288
Schraml B, Baker MA, Reilly BD. A complement receptor for opsonized immune complexes on erythrocytes from Oncorhynchus mykissbut not Ictalarus punctatus. Molecular Immunology. 2006; 43(10):1595-1603
Schifferli JA, Ng YC, Peters DK. The role of complement and its receptor in the elimination of immune complexes. The New England Journal of Medicine. 1986; 315(8):488-495
Krych-Goldberg M, Atkinson JP. Structure-function relationships of complement receptor typ. 1. Immunological Reviews. 2001; 180:112-122
Carlisle RC et al. Human erythrocytes bind and inactivate typ. 5 adenovirus by presenting Coxsackie virus-adenovirus receptor and complement receptor 1. Blood. 2009; 113(9):1909-1918
Espenes A et al. Immune-complex trapping in the splenic ellipsoids of rainbow trout ( Oncorhynchus mykiss). Cell and Tissue Research. 1995; 282(1):41-48
Akintude ME, Heuer L, Van de Water J. Immune abnormalities and autism spectrum disorders. Editors: Joseph D. Buxbaum, Patrick R. Hof. Academic Press. In: The Neuroscience of Autism Spectrum Disorders. 2013. pp. 233-248. ISBN 9780123919243
Janeway CA et al. Immunobiology. 6th ed. Garland Science; 2005. ISBN 0443073104
Sarder MR et al. The MHC class I linkage group is a major determinant in the in vivo rejection of allogeneic erythrocytes in rainbow trout ( Oncorhynchus mykiss). Immunogenetics. 2003; 55(5):315-324
Nedelkovska H et al. Effective RNAi-mediated beta2-microglobulin loss of function by transgenesis in Xenopus laevis. Biology Open. 2013; 2(3):335-342
Delany ME et al. Cellular expression of MHC glycoproteins on erythrocytes from normal and aneuploid chickens. Developmental and Comparative Immunology. 1987; 11(3):613-625
Villadangos JA, Schnorrer P, Wilson NS. Control of MHC class II antigen presentation in dendritic cells: A balance between creative and destructive forces. Immunological Reviews. 2005; 207:191-205
Puente-Marin S et al. In silico functional networks identified in fish nucleated red blood cells by means of transcriptomic and proteomic profiling. Genes (Basel). 2018; 9(4):E202
Fonseca AM et al. Red blood cells promote survival and cell cycle progression of human peripheral blood T cells independently of CD58/LFA-3 and heme compounds. Cellular Immunology. 2003; 224(1):17-28
Shau H, Gupta RK, Golub SH. Identification of a natural killer enhancing factor (NKEF) from human erythroid cells. Cellular Immunology. 1993; 147(1):1-11
Passantino L et al. Fish immunology. I. Binding and engulfment of Candida albicansby erythrocytes of rainbow trout ( Salmo gairdneriRichardson). Immunopharmacology and Immunotoxicology. 2002; 24(4):665-678
Humphrey MB, Lanier LL, Nakamura MC. Role of ITAM-containing adapter proteins and their receptors in the immune system and bone. Immunological Reviews. 2005; 208:50-65
Ohashi K et al. A molecule in teleost fish, related with human MHC-encoded G6F, has a cytoplasmic tail with ITAM and marks the surface of thrombocytes and in some fishes also of erythrocytes. Immunogenetics. 2010; 62(8):543-559
Gatto D et al. Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses. Immunity. 2009; 31(2):259-269
Gotting M, Nikinmaa MJ. Transcriptomic analysis of young and old erythrocytes of fish. Frontiers in Physiology. 2017; 8:1046
Xia J, Gill EE, Hancock RE. Network analyst for statistical, visual and network-based meta-analysis of gene expression data. Nature Protocols. 2015; 10(6):823-844