Skip to main content

Advertisement

Log in

Expression and distribution of immunoglobulin G and its receptors in an immune privileged site: the eye

  • Research Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

It has recently been demonstrated that not only mature B lymphocytes, but also non-lymphoid cells, including cancer cells and neurons, express IgG. In the eye, an important immune privileged site, the presence of IgG has been ascribed to IgG entering the eye through breaches of the blood–ocular barrier. Here we demonstrate that the eye itself can produce IgG intrinsically. Applying immunohistochemistry, in situ hybridization, and RT-PCR, several intraocular structures were found to express proteins and mRNA transcripts of IgG heavy chains, light chains, V(D)J rearrangements, and enzymes required for V(D)J recombination. IgG receptors were also detected in the intraocular epithelium and endothelium. The extensive distribution of IgG and its receptors in intraocular structures indicates that locally produced IgG could play a significant role in maintaining the ocular microenvironment and protection of the eyes, and it might also be involved in the pathogenesis of age-related macular degeneration and some inflammatory diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

AEC:

3-amino-9-ethyl-carbazole

AH:

Aqueous humor

AID:

Activation-induced cytidine deaminase

AMD:

Age-related macular degeneration

CPE:

Ciliary pigmented epithelia

FcγRs:

Fc gamma receptors

FcRn:

Neonatal Fc receptors

Igγ:

IgG Gamma chain γ

Igκ:

Ig Kappa light chain κ

Igλ:

Ig Lambda chain λ

IGHG:

Mouse IgG heavy chains

IGHG1:

Constant regions of human IgG1

IHC:

Immunohistochemistry

IPE:

Iris pigmented epithelium

ISH:

In situ hybridization

µMT:

µ chain mutated

RAG1:

Recombination activating gene -1

RAG2:

Recombination activating gene -2

RPE:

Retinal pigment epithelium

SCID:

Severe combined immune deficient

VDJн :

VDJ segment of Igγ

References

  1. Ferguson TA, Griffith TS (2006) A vision of cell death: Fas ligand and immune privilege 10 years later. Immunol Rev 213:228–238

    Article  PubMed  CAS  Google Scholar 

  2. Taylor AW (2009) Ocular immune privilege. Eye (Lond) 23:1885–1889

    CAS  Google Scholar 

  3. Lee HO, Herndon JM, Barreiro R, Griffith TS, Ferguson TA (2002) TRAIL: a mechanism of tumor surveillance in an immune privileged site. J Immunol 169:4739–4744

    PubMed  Google Scholar 

  4. Allansmith MR, Whitney CR, McClellan BH, Newman LP (1973) Immunoglobulins in the human eye. Location, type, and amount. Arch Ophthalmol 89:36–45

    PubMed  CAS  Google Scholar 

  5. Waldrep JC, Schulte JR (1989) Characterization of human IgG subclasses within intraocular compartments. Reg Immunol 2:22–32

    PubMed  CAS  Google Scholar 

  6. Von Sallmann L, Moore DH (1948) Electrophoretic patterns of concentrated aqueous humor of rabbit, cattle and horse. Arch Ophthal 40:279–284

    Google Scholar 

  7. Sen DK, Sarin GS, Saha K (1977) Immunoglobulins in human aqueous humour. Br J Ophthalmol 61:216–217

    Article  PubMed  CAS  Google Scholar 

  8. Murray PI, Hoekzema R, Luyendijk L, Konings S, Kijlstra A (1990) Analysis of aqueous humor immunoglobulin G in uveitis by enzyme-linked immunosorbent assay, isoelectric focusing, and immunoblotting. Invest Ophthalmol Vis Sci 31:2129–2135

    PubMed  CAS  Google Scholar 

  9. Bloch-Michel E, Lambin P, Debbia M, Tounsi Y, Trichet C, Offret H (1997) Local production of IgG and IgG subclasses in the aqueous humor of patients with Fuchs heterochromic cyclitis, herpetic uveitis and toxoplasmic chorioretinitis. Int Ophthalmol 21:187–194

    Article  PubMed  Google Scholar 

  10. Kim H, Fariss RN, Zhang C, Robinson SB, Thill M, Csaky KG (2008) Mapping of the neonatal Fc receptor in the rodent eye. Invest Ophthalmol Vis Sci 49:2025–2029

    Article  PubMed  Google Scholar 

  11. Huang J, Sun X, Mao Y, Zhu X, Zhang P, Zhang L, Du J, Qiu X (2008) Expression of immunoglobulin gene with classical V-(D)-J rearrangement in mouse brain neurons. Int J Biochem Cell Biol 40:1604–1615

    Article  PubMed  CAS  Google Scholar 

  12. Chen Z, Gu J (2007) Immunoglobulin G expression in carcinomas and cancer cell lines. FASEB J 21:2931–2938

    Article  PubMed  Google Scholar 

  13. Qiu X, Zhu X, Zhang L, Mao Y, Zhang J, Hao P, Li G, Lv P, Li Z, Sun X, Wu L, Zheng J, Deng Y, Hou C, Tang P, Zhang S, Zhang Y (2003) Human epithelial cancers secrete immunoglobulin g with unidentified specificity to promote growth and survival of tumor cells. Cancer Res 63:6488–6495

    PubMed  CAS  Google Scholar 

  14. Hulse RE, Swenson WG, Kunkler PE, White DM, Kraig RP (2008) Monomeric IgG is neuroprotective via enhancing microglial recycling endocytosis and TNF-alpha. J Neurosci 28:12199–12211

    Article  PubMed  CAS  Google Scholar 

  15. Arumugam TV, Tang SC, Lathia JD, Cheng A, Mughal MR, Chigurupati S, Magnus T, Chan SL, Jo DG, Ouyang X, Fairlie DP, Granger DN, Vortmeyer A, Basta M, Mattson MP (2007) Intravenous immunoglobulin (IVIG) protects the brain against experimental stroke by preventing complement-mediated neuronal cell death. Proc Natl Acad Sci USA 104:14104–14109

    Article  PubMed  CAS  Google Scholar 

  16. Campa C, Costagliola C, Incorvaia C, Sheridan C, Semeraro F, De Nadai K, Sebastiani A, Parmeggiani F (2010) Inflammatory mediators and angiogenic factors in choroidal neovascularization: pathogenetic interactions and therapeutic implications. Mediators Inflamm (Epub ahead of print)

  17. Clark SJ, Bishop PN, Day AJ (2010) Complement factor H and age-related macular degeneration: the role of glycosaminoglycan recognition in disease pathology. Biochem Soc Trans 38:1342–1348

    Article  PubMed  CAS  Google Scholar 

  18. Anderson DH, Radeke MJ, Gallo NB, Chapin EA, Johnson PT, Curletti CR, Hancox LS, Hu J, Ebright JN, Malek G, Hauser MA, Rickman CB, Bok D, Hageman GS, Johnson LV (2010) The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res 29:95–112

    Article  PubMed  CAS  Google Scholar 

  19. Niu N, Zhang J, Guo Y, Yang C, Gu J (2009) Cystic fibrosis transmembrane conductance regulator expression in human spinal and sympathetic ganglia. Lab Invest 89:636–644

    Article  PubMed  CAS  Google Scholar 

  20. Bosma GC, Custer RP, Bosma MJ (1983) A severe combined immunodeficiency mutation in the mouse. Nature 301:527–530

    Article  PubMed  CAS  Google Scholar 

  21. Kitamura D, Roes J, Kuhn R, Rajewsky K (1991) A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature 350:423–426

    Article  PubMed  CAS  Google Scholar 

  22. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T (2000) Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102:553–563

    Article  PubMed  CAS  Google Scholar 

  23. McBlane JF, van Gent DC, Ramsden DA, Romeo C, Cuomo CA, Gellert M, Oettinger MA (1995) Cleavage at a V(D)J recombination signal requires only RAG1 and RAG2 proteins and occurs in two steps. Cell 83:387–395

    Article  PubMed  CAS  Google Scholar 

  24. Kim J, Mohanty S, Ganesan LP, Hua K, Jarjoura D, Hayton WL, Robinson JM, Anderson CL (2009) FcRn in the yolk sac endoderm of mouse is required for IgG transport to fetus. J Immunol 182:2583–2589

    Article  PubMed  CAS  Google Scholar 

  25. Roopenian DC, Akilesh S (2007) FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 7:715–725

    Article  PubMed  CAS  Google Scholar 

  26. Schlachetzki F, Zhu C, Pardridge WM (2002) Expression of the neonatal Fc receptor (FcRn) at the blood–brain barrier. J Neurochem 81:203–206

    Article  PubMed  CAS  Google Scholar 

  27. Zhang Y, Pardridge WM (2001) Mediated efflux of IgG molecules from brain to blood across the blood–brain barrier. J Neuroimmunol 114:168–172

    Article  PubMed  CAS  Google Scholar 

  28. Kim H, Robinson SB, Csaky KG (2009) FcRn receptor-mediated pharmacokinetics of therapeutic IgG in the eye. Mol Vis 15:2803–2812

    PubMed  CAS  Google Scholar 

  29. Ghetie V, Ward ES (2000) Multiple roles for the major histocompatibility complex class I-related receptor FcRn. Annu Rev Immunol 18:739–766

    Article  PubMed  CAS  Google Scholar 

  30. Ravetch JV (1994) Fc receptors: rubor redux. Cell 78:553–560

    Article  PubMed  CAS  Google Scholar 

  31. Ravetch JV, Bolland S (2001) IgG Fc receptors. Annu Rev Immunol 19:275–290

    Article  PubMed  CAS  Google Scholar 

  32. Young JD, Ko SS, Cohn ZA (1984) The increase in intracellular free calcium associated with IgG gamma 2b/gamma 1 Fc receptor-ligand interactions: role in phagocytosis. Proc Natl Acad Sci USA 81:5430–5434

    Article  PubMed  CAS  Google Scholar 

  33. Anderson CL, Shen L, Eicher DM, Wewers MD, Gill JK (1990) Phagocytosis mediated by three distinct Fc gamma receptor classes on human leukocytes. J Exp Med 171:1333–1345

    Article  PubMed  CAS  Google Scholar 

  34. Titus JA, Perez P, Kaubisch A, Garrido MA, Segal DM (1987) Human K/natural killer cells targeted with hetero-cross-linked antibodies specifically lyse tumor cells in vitro and prevent tumor growth in vivo. J Immunol 139:3153–3158

    PubMed  CAS  Google Scholar 

  35. Kennedy PG, Lisak RP, Raff MC (1980) Cell type-specific markers for human glial and neuronal cells in culture. Lab Invest 43:342–351

    PubMed  CAS  Google Scholar 

  36. Sugita S (2009) Role of ocular pigment epithelial cells in immune privilege. Arch Immunol Ther Exp (Warsz) 57:263–268

    Article  Google Scholar 

  37. Chugh A, Eudes F, Shim YS (2010) Cell-penetrating peptides: nanocarrier for macromolecule delivery in living cells. IUBMB Life 62:183–193

    Article  PubMed  CAS  Google Scholar 

  38. Doherty GJ, McMahon HT (2009) Mechanisms of endocytosis. Annu Rev Biochem 78:857–902

    Article  PubMed  CAS  Google Scholar 

  39. Andoh T, Kuraishi Y (2004) Direct action of immunoglobulin G on primary sensory neurons through Fc gamma receptor I. FASEB J 18:182–184

    PubMed  CAS  Google Scholar 

  40. Kerschensteiner M, Meinl E, Hohlfeld R (2009) Neuro-immune crosstalk in CNS diseases. Neuroscience 158:1122–1132

    Article  PubMed  CAS  Google Scholar 

  41. Deane R, Sagare A, Hamm K, Parisi M, LaRue B, Guo H, Wu Z, Holtzman DM, Zlokovic BV (2005) IgG-assisted age-dependent clearance of Alzheimer’s amyloid beta peptide by the blood–brain barrier neonatal Fc receptor. J Neurosci 25:11495–11503

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (code: 30570686), Project 111 (B07001) of the Ministry of Education, China to Dr. Jiang Gu.

Conflicts of interest

No author had any conflict of interest. Dr. Jiang Gu had full access to all the data in this study and had final responsibility for the decision of publication.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jiang Gu.

Additional information

The first two institutions contributed equally to this study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 225 kb)

Supplementary material 2 (PDF 41 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Niu, N., Zhang, J., Sun, Y. et al. Expression and distribution of immunoglobulin G and its receptors in an immune privileged site: the eye. Cell. Mol. Life Sci. 68, 2481–2492 (2011). https://doi.org/10.1007/s00018-010-0572-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-010-0572-7

Keywords

Navigation