Skip to main content

MINI REVIEW article

Front. Immunol., 16 December 2013
Sec. Antigen Presenting Cell Biology
This article is part of the Research Topic Processing, editing, and presenting the MHC class II peptidome View all 21 articles

The Lymph Self-Antigen Repertoire

  • 1Department of Pathology, Albert Einstein College of Medicine, New York, NY, USA
  • 2Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY, USA

The lymphatic fluid originates from the interstitial fluid which bathes every parenchymal organ and reflects the “omic” composition of the tissue from which it originates in its physiological or pathological signature. Several recent proteomic analyses have mapped the proteome-degradome and peptidome of this immunologically relevant fluid pointing to the lymph as an important source of tissue-derived self-antigens. A vast array of lymph-circulating peptides have been mapped deriving from a variety of processing pathways including caspases, cathepsins, MMPs, ADAMs, kallikreins, calpains, and granzymes, among others. These self peptides can be directly loaded on circulatory dendritic cells and expand the self-antigenic repertoire available for central and peripheral tolerance.

Lymph Formation

The lymphatic fluid originates from the interstitial fluid which bathes every parenchymal organ and it is generated through a process of ultrafiltration of the plasma, circulating through the blood capillaries, as well as by the addition of metabolic and catabolic products collected from the tissue of origin (14).

Once the proteins have been filtered into the extracellular space, they will not re-enter the blood circulatory system by uptake into the venous capillaries as previously thought. Indeed, what was known as the Starling principle has been recently revisited and it is now apparent that almost all the extravasated fluid will be drained into the lymphatics (5).

In addition to the proteins and molecules originating from plasma ultrafiltration, the interstitial fluid will be further enriched with products derived from tissue/organ catabolism/metabolism (613).

The interstitial fluid will then drain into open end lymphatic capillaries and hence forth be called lymph (14, 15). The pre-nodal lymph will flow into progressively larger collectors up to the draining lymph nodes (500–600 in humans), disseminated throughout the body. All lymph passes through one or more lymph nodes and each node collects lymph from a distinct region of the body (4). Thus, a molecular signature of tissue-specific self proteins is collected in each node.

Lymph Proteome, Degradome, and Peptidome

During the last two decades there has been an increasing interest in the analysis of the protein composition of human and rodent lymph under physiological and pathological conditions and in the comparative analysis with plasma samples (613, 1620). This analysis has been elusive for many years due to the difficulty in cannulating lymphatics, which run much deeper then veins and have a smaller diameter and more fragile walls. Additionally, mass spectrometric techniques employed just a few years ago were much less sensitive than they are now in mapping proteins expressed at low levels within scarce amounts of collected fluid.

Proteomic profiles have been reported for human, rodent, bovine, and ovine lymph, and two major conclusions can be drawn from the compilation of these: (613, 1620).

(i) The lymph proteomic profile is not merely overlapping with the one from the plasma but qualitative and quantitative differences can be appreciated; indeed the lymph proteome appears to be enriched in products deriving from tissue and cellular metabolism/catabolism, organ remodeling, extracellular matrix processing, and cellular apoptosis.

(ii) The proteomic molecular signature reflects the tissue from where the lymph is collected and the organ’s physiological or pathological condition. Indeed tissue-specific proteins have been mapped in the lymph collected from capillaries draining specific organs and infectious or inflammatory tissue conditions are reflected in proteomic changes in lymph more so than in plasma.

The proteomic profile of the lymph also revealed the presence of several low molecular weight products composed by fragments, derived from protein processing, and short peptides (12). A similar degradome and peptidome was previously mapped in the plasma and serum and other biological fluids; the most comprehensive analysis so far reports up to 6000 peptides, identified with high confidence in mouse serum (21). Several more groups reported on the low molecular weight cleaved proteome and peptidome revealing the remarkable richness of protein fragments and naturally processed peptides present in lymph, plasma, synovial fluid, urine, and cerebrospinal fluid (2228). Our group recently mapped the first peptidome transported by the human lymph. Over 300 self peptides were sequenced which derived from the catabolic processing of both intracellular and extracellular proteins (12). The peptidome comprised processed proteins derived from extracellular matrix proteins, cell adhesion molecules, and plasma membrane/receptors as well as an intracellular-derived peptidome consisting of fragments of cytosolic, nuclear (transcription factors and regulators of gene expression), mitochondrial, endosomal, Golgi, and endoplasmic reticulum proteins (12).

Peptide quantification by 14N/15N labeling and amino acid sequencing from 2D-DIGE spots indicated that many peptides were present in human lymph in at least nanomolar concentrations (12) and analysis of peptide half life in biological fluids indicated a stability of over 24 h (22).

Collectively all the experimental findings point to the lymph as an important biological fluid that transport the tissue “omics” (proteomes, degradomes, peptidomes) to the draining lymph nodes to convey a snapshot of each parenchymal organ in physiological and pathological conditions.

Processing the Lymph and Plasma Degradome and Peptidome

Two major advances have improved our capability in identifying the lymph and plasma degradome and peptidome’s processing pathways; (i) improved mass spectrometric techniques, which allow high confidence peptide identification and correct amino acid assignment and (ii) increased representation of proteins in databases (Brenda, CutD, MEROPS), which facilitated prediction of the processing enzymes involved in peptide cleavage. Analysis of the human lymph- and plasma-carried peptidome identified peptides derived from both intra and extracellular sources and mapped several proteases likely involved in peptide processing including caspases, cathepsins, MMPs, plasmin, kallikreins, calpains, and granzymes (4, 21, 22, 24, 2931). Peptides derived from intracellular proteins are likely released by damaged and apoptotic cells, several of which are normally found in the lymph (17, 32). These proteins could be cleaved by the proteasome, furins, calpains, cytosolic proteases, and caspases as well as extracellular proteases. Several peptides cleaved by cathepsins and other endosomal proteases were also found. These peptides were likely released from endosomal compartments during exosome exocytosis or processed extracellularly by released cathepsins (33). Peptides generated by the processing of matrix proteins and collagens could be generated by MMPs and ADAMs whose activity controls the constant remodeling of the extracellular matrix to accommodate organ growth, cell migration, and cell replenishment (3436). Surface receptors, adhesion molecules, growth factors, and cytokines/chemokine, represent another category of processed peptides found in lymphatic fluid (37, 38). Additionally, products deriving from the complement cascade, thrombin and plasmin peptidases, and the kallikrein system were also found in the lymph.

Several other studies mapped the peptidome present in plasma, serum, and other biological fluids in physiological and pathological conditions including various types of cancer, inflammatory, and degenerative pathologies (4, 21, 22, 24, 2931, 39, 40). Altogether, two major conclusions can be derived from these analyses:

(i) there is a great variety of processing pathways involved in the formation of the degradome/peptidome present in different biological fluids and

(ii) the degradome/peptidome profile changes according to the physiological or pathological state of the organ from where the lymph/plasma are collected.

Indeed, in pathological conditions, the mapped peptidome/degradome is highly enriched with new peptides as compared to the peptidome/degradome found in healthy physiological conditions (4, 7, 21, 22, 24, 29, 31, 39, 41, 42). This reflects the increased number of peptide fragments cleaved by proteases up-regulated during inflammation (21, 22, 24).

MHC II Loading of the Self Peptidome

MHC II peptide complexes can be loaded in late endosomal MIIC compartments, early endosomes and at the plasma membrane (4353). In the late endosomal compartment, antigen processing is dependent on cysteine, aspartic and asparagine endo-peptidases, and MHC II loading depends on the editing molecule HLA-DM (5457). In early endosomes the antigen processing and MHC II loading is cathepsins and mostly HLA-DM-independent (49, 53, 5860). Similarly extracellular peptides can be loaded at the cell surface either on empty MHC II molecules or through peptide exchange (47, 50, 52, 6163).

Having distinct MHC class II loading compartments allows presentation of a larger array of peptides. Indeed many of the peptides loaded in recycling/early endosomes and at the cell surface are low affinity and are eliminated by HLA-DM in endosomal compartments (64). Thus, if the MIIC endosomal antigen processing and loading machinery restrict the array of presented peptides by kinetic stability and HLA-DM editing, generating an overall higher affinity, higher stability, long-lived MHC II peptidome (65), the HLA-DM-independent pathway generates a broader, lower stability/easily exchangeable MHC II peptidome.

These two different pathways are exploited by the antigen-presenting cells (APC) to control immunogenicity (65, 66).

Indeed the early endosomes/plasma membrane MHC II loading pathway is active in immature dendritic cells (DC) and down-regulated upon DC maturation (5052, 64). As a result immature DC present an overall broader MHC II peptidome that includes low affinity/stability peptides which, by diluting the high affinity self peptides, contribute to the maintenance of self tolerance. The importance of maintaining a broader MHC II peptidome under physiological conditions is further supported by the notion that in immature DC and non-stimulated B cells the HLA-DM editing activity is down regulated, within the MHC II endosomal pathway, by HLA-DO; resulting in decreased presentation of high affinity self peptides that could induce autoimmunity (66, 67). Upon APC maturation/activation surface MHC II loading is shut off (5052) and HLA-DM editing activity is up-regulated (66, 67). This would favor presentation of high affinity pathogen-derived peptides to generate immunity.

MHC II Presentation of the Self Peptidome

Different mechanisms ensure that tissue-derived self antigens are constantly presented to the immune system for the maintenance of central and peripheral self tolerance (6870).

In the thymus, medullary epithelial cells (mTEC), conventional dendritic cells (cDC) (Sirpα+ CD11c+ CD8), CD8+ DC (Sirpα CD11c+ CD8+), and plasmacytoid DC delete immature thymocytes with high affinity for the self MHC II peptidome (71). These populations of APC display an MHC II-bound peptidome derived from exogenous antigens, acquired through phagocytosis, and endogenous antigen acquired through autophagy (69, 72). Additionally, a subset of mTEC expresses the transcriptional regulator AIRE which promotes expression of tissue-specific antigens, expanding the antigen repertoire to be presented (73). Since mTEC are equipped with all the proteins associated with the antigen processing and presentation machinery, they can directly process the AIRE-expressed antigens. Indeed the presence of autophagosomes in these cells indicates that antigens could enter the endosomal tract through autophagy (72). On the other hand several reports also indicate that mTEC can hand over AIRE-acquired antigens to cDC for thymic selection (74).

Self-antigens in the thymus can also give rise to natural or thymic T regs, through an avidity-dependent selection process. The APC controlling the formation of Treg are the same as those involved in the process of negative selection (75).

Cells that escape thymic deletion are tolerized in the periphery through anergy or Treg-mediated suppression by tissue and nodal resident dendritic cells (DCs) and macrophages (MΦ) which continuously process and present the self proteome of parenchymal organs. Additionally, AIRE-independent mechanisms have also been described in the periphery which mediate expression of tissue-specific self antigens by lymphatic endothelial cells, further expanding the presentation of the self proteome (76).

All the above described mechanisms depend on self-antigen delivery to endosomal compartments, through endocytosis or autophagy. Thus, they generate an MHCII peptidome mostly restricted by endosomal processing enzymes (77).

Recently, circulating cDC have been shown to promote both central and peripheral tolerance by displaying circulating self-antigens to immature thymocytes or mature peripheral T cells (78, 79). Indeed, even though it has been known for some time that intrathymic injection of organ specific APC induce long lasting tolerance to the organ self antigens (80, 81) it was the Goldschneider group that linked thymic tolerance, to extrathymic self antigens, to the role of cDC (82, 83). Work from his group and others indicated that under physiological conditions migratory DC transport self-antigens to mediate thymic negative selection or peripheral T cell anergy and Treg differentiation. In both humans and mice, circulating DC differentiate in a FLT3-dependent manner and are CD11c+, CCR7+, CD103+, and express high levels of MHC II and intermediate expression of co-stimulatory molecules (84). Importantly, migratory DC do not only rely on endosomal processing to display the MHC II peptidome but are capable of loading exogenous peptides as well. Indeed peptides have been shown to induce thymic negative selection not only when directly injected in the thymus (85) but also when injected in the blood stream (78, 86) or in the peritoneum (8790) which is connected to mesenteric lymphatic drainage (91). Importantly, circulating self antigens have been shown to induce thymic negative selection at physiological concentrations, as the ones achieved on MHC II on the surface of APC (92).

Conclusion

The interaction between MHC II-peptides and TCRs constitutes the molecular base for all CD4 T cell-mediated immune responses and the displayed MHC II peptidome is critical to the generation of tolerance, immunity, and autoimmunity. The loaded MHC II peptidome is selected based on MHC II affinity, presence or absence of HLA-DM activity, and arrays of available peptides. The degradome/peptidome present in the extracellular milieu and transported by the plasma, lymph, and other biological fluids could contributes to the generation of the MHC II peptidome. Indeed, in the last few years a series of proteomic analysis indicated that the amount of peptides present in biological fluids (lymph, blood, urine, peritoneal fluid) is much higher then what previously known, it is broader in repertoire and has a long half life (4, 21, 22, 24, 2931, 39). These peptides could function in thymic negative selection similarly to the ones injected exogenously (78, 8590, 92). Distinct from the peptidome generated in MIIC, the peptidome carried by the lymph/plasma is not restricted by endosomal proteases but originates from several other processing pathways, further expanding the self antigen repertoire presented by circulating DC for the maintenance of tolerance.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We would like to thank Drs Teresa Di Lorenzo and Moshe Sadofsky for critical reading of this review.

References

1. Levick JR, Michel CC. Microvascular fluid exchange and the revised Starling principle. Cardiovasc Res (2010) 87:198–210. doi:10.1093/cvr/cvq062

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

2. Rockson SG. The lymphatic continuum revisited. Ann N Y Acad Sci (2008) 1131:XI–X. doi:10.1196/annals.1413.000

CrossRef Full Text

3. Interewicz B, Olszewski WL, Leak LV, Petricoin EF, Liotta LA. Profiling of normal human leg lymph proteins using the 2-D electrophoresis and SELDI-TOF mass spectrophotometry approach. Lymphology (2004) 37:65–72.

Pubmed Abstract | Pubmed Full Text

4. Clement CC, Rotzschke O, Santambrogio L. The lymph as a pool of self-antigens. Trends Immunol (2011) 32:6–11. doi:10.1016/j.it.2010.10.004

CrossRef Full Text

5. Michel CC. Microvascular Fluid Filtration and Lymph Formation. New York: Springer Press (2013). p. 35–51.

6. Leak LV, Liotta LA, Krutzsch H, Jones M, Fusaro VS, Ross SJ, et al. Proteomic analysis of lymph. Proteomics (2004) 4:753–65. doi:10.1002/pmic.200300573

CrossRef Full Text

7. Meng Z, Veenstra TD. Proteomic analysis of serum, plasma, and lymph for the identification of biomarkers. Proteomics Clin Appl (2007) 8:747–57. doi:10.1002/prca.200700243

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

8. Goldfinch GM, Smith WD, Imrie L, McLean K, Inglis NF, Pemberton AD. The proteome of gastric lymph in normal and nematode infected sheep. Proteomics (2008) 8:1909–18. doi:10.1002/pmic.200700531

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

9. Mittal A, Middleditch M, Ruggiero K, Buchanan CM, Jullig M, Loveday B, et al. The proteome of rodent mesenteric lymph. Am J Physiol Gastrointest Liver Physiol (2008) 295:G895–903. doi:10.1152/ajpgi.90378.2008

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

10. Mittal A, Phillips AR, Middleditch M, Ruggiero K, Loveday B, Delahunt B, et al. The proteome of mesenteric lymph during acute pancreatitis and implications for treatment. JOP (2009) 10:130–42.

Pubmed Abstract | Pubmed Full Text

11. Zurawel A, Moore EE, Peltz ED, Jordan JR, Damle S, Dzieciatkowska M, et al. Proteomic profiling of the mesenteric lymph after hemorrhagic shock: differential gel electrophoresis and mass spectrometry analysis. Clin Proteomics (2010) 8:1–6. doi:10.1186/1559-0275-8-1

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

12. Clement CC, Cannizzo ES, Nastke MD, Sahu R, Olszewski W, Miller NE, et al. An expanded self-antigen peptidome is carried by the human lymph as compared to the plasma. PLoS One (2010) 5:e9863. doi:10.1371/journal.pone.0009863

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

13. Clement CC, Aphkhazava D, Nieves E, Callaway M, Olszewski W, Rotzschke O, et al. Protein expression profiles of human lymph and plasma mapped by 2D-DIGE and 1D SDS-PAGE coupled with nanoLC-ESI-MS/MS bottom-up proteomics. J Proteomics (2013) 78:172–87. doi:10.1016/j.jprot.2012.11.013

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

14. Zawieja DC. Contractile physiology of lymphatics. Lymphat Res Biol (2009) 7:87–96. doi:10.1089/lrb.2009.0007

CrossRef Full Text

15. Gashev AA, Zawieja DC. Hydrodynamic regulation of lymphatic transport and the impact of aging. Pathophysiology (2010) 17:277–87. doi:10.1016/j.pathophys.2009.09.002

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

16. Nanjee MN, Cooke CJ, Olszewski WL, Miller NL. Lipid and apolipoprotein concentrations in prenodal leg lymph of fasted humans. Associations with plasma concentrations in normal subjects, lipoprotein lipase deficiency, and LCAT deficiency. J Lipid Res (2000) 41:1317–27.

Pubmed Abstract | Pubmed Full Text

17. Olszewski WL, Pazdur J, Kubasiewicz E, Zaleska M, Cooke CJ, Miller NE. Lymph draining from foot joints in rheumatoid arthritis provides insight into local cytokine and chemokine production and transport to lymph nodes. Arthritis Rheum (2001) 44:541–9.

Pubmed Abstract | Pubmed Full Text

18. Masuno T, Moore EE, Cheng AM, Sarin EL, Banerjee A. Bioactivity of postshock mesenteric lymph depends on the depth and duration of hemorrhagic shock. Shock (2006) 26:285–9. doi:10.1097/01.shk.0000223132.72135.52

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

19. Peltz ED, Moore EE, Zurawel AA, Jordan JR, Damle SS, Redzic JS, et al. Proteome and system ontology of hemorrhagic shock: exploring early constitutive changes in postshock mesenteric lymph. Surgery (2009) 2:347–57. doi:10.1016/j.surg.2009.02.022

CrossRef Full Text

20. Dzieciatkowska M, Wohlauer MV, Moore EE, Damle S, Peltz E, Campsen J, et al. Proteomic analysis of human mesenteric lymph. Shock (2011) 5:331–8. doi:10.1097/SHK.0b013e318206f654

CrossRef Full Text

21. Hood BL, Lucas DA, Kim G, Chan KC, Blonder J, Issaq HJ, et al. Quantitative analysis of the low molecular weight serum proteome using 18O stable isotope labeling in a lung tumor xenograft mouse model. J Am Soc Mass Spectrom (2005) 8:1221–30. doi:10.1016/j.jasms.2005.02.005

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

22. Antwi K, Hostetter G, Demeure MJ, Katchman BA, Decker GA, Ruiz Y, et al. Analysis of the plasma peptidome from pancreas cancer patients connects a peptide in plasma to over-expression of the parent protein in tumors. J Proteome Res (2009) 10:4722–31. doi:10.1021/pr900414f

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

23. Zheng X, Wu SL, Hincapie M, Hancock WS. Study of the human plasma proteome of rheumatoid arthritis. J Chromatogr (2009) 1216:3538–45. doi:10.1016/j.chroma.2009.01.063

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

24. Shen Y, Tolic N, Liu T, Zhao R, Petritis BO, Gritsenko MA, et al. Blood peptidome-degradome profile of breast cancer. PLoS One (2010) 5:e13133. doi:10.1371/journal.pone.0013133

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

25. Koomen JM, Li D, Xiao LC, Liu TC, Coombes KR, Abbruzzese J, et al. Direct tandem mass spectrometry reveals limitations in protein profiling experiments for plasma biomarker discovery. J Proteome Res (2005) 3:972–81. doi:10.1021/pr050046x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

26. Shen Z, Want EJ, Chen W, Keating W, Nussbaumer W, Moore R, et al. Sepsis plasma protein profiling with immunodepletion, three-dimensional liquid chromatography tandem mass spectrometry, and spectrum counting. J Proteome Res (2006) 5:3154–60. doi:10.1021/pr060327k

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

27. Farrah T, Deutsch EW, Omenn GS, Campbell DS, Sun Z, Bletz JA, et al. A high confidence human plasma proteome reference set with estimated concentrations in Peptide Atlas. Mol Cell Proteomics (2011) 10:M110. doi:10.1074/mcp.M110.006353

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

28. Omenn GS, States DJ, Adamski M, Blackwell TW, Menon R, Hermjakob H, et al. Proteome and system ontology of hemorrhagic shock: exploring early constitutive changes in postshock mesenteric lymph. Surgery (2009) 6:347–57. doi:10.1016/j.surg.2009.02.022

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

29. Geho DH, Liotta LA, Petricoin EF, Zhao W, Araujo RP. The amplified peptidome: the new treasure chest of candidate biomarkers. Curr Opin Chem Biol (2006) 1:50–5. doi:10.1016/j.cbpa.2006.01.008

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

30. Schilling O, Overall CM. Proteome-derived, database-searchable peptide libraries for identifying protease cleavage sites. Nat Biotech (2008) 26:685–94. doi:10.1038/nbt1408

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

31. Dittwald P, Ostrowski J, Karczmarski J, Gambin A. Inferring serum proteolytic activity from LC-MS/MS data. BMC Bioinformatics (2012) 13(Suppl 5):S7. doi:10.1186/1471-2105-13-S5-S7

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

32. Olszewski WL. Human afferent lymph contains apoptotic cells and “free” apoptotic DNA fragments – can DNA be reutilized by the lymph node cells? Lymphology (2001) 34:179–83.

33. Fiebiger E, Maehr R, Villadangos J, Weber E, Erickson A, Bikoff E, et al. Invariant Chain controls the activity of extracellular cathepsin L. J Exp Med (2002) 196:1263–9. doi:10.1084/jem.20020762

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

34. Cauwe B, Van den Steen PE, Opdenakker G. The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases. Crit Rev Biochem Mol Biol (2007) 42:113–85. doi:10.1080/10409230701340019

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

35. Reiss K, Saftig P. The “ADisintegrin And Metalloprotease” (ADAM) family of sheddases: physiological and cellular functions. Semin Cell Dev Biol (2009) 20:126–37. doi:10.1016/j.semcdb.2008.11.002

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

36. Lai ZW, Steer DL, Smith AI. Membrane proteomics: the development of diagnostics based on protein shedding. Curr Opin Mol Ther (2009) 11:623–31.

Pubmed Abstract | Pubmed Full Text

37. Murphy G. Regulation of the proteolytic disintegrin metalloproteinases, the ‘Sheddases’. Semin Cell Dev Biol (2009) 20:138–45. doi:10.1016/j.semcdb.2008.09.004

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

38. Heinrich J, Wiegert T. Regulated intramembrane proteolysis in the control of extracytoplasmic functions. Res Microbiol (2009) 160:696–703. doi:10.1016/j.resmic.2009.08.019

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

39. Ahn SM, Simpson RJ. Body fluid proteomics: prospects for biomarker discovery. Proteomics Clin Appl (2007) 1:1004–15. doi:10.1002/prca.200700217

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

40. Yoo JS, Ping P, Pounds J, Adkins J, Qian X, Wang R, et al. Overview of the HUPO Plasma Proteome Project: results from the pilot phase with 35 collaborating laboratories and multiple analytical groups, generating a core dataset of 3020 proteins and a publicly-available database. Proteomics (2005) 13:3226–45.

Pubmed Abstract | Pubmed Full Text

41. Meng Z, Veenstra TD. Targeted mass spectrometry approaches for protein biomarker verification. J Proteomics (2011) 74:2650–9. doi:10.1016/j.jprot.2011.04.011

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

42. Veenstra TD, Conrads TP, Hood BL, Avellino AM, Ellenbogen RG, Morrison RS. Biomarkers: mining the biofluid proteome. Mol Cell Proteomics (2005) 4:409–18. doi:10.1074/mcp.M500006-MCP200

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

43. Tulp A, Verwoerd D, Dobberstein B, Ploegh HL, Pieters J. Isolation and characterization of the intracellular MHC class II compartment. Nature (1994) 369:120–6. doi:10.1038/369120a0

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

44. Vergelli M, Pinet V, Vogt AB, Kalbus M, Malnati M, Riccio P, et al. HLA-DR-restricted presentation of purified myelin basic protein is independent of intracellular processing. Eur J Immunol (1997) 27:941–51. doi:10.1002/eji.1830270421

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

45. Pinet V, Vergelli M, Martin R, Bakke O, Long EO. Antigen presentation mediated by recycling of surface HLA-DR molecules. Nature (1995) 375:603–6. doi:10.1038/375603a0

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

46. Sanderson F, Kleijmeer MJ, Kelly A, Verwoerd D, Tulp A, Neefjes JJ, et al. Accumulation of HLA-DM, a regulator of antigen presentation, in MHC class II compartment. Science (1994) 266:1566–9. doi:10.1126/science.7985027

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

47. Nygard NR, Giacoletto KS, Bono C, Gorka J, Kompelli S, Schwartz BD. Peptide binding to surface class II molecules is the major pathway of formation of immunogenic class II-peptide complexes for viable antigen presenting cells. J Immunol (1994) 152:1082–93.

Pubmed Abstract | Pubmed Full Text

48. Sinnathamby G, Eisenlohr LC. Presentation by recycling MHC class II molecules of an influenza hemagglutinin-derived epitope that is revealed in the early endosome by acidification. J Immunol (2003) 170:3504–13.

Pubmed Abstract | Pubmed Full Text

49. Villadangos JA, Driessen C, Shi GP, Chapman HA, Ploegh HL. Early endosomal maturation of MHC class II molecules independently of cysteine proteases and H-2DM. EMBO J (2000) 19:882–91. doi:10.1093/emboj/19.5.882

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

50. Santambrogio L, Sato AK, Carven GJ, Belyanskaya SL, Strominger JL, Stern LJ. Extracellular antigen processing and presentation by immature dendritic cells. Proc Natl Acad Sci USA (1999) 96:15056–61. doi:10.1073/pnas.96.26.15056

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

51. Santambrogio L, Sato AK, Fischer FR, Dorf ME, Stern LJ. Abundant empty class II MHC molecules on the surface of immature dendritic cells. Proc Natl Acad Sci USA (1999) 96:15050–5. doi:10.1073/pnas.96.26.15050

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

52. Venkatraman P, Nguyen TT, Sainlos M, Bilsel O, Chitta S, Imperiali B, et al. Fluorogenic probes for monitoring peptide binding to class II MHC proteins in living cells. Nat Chem Biol (2007) 4:222–8. doi:10.1038/nchembio868

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

53. Strong BS, Unanue ER. Presentation of type B peptide-MHC complexes from hen egg white lysozime by TLR ligands and type I IFNs independent of H2-DM regulation. J Immunol (2011) 187:2193–201. doi:10.4049/jimmunol.1100152

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

54. Riese RJ, Chapman HA. Cathepsins and compartmentalization in antigen presentation. Curr Opin Immunol (2000) 12:107–13. doi:10.1016/S0952-7915(99)00058-8

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

55. Jensen PE. Antigen processing: HLA-DO a hitchhiking inhibitor of HLA-DM. Curr Biol (1998) 8:128–31. doi:10.1016/S0960-9822(98)70988-1

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

56. Manoury B, Mazzeo D, Li DN, Billson J, Loak K, Benaroch P, et al. Asparagine endopeptidase can initiate the removal of the MHC class II invariant chain chaperone. Immunity (2003) 18:489–98. doi:10.1016/S1074-7613(03)00085-2

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

57. Busch R, Rinderknecht CH, Roh S, Lee AW, Harding JJ, Burster T, et al. Achieving stability through editing and chaperoning: regulation of MHC class II peptide binding and expression. Immunol Rev (2005) 207:242–60. doi:10.1111/j.0105-2896.2005.00306.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

58. Khanna R, Burrows SR, Steigerwald-Mullen PM, Moss DJ, Kurilla MG, Cooper L. Targeting Epstein-Barr virus nuclear antigen 1 (EBNA1) through the class II pathway restores immune recognition by EBNA1-specific cytotoxic T lymphocytes: evidence for HLA-DM-independent processing. Int Immunol (1997) 9:1537–43. doi:10.1093/intimm/9.10.1537

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

59. Griffin JP, Chu R, Harding CV. Early endosomes and a late endocytic compartment generate different peptide-class II MHC complexes via distinct processing mechanisms. J Immunol (1997) 58:1523–6.

Pubmed Abstract | Pubmed Full Text

60. Pu Z, Lovitch SB, Bikoff EK, Unanue ER. T cells distinguish MHC-peptide complexes formed in separate vesicles and edited by H2-DM. Immunity (2004) 20:467–76. doi:10.1016/S1074-7613(04)00073-1

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

61. Chou CL, Mirshahidi S, Su KW, Kim A, Narayan K, Khoruzhenko S, et al. Short peptide sequences mimic HLA-DM functions. Mol Immunol (2008) 45:1935–43. doi:10.1016/j.molimm.2007.10.033

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

62. Potolicchio I, Chitta S, Xu X, Fonseca D, Crisi G, Horejsi V, et al. Conformational variation of surface class II MHC proteins during myeloid dendritic cell differentiation accompanies structural changes in lysosomal MIIC. J Immunol (2005) 175:4935–47.

Pubmed Abstract | Pubmed Full Text

63. Eisen HN, Hou XH, Shen C, Wang K, Tanguturi VK, Smith C, et al. Promiscuous binding of extracellular peptides to cell surface class I MHC protein. Proc Natl Acad Sci U S A (2012) 109:4580–5. doi:10.1073/pnas.1201586109

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

64. Lovitch SB, Esparza TJ, Schweitzer G, Herzog J, Unanue ER. Activation of type B T cells after protein immunization reveals novel pathways of in vivo presentation of peptides. J Immunol (2007) 178:122–33.

Pubmed Abstract | Pubmed Full Text

65. Lazarski CA, Chaves FA, Jenks SA, Wu S, Richards KA, Weaver JM, et al. The kinetic stability of MHC class II peptide complexes is a key parameter that dictates immunodominance. Immunity (2005) 23:29–40. doi:10.1016/j.immuni.2005.05.009

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

66. Yi W, Seth NP, Martillotti T, Wucherpfennig KW, Sant’Angelo DB, Denzin LK. Targeted regulation of self-peptide presentation prevents type I diabetes in mice without disrupting general immunocompetence. J Clin Invest (2010) 120:1324–6. doi:10.1172/JCI40220

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

67. Fallas JL, Tobin HM, Lou O, Guo D, Sant’Angelo DB, Denzin LK. Ectopic expression of HLA-DO in mouse dendritic cells diminishes MHC class II antigen presentation. J Immunol (2004) 173:1549–60.

Pubmed Abstract | Pubmed Full Text

68. Kappler JW, Roehm N, Marrack P. T cell tolerance by clonal elimination in the thymus. Cell (1987) 49:273–80. doi:10.1016/0092-8674(87)90568-X

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

69. Gallegos AM, Bevan MJ. Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J Exp Med (2004) 200:1039–49. doi:10.1084/jem.20041457

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

70. Skokos D, Shakhar G, Varma R, Waite JC, Cameron TO, Lindquist RL, et al. Peptide-MHC potency governs dynamic interactions between T cells and dendritic cells in lymph nodes. Nat Immunol (2007) 8:835–44. doi:10.1038/ni1490

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

71. Mouchess ML, Anderson M. Central tolerance induction. Curr Top Microbiol Immunol (2014) 373:69–86. doi:10.1007/82_2013_321

CrossRef Full Text

72. Nedjic J, Aichinger M, Emmerich J, Mizushima N, Klein L. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature (2008) 455:396–400. doi:10.1038/nature07208

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

73. Abramson J, Giraud M, Benoist C, Mathis D. Aire’s partners in the molecular control of immunological tolerance. Cell (2010) 140:123–35. doi:10.1016/j.cell.2009.12.030

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

74. Hubert FX, Kinkel SA, Davey GM, Phipson B, Mueller SN, Liston A, et al. Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood (2011) 118:2462–72. doi:10.1182/blood-2010-06-286393

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

75. Itoh M, Takahashi T, Sakaguchi N, Kuniyasu Y, Shimizu J, Otsuka F, et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol (1999) 162:5317–26.

Pubmed Abstract | Pubmed Full Text

76. Cohen JN, Guidi CJ, Tewalt EF, Qiao H, Rouhani SJ, Ruddell A, et al. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J Exp Med (2010) 207:681–98. doi:10.1084/jem.20092465

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

77. Honey K, Rudensky AY. Lysosomal cysteine proteases regulate antigen presentation. Nat Rev Immunol (2003) 3:472–82. doi:10.1038/nri1110

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

78. Bonasio R, Scimone ML, Schaerli P, Grabie N, Lichtman AH, von Andrian UH. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat Immunol (2006) 7:1092–100. doi:10.1038/ni1385

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

79. Cavanagh LL, VonAndrian UH. Travellers in many guises: the origins and destinations of dendritic cells. Immunol Cell Biol (2002) 80:448–62. doi:10.1046/j.1440-1711.2002.01119.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

80. Clare-Salzler MJ, Brooks J, Chai A, Van Herle K, Anderson C. Prevention of diabetes in nonobese diabetic mice by dendritic cell transfer. J Clin Invest (1992) 90:741–8. doi:10.1172/JCI115946

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

81. Oluwole SF, Jin MX, Chowdhury NC, Engelstad K, Ohajekwe OA, James T. Induction of peripheral tolerance by intrathymic inoculation of soluble alloantigens: evidence for the role of host antigen-presenting cells and suppressor cell mechanism. Cell Immunol (1995) 162:33–41. doi:10.1006/cimm.1995.1048

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

82. Donskoy E, Goldschneider I. Two developmentally distinct populations of dendritic cells inhabit the adult mouse thymus: demonstration by differential importation of hematogenous precursors under steady state conditions. J Immunol (2003) 170:3514–21.

Pubmed Abstract | Pubmed Full Text

83. Goldschneider I, Cone RE. A central role for peripheral dendritic cells in the induction of acquired thymic tolerance. Trends Immunol (2003) 24:77–81. doi:10.1016/S1471-4906(02)00038-8

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

84. Li J, Park J, Foss D, Goldschneider I. Thymus-homing peripheral dendritic cells constitute two of the three major subsets of dendritic cells in the steady-state thymus. J Exp Med (2009) 206:607–22. doi:10.1084/jem.20082232

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

85. Khoury SJ, Gallon L, Chen W, Betres K, Russell ME, Hancock WW, et al. Mechanisms of acquired thymic tolerance in experimental autoimmune encephalomyelitis: thymic dendritic-enriched cells induce specific peripheral T cell unresponsiveness in vivo. J Exp Med (1995) 182:357–66. doi:10.1084/jem.182.2.357

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

86. Liblau RS, Tisch R, Shokat K, Yang X, Dumont N, Goodnow CC, et al. Intravenous injection of soluble antigen induces thymic and peripheral T-cells apoptosis. Proc Natl Acad Sci U S A (1996) 93:3031–6. doi:10.1073/pnas.93.7.3031

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

87. Murphy KM, Heimberger AB, Loh DY. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science (1990) 250:1720–3. doi:10.1126/science.2125367

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

88. Mamalaki C, Norton T, Tanaka Y, Townsend AR, Chandler P, Simpson E, et al. Thymic depletion and peripheral activation of class I major histocompatibility complex-restricted T cells by soluble peptide in T-cell receptor transgenic mice. Proc Natl Acad Sci U S A. (1992) 89:11342–6. doi:10.1073/pnas.89.23.11342

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

89. Zal T, Volkmann A, Stockinger B. Mechanisms of tolerance induction in major histocompatibility complex class II-restricted T cells specific for a blood-borne self-antigen. J Exp Med (1994) 180:2089–99. doi:10.1084/jem.180.6.2089

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

90. Martin S, Bevan MJ. Antigen-specific and nonspecific deletion of immature cortical thymocytes caused by antigen injection. Eur J Immunol (1997) 27:2726–36. doi:10.1002/eji.1830271037

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

91. Asghar RB, Davies SJ. Pathways of fluid transport and reabsorption across the peritoneal membrane. Kidney Int (2008) 73:1048–53. doi:10.1038/ki.2008.32

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

92. Volkmann A, Zal T, Stockinger B. Antigen-presenting cells in the thymus that can negatively select MHC class II-restricted T cells recognizing a circulating self antigen. J Immunol (1997) 158:693–706.

Pubmed Abstract | Pubmed Full Text

Keywords: lymph, antigen processing, antigen presentation, MHC class II

Citation: Clement CC and Santambrogio L (2013) The lymph self-antigen repertoire. Front. Immunol. 4:424. doi: 10.3389/fimmu.2013.00424

Received: 03 September 2013; Accepted: 20 November 2013;
Published online: 16 December 2013.

Edited by:

Lawrence J. Stern, University of Massachusetts Medical School, USA

Reviewed by:

Philippe Pierre, Centre National de la Recherche Scientifique, France
Josef Mautner, Technische Universität München, Germany

Copyright: © 2013 Clement and Santambrogio. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Laura Santambrogio, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer Building Room 140, Bronx, New York, NY 10461, USA e-mail: laura.santambrogio@einstein.yu.edu

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.