Our laboratory has been involved in the molecular analysis of MHC class II-restricted antigen processing and presentation for the last 15 years.  We are focused on the characterization of both endogenous and exogenous antigen pathways.  As part of our analysis of exogenously delivered antigen we recently mapped the human proteome and peptidome carried by the human lymph. The peptidome, generated by physiological tissue catabolism, and transported by the pre-nodal lymph, is distinct from the self-peptidome generated in the endosomal compartment.  Importantly, unlike self antigen processed by local or nodal antigen presenting cells, which produce epitopes constrained by the endosomal processing activity, self antigens present in the lymph are derived from a wider variety of processing pathways; thus expanding the tissue-specific self-repertoire available for the maintenance of immunological tolerance. A second line of ongoing research involves the characterization of the transport of endogenous antigen from the cytosol to the late endosomal compartments by autophagy. In particular we recently characterized the intersection between microautophagy and the ESCRT system as a way to deliver cytosolic antigens to the inner vesicles of multivesicular late endosomes for antigen processing and MHC class II loading. Finally, a third line of research involves the molecular analysis of dendritic cells and MHC class II-restricted immune responses in immune senescence. We recently discovered that dendritic cells generated from aging bone marrow present an extensively oxidized, glycated and lipoxidated proteome that interferes with  processing and presentation of MHC class II restricted exogenous and endogenous antigens.

Clement CC, Wang W, Dzieciatkowska M, Cortese M, Hansen KC, Becerra A, Thangaswamy S, Nizamutdinova I, Moon JY, Stern LJ, Gashev AA, Zawieja D, Santambrogio L. Quantitative Profiling of the Lymph Node Clearance Capacity. Scientific Reports 2018 Jul 26;8(1): 11253.

Wan X, Zinselmeyer BH, Zakharov PN, Vomund AN, Taniguchi R, Santambrogio L, Anderson MS, Lichti CF, Unanue ER. Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides. Nature. 2018 Aug;560(7716):107-111.

Mondanelli G, Bianchi R, Pallotta MT, Orabona C, Albini E, Iacono A, Belladonna ML, Vacca C, Fallarino F, Macchiarulo A, Ugel S, Bronte V, Gevi F, Zolla L, Verhaar A, Peppelenbosch M, Mazza EM, Bicciato S, Laouar Y, Santambrogio L, Puccetti P, Volpi C, Grohmann U. A Relay Pathway between Arginine and Tryptophan Metabolism Confers Immunosuppressive Properties on Dendritic Cells. Immunity. 2017 Feb 13.

Russo E, Teijeira A, Vaahtomeri K, Willrodt A, Block J, Nitschke’ M, Santambrogio L, Kerjaschki D, Sixt M, Halin C. CCL21 guides dendritic cell migration within lymphatic capillaries in the downstream direction of the draining lymph node. Cell Reports 2016 Feb 23;14(7):1723-34.

Tanase M, Urbanska A, Zolla V, Clement C, Morozova K, Roda B, Reschiglian P, Santambrogio L. Role of Carbonyl Modifications on Aging-Associated Protein Aggregation. Scientific Reports 2016 Jan 18;6:19311.

Clement C, Becerra A, Yin L, Zolla V, Merlin S, Follenzi A,  Shafer S, Stern L, Santambrogio L. The dendritic cell MHC II peptidome derives from a variety of processing pathways and includes peptides with a broad spectrum of HLA-DM sensitivity. J. Biol. Chemistry 2016 Jan 6.

Autoimmune response to transthyretin in juvenile idiopathic arthritis. Clement CC, Moncriefe H, Lele A, Janow G, Becerra A, Bauli F, Saad FA, Perino G, Montagna C, Cobelli N, Hardin J, Stern LJ, Ilowite N, Porcelli SA, Santambrogio L. Journal Clinical Investigation  Insight. 2016 Feb;1(2).

Morozova K, Zolla V, Sidhar S, Clement CC, Scharf B, Verzani Z, LaRocca J, Hajjar K, Cuervo AM, Santambrogio L.  Role of Annexin A2 in Atg16+ Vesicle Biogenesis and Homotypic Fusion. Nature Comms, 2015 Jan 19;6:5856.

Tanase M, Zolla V, Clement CC, Borghi F, Urbanska A,  Rodriguez-Navarro JA, Roda B, Zattoni A, Reschiglian P, Cuervo AM, Santambrogio L. Hydrodynamic-size based separation and characterization of protein aggregates from total cell lysates. Nature Protocols 2015 Jan;10(1):134-48.

Scharf, C. C. Clement, S. Yodmuang, A. urbanska, S. Suadicani, D. Aphkhazava, M. Thi, G. Perino, J. Hardin, N. Cobelli, G. Vunjak-Novakovic, L. Santambrogio. Age-Related Carbonylation of Fibrocartilage Structural Proteins Drives Tissue Degenerative Modification Cell Chemical Biology 2013 Jul 25;20(7):922-34.

Scharf, C. C. Clement, X. Wu, D, Zanolini, A Follenzi J. N. Larocca, K Levon, F. S. Sutterwala, K. A. Hajjar, J. Rand, N Cobelli, E.  Purdue, L. Santambrogio. Annexin II endosomal binding induced by damage to the organelle limiting membrane. Nature Comm. 2012 Mar 27; 3:755.

E. S. Cannizzo, C. C. Clement1, R. Valdor,  S. Kaushik , C. Follo, A.M. Cuervo, F. J. Macian, L. Santambrogio. Age-related Oxidative Stress Compromises Endosomal Antigen Processing and Presentation. Cell Reports 2012 Jul 26;2(1):136-49.

R. Sahu, S. Kaushik, C. C. Clement, E. S. Cannizzo, B. Scharf, A. Follenzi, I.Potolicchio, E. Nieves, A.M. Cuervo, L. Santambrogio. Microautophagy of cytosolic proteins by late endosomes. Developmental Cell 2011 Jan 18;20(1):131-9. doi: 10.1016/j.devcel.2010.12.003. (News and Views in Nature Review of Cell Biology)

Zolla V, Tsoy Nizamutdinova I, Scharf B, Clement CC,  Maejima D, Akl T, Nagai T, Luciani P, Leroux JC, Halin C,  Stukes S, Tiwari S, Casadevall A, Jacobs W, Entenberg D, Zawieja D, Condeelis J, Fooksman D, Gashev A, Santambrogio L. Aging-related anatomical and biochemical changes in lymphatic collectors impair lymph transport, fluid homeostasis and pathogen clearance. Aging Cell, in press

Morozova K, Zolla V, Sidhar S, Clement CC, Scharf B, Verzani Z, LaRocca J, Hajjar K, Cuervo AM, Santambrogio L.  Role of Annexin A2 in Atg16⁺ Vesicle Biogenesis and Homotypic Fusion. Nature Comms, 2015 Jan 19;6:5856. doi: 10.1038/ncomms6856

Tanase M, Zolla V, Clement CC, Borghi F, Urbanska A,  Rodriguez-Navarro JA,   Roda B, Zattoni A, Reschiglian P, Cuervo AM, Santambrogio L. Hydrodynamic-size based separation and characterization of protein aggregates from total cell lysates. Nature Protocols 2015 Jan;10(1):134-48. doi: 10.1038/nprot.2015.009.

 E. S. Cannizzo, C. C. Clement,R. Valdor,  S. Kaushik, C. Follo, A.M. Cuervo, F.   J. Macian, L. Santambrogio. Age-related Oxidative Stress Compromises  Endosomal Antigen Processing and Presentation. (2012) Cell Reports 2(1):136-49.

B. Scharf, C. C. Clement, X. Wu, D, Zanolini, A Follenzi J. N. Larocca, K Levon, F. S. Sutterwala, K. A. Hajjar, J. Rand, N Cobelli, E.  Purdue, L. Santambrogio. Annexin II endosomal binding induced by damage to the organelle limiting membrane. (2012) Nature Comm. 27;3:755.

R. Sahu, S. Kaushik, C. C. Clement, E. S. Cannizzo, B. Scharf, A. Follenzi, I. Potolicchio, E. Nieves, A.M. Cuervo, L. Santambrogio. Microautophagy of cytosolic proteins by late endosomes. (2011). Developmental Cell 20 (1): 131-139 (News and Views in Nature Review of Cell Biology)

C. C. Clement, D. Aphkhazava, E. Nieves, M. Callaway, W. Olszewski, O. Rotzschke, L. Santambrogio. 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 (2013). J Proteomics 12 (78): 172-187

C.C. Clement, O. Rotzschke, L. Santambrogio. (2011) The Human Lymph: A pond of self-antigens for the fishing APC. (2011) Trends in Immunology 32 (1); 1-5.

Cannizzo ES, Clement CC, Sahu R, Follo C, Santambrogio L. Oxidative Stress, inflamm-aging and immunosenescence (2011) J Proteomics. 74(11):2313-23.

A. Bunbury, I. Potolicchio, L. Santambrogio. Calcium regulated lysosomal exocytosis in human monocytes mediates surface MHC class II expression. (2009) FASEB J. Jan;23(1):164-71.

Stern, L..J., I Potolicchio, L. Santambrogio. Structure, development and cell biology of antigen processing compartments. (2006). Current Opinion in Immunology. 18 (1):64-9.