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.
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.
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