Michael B. Brenner

Division of Rheumatology, Immunology and Allergy

Department of Medicine
Brigham and Women's Hospital
Smith Building, Room 552
One Jimmy Fund Way
Boston, MA 02115
Tel: (617) 525-1000
Fax: (617) 525-1001
Email: mbrenner@rics.bwh.harvard.edu
8 postdoctoral fellows, 2 junior faculty, 3 graduate students

Antigen Presentation by CD1:

This laboratory showed that the cellular immune system is capable not only of recognizing peptides in the context of MHC, but it is also capable of recognizing lipid antigens in the context of CD1 antigen presenting molecules. CD1 molecules (CD1a, b, c and d) are MHC class I-like proteins that contain hydrophobic antigen pockets that bind the lipid tails of antigens, rather than the side chains and backbones of peptides. The genes encoding the CD1a, b, c and d molecules represent a distinct lineage of antigen presenting elements that open T cell recognition to the universe of lipid containing self and foreign antigens. These antigens include glycolipids (including sphiogolipids, diacylglycerols), lipopeptides and fatty acids) that are found in the cell walls of bacteria and parasites or are self-lipids in mammalian cells. CD1 restricted T cells include all phenotypic subsets, CD8+, CD4+, double negative T cells and NKT cells that recognize professional APCs including macrophages, dendritic cells and B cells. CD1 restricted T cells that are cytotoxic or secrete IFN-g are implicated in host defense against microbial infections. The self-antigen specific CD1 restricted NKT cells are critical both in host defense against infection and have been demonstrated to play important roles in autoimmunity, asthma, colitis and tumor immunity. Our laboratory is studying the biochemical and molecular aspects of antigen delivery and loading and T cell activation in human in vitro systems and in mouse models. We have defined the intracellular trafficking of CD1 molecules and demonstrated how they survey endosomal compartments to intersect with antigens and how this process occurs in infected APCs. We are studying the activation and inactivation of NKT cells in host defense and identifying their specific antigen structures. Together, these studies are defining a previously unexpected pathway of cell mediated immunity directed against the universe of lipid containing antigens that is important in infection, tumor and autoimmunity.

Pathophysiology Rheumatoid Arthritis:

We are also studying the immunological basis of inflammatory arthritis. We have made the original finding that cadherins, important adhesion molecules in tissue morphogenesis during development and in the maintenance of tissue architecture in adults, play a key role in the proliferative and invasive nature of synoviocytes in rheumatoid arthritis and in mouse models of inflammatory arthritis. In the absence of the synovial cadherin, synovial lining formation is attenuated and the inflammatory response in the joint is abated. The synovial tissue response to inflammation is altered and attachment of the synoviocytes to cartilage is averted. These studies now provide an underlying concept for rheumatoid arthritis in which the pathologic response is dependent on the reaction of cells that are specific to the tissue. Thus, synovial lining cells are organized in the synovium in the normal tissue and undergo an orchestrated response to inflammation that results in damage by attachment to and invasion of the cartilage. This orchestrated response requires the cadherin adhesion molecules that mediate the organization of the synovial lining and its pathological behavior in inflammatory arthritis. We speculate that the tissue specificity of other autoimmune disease is likely also linked to the organized and specific reaction that each tissue makes in response to inflammation.

References:

• Moody DB, Young DC, Cheng T-Y, Rosat J-P, Roura-mir C, OConnor PB, Zajonc DM, Walz A, Miller MJ, Levery SB, Wilson IA, Costello CE, Brenner MB. T cell activation by lipopeptide antigens. Science 2004; 303:527-531.
• van den Elzen P, Garg S, León L, Brigl M, Leadbetter EA, Gumperz JE, Dascher CC, Cheng T-Y, Sacks FM, Illarionov PA, Besra GS, Kent SC, Moody DB, Brenner MB. Apolipoprotein-mediated pathways of lipid antigen presentation. Nature 2005; 437:906-910.
• Lee DM, Friend DS, Gurish MF, Benoist C, Mathis D, Brenner MB. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 2002; 297:1689-1692.