Asthma; Autoimmune Diseases; Blood Group Incompatibility; Immune System Diseases
Our research centers on how the innate branch of the immune system regulates adaptive immunity in disease states such as allergy, autoimmunity and alloimmunization and in beneficial states such as vaccination and spans both mouse and human studies. We are currently focused on the function of a more recently discovered family of innate immune receptors, the NOD-like receptors (NLRs). In particular, we recently identified an unusual role for one structurally unique NLR, NLRP10, in regulating adaptive immunity via dendritic cell migration. In a process that was not previously known to require an innate immune signal, the emigration of activated dendritic cells from inflamed tissue is a crucial decision point in the generation of a productive lymphocyte-driven adaptive immune response. Yet how NLRP10 regulates this step or the immunological consequences of its activation remain unanswered questions that we are actively studying.
Extensive Research DescriptionThe mammalian immune system can be divided into two arms that act together to provide both immediate and long-term immunity to pathogens, the innate and adaptive immune branches, respectively. The more primitive, innate branch of the immune system provides critical regulation of adaptive immunity, in part through numerous germline-encoded pattern recognition receptors (PRR). These receptors include Toll-like receptors (TLR), NOD-like receptors (NLR), RIG-I-like RNA helicases and C-type lectin receptors. TLRs have been extensively studied in this innate-adaptive interface, however a new class of PRRs, the NOD-like receptors, has recently been found to also regulate adaptive immune responses. However, for a majority of the 22 known NLR human family members, their triggers and physiologic function remain unknown. We discovered that the NLR Nlrp3, which forms an inflammasome with caspase-1 and ASC, is critical in the adjuvant function of aluminum hydroxide and nanoparticles during vaccination. Yet how inflammasome activation regulates adaptive immunity is still a mystery. Further, we have found that a number of novel NLR family members are also critical in the initiation of T and B cells responses. We are actively working on answering these questions in the context of animal autoimmunity and vaccine models as well as in human studies.
The role of novel NLRs in shaping adaptive immunity
Identifying how NLRP10 regulates dendritic cell movement
Characterizing the molecular pathways critical in regulating NLR activation and effector function
Identifying innate immune receptors critical to red blood cell alloimmunization
- Krishnaswamy, JK, Chu, T, Eisenbarth, SC. Beyond Pattern Recognition: NOD-like Receptors in Dendritic Cells. Trends in Immunology, Jan 2013, in press.
- Eisenbarth, SC, Williams A, Colegio, OR, Meng, H, Strowig, T, Rongvaux, A, Henao-Mejia, J, Thaiss, C, Joly, S, Gonzalez, DG, Xu, L, Zenewicz, L, Haberman, AM, Elinav, E, Kleinstein S, Sutterwala, FS, Flavell, RA. Nlrp10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells. Nature, April 2012, 484: 510-515. [PMCID: PMC3340615]
- Williams, A., Flavell, RA., Eisenbarth, SC. The Role of NOD-like Receptors in Shaping Adaptive Immunity. Current Opinion in Immunology. Feb 2010, 22: 1-7.
- Eisenbarth, SC, Colegio, OR, O’Connor, W, Sutterwala, FS, Flavell, RA. Crucial Role for the Nalp3 Inflammasome in the Immunostimulatory Properties of Aluminum Adjuvants. Nature. Jun 2008, 36: 135-137.
- Eisenbarth, SC, Piggott, D, Huleatt, J, Visintin, I, Herrick, C, Bottomly, K. Lipopolysaccharide-enhanced, Toll-like Receptor 4-dependent T Helper Cell Type 2 Responses to Inhaled Antigen. Journal of Experimental Medicine. Dec 2002, 196: 1645-1651.