Immunology, diabetes, mast cells, autoimmunity, obesity

The aim of this project is to determine the role mast cells induced by GIN infection play in the induction, amplification and perpetuation of inflammatory responses in rheumatoid arthritis

Mast cells play key roles in the pathology associated with host defence against gastrointestinal nematode parasites (GIN) in particular and a variety of inflammatory diseases. They are a potent source of enzymes, cytokines and possess costimulatory and antigen presenting capacity. Recent studies implicate mast cells in inflammatory arthritis pathogenesis. However such studies have focussed mainly on innate immune mechanisms elucidated via immune complex driven models and leave many unanswered questions that preclude optimal therapeutic targeting. In contrast, infection with GIN has been shown to be both induce mast cells and to suppress inflammatory autoimmune disease and asthma.  We will determine how mast cells, dendritic cells and T cells induced following infection with GIN interact during the development of synovitis and thereafter evaluate the role that mast cells play in the induction and perpetuation of the inflammatory response therein. We will test the hypothesis that induction of mast cells by GIN infection, either directly or indirectly, regulate the onset of synovitis via effects on antigen presentation, costimulation and T cell / APC activation and trafficking. Confirmation of this will directly inform the design of optimal MC targeting therapeutic strategies.

Inflammatory arthritis will be induced in wild type and mast cells deficient W-sh mice and then infected with GIN.  The development of pathology determined using a range of techniques.

Histology, ELISA, tissue culture, in vivo biology, FACS, confocal microscopy, 2 photon microscopy, IVIS, parasitology

McKittrick CM, Lawrence CE, Carswell HV.  Mast cells promote blood brain barrier breakdown and neutrophil infiltration in a mouse model of focal cerebral ischemia.  J Cereb Blood Flow Metab. 2015 35:638-47

Wu J, Grassia G, Cambrook H, Ialenti A, MacRitchie N, Carberry J, Wadsworth RM, Lawrence C, Kennedy S, Maffia P.  Perivascular mast cells regulate vein graft neointimal formation and remodeling.  Peer J. 2015 Aug 18;3:e1192

Saunders KA1, Raine T, Cooke A, Lawrence CE.  Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection. Infect Immun. 2007 75:397-407.

Schubert N, Dudeck J, Liu P, Karutz A, Speier S, Maurer M, Tuckermann J, Dudeck A.  Mast cell promotion of T cell-driven antigen-induced arthritis despite being dispensable for antibody-induced arthritis in which T cells are bypassed.  Arthritis Rheumatol. 2015 67:903-13.