Our Projects
Our Goals
The memory of high affinity IgE responses
The affinity of IgE for an allergen is a determinant factor in allergic reactions. We study how is high affinity IgE generated. During immune responses the affinity of antibodies for an antigen improves through somatic mutation and selection in germinal centers, which output plasma cells and memory B cells. Interestingly, we found that IgE germinal center cells are functionally impaired and fail to generate high affinity IgE plasma cells and IgE memory B cells. A unique pathway generates high affinity IgE-producing cells: it involves affinity-matured IgG precursors that switch to IgE and become IgE plasma cells. Thus, IgG memory cells are the likely reservoir of yet-to-be pathogenic IgE plasma cells. We are studying the cell-intrinsic and micro-environment conditions that lead IgG1 memory B cells to give rise to IgE plasma cells.
Human memory B cells in Food Allergy
Food allergy is on the rise, and food allergic reactions are now the most common cause of anaphylaxis. Most food allergies develop in childhood, but while allergies to some foods spontaneously cure, others persist. A key to the evolution of food allergy may reside in the mechanisms that maintain the B cell memory of high affinity IgE responses. We hypothesize that the existence of high affinity food-specific IgG cells and their ability to undergo class switching to IgE are critical for allergy persistence. This poses an important question: are IgG memory B cells different in allergic individual and non-allergic individuals? Are food specific memory B cells different from memory B cells that recognize microorganism or vaccine antigens? We are trying to answer these questions by studying lymphocytes responses in pediatric food allergy.
What is special about IgE plasma cells?
Most IgE cells in human and mouse are plasma cells, yet not much is known about unique features of IgE plasma cells that underlie their biology. IgE plasma cells persist longer in lymphoid organs after immunization and are less efficient than IgG1 plasma cells to home to the bone marrow niche. Nonetheless long-lived bone marrow IgE plasma cells can be formed during repeated exposure to allergens. We are studying how IgE plasma cells differ from IgG1 plasma cells generated in the same immune responses and the spaciotemporal generation of IgE plasma cells during primary and recall immune responses. We use established mouse models of immunization and parasite infection, and mouse strains that allow to temporally label and track all plasma cells, or those plasma cells that have been generated through a germinal center response.
Mechanisms of lung pathology in allergic inflammation and hyper IgE syndrome
We are interested in understanding the immune pathology of lung inflammation in chronic conditions such as chronic allergic asthma and hyper IgE syndrome. Allergic asthma is associated with permanent alterations in lung tissue structure and function known as lung remodeling. And individuals with dominant negative STAT3 mutations which cause hyper IgE (also known as Job Syndrome), also develop alterations in lung structure and function. It is possible that the persistent activation of lung repair mechanisms, or defective lung repair, are responsible for progressive lung abnormalities in these diseases. Our goal is to identify critical synergistic interactions between inflammation and tissue repair pathways in lung pathology. We have established mouse models of allergic asthma using relevant allergens such as house dust mite and fungal extracts, and a model of LPS induced lung injury, to probe the role of the hedgehog pathway and of the dominant negative STAT3 mutation in lung pathology.