The overall goal of the Adaptive Immunity and Immunoregulation Section is to define the cellular and molecular mechanisms that regulate the balance between protective and pathogenic adaptive immune responses to allergens. Ultimately, our research aims to develop new immunotherapies to treat and prevent food and respiratory allergies without inducing profound immunosuppression.

We focus on three main areas:

1. Tolerance vs. Inflammation: Tolerance prevents immune overactivation and maintains tissue homeostasis, while inflammation is critical for fighting infections. However, when these processes occur simultaneously, inflammation can disrupt tolerance, amplifying immune responses to harmless antigens such as allergens. Conversely, persistent allergic reactions can induce cellular and environmental changes that impair responses to pathogens and vaccines. We study how viral infections contribute to allergic responses and how allergies affect immune responses to pathogens. This knowledge is vital for designing therapies that prevent unwanted immune responses while preserving protective immunity.
2. T Follicular Helper (Tfh) Cells: Tfh cells are crucial for supporting B cells and maintaining germinal centers. Recent findings from our lab have revealed that Tfh cells are more diverse than previously expected, secreting effector cytokines and playing broader regulatory roles. There is also growing evidence of an ontogenetic link between Tfh cells and other effector and regulatory T cell subsets. We study Tfh cell plasticity and heterogeneity, exploring their impact on tolerance induction and allergy development.
3. Lung-Resident Memory T and B Cells: Lung-resident memory T and B cells are non-circulating memory cells that develop in response to respiratory challenges and permanently reside in the lungs. While the role of tissue-resident memory cells in response to respiratory pathogens has been established, their involvement in respiratory allergies remains elusive. We investigate how allergen-specific lung-resident memory T and B cells are generated and maintained, defining the factors controlling tissue memory generation and assessing their role in allergic responses. We also evaluate the potential of targeting these cells to prevent allergic reactions.

By integrating these projects, we aim to elucidate the complex mechanisms that balance protective and pathogenic immune responses and generate the necessary knowledge to develop novel treatments for food and respiratory allergies.

Allergic diseases such as allergic rhinitis, asthma, and atopic dermatitis are characterized by an exaggerated immune response to otherwise harmless environmental proteins found in pollen, house dust mites, mold, cockroach debris, and pet dander. The immune system’s failure to maintain tolerance towards these allergens triggers a cascade of immune events, leading to chronic inflammation and tissue damage.

At the heart of allergic pathology is the intricate interaction between innate and adaptive immune cells, which coordinates the body's response to allergens. Key players in this process are T-helper type 2 (Th2) cells, a subset of T cells that orchestrate many of the immune mechanisms driving allergic inflammation.

Upon exposure to allergens, dendritic cells capture and process allergen-derived antigens, presenting them to naïve T cells in lymphoid tissues. In genetically or environmentally susceptible individuals, these naïve T cells differentiate into Th2 cells, which produce cytokines such as IL-4, IL-5, IL-9, and IL-13. These T cell-derived cytokines promote the production of IgE antibodies by B cells, sensitizing mast cells and basophils to allergens.

Additionally, these cytokines induce the activation and recruitment of eosinophils. Mast cells, basophils, and eosinophils then release mediators like histamine and proteases, leading to inflammation and allergic symptoms. Moreover, Th2 cells maintain a feedback loop that perpetuates chronic inflammation, contributing to conditions such as asthma, allergic rhinitis, and atopic dermatitis. Understanding the underlying immune mechanisms that lead to Th2 responses and their maintenance is crucial for developing novel therapeutic strategies to prevent and treat allergic conditions.

Our research team is dedicated to uncovering the fundamental mechanisms of airway and cutaneous allergic inflammation, primarily using mouse models. We focus on understanding how environmental allergens trigger and sustain allergic diseases, with particular attention to interactions between innate immune cells—such as monocytes, macrophages, and dendritic cells—and adaptive immune responses, especially Th2 cells. We explore how these immune interactions are influenced by the nature of allergens, environmental exposures, genetic factors, and microbiota.

Additionally, we investigate how these processes vary during sensitive periods, such as infancy and pregnancy, to better understand the onset and persistence of allergic inflammation. To advance our knowledge, we utilize advanced techniques, including conditional knockout murine models, multi-color flow cytometry, histology, functional lung assessment, microscopy, RNA-Seq, and single-cell technologies. Our ultimate goal is to identify targets for preventing or treating human allergic diseases.

Dr. Adriana de Jesus is an assistant research physician in pediatric rheumatology translational research, particularly studying the genetic basis and pathogenic mechanisms of systemic autoinflammatory diseases (SAIDs).

She began investigating the genetic causes of autoinflammatory diseases while working on her Ph.D. in Brazil. She collaborated with the Translational Autoinflammatory Diseases Section (TADS) at NIH to report the first two Brazilian patients with a deficiency of interleukin 1 receptor antagonist (DIRA).

She also led a multicenter study for the genetic investigation of 102 patients with clinically suspected autoinflammatory diseases in Brazil. Since joining TADS in 2012, under the leadership of Dr. Raphaela Goldbach-Mansky, she has been responsible for the genetic investigation of patients with undifferentiated SAIDs enrolled into an NIH natural history protocol who undergo trio exome or genome sequencing.

Dr. Adriana de Jesus’ role in TADS involves generating and interpreting genetic data and playing a key part in the phenotypic characterizations of the patient cohorts. At TADS, she identified de novo variants in STING1 as the cause of STING-associated vasculopathy with onset in infancy (SAVI), allowing these patients to be treated with interferon-blocking therapies. She also identified de novo variants in NLRC4 and CDC42 as the genetic defect in two novel autoinflammatory diseases associated with macrophage activation syndrome (MAS).

Other significant contributions included the identification of variants in PSMG2 and PSMA5 in patients with proteasome-associated autoinflammatory syndromes (PRAAS), and IKBKG splice-site variants and SAMD9L frame-shift variants in patients with NEMO-deleted exon 5 autoinflammatory syndrome (NEMO-NDAS) and SAMD9L-associated autoinflammatory disease (SAAD), respectively.

She has also described a novel SAID caused by gain-of-function variants in LYN and characterized by skin vasculitis and liver fibrosis. Her contributions to the research on SAIDs also extend to the development and validation of a Type I interferon score assay, which is used as a biomarker to aid in the diagnosis and assessment of treatment responses in patients with Type I interferonopathies.