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Research at Mass General
Principal Investigator, Center for Immunology and Inflammatory Diseases
Assistant Physician, Massachusetts General Hospital
Assistant Professor of Medicine, Harvard Medical School
Immune mechanisms operative at the skin barrier interface promote effective immunity to pathogens, while simultaneously promoting tolerance to innocuous environmental antigens and commensal microorganisms. Chronic inflammatory conditions of the skin arise when homeostatic tolerance mechanisms are subverted to facilitate inappropriate immune activation.
Atopic dermatitis is the most common chronic inflammatory skin disorder. It has a complex poorly understood pathogenesis characterized by Th2 inflammation, skin eosinophilia, skin-barrier dysfunction, and a chronic relapsing course that causes much morbidity. A major goal of my lab is to advance our understanding of the immune and inflammatory pathways that sustain chronic atopic dermatitis. We are specifically interested in deciphering how innate leukocytes such as IL-4-spectrum macrophages and Group 2 innate lymphoid cells fuel the chronic inflammation of atopic dermatitis. Our research builds on our prior work in which we discovered that the human chemokine CCL18 and its functional mouse homolog are novel agonists of the CCR8 chemokine receptor. A key translational impetus for our mechanistic and in vivo studies is that, in multiple clinical trials, CCL18 is a top cutaneous biomarker of atopic dermatitis disease activity. We are thus intent on defining the cellular, molecular and epigenetic mechanisms by which the innate immune system sustains inflammation and eosinophilia in chronic atopic dermatitis, and are pursuing this with mouse and human model systems.
Another research focus, though in its early stages, is to elucidate mechanisms by which skin innate cells elicit effective adaptive immunity to Staphylococcus aureus. This is an exciting research direction for both its scientific and translational impact.
Mechanisms by which pro-inflammatory M(IL-4)s undergo innate training
Cutaneous Th2 cytokine differentiated macrophages or IL-4 spectrum macrophages, M(IL-4)s, also known as alternatively activated or M2 macrophages, induced in the chronic phase of atopic dermatitis are pro-inflammatory. These M(IL-4)s are distinct from anti-inflammatory M(IL-4)s elicited in the acute phase of an inflammatory response which serve to dampen inflammation and immune pathology. Our work and published studies suggest that macrophages in the chronic phase of inflammation can be phenotypically and functionally altered after repeated antigenic and inflammatory stimulation, likely as a result of “innate training”. We believe these phenotypically and functionally altered pro-inflammatory M(IL-4)s are key cellular drivers that sustain the chronic inflammation of atopic dermatitis. Thus we are interested in elucidating the unique cellular, molecular and epigenetic mechanisms by which “innate training” facilitates the induction of pro-inflammatory M(IL-4)s in atopic dermatitis.
Importance of innate lymphoid cells in chronic eosinophilic allergic disorders
Our interest in the recently described Group 2 innate lymphoid cells (ILC2s) stems from findings that ILC2s maintain M(IL-4)s and eosinophils in steady state adipose tissue, are implicated in models of acute allergic disease in mice and in human allergic diseases, and that CCR8 is a top gene expressed by ILC2s in multiple mouse transcriptional profiling studies. The contribution of ILC2s to chronic phase allergic inflammation and eosinophilia is currently not understood. Our in vivo studies link the CCR8 pathway to ILC2s in a mouse model of chronic human atopic dermatitis-like disease. We thus want to decipher how ILC2s contribute to the immune pathology of chronic eosinophilic allergic inflammation and atopic dermatitis.
Mechanisms of host immunity to cutaneous bacterial infection
Staphylococcus aureus (S. aureus) is a major cause of morbidity and mortality in normal and immune-compromised hosts, causes the vast majority of human skin and soft tissue infections, and often causes recalcitrant recurrent infections, particularly in immune-compromised hosts. S. aureus has become more resistant to existing antibiotics. A detailed understanding of the immune responses to S. aureus infection and if discrete immune mechanisms are required to induce protective immunity in different tissue compartments is currently lacking. Recent studies suggest that vaccine strategies that elicit interleukin-17-producing Th17 cells may be feasible in the treatment and prevention of S. aureus skin infections. Thus, we are interested in defining mechanisms by which skin dendritic cells and macrophages might elicit effective adaptive immunity to S. aureus infection, which may be important for the development of novel vaccine strategies.
If you are interested in applying for a postdoctoral position, please e-mail your CV and a list of references to Dr. Sabina Islam.
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