Oral Microbial and Immunological Characterization of Patients with Immune Dysfun

National Institute Of Dental & Craniofacial Research

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Abstract

In this period our work involving patients with genetic immune dysfunction has focused on two main cohorts. A. Leukocyte Adhesion Deficiency 1 (LAD1). B. Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dysplasia Syndrome (APECED)- in collaborative studies with Dr. M Lionakis and team LAD1 is a primary immunodeficiency resulting from mutations in ITGB2, which encodes for the common CD18 subunit of the 2 integrins, which are required for the adhesion of neutrophils to the endothelium and transmigration into tissues. Patients with LAD1 suffer from severe early onset periodontitis and typically lose their dentition during their teenage years. Until recently, LAD1- associated periodontitis was considered an infection. However, work from our laboratory and collaborators has changed the paradigm of infection in LAD1 to establish that a dysregulated inflammatory response is driving pathology. In fact, the periodontitis of LAD1 patients has been treated unsuccessfully with antibiotics for decades. We identified that LAD1 periodontal lesions have a strong IL23IL17 signature, which drives local immunopathology and bone resorption. Amplification of IL23/Th17 responses was attributed to the absence of tissue neutrophils, which regulate macrophage IL23-mediated immunity. Preclinical studies in animal models of LAD1 demonstrated that inhibition of the IL23IL17 axis was protective from periodontal immunopathology. Therefore, based on human and murine experimental evidence, we previously had treated a single patient with ustekinumab (an antibody that binds to the common IL-12/23b p40 chain and inhibits both IL-23 and IL-12) for over two years an LAD1 patient. This patient had severe periodontitis and an intractable, deep, nonhealing sacral wound. After 1 year of therapy, our patient had resolution of his inflammatory lesions without serious infections or adverse reactions. Based on this proof-of-principle index case, we have developed an interventional protocol for the treatment of LAD-1-associated immunopathology with ustekinumab. In collaboration with the NIAID team led by Drs Holland and Marciano we have initiated an IRB approved interventional clinical protocol Use of ustekinumab (anti-IL23/12-p40 chain) in Patients with Leukocyte Adhesion Deficiency (LAD1)-associated Inflammatory Pathology (NCT03366142). Aim: To investigate the safety and efficacy of IL23 blockade in LAD1-periodontitis and to understand the mechanisms by which IL23-Th17 drives disease. Progress: Clinical protocol is ongoing at the NIH CC. Our collaborative studies in APECED have uncovered novel pathways involved in oral fungal susceptibility. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-g (IFN-g) and signal transducer and activator of transcription 1 (STAT1)dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-g or Janus kinase (JAK)STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T celldependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.