Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1

Abstract

Summ a r yA patient with leukocyte adhesion deficiency type 1 (LAD1) had severe periodontitis and an intractable, deep, nonhealing sacral wound.We had previously found a dominant interleukin-23-interleukin-17 signature at inflamed sites in humans with LAD1 and in mouse models of the disorder.Blockade of this pathway in mouse models has resulted in resolution of the immunopathologic condition.We treated our patient with ustekinumab, an antibody that binds the p40 subunit of interleukin-23 and interleukin-12 and thereby blocks the activity of these cytokines, inhibiting interleukin-23-dependent production of interleukin-17.After 1 year of therapy, our patient had resolution of his inflammatory lesions without serious infections or adverse reactions.Inhibition of interleukin-23 and interleukin-17 may have a role in the management of LAD1.(Funded by the National Institute of Allergy and Infectious Diseases and others.)L AD1 is a primary immunodeficiency resulting from mutations in ITGB2, which encodes the common CD18 subunit of the β2 integrins; the β2 integrins are required for the adhesion of neutrophils to endothelium and the transmigration of neutrophils into tissues.Patients with LAD1 typically have recurrent skin infections that can be chronic and refractory.Recurrent oral ulcers cause severe pain and difficulty eating, and severe periodontitis leads to complete loss of adult teeth in almost all patients.1 The mucocutaneous lesions in LAD1 were widely assumed to be due to infections that were a result of the relative tissue neutropenia caused by the inability of LAD1 neutrophils to enter the tissue and control microbes.2 However, recent work has shown that LAD1-associated oral disease is actually a microbe-induced hyperinflammatory response.3,4 LAD1 periodontal lesions have a strong interleukin-23-interleukin-17 signature, which drives local immunopathologic processes and bone resorption.Animal models of LAD1 have aberrant interleukin-23 and interleukin-17 responses in peripheral tissues 5,6 as well as spontaneous development of periodontitis that can be inhibited by blockade of the interleukin-23-interleukin-17 axis.3 In humans, LAD1 periodontitis is typically progressive and refractory to conventional management and results in almost universal loss of the teeth and surrounding alveolar bone by late adolescence.Other than bone marrow transplantation, no directed approaches for the management of LAD1 are currently known.A video about LAD1 and its physiological basis is available at NEJM.org.