Macabre TH2 skewing in DOCK8 deficiency

Patients with DOCK8 deficiency present in early childhood recurrent infections, especially sinopulmonary infections and chronic viral skin infections. In addition, they have an extremely high incidence of allergic “type 2” immune responses, which include elevated levels serum IgE, eosinophilia, asthma, food-related anaphylaxis, atopic dermatitis.1Aydin S.E. Kilic S.S. Aytekin C. Kumar A. Porras O. Kainulainen L. et al.DOCK8 deficiency: clinical immunological phenotype treatment options—a review 136 patients.J Clin Immunol. 2015; 35: 189-198Crossref PubMed Scopus (179) Google Scholar DOCK8-deficient patients suffer from long-term consequences associated including disfiguring disease, related malignancies, mortality. Treatment the form hematopoietic stem cell transplantation offers markedly improved outcomes. is a CDC42 guanine nucleotide exchange factor expressed selectively cells. exists complex Wiskott-Aldrich syndrome protein (WASP) its partner WASP interacting protein.2Janssen E. Tohme M. Hedayat Leick Kumari S. Ramesh N. al.A DOCK8-WIP-WASp links T receptors to actin cytoskeleton.J Invest. 2016; 126: 3837-3851Crossref (66) Following T-cell receptor engagement, activity critical for CDC42-dependent activation remodeling subcortical network, lending stability synapse, modulating signaling events that signal transducer activator transcription 5 (STAT5) 3 (STAT3) signaling.2Janssen Scholar,3Janssen Ullas Barrera V. Tas J.M. enforces tolerance by promoting IL-2 synapse formation Tregs.JCI Insight. 2017; 2Crossref (17) important motility cells their survival when migrating through 3-dimensional spaces.4Zhang Q. Dove C.G. Hor J.L. Murdock H.M. Strauss-Albee D.M. Garcia J.A. regulates lymphocyte shape integrity antiviral immunity.J Exp Med. 2014; 211: 2549-2566Crossref (106) Scholar,5Harada Y. Tanaka Terasawa Pieczyk Habiro K. Katakai T. Cdc42 interstitial dendritic migration during responses.Blood. 2012; 119: 4451-4461Crossref (163) Both (DCs) undergo shattering or cytothripsis moving vitro collagen matrices.4Zhang Scholar,6Schneider Shen Gopal A.A. Douglas Forestell B. Kauffman K.D. al.Migration-induced due causes type 2-biased helper response.Nat 2020; 21: 1528-1539Crossref (8) Despite varied defects observed cells, mice are still able mount significant inflammatory responses certain stimuli, albeit often exaggerated 2 skewing. December 2020 issue Nature Immunology, Schneider al6Schneider developed model system examine proclivity toward patients. Intrapharyngeal instillation Cryptococcus neoformans was performed on Dock8?/? wild-type (WT) controls. Although cryptococcal antigens can elicit mixed-type effective response TH1 TH17 necessary C clearance limiting destructive inflammation. comparison WT mice, lungs infected had increase CD4+ producing cytokines, IL-4, IL-5, IL-13, as well GM-CSF. There also dead compared mice. Type cytokine skewing increased death were not selective DCs, macrophages, neutrophils, eosinophils. Furthermore, transferred produced more cytokines The role this traced non-DC mononuclear phagocytes (MNPs), monocytes tissue macrophages. Non-DC MNPs express CX3CR1 other lung. To TH2 skewing, generated CX3CR1-ERT2-Cre/Dock8flox/flox these tamoxifen induces MNPs. infection neoformans, exhibited similar Cell appeared be driver reaction. cleaved caspase-3. (through production GM-CSF) poor control likely provided positive feedback further recruitment subsequent cytothripsis, triggering IL-1? production. caspase inhibitors IL-1 blockade prevented bias infection, no effect expansion Importantly, injection apoptotic into drove response. These results support authors’ migration-induced leads release mediators, but limited IL-1?, amplify promote (Fig 1, left panel). Over 10 years after identification major cause autosomal-recessive hyper-IgE syndrome, much unknown regarding molecular mechanisms driving disease. abnormalities shape, migration, been known some time, report susceptibility specific population deficiency. This intriguing observation suggests novel mechanism development disease invites number questions. highly MNPs, found subset natural killer CD8+ cells.7Gerlach Moseman E.A. Loughhead S.M. Alvarez D. Zwijnenburg A.J. Waanders al.The chemokine defines three antigen-experienced CD8 subsets distinct roles surveillance homeostasis.Immunity. 45: 1270-1284Abstract Full Text PDF (257) Moreover, prone cytothripsis.4Zhang Thus, do and/or contribute via death–dependent death–independent mechanisms? Is there something unique about DOCK8-dependent phagocytic makes them death? play infection. has successfully used treat autoinflammatory conditions; thus, it could benefit awaiting transplantation. neoformans–infected sufficient. What mediators released shattered response? How generalizable immunodeficiencies? Capsular proteins induce particular way dying process increases capsular presentation adaptive system? Previously, reduced expression p-21 activated kinase (PAK) expression, whereas loss showed such effect.4Zhang implicates DOCK8-CDC42-PAK pathway, actin, myosin, microtubule (MT) cytoskeletal structures, rather than WASP-regulated dynamics, protecting against cytothripsis. Does yet-to-be identified immunodeficiencies MT-associated predispose what effects drugs affect MT organization events? alone responsible all maladaptive antigen animals. shown impaired regulatory (Treg)-cell function.8Alroqi F.J. Charbonnier L.M. Keles Ghandour F. Mouawad P. Sabouneh R. presenting IPEX-like disorder.J 37: 811-819Crossref (28) Scholar,9Janssen Morbach H. Bannock Massad Menard al.Dedicator cytokinesis 8-deficient breakdown peripheral B-cell defective cells.J Allergy 134: 1365-1374Abstract (67) Similarly, mouse models, Treg-cell functions compromised. oxazolone contact hypersensitivity (CHS), ear challenge sensitized hapten predominantly 1 characterized IFN-?. mounted without evidence Treg suppressive vivo self-reactive unstable.3Janssen Recently, function underlie response.10Wilkie H, Janssen E, Leyva-Castillo JM, Geha RS. maintains limits [published online ahead print November 7, 2020]. J Invest Dermatol. https://doi.org/10.1016/j.jid.2020.09.027.Google Mice inducible like demonstrated TH1-dominated CHS adoptive transfer reversed recipients. unstable, acquiring pathogenic TH1-like losing FOXP3 at sites hapten-driven relevance findings TH2-dominated food inhaled allergens? question allergists because allergens individuals. common variety dermatitis, allergen exposure occurs eczematous skin. Intriguingly, did observe augmented H polygyrus, pathogen normally response.6Schneider Under circumstances 2–provoking particularly allergens, get amplified deficiency? malfunction implicated antigens, right panel)? many questions yet answered response, work linking death.