UNC93B1 deficiency - HSE

Stable Identifier
Homo sapiens
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UNC93B1 is an endoplasmic reticulum protein with 12 membrane-spanning domains. Signaling cascades of nucleotide-sensing endosomal toll like receptors (TLR3 and TLR7-9) depends on functional UNC93B1, which is thought to deliver these TLRs from the ER to the endosome where they recognize specific pathogenic patterns and initiate host immune responses.

UNC93B deficiency has been implicated in the increased susceptibility to herpes simplex virus type 1 (HSV1) encephalitis (HSE), a rare complication during HSV-1 infection of the central nervous system (CNS) (Casrouge A et al. 2006). Patients-derived UNC96B1-deficient fibroblasts showed an impaired production of IFN-beta and -gamma following stimulation with TLR3 agonist poly(I:C) (Casrouge A et al. 2006). These cells were also more susceptible to HSV1 infection, showing rapid viral replication together with high mortality rates. Furthermore, pluripotent stem cells (iPSC) derived from HSE patient dermal fibroblasts were differentiated into populations of neural stem cells (NSC), neurons, astrocytes and oligodendrocytes (Lafaille FG et al. 2012). The impaired induction of IFN beta and gamma was observed in all tested CNS cells upon stimulation with poly(I:C). However, HSV1 infection selectively affected type I and III IFN production in UNC93B1-deficient neurons and oligodendrocytes (Lafaille FG et al. 2012). Thus, impaired TLR3-mediated UNC93B-dependent type I and III IFN production in respose to HSV1 infection in CNS, in neurons and oligodendrocytes in particular, may underline the pathogenesis of HSE in patients with UNC93B1 deficiency (Casrouge A et al. 2006; Lafaille FG et al. 2012).

Defective UNC93B1 also impairs the TLR7, TLR8 and TLR9 signaling pathways. Peripheral blood mononuclear cells (PBMCs) from UNC93B-deficient patients did not respond to the stimulation of TLR7, TLR8, or TLR9, in terms of the production of type I and III interferons, and other cytokines tested (Casrouge A et al. 2006). Moreover, no inducible CD62L shedding on granulocytes was detected after stimulation of whole blood cells derived from UNC93B-deficients patients with R-848 (agonist of TLR7 and TLR8) (von Bernuth H. et al. 2008). However, no clinical condition has been so far associated with impaired TLR7, TLR8, TLR9 due to UNC93B1 deficiency so this defect is not annotated here.

Literature References
PubMed ID Title Journal Year
16973841 Herpes simplex virus encephalitis in human UNC-93B deficiency

Beutler, B, Abel, L, Alcais, A, Dulac, O, Lebon, P, Lorenzo, L, Plancoulaine, S, Du, X, Nicolas, N, Rozenberg, F, Sénéchal, B, Miller, RL, Tabeta, K, Geissmann, F, Casrouge, A, Héron, B, Yang, K, Jouanguy, E, de Villemeur, TB, Puel, A, Picard, C, Eidenschenk, C, Mignot, C, Zhang, SY, Hoebe, K, Mahfoufi, N, Casanova, JL, Tardieu, M

Science 2006
23103873 Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells

Abel, L, Ordovas-Montanes, J, Schlaeger, TM, Al-Muhsen, S, Pessach, IM, Abhyankar, A, Herman, M, Elkabetz, Y, Plancoulaine, S, Jouanguy, E, Ciancanelli, MJ, Lafaille, FG, Goldstein, PA, Studer, L, Tu, E, Keros, S, Zhang, SY, Notarangelo, LD, Mostoslavsky, G, Daley, GQ, Ying, SW, Casanova, JL, Tardieu, M

Nature 2012
Name Identifier Synonyms
primary immunodeficiency disease DOID:612 immune deficiency disorder, immunodeficiency syndrome, hypoimmunity
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