title: Innate immune recognition of molds and homology to the inner ear protein, cochlin, in patients with autoimmune inner ear disease.
abstract: Autoimmune Inner Ear Disease (AIED) is characterized by bilateral, fluctuating sensorineural hearing loss with periods of hearing decline triggered by unknown stimuli. Here we examined whether an environmental exposure to mold in these AIED patients is sufficient to generate a pro-inflammatory response that may, in part, explain periods of acute exacerbation of disease. We hypothesized that molds may stimulate an aberrant immune response in these patients as both several Aspergillus species and penecillium share homology with the LCCL domain of the inner ear protein, cochlin. We showed the presence of higher levels of anti-mold IgG in plasma of AIED patients at dilution of 1:256 (p = 0.032) and anti-cochlin IgG 1:256 (p = 0.0094 and at 1:512 p = 0.024) as compared with controls. Exposure of peripheral blood mononuclear cells (PBMC) of AIED patients to mold resulted in an up-regulation of IL-1β mRNA expression, enhanced IL-1β and IL-6 secretion, and generation of IL-17 expressing cells in mold-sensitive AIED patients, suggesting mold acts as a PAMP in a subset of these patients. Naïve B cells secreted IgM when stimulated with conditioned supernatant from AIED patients' monocytes treated with mold extract. In conclusion, the present studies indicate that fungal exposure can trigger autoimmunity in a subset of susceptible AIED patients.
authors.affiliation: The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Shresh
authors.initials: S
authors.lastname: Pathak
authors.forename: Lynda J
authors.initials: LJ
authors.lastname: Hatam
authors.forename: Vincent
authors.initials: V
authors.lastname: Bonagura
authors.forename: Andrea
authors.initials: A
authors.lastname: Vambutas
mesh_terms: D000328:Adult; D000368:Aged; D000908:Antibodies, Fungal / Q000097:blood; D000946:Antigens, Fungal / Q000276:immunology; D001228:Aspergillosis / Q000276:immunology*; D001230:Aspergillus / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D002478:Cells, Cultured; D003429:Cross Reactions; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000097:blood; D007759:Labyrinth Diseases / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D017386:Sequence Homology, Amino Acid
chemical_list: D000908:Antibodies, Fungal; D000946:Antigens, Fungal; C110668:COCH protein, human; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D007074:Immunoglobulin G
references.citation: PLoS One. 2011;6(10):e26759
references.pmid: 22053211
references.citation: Immunopharmacol Immunotoxicol. 2011 Jun;33(2):329-33
references.pmid: 20718578
references.citation: Med Mycol. 2005 Nov;43(7):613-21
references.pmid: 16396246
references.citation: Laryngoscope. 2003 Jan;113(1):33-6
references.pmid: 12514378
references.citation: Curr Opin Neurol. 2006 Feb;19(1):26-32
references.pmid: 16415674
references.citation: Immunity. 2004 Oct;21(4):467-76
references.pmid: 15485625
references.citation: Rheumatology (Oxford). 2008 Feb;47(2):145-9
references.pmid: 18160420
references.citation: Immunity. 2009 Apr 17;30(4):576-87
references.pmid: 19362022
references.citation: Nature. 1986 Nov 6-12;324(6092):73-6
references.pmid: 3491322
references.citation: Laryngoscope. 1983 Apr;93(4):410-7
references.pmid: 6834965
references.citation: Curr Allergy Asthma Rep. 2012 Jun;12(3):255-60
references.pmid: 22457225
references.citation: PLoS One. 2011;6(5):e20014
references.pmid: 21637346
references.citation: Gut Microbes. 2010 Jul;1(4):224-233
references.pmid: 21327029
references.citation: J Immunol. 2006 Sep 15;177(6):4203-10
references.pmid: 16951386
references.citation: J Leukoc Biol. 2002 Jan;71(1):1-8
references.pmid: 11781375
references.citation: BMC Bioinformatics. 2010 Nov 22;11:568
references.pmid: 21092157
references.citation: Front Cell Infect Microbiol. 2012 Nov 22;2:142
references.pmid: 23189270
references.citation: PLoS Comput Biol. 2008 Apr 04;4(4):e1000048
references.pmid: 18389056
references.citation: Hum Mol Genet. 1996 Jul;5(7):1047-50
references.pmid: 8817345
references.citation: Otol Neurotol. 2005 Sep;26(5):908-17
references.pmid: 16151337
references.citation: Genome Biol. 2000;1(1):RESEARCH002
references.pmid: 11104518
references.citation: Immunogenetics. 2013 May;65(5):345-55
references.pmid: 23370977
references.citation: J Immunol. 2011 Feb 1;186(3):1870-9
references.pmid: 21199898
references.citation: Nat Immunol. 2007 Sep;8(9):950-7
references.pmid: 17676044
references.citation: Laryngoscope. 2002 Sep;112(9):1627-34
references.pmid: 12352677
references.citation: J Immunol. 2006 Jul 1;177(1):322-32
references.pmid: 16785528
references.citation: J Comp Neurol. 2005 Aug 22;489(2):180-94
references.pmid: 15983998
references.citation: Immunity. 2009 Jun 19;30(6):860-74
references.pmid: 19501001
references.citation: Audiol Neurootol. 2005 Jan-Feb;10(1):35-43
references.pmid: 15567913
references.citation: Trends Genet. 2000 Jun;16(6):276-7
references.pmid: 10827456
references.citation: Immunopharmacol Immunotoxicol. 2011 Dec;33(4):620-5
references.pmid: 21348812
references.citation: Arch Otolaryngol Head Neck Surg. 2012 Nov;138(11):1052-8
references.pmid: 23165380
references.citation: J Neurosci Res. 2006 Mar;83(4):575-83
references.pmid: 16429448
references.citation: Clin Lab Med. 1988 Jun;8(2):385-98
references.pmid: 3284702
references.citation: Cytokine Growth Factor Rev. 2003 Apr;14(2):155-74
references.pmid: 12651226
references.citation: Eur J Immunol. 2007 Oct;37(10):2695-706
references.pmid: 17899546
references.citation: J Exp Med. 2006 Jul 10;203(7):1685-91
references.pmid: 16818675
references.citation: BMC Genomics. 2006 Oct 09;7:251
references.pmid: 17029625
references.citation: J Immunol. 2008 Mar 15;180(6):4022-31
references.pmid: 18322211
references.citation: Am J Respir Cell Mol Biol. 1996 Jul;15(1):88-96
references.pmid: 8679226
references.citation: PLoS One. 2009;4(4):e5293
references.pmid: 19401759
references.citation: Autoimmun Rev. 2012 Aug;11(10):731-8
references.pmid: 22306860
references.citation: Eur J Immunol. 2011 May;41(5):1203-17
references.pmid: 21523780
references.citation: Proc Natl Acad Sci U S A. 2003 May 13;100(10):5986-90
references.pmid: 12721360
references.citation: Ann Otol Rhinol Laryngol. 2004 Jun;113(6):445-9
references.pmid: 15224826
references.citation: Med Mycol. 2009;47 Suppl 1:S162-9
references.pmid: 18608926
references.citation: Clin Chem. 2002 Oct;48(10):1661-7
references.pmid: 12324481
references.citation: Otolaryngol Head Neck Surg. 2000 Jul;123(1 Pt 1):69-75
references.pmid: 10889484
references.citation: Blood. 2011 Apr 7;117(14):3720-32
references.pmid: 21304099
references.citation: Cell Host Microbe. 2010 Feb 18;7(2):140-50
references.pmid: 20159619
references.citation: Otol Neurotol. 2001 Sep;22(5):614-8
references.pmid: 11568667
references.citation: J Exp Med. 1997 Jan 20;185(2):207-18
references.pmid: 9016870
references.citation: Ann Otol Rhinol Laryngol. 1996 Aug;105(8):628-33
references.pmid: 8712634
references.citation: J Exp Med. 2000 Jan 17;191(2):313-20
references.pmid: 10637275
references.citation: Mol Immunol. 2004 Feb;40(14-15):1019-25
references.pmid: 15036905
references.citation: Nat Immunol. 2007 Sep;8(9):942-9
references.pmid: 17676045
references.citation: Genomics. 1997 Dec 15;46(3):345-54
references.pmid: 9441737
references.citation: Curr Protoc Immunol. 2002 May;Chapter 7:Unit 7.19
references.pmid: 18432890
references.citation: PLoS One. 2010 Apr 02;5(4):e10008
references.pmid: 20368800
references.citation: J Med Genet. 2003 Jul;40(7):479-86
references.pmid: 12843317
references.citation: Laryngoscope. 1987 Jan;97(1):7-9
references.pmid: 3491944
references.citation: Ann Otol Rhinol Laryngol. 1979 Sep-Oct;88(5 Pt 1):585-9
references.pmid: 496191
references.citation: Eur Arch Otorhinolaryngol. 2009 Jan;266(1):37-40
references.pmid: 18777037