Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen.
BACKGROUND
Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disorder caused by mutations in AIRE, the autoimmune regulator gene. Though recent studies concerning AIRE deficiency have begun to elucidate the molecular pathogenesis of organ-specific autoimmunity in patients with APS-1, the autoantigen responsible for hypoparathyroidism, a hallmark of APS-1 and its most common autoimmune endocrinopathy, has not yet been identified.


METHODS
We performed immunoscreening of a human parathyroid complementary DNA library, using serum samples from patients with APS-1 and hypoparathyroidism, to identify patients with reactivity to the NACHT leucine-rich-repeat protein 5 (NALP5). Subsequently, serum samples from 87 patients with APS-1 and 293 controls, including patients with other autoimmune disorders, were used to determine the frequency and specificity of autoantibodies against NALP5. In addition, the expression of NALP5 was investigated in various tissues.


RESULTS
NALP5-specific autoantibodies were detected in 49% of the patients with APS-1 and hypoparathyroidism but were absent in all patients with APS-1 but without hypoparathyroidism, in all patients with other autoimmune endocrine disorders, and in all healthy controls. NALP5 was predominantly expressed in the cytoplasm of parathyroid chief cells.


CONCLUSIONS
NALP5 appears to be a tissue-specific autoantigen involved in hypoparathyroidism in patients with APS-1. Autoantibodies against NALP5 appear to be highly specific and may be diagnostic for this prominent component of APS-1.
Alimohammadi
Mohammad
M
University Hospital, Uppsala University, Uppsala, Sweden.
Björklund
Peyman
P
Hallgren
Asa
A
Pöntynen
Nora
N
Szinnai
Gabor
G
Shikama
Noriko
N
Keller
Marcel P
MP
Ekwall
Olov
O
Kinkel
Sarah A
SA
Husebye
Eystein S
ES
Gustafsson
Jan
J
Rorsman
Fredrik
F
Peltonen
Leena
L
Betterle
Corrado
C
Perheentupa
Jaakko
J
Akerström
Göran
G
Westin
Gunnar
G
Scott
Hamish S
HS
Holländer
Georg A
GA
Kämpe
Olle
O
D001323:Autoantibodies / Q000032:analysis / Q000097:blood*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D018076:DNA, Complementary / Q000032:analysis; D015723:Gene Library; D006801:Humans; D007011:Hypoparathyroidism / Q000175:diagnosis* / Q000209:etiology / Q000276:immunology; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D010280:Parathyroid Glands / Q000737:chemistry / Q000276:immunology*; D016884:Polyendocrinopathies, Autoimmune / Q000150:complications / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis
D001323:Autoantibodies; D001324:Autoantigens; D015415:Biomarkers; D018076:DNA, Complementary; D024101:Mitochondrial Proteins; C527221:NLRP5 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger