Tryptophan hydroxylase autoantibodies as markers of a distinct autoimmune gastrointestinal component of autoimmune polyendocrine syndrome type 1.
BACKGROUND
Autoantibodies to tryptophan hydroxylase (TPHAbs) directed against serotonin-producing enterochromaffin cells (EC) have been reported in autoimmune-polyendocrine-syndrome type 1 (APS-1) patients with gastrointestinal dysfunction (GID). Serotonin plays a critical role in enteric function and its peripheral blood levels reflect serotonin release from the gastrointestinal tract.


OBJECTIVE
We test the hypothesis that TPHAbs mark a distinct autoimmune component of APS-1 characterized by an autoimmune attack toward EC, which results in clinical GID.


METHODS
TPHAbs were measured in 64 APS-1 patients. Endoscopy with gastric (antrum/body) and duodenal biopsy was carried in 16 TPHAbs+ patients (8 with and 8 without GID) and in 2 TPHAbs- patients (without GID). Immunohistochemistry of biopsy specimens was carried out using antibodies to serotonin, chromogranin-A, CD3, CD4, CD8, and CD20. Serotonin serum levels were measured in TPHAbs+ and TPHAbs- patients who had endoscopy.


RESULTS
Thirty-seven of 64 patients were TPHAbs+ (11/12 with GID and 26/52 without GID; P < .001). Gastric and duodenal biopsies in all 8 TPHAb+ patients with GID showed lymphocytic infiltration with increased CD3+CD8+ intraepithelial lymphocytes and absence of EC. Furthermore, mean serotonin serum levels were below the normal range in TPHAb+ patients with GID (P < .01). In 8 TPHAb+ patients without GID gastric and duodenal biopsies showed different grades of inflammatory infiltration and reduced number of EC. Mean serotonin serum levels were near the lower limit of the normal range. In all TPHAbs+ patients the biopsies showed a reduced number of chromogranin-A positive cells consistent with enteroendocrine cells depletion. TPHAbs- patients without GID showed normal gastrointestinal mucosa and serotonin serum levels.


CONCLUSIONS
TPHAbs appear to be markers of a distinct autoimmune component of APS-1. Progressive involvement of the gastrointestinal EC leads to the transition from preclinical to clinical disease, characterized by GID and reduced serotonin serum levels.
Department of Medicine (DIMED), University of Padua, Padua 35128, Italy.
R
R
Scarpa
R
R
Alaggio
L
L
Norberto
J
J
Furmaniak
S
S
Chen
B Rees
BR
Smith
S
S
Masiero
L
L
Morlin
M
M
Plebani
F
F
De Luca
M C
MC
Salerno
R
R
Giordano
G
G
Radetti
L
L
Ghizzoni
G
G
Tonini
F
F
Farinati
C
C
Betterle
D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D002648:Child; D004759:Enterochromaffin Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D041981:Gastrointestinal Tract / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D016884:Polyendocrinopathies, Autoimmune / Q000276:immunology* / Q000378:metabolism; D012701:Serotonin / Q000097:blood; D014365:Tryptophan Hydroxylase / Q000276:immunology*
D015703:Antigens, CD; D001323:Autoantibodies; D012701:Serotonin; D014365:Tryptophan Hydroxylase