Dataset Information

Small intestinal immunopathology and GI-associated antibody formation in hereditary alpha-tryptasemia.

ABSTRACT:

Background

Hereditary alpha-tryptasemia (HαT) is characterized by elevated basal serum tryptase due to increased copies of the TPSAB1 gene. Individuals with HαT frequently present with multisystem complaints, including anaphylaxis and seemingly functional gastrointestinal (GI) symptoms.

Objective

We sought to determine the prevalence of HαT in an irritable bowel syndrome cohort and associated immunologic characteristics that may distinguish patients with HαT from patients without HαT.

Methods

Tryptase genotyping by droplet digital PCR, flow cytometry, cytometry by time-of-flight, immunohistochemistry, and other molecular biology techniques was used.

Results

HαT prevalence in a large irritable bowel syndrome cohort was 5% (N = 8/158). Immunophenotyping of HαT PBMCs (N ≥ 27) revealed increased total and class-switched memory B cells. In the small bowel, expansion of tissue mast cells with expression of CD203c, HLA-DR, and FcεRI, higher intestinal epithelial cell pyroptosis, and increased class-switched memory B cells were observed. IgG profiles in sera from individuals with HαT (N = 21) significantly differed from those in individuals with quiescent Crohn disease (N = 20) and non-HαT controls (N = 19), with increased antibodies directed against GI-associated proteins identified in individuals with HαT.

Conclusions

Increased mast cell number and intestinal epithelial cell pyroptosis in the small intestine, and class-switched memory B cells in both the gut and peripheral blood associated with IgG reactive to GI-related proteins, distinguish HαT from functional GI disease. These innate and adaptive immunologic findings identified in association with HαT are suggestive of subclinical intestinal inflammation in symptomatic individuals.

SUBMITTER: Konnikova L

PROVIDER: S-EPMC9017395 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Publications

Small intestinal immunopathology and GI-associated antibody formation in hereditary alpha-tryptasemia.

Konnikova Liza L Robinson Tanya O TO Owings Anna H AH Shirley James F JF Davis Elisabeth E Tang Ying Y Wall Sarah S Li Jian J Hasan Mohammad H MH Gharaibeh Raad Z RZ Mendoza Alvarez Lybil B LB Ryan Lisa K LK Doty Andria A Chovanec Jack F JF O'Connell Michael P MP Grunes Dianne E DE Daley William P WP Mayer Emeran E Chang Lin L Liu Julia J Snapper Scott B SB Milner Joshua D JD Glover Sarah C SC Lyons Jonathan J JJ

The Journal of allergy and clinical immunology 20210415 3

<h4>Background</h4>Hereditary alpha-tryptasemia (HαT) is characterized by elevated basal serum tryptase due to increased copies of the TPSAB1 gene. Individuals with HαT frequently present with multisystem complaints, including anaphylaxis and seemingly functional gastrointestinal (GI) symptoms.<h4>Objective</h4>We sought to determine the prevalence of HαT in an irritable bowel syndrome cohort and associated immunologic characteristics that may distinguish patients with HαT from patients without ...[more]

PMID: 33865872

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Project description:Background & aimsSmall intestinal carcinoids are rare and difficult to diagnose and patients often present with advanced incurable disease. Although the disease occurs sporadically, there have been reports of family clusters. Hereditary small intestinal carcinoid has not been recognized and genetic factors have not been identified. We performed a genetic analysis of families with small intestinal carcinoids to establish a hereditary basis and find genes that might cause this cancer.MethodsWe performed a prospective study of 33 families with at least 2 cases of small intestinal carcinoids. Affected members were characterized clinically and asymptomatic relatives were screened and underwent exploratory laparotomy for suspected tumors. Disease-associated mutations were sought using linkage analysis, whole-exome sequencing, and copy number analyses of germline and tumor DNA collected from members of a single large family. We assessed expression of mutant protein, protein activity, and regulation of apoptosis and senescence in lymphoblasts derived from the cases.ResultsFamilial and sporadic carcinoids are clinically indistinguishable except for the multiple synchronous primary tumors observed in most familial cases. Nearly 34% of asymptomatic relatives older than age 50 were found to have occult tumors; the tumors were cleared surgically from 87% of these individuals (20 of 23). Linkage analysis and whole-exome sequencing identified a germline 4-bp deletion in the gene inositol polyphosphate multikinase (IPMK), which truncates the protein. This mutation was detected in all 11 individuals with small intestinal carcinoids and in 17 of 35 family members whose carcinoid status was unknown. Mutant IPMK had reduced kinase activity and nuclear localization, compared with the full-length protein. This reduced activation of p53 and increased cell survival.ConclusionsWe found that small intestinal carcinoids can occur as an inherited autosomal-dominant disease. The familial form is characterized by multiple synchronous primary tumors, which might account for 22%-35% of cases previously considered sporadic. Relatives of patients with familial carcinoids should be screened to detect curable early stage disease. IPMK haploinsufficiency promotes carcinoid tumorigenesis.

Dataset Information

Small intestinal immunopathology and GI-associated antibody formation in hereditary alpha-tryptasemia.

Background

Objective

Methods

Results

Conclusions

Publications

Small intestinal immunopathology and GI-associated antibody formation in hereditary alpha-tryptasemia.

Similar Datasets

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