Hypogammaglobulinemia with decreased class-switched B-cells and dysregulated T-follicular-helper cells in IPEX syndrome

Oded Shamriz; Kiran Patel; Rebecca A Marsh; Jacob Bleesing; Avni Y Joshi; Laura Lucas; Chengyu Prince; Bojana B Pencheva; Lisa Kobrynski; Shanmuganathan Chandrakasan

doi:10.1016/j.clim.2018.10.005

Hypogammaglobulinemia with decreased class-switched B-cells and dysregulated T-follicular-helper cells in IPEX syndrome

Clin Immunol. 2018 Dec:197:219-223. doi: 10.1016/j.clim.2018.10.005. Epub 2018 Oct 24.

Authors

Affiliations

¹ Division of Bone Marrow Transplant, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA; Pediatric Division, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
² Allergy/Immunology, Emory University, Atlanta, GA, USA.
³ Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁴ Division of Pediatric Allergy and Immunology, Mayo Clinic Children's Center, Rochester, MN, USA.
⁵ Division of Bone Marrow Transplant, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA.
⁶ Pediatric Cancer Predisposition Clinic, Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA.
⁷ Division of Bone Marrow Transplant, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA. Electronic address: [email protected].

PMID: 30368009
DOI: 10.1016/j.clim.2018.10.005

Abstract

Early onset multisystem autoimmunity is commonly the defining feature of IPEX. Recurrent sinopulmonary infections and CVID-like phenotype were not previously recognized as a presentation in IPEX. Herein, we describe three extended family members with IPEX. In addition to autoimmunity, all three had a CVID-like presentation consisting of recurrent sinopulmonary infections, hypogammaglobulinemia and B-cell class switching defect. In vitro studies have shown that the B cell class switching defect is not B cell intrinsic. Additionally, a marked increase in circulating T follicular helper (cTFH) cells with high IFN-γ and IL-17 secretion on stimulation was noted in our patients. The dysregulated cTFH cells could contribute to a decreased B cell class switching. However, the exact mechanism of how expanded and dysregulated cTFH lead to B cell class switching defect and hypogammaglobulinemia in our patients is not clear. Our study could extend the clinical spectrum of IPEX to include a CVID-like presentation.

Keywords: B cell class switching; CVID-like; Follicular T helper cells; Hypogammaglobulinemia; IPEX; cTFH.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Agammaglobulinemia / immunology*
Agammaglobulinemia / therapy
Anemia, Hemolytic, Autoimmune / immunology
Autoimmunity / immunology*
B-Lymphocytes / immunology*
Diabetes Mellitus, Type 1 / congenital*
Diabetes Mellitus, Type 1 / genetics
Diabetes Mellitus, Type 1 / immunology
Diabetes Mellitus, Type 1 / therapy
Diarrhea / genetics
Diarrhea / immunology*
Diarrhea / therapy
Eczema / immunology
Family
Female
Forkhead Transcription Factors / genetics
Genetic Diseases, X-Linked / genetics
Genetic Diseases, X-Linked / immunology*
Genetic Diseases, X-Linked / therapy
Heterozygote
Humans
Immune System Diseases / congenital*
Immune System Diseases / genetics
Immune System Diseases / immunology
Immune System Diseases / therapy
Immunoglobulin Class Switching / immunology
Immunoglobulins, Intravenous / therapeutic use
Immunologic Factors / therapeutic use
Intestinal Diseases / immunology
Male
Middle Aged
Pedigree
Pneumonia / immunology
Recurrence
Sinusitis / immunology
T-Lymphocytes, Helper-Inducer / immunology*
Young Adult

Substances

FOXP3 protein, human
Forkhead Transcription Factors
Immunoglobulins, Intravenous
Immunologic Factors

Supplementary concepts

Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome