A 1-year-old boy is brought to the office for medical evaluation. The patient was recently diagnosed with type 1 diabetes mellitus. He has also had chronic diarrhea, failure to thrive, and eczematous dermatitis since early infancy. Small bowel biopsy reveals villous atrophy and extensive lymphocytic infiltration. Immunologic testing shows significantly increased serum immunoglobulins and decreased IL-10 and transforming growth factor-beta levels. Genetic testing reveals a missense mutation affecting FOXP3. Which of the following is the most likely cause of this patient's current condition?
Show Explanatory Sources
FOXP3 encodes a transcriptional regulator that converts activated CD4 cells into regulatory T cells (Treg), a population of T lymphocytes that inhibit immune activation. Expression of FOXP3 drives the production of the following inhibitory cytokines and surface ligands:
IL-10 inhibits macrophage function, blocks inflammatory cytokine release by CD4+ T cells, and downregulates expression of major histocompatibility complex (MHC) class II on antigen-presenting cells (APCs).
Transforming growth factor-beta (TGF-β) inhibits B-lymphocyte proliferation/activation and promotes Treg differentiation (eg, FOXP3 expression).
Cytotoxic T-lymphocyte antigen-4 (CTLA-4) binds with high affinity to CD80/86 on APCs, a surface protein required for costimulation of CD4+ and CD8+ T cells; because CTLA-4 binds up CD80/86, less is available for the activation of T cells.
Mutations in FOXP3 lead to excessive and unregulated T- and B-lymphocyte activity and is associated with a rare genetic disorder called IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, and X-linked transmission); it is marked by autoimmune enteritis (eg, lymphocytic infiltrate, villous atrophy, chronic diarrhea), eczematous dermatitis, and type 1 diabetes in infancy.
(Choice A) Impaired differentiation of B cells into plasma cells is the hallmark of combined variable immunodeficiency, which typically presents after puberty with recurrent infections (eg, sinopulmonary, gastrointestinal) and autoimmune disease. Patients have dramatically reduced (not increased) serum immunoglobulins due to a lack of functioning plasma cells.
(Choice C) T-helper cell type 17 (Th17) dysfunction is associated with hyperimmunoglobulin E (Job) syndrome. Th17 cells assist in neutrophil recruitment and are crucial for pathogen defense at mucosal sites. Although patients with Job syndrome have eczema and recurrent infection (eg, staphylococcal abscesses), they do not have FOXP3 mutation.
(Choice D) Mutations in CD40 ligand or CD40 prevent activated CD4 cells from triggering activated B cells to undergo immunoglobulin isotype (class) switching; this results in overproduction of IgM (hyper-IgM syndrome). Patients have recurrent infections and chronic diarrhea but not FOXP3 mutation.
(Choice E) Developing T cells that bind too strongly to self MHC die by apoptosis as part of negative selection; therefore, reduced negative (not positive) selection would lead to autoimmunity. In contrast, positive selection provides survival signals to developing T cells that bind to self MHC with moderate affinity.
Educational objective:
FOXP3 is a transcriptional regulator protein that is required for the development of regulatory T cells; it triggers production of cytokines (eg, IL-10, transforming growth factor-beta) and ligands (eg, cytotoxic T-lymphocyte antigen-4) that suppress immune activation. FOXP3 mutations result in immune dysregulation marked by excessive immunoglobulin production and the development of autoimmunity.