Natural History of Dysregulation and Aging of the Immune System in People With Trisomy 21 With and Without Thymectomy

Study Description:

This is a longitudinal observational study of individuals with trisomy 21 (T21) to gather data on the immune function in order to identify clinical and laboratory signatures of immunodeficiency and/or immune dysregulation, characterize their pathophysiology, evaluate their progression and evolution over time, and analyze the impact of immunomodulatory and immunosuppressive treatment. In order to assess the possible impact of thymectomy on immune dysfunction and on the risk of developing autoimmunity, malignancies, and/or increased susceptibility to infections, both individuals who have had previous thymectomy and those who have not received this procedure will be included. Affected participants will have a baseline visit and follow-up study visits every year (starting from baseline) to assess their health and collect biospecimens (including but not limited to blood). Additional visits can also be scheduled as clinically indicated. Data and excess biospecimens from routine clinical care may also be collected and used for research. Unaffected relatives who live in the same household as the corresponding affected participant will be enrolled as controls and will undergo yearly blood and stool collection for comparison of microbiome and immunological data.

Objectives:

Primary Objectives:

• Describe the immune correlates of clinical endpoints (infections, development or progression of lung damage, autoimmunity, malignancies), and their cumulative frequency over time, in individuals with T21
• Describe the possible impact of previous thymectomy on the incidence of clinical manifestations of immune deficiency and immune dysregulation, and on laboratory parameters of immune function

Secondary Objectives:

• Identify cellular and molecular mechanisms of immune dysfunction in individuals with T21

Endpoints:

Primary Endpoints:

• Incidence of severe infections requiring hospital admission (number of admissions/year; number of days of hospitalization/year)
• Nature of infections (bacterial, viral, fungal, opportunistic pathogens) requiring hospitalization
• Number and type of autoimmune manifestations/year
• Proportion of patients with evidence of lung abnormalities at chest CT and characterization of pathological radiological findings
• Proportion of T21 individuals with malignancies by age group (compared to the general population), and type of malignancies
• Frequency of individuals with abnormal T- and B-cell counts and immunoglobulin serum levels
• Frequency of T21 individuals with laboratory evidence of autoantibodies

Secondary Endpoints:

• Distribution of subsets of T helper (Th), T follicular helper, and T regulatory (Treg) cells
• Diversity of T-cell receptor (TCR) repertoire, measured as proportion of CD4+ and CD8+ cells expressing distinct T-cell receptor Beta variable gene (TRBV) families
• Proportion of T cells exhibiting expression of exhaustion markers
• Levels of specific antibodies to immunization antigens
• Proportion of dysreactive B-cell subsets (defined as CD19(hi) CD21(low) CD38(low) B cells)
• Proportion of 9G4+ B cells and determination of their phenotype
• Levels of anti-cytokine antibodies and determination of their neutralizing activity
• Proportion of patients manifesting progression of lung damage over time as detected by chest CT and/or pulmonary function tests

Exploratory Endpoints:

• Transcriptional signatures of immune dysregulation in circulating peripheral blood mononuclear cells
• Characterization of phenotypic and transcriptional abnormalities of thymic stromal cell types generated in vitro from induced pluripotent stem cells (iPSCs) from T21 individuals compared to healthy controls
• Measurement of soluble biomarkers of inflammation
• Definition of T21 endotypes (as shown by transcriptional profile and soluble markers of inflammation), analysis of endotype persistence over time, and correlation with clinical manifestations of disease
• Metabolomic and lipidomic signatures of immune dysregulation in plasma of T21 individuals
• Perturbations of microbiome diversity and composition (as shown by comparison between relatives and proband)
• Levels of circulating VH4-34 antibodies
• Diversity and composition of T- and B-cell receptor repertoire, and molecular signatures of self-reactivity
• Identification of other genetic variants that may contribute to the immune dysregulation and infection phenotype of T21

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Aged >=1 year.

• Willingness to allow storage of specimens and data for future research.

• Additional Inclusion Criteria for Affected Participants

• Documented T21 based on chromosomal karyotype test.
• Ability of participant or LAR to provide informed consent.
• Additional Inclusion Criteria for Unaffected Relatives

• Ability of participant to provide informed consent or, for individuals <18 years of age, to provide informed assent as applicable.
• Reside in the same household as the corresponding affected participant.

Exclusion criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

• Any condition that, in the judgment of the investigator, may put the participant at undue risk or make them unsuitable for participation in the study.