Immune status of patients with inherited bone marrow failure syndromes

Abstract

Immune function abnormalities have been reported in patients with Fanconi anemia (FA), dyskeratosis congenita (DC) and, rarely, in Shwachman-Diamond syndrome (SDS), and Diamond-Blackfan anemia (DBA), but large systematic studies are lacking. We assessed immunological parameters in 118 patients with these syndromes and 202 unaffected relatives. We compared the results in patients with reference values, and with values in relatives after adjusting for age, sex, corticosteroid treatment, and severe bone marrow failure (BMF). Adult patients (≥18 years) with FA had significantly lower immunoglobulins (IgG, IgA and IgM), total lymphocytes, and CD4 T cells than reference values or adult relatives (P < 0.001); children with FA had normal values. Both children and adults with FA had lower B- and NK cells (P < 0.01) than relatives or reference values. Patients with DC had essentially normal immunoglobulins but lower total lymphocytes than reference values or relatives, and lower T-, B-, and NK-cells; these changes were more marked in children than adults (P < 0.01). Most patients with DBA and SDS had normal immunoglobulins and lymphocytes. Lymphoproliferative responses, serum cytokine levels, including tumor necrosis factor-α and interferon-γ, and cytokine levels in supernatants from phytohemagglutinin-stimulated cultures were similar across patient groups and relatives. Only patients with severe BMF, particularly those with FA and DC, had higher serum G-CSF and Flt3-ligand and lower RANTES levels compared with all other groups or relatives (P < 0.05). Overall, immune function abnormalities were seen mainly in adult patients with FA, which likely reflects their disease-related progression, and in children with DC, which may be a feature of early-onset severe disease phenotype.

Trial registration: ClinicalTrials.gov NCT00027274.

© 2015 Wiley Periodicals, Inc.

Figures

Figure 1. Serum immunoglobulin and lymphocyte subsets in patients

Fanconi anemia (FA), red circles (open circles are patients with cancer); dyskeratosis congenita (DC), blue squares (open squares are patients with Hoyerral-Hreidarsson syndrome); Diamond-Blackfan anemia (DBA), black triangles; Shwachman-Diamond syndrome (SDS), green diamonds. Upper and lower dotted lines represent the 90th and the 10th percentile respectively, of the normal ranges for age as established by the National Institutes of Health Clinical Center Department of Laboratory Medicine (http://cclnprod.cc.nih.gov/dlm/testguide.nsf).

Figure 2. Comparison of serum immunoglobulins and lymphocyte subsets in patients with relatives

● Children; x Adults. Adjusted mean (adjusted for age, sex, treatment with corticosteroids, and severe bone marrow failure) and 95% confidence intervals are shown. Group comparisons are between children (<18 year old) with each syndrome and combined pediatric relatives, and between adult patients (≥18 years) with syndromes and combined adult relatives. *Significant (p<0.05). A) IgG levels were low in adults with FA (p<0.0001) and children and adults with DBA and SDS (p<0.001) compared with patients with other syndromes and relatives within the same age range. B) IgA levels were lower in adults with FA and higher in adults with DC (p<0.0001). C) All children had lower IgM than all adults (p=0.03). Children with FA, DBA and SDS had low IgM, as did adults with FA compared with relatives within the same age groups (p=0.0001). D) Absolute lymphocyte counts (ALCs) were low in adults with FA and in children and adults with DC (p<0.001). E and F) Adults with FA and children and adults with DC had low CD3 and CD4+/CD3+ T cells (p<0.001). G) Children with DC and DBA had low CD8+/CD3+ T cells (p=0.005). H) Children and adults with FA and children with DC had low CD19+ B cells (p<0.001). I) Children with all four syndromes as well as adults with FA had low NK cells (p=0.004).

Figure 3. Comparison of serum cytokine levels in patients with relatives

● Children; x Adults. Adjusted mean and 95% confidence intervals are shown. Group comparisons are between children (<18 year old) with each syndrome and pediatric relatives, and between adult patients (≥18 years) with syndromes and adult relatives. A, B, C, D) Serum TNF-α, IFN-γ, IL-6 and IL-1β were similar in patients and relatives. E) Children and adults with FA had high IL-8 than relatives or patients with other syndromes within the same age groups (p=0.004). F) Adults with FA had high G-CSF (p=0.006). G) Children and adults with FA had high Flt3L (p<0.0001). H) Children and adults with DC had low eotaxin (p=0.03). Children with FA, and children and adults with DC had low RANTES (p=0.02).