Decreased Levels of Total Immunoglobulin in Children with Autism Is Not a Result of B-Cell Dysfunction

Background: Autism spectrum disorders are a heterogeneous group of behaviorally defined disorders of unknown etiology. Current research has implicated immunological, neurological, genetic, and environmental factors as possible contributors to this complex disorder. Recently, we have reported a correlation between decreased levels of immunoglobulin (Ig) and behavioral outcome in children with autism. Immunoglobulin production is the end result of B-cell activation generated during an immune response and decreased levels are indicative of an immune defect. Evidence of an immune deficiency coupled with severity of behavioral measures would suggest a common defect in both neuro- and immunodevelopment. Thus, identification of the immune defect responsible for reduced Ig production may provide insight into common affected pathways in neurodevelopment. Objectives: To determine if reduced plasma levels of Ig in children with autism are the result of defective B-cell development, activation, or function. Methods: Subject selection was determined based upon Ig status. B-cell development was evaluated by phenotypic analysis of population densities in peripheral blood through flow cytometry. B-cell activation was assessed in-vitro using pokeweed mitogen, Staphylococcus aureus, T-cell conditioned medium, and the TLR-9 ligand, CpG. Activation was measured by flow cytometry for proliferation and intracellular production of Ig. Cell function was assessed through measurement of total Ig production in the supernatants of stimulated cells. Results: Phenotypic analysis of B-cell populations in the peripheral blood of autism patients and typically developing controls showed no difference between groups in the absolute number of naïve or memory B-cells. The ability of these B-cells to receive and respond to activation signals is the same across groups based on both proliferation and initiation of Ig production. Likewise, we were unable to detect any difference between the autism and typically developing groups with respect to the production of soluble Ig in the supernatants of stimulated cell cultures. Conclusions: We observed no difference in B-cell number, response to activation, or functional production of immunoglobulin between autism children and typically developing controls. Thus, the previously observed decrease in Ig levels within autism children does not appear to be the result of B-cell dysfunction. This suggests that the reduced production of Ig may be the result of a defect in the T cell and/or monocyte/macrophage populations, both of which play a role in B-cell differentiation and Ig production.