Intestinal Lymphocyte Populations in Children with Regressive Autism: Evidence for Extensive Mucosal Immunopathology

Abstract

Inflammatory intestinal pathology has been reported in children with regressive autism (affected children). Detailed analysis of intestinal biopsies in these children indicates a novel lymphocytic enterocolitis with autoimmune features; however, links with cognitive function remain unclear. To characterize further, the nature and extent of this disease we examined the mucosal infiltrate using flow cytometry. Duodenal, ileal, and colonic biopsies were obtained from 52 affected children, 25 histologically normal, and 54 histologically inflamed, developmentally normal controls. Epithelial and lamina propria lymphocyte populations were isolated and examined by multicolor flow cytometry. Adjacent biopsies were assessed by semiquantitative histopathology. At all sites, CD3(+) and CD3(+)CD8(+) IEL as well as CD3(+) LPL were significantly increased in affected children compared with developmentally normal noninflamed control groups (p<0.01) reaching levels similar to inflamed controls. In addition, two populations--CD3(+)CD4(+) IEL and LP CD19(+) B cells--were significantly increased in affected children compared with both noninflamed and inflamed control groups including IBD, at all sites examined (p<0.01). Histologically there was a prominent mucosal eosinophil infiltrate in affected children that was significantly lower in those on a gluten- and casein-free diet, although lymphocyte populations were not influenced by diet. The data provide further evidence of a pan-enteric mucosal immunopathology in children with regressive autism that is apparently distinct from other inflammatory bowel diseases.

Histopathological alterations in irritable bowel syndrome

“…The concept of pathology that is subtle or unapparent on routine assessment is not unique to IBS. Quantitative analyses have uncovered subtle mucosal abnormalities in other conditions including food allergy, 63 regressive autism, [64][65][66][67] developmental disorders 64 and Brainerd diarrhea. 68 For example, there is an emerging pattern of mucosal immunopathology in a subpopulation of children with regressive autism who also have gastrointestinal symptoms.…”

Sex‐specific association of a common variant of the XG gene with autism spectrum disorders

“…There is emerging evidence that an abnormal immune response may be involved in some forms of ASD, in the form of decreased peripheral lymphocyte counts, incomplete T cell activation, dysregulated apoptosis mechanisms, and imbalanced serum Ig levels [Ashwood et al, 2006]. The function of Xg is not well characterized, but the structural similarity and sequence homology (48% homology of the amino acid sequence) between the Xg and CD99 molecules suggests that they may share some similar immunological functions [Warren et al, 1986;Plioplys et al, 1994; Ellis et al, 1994a,b;Krause et al, 2002;Ashwood et al, 2003]. Immune factors play an important role in the developing central nervous system.…”

Immune Dysfunction in Autism: A Pathway to Treatment

“…Studies looking at mucosal immune responses in children with ASD who have GI symptoms have shown increased infiltration of T-cell, monocyte, and eosinophil in the gut mucosa, prominent mucosal T-cell activation with increased TNF␣ but lower IL-10 production, and increased numbers of paneth cells, compared with noninflamed control subjects or compared with children with celiac disease or inflammatory bowel diseases. 51,52,58,59 Uncertainty remains as to how prevalent GI abnormalities in ASD are and how GI symptoms may relate to core features of ASD or associated behavioral symptoms. A few small studies suggest that GI symptoms in ASD may be related to symptoms of aggression and hyperactivity, and that in some cases individuals with ASD may benefit from immune therapies targeting GI issues (to resolve activated mucosal immune responses).…”