Spontaneous Mucosal Lymphocyte Cytokine Profiles in Children with Autism and Gastrointestinal Symptoms: Mucosal Immune Activation and Reduced Counter Regulatory Interleukin-10

Abstract

A lymphocytic enterocolitis has been reported in a cohort of children with autistic spectrum disorder (ASD) and gastrointestinal (GI) symptoms. This study tested the hypothesis that dysregulated intestinal mucosal immunity with enhanced pro-inflammatory cytokine production is present in these ASD children. Comparison was made with developmentally normal children with, and without, mucosal inflammation. Duodenal and colonic biopsies were obtained from 21 ASD children, and 65 developmentally normal paediatric controls, of which 38 had signs of histological inflammation. Detection of CD3+ lymphocyte staining for spontaneous intracellular TNFalpha, IL-2, IL-4, IFNgamma, and IL-10, was performed by multicolor flow cytometry. Duodenal and colonic mucosal CD3+ lymphocyte counts were elevated in ASD children compared with noninflamed controls (p<0.03). In the duodenum, the proportion of lamina propria (LP) and epithelial CD3(+)TNFalpha+ cells in ASD children was significantly greater compared with noninflamed controls (p<0.002) but not coeliac disease controls. In addition, LP and epithelial CD3(+)IL-2+ and CD3(+)IFNgamma+, and epithelial CD3(+)IL-4+ cells were more numerous in ASD children than in noninflamed controls (p<0.04). In contrast, CD3(+)IL-10+ cells were fewer in ASD children than in noninflamed controls (p<0.05). In the colon, LP CD3(+)TNFalpha+ and CD3(+)IFNgamma+ were more frequent in ASD children than in noninflamed controls (p<0.01). In contrast with Crohn's disease and non-Crohn's colitis, LP and epithelial CD3(+)IL-10+ cells were fewer in ASD children than in nondisease controls (p<0.01). There was a significantly greater proportion of CD3(+)TNFalpha+ cells in colonic mucosa in those ASD children who had no dietary exclusion compared with those on a gluten and/or casein free diet (p<0.05). There is a consistent profile of CD3+ lymphocyte cytokines in the small and large intestinal mucosa of these ASD children, involving increased pro-inflammatory and decreased regulatory activities. The data provide further evidence of a diffuse mucosal immunopathology in some ASD children and the potential for benefit of dietary and immunomodulatory therapies.

Immune Dysfunction in Autism: A Pathway to Treatment

“…89 In addition to abnormalities in the adaptive immune system in children with ASD, a number of differences have been noted in the innate immune system. Most relevant of these is the increase in proinflammatory cytokines, and the downregulation of IL-10, 51,55,90 findings that correspond to the function of monocytes where mTOR is inhibited. 91 …”

“…50 Studies that assess cytokine levels in the periphery have often shown similar increases in proinflammatory cytokines, [51][52][53][54][55] as well as decreases in anti-inflammatory cytokines such as IL-10 24,52 and TGF␤. 56 However, not all studies have shown a consistent pattern of specific cytokines, and data so far collected suggest a complex pattern of immune activation that varies among different subgroups of individuals with ASD.…”

“…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).…”

“…A lack of immune regulation has been observed in ASD, as evinced by decreased plasma TGF␤1 and decreased IL-10 producing T-cells. 51,52,56 Expression of FOXP3 has not yet been tested in ASD, but would be in line with mTOR dysregulation. 89 In addition to abnormalities in the adaptive immune system in children with ASD, a number of differences have been noted in the innate immune system.…”

Duodenal lymphocytosis with no or minimal enteropathy: much ado about nothing?

“…[31][32][33][34] Duodenal lymphocytosis in autistic children, whether or not associated with the lactase deficiency frequently recorded in these patients, also has been observed. 35 …”