The paper by Wakefield et al.  in this edition of European Journal of Gastroenterology & Hepatology documents intestinal lesions in 148 consecutive children diagnosed with autistic spectrum disorder and gastrointestinal symptoms warranting investigation by ileo-colonoscopy. The findings are compared with a control group of 30 children who were developmentally normal. The autistic children showed a higher frequency of lymphoid nodular hyperplasia (LNH) in the terminal ileum and colon. Additionally, the colon showed a diffuse colitis manifested by loss of the normal vascular pattern and mucosal granularity. Fifty of the children in this study were included in an earlier report  and a small subset of these formed the basis of a preliminary report in the Lancet . The current study serves as an examination of LNH in a considerably enlarged series of subjects, linking the lesion with age and with dietary factors.
The concept of chronic LNH as a pathological process is of central importance in this study. Lymphoid aggregates, with or without germinal centres, are normally found throughout the small and large intestine. In the terminal ileum, these coalesce to form Peyer's patches. In the colon, the number of lymphoid structures increases from caecum to rectum. Lymphoid tissue is particularly prominent in the anorectal region, just above the dentate line of the anal canal . The dome epithelium covering each lymphoid aggregate comprises specialized columnar cells called microfold (M) cells. These serve as portals of entry for antigenic material derived from the gut lumen. M cells express cathepsin E which modifies ingested material before it is passed to the invaginating dendritic processes of macrophages . Following further processing within macrophages, antigen is presented to the underlying lymphoid cells which may then elicit an immune response.
The term hyperplasia merely means an increase in cell numbers and may be applied to processes that are physiological, pathological or intermediate between the two. Taking the example of thyroid hyperplasia as a simple illustration, this may be a physiological response during puberty or pregnancy, a pathological lesion in primary thyrotoxicosis and an intermediate state in the situation of iodine deficiency. Turning to the aggregates of lymphoid tissue within the intestinal tract, these present endoscopically within the colon as smooth, yellow–white nodules up to 2 mm in diameter. These lymphoid structures are observed more frequently in young children than older children and are not associated with clinical symptoms . This form of LNH is physiological. In children presenting with gastrointestinal symptoms including rectal bleeding and abdominal pain, the number and size of lymphoid follicles is increased and the anatomical distribution of enlarged lymphoid aggregates is age-dependent [7,8]. Intestinal lymphoid hyperplasia has been associated with viral infection  and with immune deficiency states . LNH therefore exists as a pathological as well as a physiological lesion.
In demonstrating more LNH in children with autistic spectrum disorder versus developmentally normal children, it is important to know that the two groups are well matched and represent a comparable symptom complex. The fact that children with autistic spectrum disorder were less likely to present with abdominal pain and more likely to present with constipation could indeed reflect, as suggested by Wakefield et al., the relative inability of children with autism to communicate the experience of pain. The link between the pathology and symptomatology is unclear. LNH producing a mass lesion could undergo mucosal prolapse. However, the lack of an association between ileo-colonic intussusception and autism suggests that LNH is generally a diffuse process.
The link between chronic ileocolitis and autistic spectrum disorder is supported by additional data. Wakefield et al. cite three recent abstracts describing an increased frequency of chronic diarrhoea in autistic children from different North American populations. Additionally, the ileocolitis associated with autism is accompanied by a specific immunopathology. Increased γδ-T cells and CD8 lymphocyte densities together with basement membrane thickening were found in colonic mucosa while increased CD8 lymphocyte densities, crypt cell production and immune complex deposition were demonstrated in duodenal samples obtained from autistic children [11,12].
There is good evidence linking autism with a specific form of chronic ileocolitis that differs from other forms of idiopathic inflammatory bowel disease. Nevertheless, the association of chronic LNH with autism is not widely known nor has it been incorporated into standard texts. No mention of the link is made in the new edition of Morson and Dawson's Gastrointestinal Pathology . Apart from the issue of distinguishing physiological and pathological LNH, it is likely that the controversy regarding the role of measles/mumps/rubella (MMR) vaccination in the aetiology of autism has overshadowed some additional observations that demand serious attention. Epidemiological data do not support the link between MMR vaccination and the development of autism . However, if data continue to mount with respect to gastrointestinal manifestations in autistic spectrum disorder then the basis for that link will need to be thoroughly investigated. Are the intestinal and cognitive manifestations merely different components of a syndrome complex of unknown pathogenesis or could they be causally related?
The causative chain reiterated by Wakefield et al. begins with a poorly understood immune dysfunction that predisposes to a broad spectrum of immunologically based disorders to which autistic children are prone. These include upper respiratory tract infections, dietary allergy, eczema, adeno-tonsillar enlargement as well as chronic ileocolitis with LNH. The impaired cognitive function is then explained on the basis of an entero-colonic encephalopathy, analogous to hepatic encephalopathy. Specifically, the intestinal lesion results in increased intestinal permeability to exogenous peptides of dietary origin leading ultimately to disruption of neuroregulatory mechanisms and normal brain development . Alternatively, the primary lesion, perhaps involving a defect in the absorption, translocation or processing of factors derived from the intestinal lumen by dome epithelium (see above) could explain both LNH and neuropsychiatric dysfunction in a simple unitary hypothesis. These possibilities should be investigated further and hopefully will not be lost in the fog of the surrounding controversy.
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