Letter from Dr. Andrew Wakefield to the New England Journal of Medicine:

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Letter from Dr. Andrew Wakefield to the New England Journal of Medicine:

Dr Andrew J Wakefield MB.,BS FRCS FRCPath

Sir,

Population-based studies (1), in contrast with molecular and immunological studies (2-6), have not found an association between MMR vaccination and autism.  As pointed out by Madsen et al (NEJM 2002;347:1478-1482 (1)) and endorsed by others (7), epidemiological studies that have examined this relationship have been inadequate. Have Madsen et al fared better?

                                                            I have no doubt that other correspondents will deal with a principal limitation of their study, that is, the failure to disaggregate the relevant autism subset – one which they attempt to describe in the introduction to their paper - from the overall autism population. This is equivalent to looking at the totality of hepatitis, irrespective of aetiology, in a study designed to examine a possible causal relationship with a single, specific exposure that may account for a minority hepatitis subtype only. 

                                                            My purpose is to try and help clarify the hypothesis of my group, and to dissociate this from the many proxy hypotheses generously, if erroneously tested in our name. Our studies have been concerned with examining the aetiology and pathogenesis of autism in a subset of children who became encephalopathic after a period of normal development and suffer an immune-mediated gastrointestinal pathology (2-4,8-14). Within the relevant subset of children we have observed frequent atopy (especially food allergy), antibiotic use, ear infection, multiple concurrent vaccine exposure and a strong family history of atopic and autoimmune disease, as reported by others (15). Consistent with these clinical observations, there appears to be, in many affected children, a TH2 mucosal and systemic immune bias; this is evident in lymphocyte cytokine profiles (14,16), eosinophil infiltration of the intestinal mucosa, and up-regulation of class II antigen within the intestinal lamina propria that is not seen on the adjacent epithelium (8-10).  Dysregulated mucosal immunity in affected children is accompanied by an excess of TNFa-positive lymphocytes, to an extent that distinguishes the autistic lesional mucosa from both inflammatory and non-inflammatory paediatric controls (14) that is consistent with the findings of others (17). There is a profound expansion of CD19+ lymphocytes in the lamina propria, mirroring the associated hyperplastic lymphoid response that, at the macroscopic level, is particularly evident in the ileum and colon (13). In controlled, systematic studies intestinal lymphoid hyperplasia of the degree seen in affected children is clearly not, as anecdotal impression would have it, a normal variant (9,18). While the TH1-TH2 model is an oversimplification, its serves as a useful template for our working model.

                                                            Early on in the current debate, in a paper that sought to articulate the hypothetical relationship between MMR and regressive autism, we wrote, “At the level of the immune response, the newborn tends towards a TH2 response to pathogens and gradually shifts towards a TH1 response with age. If this transition does not take place appropriately, the infant is likely to be at greater risk of mounting aberrant immune responses in later life, as seen in patients with allergies. Given that, under normal circumstances the age of this transition will be different for different children, it seems inevitable that a ubiquitous viral exposure [MMR] of all 15-month-old children could induce an immune response that is consistent with the individual dynamics of this TH2-TH1 transition.” (19).

                                                            A precursor to an adverse reaction to MMR may be a congential or acquired aberrant TH2 immune programming. This would increase the likelihood of an inadequate antiviral immune response in the face of a live viral vaccine and may facilitate viral persistence and immunopathology, as described for measles virus in affected children (2,4).

                                                            The key to defining the “child at risk”, therefore, is an examination of the co-factors that may interfere with the appropriate TH2-TH1 transition prior to, or concomitant with, MMR exposure. One such factor may be mercury, for which the immuno-toxicity (putting aside for now the associated neurotoxicity) of organic and inorganic derivatives is qualitatively similar. Is a synergistic adverse interaction between mercury and a live viral vaccine biologically plausible? The immunosuppressive and immunomodulatory effects associated with mercury exposure are accompanied by increased susceptibility to challenge with infectious agents. One of the best-characterised examples of T-helper cell phenotypic polarity in response to infection is the murine model of Leishmania major. Murine susceptibility to L. major infection is dependent upon induction of a genetically restricted TH2 response. Resistant animals, that exhibit a genetically restricted TH1 response to L.major, are rendered susceptible by prior exposure to mercury (20). In previously resistant animals, sub-toxic doses of mercuric chloride induced an autoimmune syndrome characterised by the expansion of TH2 cells, IL-4 production by splenocytes and IgG1 and IgE production. This was accompanied by a non-healing phenotype with increased footpad swelling and parasite burden. Methyl mercury enhanced the immune damage and chronicity of coxsackie B3 myocarditis in mice, compared with mice infected without prior mercury exposure (21). Similarly, mercuric chloride exposure significantly impaired macrophage-mediated resistance to generalised infection with herpes simplex type-2 in a murine model (22).

                                                            Mercury is only one of several exposures to infants that may potentially influence the immune response to live viral vaccines. In testing the correct hypothesis at the population level, these factors will need to be taken into account and appropriate adjustments made. It may be, for example, that the rapidly changing pattern of infant mercury exposure - as thimerosal in bacterial and subunit vaccines - will with the necessary adjustments, reduce statistical power to the extent that such studies fail to offer any convincing evidence either way. It is my personal opinion that the answer will be found in the detailed analysis of each individual child - from clinical history to molecular idiosyncrasy.                       

                                                            The foundations of our hypothesis have not shifted. Failure to take it into account has served merely to polarise the debate, confuse the consumer, and allow the polemic of Public Health to soar a little closer to the sun.

 

References

1.                  Madsen MK., Hviid A., Vestergaard M., Schendel D., Wohlfarht J., Thorsen P., Olsen J., Melbeye M. A population-based study of measles mumps rubella vaccination and autism. NEJM 2002;347:1478-1482

2.                  Uhlmann V., Martin CM., Shiels O., Pilkington L., Silva I., Lillalea A. Murch SH., Wakefield AJ., O’Leary JJ. Potential viral pathogenic mechanism for new variant inflammatory bowel disease. Molecular Pathology. 2002;55:1-6

3.                  Wakefield AJ. Enterocolitis, autism and measles virus. Molecular Psychiatry. 2002;7 Suppl 2:S44-46

4.                  Shiels O., Smyth P., Martin C., O’Leary JJ. Development of an allelic discrimination type assay to differentiate between strain origins of measles virus detected in intestinal tissue of children with ileocolonic lymphonodular hyperplasia and concomitant developmental disorder. Journal of Pathology. 2002 .A20

5.                  Singh V., Lin S., Yang V. Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism. Clinical Immunology and Immunopathology. 1998:89;105-108

6.                  Singh VK, Lin SX., Newell E., Nelson C. Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism. J Biomed. Sci. 2002;9:359-364

7.                  Spitzer WO., Aitken KJ., Dell’Aniello S., Davis MW The natural history of autistic syndrome in British children exposed to MMR. Adverse Drug reactions and Toxicol. Rev. 2001:20;160-163

8.                  Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, et al. Ileal LNH, non-specific colitis and pervasive developmental disorder in children. Lancet 1997; 351: 637-641

9.                  Wakefield AJ, Anthony A, Murch SH, Thomson M, Montgomery SM, Davies S, et al. Enterocolitis in children with developmental disorder. American Journal of Gastroenterology 2000; 95:2285-2295

10.             Furlano RI, Anthony A, Day R, Brown A, McGavery L, Thomson MA, et al. Colonic CD8 and γδ T cell infiltration with epithelial damage in children with autism. Journal of Pediatrics  2001;138:366-372

11.             Torrente F, Machado N, Ashwood P, et al. Enteropathy with T cell infiltration and epithelial IgG deposition in autism. Molecular Psychiatry 2002;7:375-382

12.             Wakefield AJ, Puleston J., Montgomery SM., Anthony A., O’Leary JJ., Murch SH. Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands. Alimentary Pharmacology and Therapeutics 2002; 16: 663-674

13.             Ashwood P., Murch SH., Anthony A., Pellicer AA., Torrente F., Thomson M., Walker-Smith JA., Wakefield AJ.  Intestinal lymphocyte populations in children with regressive autistic spectrum disorder and entero-colitis. Gastroenterology 2002;122: Suppl. A1004

14.             Ashwood P., Walker-Smith J., Murch S., Wakefield A. Pro-inflammatory cytokine production in the duodenal and colonic mucosa of children with autistic spectrum disorder (ASD) and a novel entero-colitis; Gastroenterology 2002;122: Suppl. A617

15.             Comi AM, Zimmerman AW., Frye VH., Law PA., Peeden JH. Familial clustering of autoimmune disorders and evaluation of medical risks in autism. J. Child Neurol 1999; 14;388-394

16.             Gupta S., Aggarwal S., Rashanravan B., Lee T. Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism. J Neuroimmunol 1998; 85:106-109

17.             Jyonouchi H., Sun S., Le H. Pro-inflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression.

18.             Kokkonen J., Ruuska T., Kartunen TJ., Maki M. Lymphonodular hyperplasia of the terminal ileum associated with colitis shows an increased gd+ T-cell density in children. Am J Gastroenterol. 2002;97:667-672

19.             Wakefield AJ.and Montgomery SM. Autism, viral infection, measles-mumps-rubella vaccination. Israeli Med Assn J. 1999;1:183-187

20.             Bagenstose LM., Mentink-Kane MM., Britingham A., Mosser DM., Monestier M. Mercury enhances susceptibility to murine Leishaniasis. Parastite Immunology 2001;23:633-640

21.             Ilback NG., Wesslen L., Fohlman Friman G. Effects of methyl mercury on cytokines, inflammation and virus clearance in a common infection (Coxsackie B3 myocarditis) Toxicol. Lett. 1996;89:19-28

22.             Christensen MM., Ellermann-Eriksen S., Rungby J., Mogensen SC. Influence of mercuric chloride on resistance to generalized infection with herpes simplex virus type 2 in mice. Toxicology 1996;114:57-66

 

 

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