The human major histocompatibility complex and childhood leukemia: an etiological hypothesis based on molecular mimicry.
The extended human major histocompatibility complex (MHC) is a gene-rich region of about 7.6 Mb on chromosome 6, and includes a high proportion of genes involved in the immune response. Among these are the two Human Leukocyte Antigen (HLA) gene clusters, class I and class II, which encode highly polymorphic classical HLA-A, B, C and HLA-DR, DQ and DP genes, respectively. The protein products of the classical HLA genes are heterodimeric cell surface molecules that bind short peptides derived from non-self and self proteins, including infections and auto-antigens. The presentation of these HLA-anchored peptides to T lymphocytes triggers a cascade of responses in immune-associated genes that leads to adaptive immunity. Associations between HLA class II alleles and childhood leukemia have been reported in a number of studies. This could be due to the role of HLA allele-restricted peptide binding and T cell activation, or linkage disequilibrium to an MHC-linked "leukemia gene" in the pathogenesis of childhood leukemia. Efforts are currently in progress to resolve these questions, using large leukemia case-control sample series such as the UK Childhood Cancer Study (UKCCS) and the Northern California Childhood Leukemia Study (NCCLS). Here we review the background to these studies, and present a novel hypothesis based on the paradigm of HLA-associated auto-immune disease that might explain an infection-based etiology of childhood leukemia.
Taylor
Malcolm
M
Cancer Immunogenetics, School of Cancer Sciences, University of Manchester, Manchester, UK. gmtaylor@manchester.ac.uk
Hussain
Adiba
A
Urayama
Kevin
K
Chokkalingam
Anand
A
Thompson
Pamela
P
Trachtenberg
Elizabeth
E
Buffler
Patricia
P
D000208:Acute Disease; D000293:Adolescent; D000483:Alleles; D017951:Antigen Presentation; D001327:Autoimmune Diseases / Q000453:epidemiology / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D004781:Environmental Exposure; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007239:Infections / Q000150:complications / Q000276:immunology; D007938:Leukemia / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D015810:Linkage Disequilibrium; D008285:Major Histocompatibility Complex; D008954:Models, Biological; D018716:Molecular Mimicry; D038042:Myelopoiesis; D011110:Polymorphism, Genetic; D011289:Preleukemia / Q000276:immunology