The human major histocompatibility complex and childhood leukemia: An etiological hypothesis based on molecular mimicry

Abstract

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.

Human Leukocyte Antigen (HLA)-DRB1*14 Is Associated with a High Incidence of Acute Lymphocytic Leukemia

“…This may be because it was the firstdiseaseonwhichanMHCeffectwasreported,andthis effect was observed both in virus-induced and spontaneous leukemia [2]. We have reported the HLA correlations in chronic myeloid leukemia (CML) in Jiangsu Province patients,andsomesignificantallelesweredescribed [7].Taylor et al [8] and Ng et al [9] reported HLA-DPB1*0601 and HLA-B*67weresignificantlyassociatedwithALL.…”

“…The fact that the HLA genes are associated with lots of diseases may reflect an underlying pathogenetic pathway.Itisnowclearthattheprimarybiologicalfunction ofHLAgenesistheorchestrationoftheimmuneresponseto pathogensthroughtheformationofTCR/peptide/HLAcomplexes [2]. Since HLA plays a critical role in immune response,manydiseaseassociationstudieshavebeenconducted including acute lymphocytic leukemia (ALL) [2]. Epidemiological evidence has suggested an interactive role of genetic and environmental factors in leukemia pathogenesis, where delayedexposuretoarareimmunologicalresponsetosome antigenandinvolvementofthehost'sHLAsystemareimplicated [3].AsHLAassociationmightvaryindifferentethnic and geographic populations due to its unique genetic background, the possibility of an association of HLA molecules wasassessedinatotalof156ALLpatientsresidinginJiangsu Province,P.R.China.…”

“…The frequency of DRB1*13 was 3.85% in the ALL group versus 100 genes [1]. The fact that the HLA genes are associated with lots of diseases may reflect an underlying pathogenetic pathway.Itisnowclearthattheprimarybiologicalfunction ofHLAgenesistheorchestrationoftheimmuneresponseto pathogensthroughtheformationofTCR/peptide/HLAcomplexes [2]. Since HLA plays a critical role in immune response,manydiseaseassociationstudieshavebeenconducted including acute lymphocytic leukemia (ALL) [2].…”

Transmission of HLA-DP variants from parents to children with B-cell precursor acute lymphoblastic leukemia: Log-linear analysis using the case–parent design

“…Of these, variations in the major histocompatibility complex (MHC)-linked human leukocyte antigen (HLA) genes provide a plausible link to infection [19,20]. The notion of MHC-linked susceptibility to human leukemia originated from the studies of Lilly et al [21], who reported that susceptibility to murine Gross virus leukemia was strongly influenced by H-2 type.…”

“…The notion of MHC-linked susceptibility to human leukemia originated from the studies of Lilly et al [21], who reported that susceptibility to murine Gross virus leukemia was strongly influenced by H-2 type. Although the search for HLA associations with childhood ALL is more complicated [20], the availability of large case-control series of childhood ALL now makes the identification of HLA associations a realistic possibility [22].…”