What do anthropology, immune response, transplantation and predictive medicine have in common? Jean Dausset and his exceptional work on the human leukocyte antigens (HLA) or the HLA complex in the 1950s.
The MHC Complex
The major histocompatibility complex (MHC), where genes for HLAs are situated on the 6th chromosome is a reigon of high gene density of very tightly linked genes. HLAs code for class I and class II MHC molecules which determine an individual’s response to a particular antigen or their susceptibility to it. The MHC complex might have first evolved in small invertebrates to distinguish among “nearly identical” organisms in large colonies, which often function as a unit. With the evolution of vertebrates, the complex specialized in differentiating “self” tissues from non-self (histocompatibility: compatibility of tissues, usually during transplantation.) All HLAs are encoded by polymorphic alleles. In fact, the total possible combinations are magnitudes of orders greater than the human population. Thus, HLA typing can be used to determine every individual’s susceptibility to a plethora of diseases. The HLA is, hence, a paradigm point in the emergence of predictive medicine.
Statistical evidence shows association of certain HLAs with around 50 different diseases. The relative risk for certain HLA alleles can be calculated by the ratio of the allele frequency amongst patients and allele frequency amongst the general population. Thus, relative risk is a measure of the increased susceptibility of an individual having an allele over another individual lacking it. An allele, B27, has a relative risk of 90 in the Japanese population for ankylosing spondylitis. Another allele, DR2, has a relative risk of 130 for nacrolepsy. Just this particular allele and you are 130 times more susceptible to having sleepless nights. Let my words not make you assume that the HLA allele causes the particular disease. It just reminds us of the complexity inherent in biological systems.
HLA typing or identification of HLAs was originally performed by serological methods and cellular assays. Molecular technologies employed in HLA typing include restriction fragment length polymorphisms (RFLP), PCR-RFLP, allele-specific amplification (PCR-SSP) sequence specific oligonucleotide probe (PCR-SSOP) and DNA sequencing.
Promise in medicine
Hematopoietic stem cells and organ transplantation could allow studying complex, systemic effects of introduction of a foreign genome into an individual. Assessment of role of HLA alleles, haplotypes and combinations is crucial for donor-recipient histocompatibility. It we also be crucial for developing and validating therapies using allogenic cells and/or tissues to treat chronic diseases and aging. Along with transplantation and regenerative medicine, some autoimmune diseases could also be cured through HLA-based systems approach.
As the editorial from Genome Medicine referenced at the bottom culminates,
“Looking into the future, on the basis of its past history, we can be certain of at least one thing: the HLA system will continue to have a pivotal integrative role in the advent of P4 medicine and should therefore be considered as a hallmark of systems medicine”.
- Chakravarty, A., Immunology and Immunotechnology, 2006, OUP
- Auffray, C., Charron, D., Hood L., Predictive, preventive, personalized and participatory medicine: back to the future, Genome Medicine, 2010