HLA-A*02

Serotype

The serotyping for the most abundant A02 alleles is good. For A02:03, A02:06, A02:07 serotyping is borderline useful. There is a separate serotyping for A203 and A210. As of December 2013, there are 456 alleles identified (mostly by sequence homology) as being A2, of those 27 are nulls, and a large majority have unknown serotypes, although it is highly probable that they will all return A2 serotypes.

Disease associations

HLAs serve as the primary link between the immune system and interior of cells. Thus any alteration to the HLA that induces decreased binding to a certain peptide or increased binding to a certain peptide, is expressed as, respectively, increased susceptibility to disease or decreased susceptibility to disease. In other words, certain HLAs may be incapable of binding any of the short peptides produced by proteolysis of pathogenic proteins. If HLAs bind none of the peptides produced by a pathogen, then there is no way for the immune system to tell that a cell is infected. Thus the infection can proliferate largely unchecked. It works the other way too. Some HLAs bind pathogenic peptide fragments with very high affinity. This in essence "supercharges" their immune system in regards to that particular pathogen, allowing them to easily control an infection that might otherwise be devastating.

Spontaneous abortion

The HLA-A02 antigen has been associated with spontaneous abortion in infertile couples. In essence, there are indicators, albeit from a small study comparing HLA expression in fertile and infertile couples, that HLA-A02 may induce increased maternal immune response to the fetus. This immune response could be compared to an allergic reaction, and, if severe enough, induces abortion of the fetus. Although this is a very interesting correlation, the study which first uncovered this link was quite small and more work needs to be done to verify this hypothesis.

Human immunodeficiency virus

HLA-A02 appears to stimulate peripheral blood mononuclear cells in a manner that inhibits HIV replication. This could be the reason for a documented 9-fold reduced risk of HIV transmission to infants during childbirth. HIV has evolved mechanisms to combat immune recognition. HIV produces a protein called Nef that binds to the cytoplasmic tail of HLA-A and B and diverts it to the lysosomes for destruction. This prevents the HLAs from being expressed on the cell surface and then functioning properly. In addition, there are several HLA-A02 haplotypes that appear to contribute heavily to higher or lower viral loads in HIV patients. HLA-A02-C16 and HLA-A02-B45 have been shown to contribute to significantly increased viral loads (greater than 100,000 copies per milliliter). In summation, HLA-A*02 appears to be somewhat less effective than other HLA-As at protecting against HIV infections.

Hodgkin lymphoma

HLA-A02 has been linked with decreased risk of developing Epstein-Barr virus (EBV)-positive Hodgkin lymphoma(HL). Among patients with EBV+ HL, only 35.5% of people expressed HLA-A02 compared to 50.9% in the EBV-HL group and 53% in the control group. This is a significant decrease and is almost certainly a result of the abnormally efficient binding of HLA-A02 to peptides originating from EBV. This high affinity increases the probability of CD8+ t-cell recognition of EBV peptides held by HLA-A02 complexes. This, in turn, enhances the immune system's ability to control and clear the EBV, which decreases the change of developing Hodgkin Lymphoma as a result of the infection.

By haplotype

A02:Cw16 is associated with increased higher viral load in HIV

Alleles

A2-B haplotypes

A2-B7 (Node in Netherlands) A2-B5

• A2-B51
• A2-B52 A2-B8

A2-B13

A2-B14

• A2-B64
• A2-B65 A2-B15
• A2-B62
• A2-B63
• A2-B70,71,75,76
• A2-B46 (Node in Southern China, may be most abundant haplotype) A2-B16
• A2-B44
• A2-B45 A2-B18

A2-B27

A2-B35

A2-B37 A2-B39 (Node in North American Amerinds)

A2-B40

• A2-B60
• A2-B61 A2-B46

A2-Cw5-B44

A2-Cw5-B44 is the multi-serotype designation for the haplotype HLA-A02:01~C05:01~B*4402, the class I portion, of an ancestral haplotype (A2~B44~DR4~DQ8). The full haplotype is (for relative distances) see Human leukocyte antigens:

A ~ C ~ B ~ DRB1 ~ DQA1 ~ DQB1

Another haplotype that is more common in Central Europe is the (A2-B44-DR7-DQ2)

A ~ C ~ B ~ DRB1 ~ DQA1 ~ DQB1

Over northwestern Europe A2-B44 shows a single common ancestor which contributed the Cw5 allele to the haplotype. The haplotype appears to have been introduced early in European prehistoric period, frequencies of the haplotype generally correlate with A1-Cw7-B8 and A2-B7. The haplotype is considerably more equilibrated relative to A1-B8 and a possible reason is gene flow from iberia or the east with related haplotypes after initial migrations.

References

References

1. (Feb 1978). "The genetic control of HLA-A and B antigens in somatic cell hybrids: requirement for beta2 microglobulin". Tissue Antigens.
2. (10 Nov 2013). "HLA Nomenclature @ hla.alleles.org". Anthony Nolan Research Institute.
3. (2013). "Allele Search Tool". European Molecular Biology Laboratory.
4. Daniel M. Davis. (2014). "The Compatibility Gene. How Our Bodies Fight Disease, Attract Others, and Define Our Selves.". [[Oxford University Press]].
5. (Aug 2007). "HLA-A2 class I antigens in couples with recurrent spontaneous abortions". International Journal of Immunogenetics.
6. (Feb 2001). "Generation of alloantigen-stimulated anti-human immunodeficiency virus activity is associated with HLA-A*02 expression". The Journal of Infectious Diseases.
7. (16 September 2013). "Ability of HIV-1 Nef to downregulate CD4 and HLA class I differs among viral subtypes". Retrovirology.
8. (Aug 2002). "Favorable and unfavorable HLA class I alleles and haplotypes in Zambians predominantly infected with clade C human immunodeficiency virus type 1". Journal of Virology.
9. (Nov 2007). "HLA-A02 is associated with a reduced risk and HLA-A01 with an increased risk of developing EBV+ Hodgkin lymphoma". Blood.
10. (1992). "HLA 1991: proceedings of the eleventh International Histocompatibility Workshop and Conference, held in Yokohama, Japan, 6-13 November, 1991". Oxford University Press.
11. (1997). "Distribution of HLA-A, B and DR genes and haplotypes in the Irish population". Experimental and Clinical Immunogenetics.
12. (Dec 2000). "Frequency of HLA-B alleles in a Caucasoid population determined by a two-stage PCR-SSOP typing strategy". Human Immunology.
13. (Jun 1994). "HLA-DPB1 DNA polymorphism in the Swiss population: linkage disequilibrium with other HLA loci and population genetic affinities". European Journal of Immunogenetics.
14. (Nov 1996). "HLA gene and haplotype frequencies in Dutch blood donors". Tissue Antigens.