HLA/Major Histocompatibility Complex
15.8.5 HLA/Major Histocompatibility Complex
UPDATE: In April 2010, the WHO Nomenclature Committee for Factors of the HLA System introduced a modification of the nomenclature outlined in the manual; the new nomenclature introduces delimiters in the form of colons, which removes the restriction of only allowing 99 alleles in 1 group. Hence the former HLA-DQB1*0503 is now expressed as HLA-DQB1*05:03 (Tait BD. The ever-expanding list of HLA alleles: changing HLA nomenclature and its relevance to clinical transplantation. Transplant Rev [Orlando]. 2011;25[1]:1–8.). This change was made March 29, 2011.
- [I]n transplantation, Histocompatibility Leads to
- Acceptance; in anthropology, Human populations
- are Located by Allelic variation; in disease, HLA
- alleles in Linkage disequilibrium Account for dis-
- ease….
- Julia G. Bodmer30(p7)
Antigens of what is known as the HLA system appear on virtually all nucleated cells of human tissues and on platelets. Just as red blood cell antigens determine blood type (see 15.1, Blood Groups, Platelet Antigens, and Granulocyte Antigens), HLA antigens determine tissue type.
HLA antigens were discovered to be determinants of the success of tissue transplantation (histocompatibility, histo- meaning “relating to tissue”). They were subsequently found to be critical for activating many immune responses, and certain HLA antigens are associated with particular diseases. Because of the great variation among individuals in these antigens (polymorphism), they have been used in forensic identification.
The molecules of the HLA system are encoded by at least 47 genes (among more than 200 genes, some related to immunity, some not) in a region of the short arm of chromosome 6 known as the major histocompatibility complex (MHC). Genes of the HLA system have multiple alleles, ie, are polymorphic; nearly 2000 had been officially named by 2005.31 The magnitude of this polymorphism distinguishes the HLA system from other gene families and has resulted in a detailed system for naming alleles and antigens.
Originally identified by serologic and cellular assays, HLA alleles came to be defined by DNA sequencing techniques. Accordingly, in 1987, new nomenclature for these alleles consistent with the International System for Human Gene Nomenclature (see 15.6.2, Genetics, Human Gene Nomenclature) was built onto the original nomenclature.32,33 A prime goal was for the nomenclature to reflect the relationship between serologically defined antigen specificities and those defined by DNA technology.30 With increased emphasis on DNA technology, new alleles do not always have known serologic counterparts.34
Nomenclature.
Nomenclature of the HLA system, first formalized in 1967,35 is determined by the World Health Organization Nomenclature Committee for Factors of the HLA System. Full reports on HLA nomenclature, which present officially recognized antigens and alleles, appear annually, with monthly updates, in the journals Human Immunology, European Journal of Immunogenetics, and Tissue Antigens and are available on the Internet36 on the website of the Anthony Nolan Research Institute37 and at the IMGT/HLA Sequence Database at http://www.ebi.ac.uk/imgt/hla.38 These reports are based on international workshops that take place every few years, with the participation of more than 400 laboratories.36
HLA. This abbreviation has come to signify human leukocyte antigen(s), but “HLA antigens” is a common and acceptable expression. (The original term was HL-A, the A being a simple letter designation, not an abbreviation for “antigen.”33) The term HLA applies both to the antigens on cells and to the loci (MHC) on the human genome responsible for those antigens. The term Mhc is used in nonhuman animals (see the “Animals” section below).
HLA Class I Antigens (Class I MHC Antigens). The class I antigens are as follows:
classical: |
HLA-A |
HLA-B |
HLA-C |
nonclassical (or class Ib): |
HLA-E |
HLA-F |
HLA-G |
The components of a class I MHC molecule include the following:
α chain or heavy chain (coded in the MHC) domains: α1, α2, α3
β2 chain (β2 microglobulin; coded on chromosome 15, not on the MHC)
HLA Class II Antigens (Class II MHC Antigens). The class II antigens are as follows:
classical: |
HLA-DR |
HLA-DQ |
HLA-DP |
nonclassical: |
HLA-DO |
HLA-DM |
(DR originally signified “D-related”; the others were named alphabetically.)
The components of a class II MHC molecule include the following:
α chain domains: α1, α2
β chain domains: β1, β2
(Note: The α and β chains of class I and class II molecules are not identical, despite the similar naming convention, but rather are distinct proteins.)
Serologically Defined HLA Antigens. Antigen specificities of the major HLA loci are indicated with numbers following the major locus letter(s), eg:
HLA-A1 |
HLA-B27 |
HLA-DR1 |
A w (for “workshop”) is used for 2 specificity groups:
HLA-C (to distinguish the C antigens from complement), eg, HLA-Cw1
HLA-Bw4 and Bw6
Parenthetical numbers indicate subtypes or “splits” of a given serologically defined antigen:
HLA-A23(9) |
(A23 is a split of A9) |
HLA-A24(9) |
(A24 is a split of A9) |
HLA-B49(21) |
(B49 is a split of B21) |
HLA-Cw9(w3) |
(Cw9 is a split of Cw3) |
HLA-DR14(6) |
(DR14 is a split of DR6) |
HLA-DQ7(3) |
(DQ7 is a split of DQ3) |
The term cross-reactive group (CREG) refers to serologically related groups of antigens. The abbreviation should be expanded at first mention. Note the following sample terms:
the HLA-A1 cross-reactive group (CREG)
the HLA-A2 CREG
the B5 cross-reactive group HLA-B51, B52, and B53
B7 CREG
Phrases such as the following may be used:
HLA-A, HLA-B, and HLA-C associations
possible associations with HLA-B18 and HLA-A2, and HLA-DQB1
testing for HLA-A (A2, A26) and HLA-B (B35, B44)
high prevalence of HLA-A1 (63%) and HLA-B8 (42%)
frequencies of HLA-A2 and A29
HLA Haplotypes. The HLA haplotype is the set of HLA alleles on 1 chromosome. Each person possesses 2 such haplotypes, 1 from each parent, and thus has 2 HLA antigens determined by each major locus, ie, 2 HLA-A antigens, 2 HLA-B antigens, etc. When HLA typing is performed serologically, antigen specificities of the individual’s phenotype are presented as follows:
Phenotype |
Notes |
|---|---|
A3, A23, B51, B7, Cw2, Cw5, DR7, DR11 |
all antigens listed collectively |
A23, B7, Cw5, DR7/A3, B51, Cw2, DR11 |
virgule separates antigens of one chromosome from those of other chromosome |
A3, A23, B51, B7, Cw2, Cw5, DR11,- |
hyphen indicates undetermined antigen |
A1, B8, Cw4, DR17(3)/A2, B27, Cw5,- |
DR for this haplotype not typed or untypable |
A1, B8, Cw4, DR17(3)/A2, B27, Cw5, DR17(3) |
2 identical DR specificities |
Shorter haplotype expressions are shown below:
HLA-Cw6-bearing haplotype
the A1-B8-DR3 haplotypes
DRB1, DQA1, and DQB1 haplotypes
A25 B18 BFS DR11 haplotype
Other Histocompatibility Loci. HLA antigens represent only some of the products of the MHC. Others, also important in immunity, are as follows:
Class I loci
MIC (MHC class I-related chain)
specificities: MICA, MICB, MICC, MICD, MICE
Class II loci
TAP (transporter associated with antigen processing)
specificities: TAP1, TAP2
PSMB (proteosome-related sequence)
specificities: PSMB8 (formerly LMP7), PSMB9 (formerly LMP2)
Class III loci (loci for 4 components of complement; see also 15.8.3, Complement):
C2
C4
Bf (B factor, properdin)
A haplotype of complement types is called a complotype, eg:
BfS, C2C, C4AQO, C4B1
(QO designates a deficiency.)
Genetic and Allele Nomenclature. Use italics to distinguish HLA genes or gene loci from protein products, eg, HLA-A, HLA-DRB1 (see also 15.6.2, Genetics, Human Gene Nomenclature). HLA alleles are distinguished from HLA antigens by their names, eg, the HLA-A1 antigen is coded by the HLA-A*0101 allele. The hyphen is retained in HLA gene expressions, an exception permitted in official gene nomenclature. Terms with asterisks indicate that HLA typing has been performed by molecular techniques. Terms with 2 digits (eg, A*02) indicate antigen typing with known serologic equivalent. Terms with 4 digits (eg, A*0201) represent alleles. In contrast to other alleles, HLA alleles are usually not italicized. Authors should make clear from context whether the gene or its product is being discussed.
The following tabulation, adapted from Marsh,37 summarizes nomenclature for HLA designations:
Term |
Indicates |
Change From Previous Nomenclature (If Any) |
Former Term (If Any) |
|---|---|---|---|
HLA |
HLA region, prefix for HLA gene |
||
HLA-DRB1 or DRB1 |
a particular HLA locus, ie, DRB1 (B refers to the β-chain locus; see directly below tabulation) |
||
HLA-DRB1*13 |
a group of alleles at the DRB1 locus that encode the DR13 antigen (antigen conferring DR13 specificity) |
||
HLA-DRB1*1301 |
a specific HLA allele, ie, DRB1*1301 |
||
HLA-DRB1*1301N |
a null (N) allele |
||
HLA-DRB1*130102 |
5th and 6th digits (02) indicate synonymous mutation |
5th digit only (2) for synonymous mutation |
HLA-DRB1*13012 |
HLA-DRB1*13010102 |
allele with mutation outside coding region |
||
HLA-DRB1*13010102N |
null allele with mutation outside the coding region |
||
HLA-A*24020102L |
low expression (L) |
||
HLA-B*44020102S |
secreted (S) |
new as of 2002 report |
|
cytoplasm (C) |
new as of 2002 report |
||
aberrant (A) expression |
new as of 2002 report |
||
HLA-A*3211Q |
unconfirmed, ie, questionable (Q) effect of allele with mutation |
||
sHLA-G*0101 |
soluble (s) form |
||
mHLA-G*0101 |
membrane-bound (m) form |
For the HLA-D region, the gene name includes a letter for the chain that the gene codes for (A for α, B for β), often followed by a number for the chain gene (not the domain number, as described in the previous section on class I and class II molecules). For instance,
DRB1 |
gene for first DR β chain |
DQA1 |
gene for first DQ α chain |
The HLA prefix (including the hyphen) may be dropped from allele designations in series after first mention, eg:
comparative frequencies of HLA-DRB1*14, DQA1*03, DQA1*05, DQA1*01, DQB1*06
(not: HLA-DRB1*14, -DQA1*03, -DQA1*05, -DQA1*01, -DQB1*06)
The conjunction and may be used to separate haplotypes but is not used before the final element in any single haplotype:
HLA-B38, DRB1*0402, DRB4*0101, DQB1*0201, DQB1*0302 [not and DQB1*0302]
HLA-B38, DRB1*0402, DRB4*0101, DQB1*0201, DQB1*0302 and HLA-B*0702, DRB1*1601, DRB5*02, DQB1*0502 haplotypes
The portion of the term before the asterisk may be dropped in a series, provided it would be the same in each term:
DRB4*01010101, *01030102N, *010302, *010303, *0105
Commas signify and, and virgules (forward slashes) signify or.39 Thus, commas indicate corresponding alleles from chromosome pairs (see the “Haplotypes” section above), eg:
Donor: A*01, 02; B*08, 44; DRB1*01, 03; DRB3.
Recipient: A*02, 11; B*40, 15; DRB1*09, 11; DRB3, DRB4
Virgules (forward slashes) indicate an ambiguous result in HLA typing, eg:
Term |
Meaning |
|---|---|
A*0201/0203/0205 |
A*0201 or A*0203 |
(also A*0201/03/05) |
or A*0205 is present |
Serologically defined antigens and the corresponding alleles may or may not be structurally similar and therefore may or may not be numerically similar.37 Also, alleles not defined serologically may have no known associated antigenic specificity:
Specificity |
Allele Name |
|---|---|
A203 |
A*0203 |
B78 |
B*7801, B*780201, B*780202 |
B65(14) |
B*1402 |
B50(21) |
B*5001 |
DR53 |
DRB4 (various, eg, DRB4*0102, *010303) |
none |
the E alleles (E*0101, 0102, etc) |
none |
the F allele F*0101 |
none |
the G alleles (G*010101, 010102, etc) |
HLA pseudogenes (see also 15.6.2, Genetics, Human Gene Nomenclature) resemble and are located near the HLA loci but are not transcribed to produce functional products. The class I pseudogenes end in letters after G, and the class II pseudogenes end in numbers after 1:
HLA-H |
HLA-J |
HLA-K |
HLA-L |
HLA-N |
HLA-S |
HLA-X |
HLA-Z |
||
HLA-DRB2 |
HLA-DRB6 |
HLA-DRB6 |
HLA-DRB8 |
HLA-DRB9 |
HLA-DQA2 |
HLA-DQB2 |
HLA-DQB3 |
HLA-DPA2 |
HLA-DPB2 |
Animals.
In animals, major histocompatibility locus is abbreviated Mhc, using uppercase and lowercase.
The names for the Mhc in other animals40 usually correspond to the expression HLA for humans (but not always, eg, the prototypical mouse locus, H-2). In this convention, the name is based on a common name or species name combined with LA (leukocyte antigen):
cat |
FLA |
dog |
DLA |
domestic cattle |
BoLA |
domestic fowl |
B |
guinea pig |
GPLA |
horse |
EqLA |
mole rat |
Smh |
mouse |
H-2 |
pig |
SLA |
rabbit |
RLA |
rat |
RT1 |
Primate researchers use an alternative style based on the genus and species name (see 15.14, Organisms and Pathogens), which substitutes Mhc for LA.40 Note the following examples:
Common Animal Name |
Species Designation |
Mhc Term |
Former LA Term |
|---|---|---|---|
chimpanzee |
Pan troglodytes |
MhcPatr |
ChLA |
gorilla |
Gorilla gorilla |
MhcGogo |
GoLA |
orangutan |
Pongo pygmaeus |
MhcPopy |
OrLA |
rhesus macaque |
Macaca mulatta |
MhcMamu |
RhLA |