• immunogenetics
• structure and function of MHC molecules
• major histocompatibility complex (MHC) antigens
• CREG
• HLA disease association
• KIR
• minor histocompatibility antigens (mHA)

HLA-B and HLA-C alleles always maintain the additional "w" to distinguish them from the loci for complement factors B and C2 and C4, respectively, which are located in the MHC region, too. Also D alleles (now renamed DR) were once termed with the additional "w" to distinguish them from the locus for the complement factor D.

Serological nomenclature :

• HLA-( _ ( _ _ ) : locus (and sublocus of protein chain for class II only))(eventual paralogous gene)*( _ _ : type / serological group defined looking for microcytotoxicity in serological assays using mAb or sera from multiparous females (immunized by microchimerism))
• types defined with one-way heterologous mixed lymphocytary reaction (MLR) are marked with an additional "w" (for workshop) after the locus :
• serologically defined haplotypes are termed according to the detected type. Staining with HLA tetramers provides a means for identifying, quantifying, and isolating HLA-specific B cells^ref. The phenotype of HLA-specific B cells reflects current or historic sensitization to HLA and may reflect inherent differences between groups defined by race and/or gender. The frequencies of HLA-specific B cells may predict patients at risk for production of donor-specific antibody after transplantation^ref
• supertypes are group of types presenting at least a shared epitope. E.g. :
• HLA-A1 supertype
• HLA-A2 supertype
• HLA-A3 supertype
• HLA-A24 supertype
• HLA-B7 supertype
• HLA-B27 supertype
• HLA-B44 supertype
• HLA-B58 supertype
• HLA-B62 supertype
• HLA-DRw52 supertype (including HLA-DR3, HLA-DR5, HLA-DRw6, and HLA-DRw8 types) has nowadays been proved to correspond to HLA-DR ab₃ molecule
• HLA-DRw53 supertype (including HLA-DR4, HLA-DR7, and HLA-DR9) has nowadays been proved to correspond to HLA-DR ab₄ molecule

Molecular nomenclature :

• HLA-( _ ( _ _ ) : locus (and sublocus))(eventual paralogous gene)*( _ _ : type / allele group defined as a group of closely-related alleles at a locus)(_ _ : subtype / specific allele defined by DNA hybridization)(_ : samesense SNP in cds detected with DNA sequencing)(_ _ : SNP in intron or flanking region)( _ : expression level (N = null allele or no expression ; L = low cell surface expression ; no letter = normal level of expression; S = soluble secreted allele not found on cell surface; C = cytoplasm-only; A = aberrant expression; Q = questionable expression)
• e.g. HLA-DRB4*0103102N

Resolution :

• low resolution : samples typed at the allele group level
• intermediate resolution : samples typed to a subset of alleles. E.g. DRB1*15(01,03,06)
• high resolution : samples typed to the allele level

• since the HLA-A and HLA-B loci were discovered first they do not share type designations
• serological splits are sometimes written as broad sero name(split) or split(broad sero name)

HLA allele nucleotides are numbered based upon an archetypal cDNA sequence : that means new alleles are aligned with the archetype even if they have small insertions and deletions.

locus	DRB1/3/4/5	DPB1	DQA1	DQB1	A	B	Cw
archetype	DRB1*0101	DPB1*01011	DQA1*0501	DQB1*0501	class I cons.	class I cons	class  I cons.
start	1	1	-69	1	1	1	1
exon 1	13	13	13	13	73	73	73
exon 2	283	277	262	283	343	343	343
exon 3	565	559	544	565	619	619	619
exon 4	676	670	699(end)	676	895	895	895
exon 5	700	690(end)		703	1015	1015	1015
exon 6	714(end)			714(end)	1057	1057	1057
exon 7					1096	1096	1096
exon 8					1101(end)	1101(end)	1101(end)

The strongest linkage disequilibria are between :

• B-Cw
• DRB1-DRB3/4/5

• serologic cross-reactivity patterns^ref (Rodey, Fuller, 1987 : 14 CREGs)
• modified Rodey (1994^ref (Rodey GE. 2nd ed. Durango CO: De Novo; 2000. HLA Beyond Tears) : 8 CREGs)



CREG	antigen specificities included
1C	A1, 3, 9 (23, 24), 11, 29, 30, 31, 36, 80
10C	A10 (25, 26, 34, 66), 11, 28 (68, 69), 32, 33, 43, 74
2C	A2, 9 (23, 24), 28 (68, 69), B17 (57, 58)
5C	B5 (51, 52), 15 (62, 63, 75, 76, 77), 17 (57, 58), 18, 21 (49, 50), 35, 46, 53, 70 (71, 72), 73, 78
7C	B7, 8, 13, 22 (54, 55, 56), 27, 40 (60, 61), 41, 42, 47, 48, 59, 67, 81, 82
8C	B8, 14 (64, 65), 16 (38, 39), 18, 59, 67
12C	B12 (44, 45), 13, 21 (49, 50), 37, 40 (60, 61), 41, 47
Bw4	A23, 24, 25, 32, B13, 27, 37, 38, 44, 47, 49, 51, 52, 53, 57, 58, 59, 63, 77
Bw6	B7, 8, 18, 35, 39, 41, 42, 45, 46, 48, 50, 54, 55, 56, 60, 61, 62, 64, 65, 67, 71, 72, 73, 75, 76, 78, 81, 82

• associative analyses^{ref1, ref2} (Thompson, 1998; Duquesnoy, 2003)

 
• shared amino acid sequence polymorphisms^ref (McKenna and Takemoto, 1996 : 10 CREGs)



CREG	antigens included
A1C	A1, 3, 11, 19 (29, 30, 31), 36, 80
A2	A2, 9 (23, 24), 28 (68, 69), B17 (57, 58)
A10C	A10 (25, 26, 34, 66), 32, 33, 43, 74
BW4	A9 (23, 24), 25, 32, B13, 27, 37, 38, 44, 47, 49, 51, 52, 53, 57, 58, 59, 63, 77
B5C	B5 (51, 52.) 18, 35, 53
B5C2	B5 (51, 52), 15 (62, 63, 71, 72, 75, 76, 77), 17 (57, 58), 21 (49, 50), 35, 53, 73,78
BW6	B7, 8, 18, 35, 39, 40 (60, 61), 41, 42, 45, 46, 48, 50, 54, 55, 56, 62, 64, 65, 67, 71, 72, 73, 75, 76
B7C	B7, 8, 13, 27, 41, 42, 47, 48, 54, 55, 56, 60, 61, 81
B8C	B8, 18, 38, 39, 64, 65
B12C	B12 (44, 45), 13, 37, 41, 47, 21 (49, 50), 40 60, 61)

• LABScreen Analysis software-2 (Japanese Red Cross Tokyo Blood Center)

 


	CREG	antigens of CREG	%
1	INTL3	A11+Cw3+Bw6	36%
2	INTL2	A32+A23+A24+A9+Bw4	33%
3	5C	B51+B52+B35+B53+B62+B63+B71+B72+B75+B76+B77+B57+B58+B18	27%
4	28C	A25+A26+A34+A66+A11+A68+A69+A30+A31+A33	21%
5	2C1	A2+A28+A68+A69	18%
6	B4	B51+B52+B53+B44+B49+B57+B58+B63+B77+B37+B13+B47+B27+B38+B59	18%
7	22C	B7+B22+B54+B55+B56+B27+B17+B57+B58+B46	18%
8	2C2	A2+A28+A68+A69+A9+A23+A24	12%
9	12C	B44+B45+B49+B50+B13+B41+B47+B60+B37+B61	12%
10	8C	B8+B14+B64+B65+B18+B51+B38+B39	12%
11	21C	B49+B50+B51+B52+B35+B62+B63+B75+B76+B77	6%
12	1C2	A1+A36+A9+A23+A24+A11	6%
13	27C	B7+B27+B13+B40+B60+B61+B47	6%
14	1C3	A25+A26+A34+A66+A11+A1+A36+A29	6%
15	1C1	A1+A36+A3+A11	6%
16	B6	B35+B18+B45+B50+B62+B75+B76+B71+B72+B46+B41+B60+B61+B7+B42+B54+B55+B56+B67+B39+B8+B64+B65	6%

Blank : absence of detection of a second allele can be due to ...

• monozygosis :
• absent in that haplotype (eg DR10-DQ5 class II haplotype lacks a DRB3/4/5)
• gene deletion
• (true) homozygosis, to be proved by family studies
• pseudogene : null alleles cannot be detected serologically
• technical limitations :
• some Cw antigens cannot be detected serologically
• due to high paralogy : apparent homozygosis (serology is unable to split the 2 alleles)

For MHC haplotype matching, the MHC block matching technique was developed to match for genomic blocks rather than for individual HLA loci and to enable the identification of donors and recipients who are matched for HLA and non-HLA sequences in the MHC equivalent to HLA identical siblings. MHC block matching is based upon the premise that the MHC includes the following polymorphic blocks^{ref1, ref2, ref3}:

• the alpha block corresponding to a gene cluster around HLA-A

the beta block corresponding to a gene cluster around HLA-B and HLA-Cw, spans about 300 kb^ref and contains the immunologically relevant HLA-B, HLA-Cw, MICA, and MICB genes. MICA and MICB are highly polymorphic with at least 59 alleles for MICA (considering polymorphisms at both extracellular and transmembrane domains) and 19 alleles for MICB. MICA and MICB are located 46.4 and 141.2 kb centromeric to HLA-B, respectively^{ref1, ref2, ref3}. Recent studies have shown that the highly polymorphic MIC antigens are expressed in transplanted organs and may cause early graft rejection^{ref1, ref2}. Thus, the polymorphisms of MICA and MICB may be involved in allogeneic BMT and GVHD^ref. Although it is known that the MIC gene products are ligands of NKG2D^ref, an activating receptor on several immune cells, the actual roles of MICA and MICB in bone marrow transplantation have not yet been demonstrated. However, it is evident that the MHC beta block marker is also a marker for the MICA and MICB genes^ref.
• the gamma block corresponding to a gene cluster around Bf and C4
• the delta block corresponding to a gene cluster around HLA-DR and DQ

 
Genetic variation within these HLA loci can have profound effects on an individual's susceptibility to infection, autoimmune disorders, or response to vaccines. Similarly, homozygosity within HLA could restrict the host's ability to present a wider repertoire of immunogenic peptides and could result in diminished or ineffective cellular immunity because of missing epitope presentation. For example, homozygosity at HLA class I loci is associated with more rapid HIV progression^{ref1, ref2, ref3}, impaired CD4⁺ T-cell recovery after antiretroviral therapy^ref, increased risk of HIV transmission to the fetus in pregnant women^ref, and severe bacterial infections in sickle cell anemia patients^{ref1, ref2}. Likewise, heterozygosity at HLA class II loci is associated with protection against persistent disease after hepatitis B virus (HBV) infection^ref and may confer resistance to infection with hepatitis C virus (HCV)^ref. several HLA class II alleles are associated with variations in rubella-specific antibody levels as well as lymphoproliferative responses to rubella^ref. In addition, individuals homozygous at either the HLA-A or HLA-DQA1 loci were more likely to be seronegative after measles vaccination^ref. Interestingly, two doses of MMR appear to overcome this “homozygote disadvantage”^ref. After 2 doses of measles vaccine, HLA class II homozygosity was associated with increased interferon (IFN)–g secretion^ref. Homozygosity within the HLA DPB1 locus is associated with increased levels of rubella-specific IgG, an effect driven by a common allele DPB1*0401. Homozygosity within different HLA class I and class II loci is correlated with variations (but not necessarily decreases) in IL–2, IL-5, and IL-10 secretion after rubella virus stimulation^ref

HLA disease associations
 

phenotype		HLA-A	HLA-C	HLA-B	C4	DRB1	DQA1	DQB1	DPB1	RR	comments
autoimmunity	acute anterior uveitis			*27
	ankylosing sponylitis			*2702 *2704 *2705						90
	Goodpasture's syndrome					*1501/2				16
	Graves' disease			*0801		*0301				4
	Hashimoto's thyroiditis					*0301	*0501
	multiple sclerosis					*1501	*0102	*0602		4
	myasthenia gravis			*0801		*0301	*0501	*0201		2.5
	narcolepsy					*1501	*0102	*0602		90
	pemphigus vulgaris					*0402pp				14
	rheumatoid arthritis					*0101 *0401 *0404 *0405 *1402				1-2 7 8 8 2	Europe Europe Europe Oriental Native Amer.
	SLE	*0101		*0801	C4AQ*0	*0301	*0501	*0201		6
	Sjogren syndrome			*0801		*0301				3-20	DR2,DR5, DR11 some populations
	type 1 DM					*04 *03 *09 *03 *08 *04 *0401 *0402 *0403 *0404	*0301 *0501 *0301 *0501 *0301 *0301 *0301 *0301 *0301 *0301	*0302 *0201 *0303 *0201 *0402 *0302 *0302 *0302 *0302 *0302			heterozygotes
	polymyositis/ dermatomyositis										MICA5.1/ TNF2/TNFa2/ DRB1*03 haplotype (8.1 ancestral haplotype) 7.1 ancestral haplotype protective
	actinic prurigo					*0407
other immune	Behcet disease			*5101 *57
	bird-shot retinopathy	*A20		*12						49.9-224
	celiac disease			*0801		*0301	*0501	*02			DQA1*1501/ DQB*102 in cis or trans
	Crohn's disease										DR7 (not confirmed in all studies)
	Ig deficiency										class II or class III
	psoriasis		*0602								PSORS1 cluster of loci near HLA-C
	sarcoidosis			*07		*12/14					BTNL2 near DRA1 implicated various class I and II
	Lofgren's syndrome					*0301		*0201		21
	type II mixed cryoglobulinemia (HCV -associated)					DR11					HLA-DR7 is protective
hypersensitivity	abacavir			*5701ref1, ref2,  ref3, ref4							mapped to class II HSP70 ?
	allopurinol			*5801ref
	asthma										various class II - not seen in all cases dependent on allergen. HLA-G
	berylliosis : solvent-exposed amino acids on the MHCpeptide and TCR proteins jointly coordinate the nickel ions (Lu et al., 2003), directly linking  the TCR-MHC-peptide-like weak superantigens (Gamerdinger et al., 2003; Lombardi et al., 2001; Richeldi et al., 1993).								*0201		DPB1 Glu69 susceptible, Lys69 protective
	carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN	*3101 in Europeansref		*1502 in Asians
	pigeon breeder's lung										class II
	pollen-induced allergic rhinitis						*0302
infection	AIDS progression			*35Px							mostly HLA-B, protective; e.g. B*27/*57/*51
	leprosy/ tuberculosis						*02	*0503			Cambodian
	Lyme disease					*0401
	malaria			*5301							DRB1*1302 protective
	SARS			*4601
	Kaposi sarcoma, HIV-associated					alleles with F13					DRB1 phe13 susceptible / gly13 protective
other disease	hemachromatosis	*03									due to linked HFE-class I gene
	21-OH deficiency										CYP21 in class II region
	cervical cancer										class II
	nasopharyngeal carcinoma	*0207									Chinese
	smoking behaviour				C4AQ*0
	hyertrophic cardiomyopathy			*51							A2-B51-DR2 haplotype, Asian Indian population
	non-response to HBV vaccine					*07				RO 5,18
	HCV sustained response to therapy			*44		*04051
	gastric cancer										Japanese

There are several explanations for this, including:

• multiple conflicting or underpowered studies
• data from different populations
• multiple susceptibility and protective alleles at different linked loci (e.g. HLA-DQ and -DR)

KIR-ligands are HLA molecules that can be grouped into three major categories based on the amino acid sequence determining the KIR-binding epitope in HLA-C and HLA-B molecules. All expressed HLA-C alleles are of the C1 or C2 group^ref and most HLA-B alleles can be classified as either Bw4 or Bw6^ref. KIR2DL1, KIR2DL2 and KIR3DL1 bind KIR-ligand C2, C1 and Bw4 respectively, resulting in inhibition of NK cell mediated lysis.

locus	motif	amino acid residue 77 in HLA	amino acid residue 80	inhibiting KIR
HLA-B	Bw4	N (asparagine)	I (isoleucine )	KIR3DL1
		N (asparagine)	T (threonine)
		D (aspartic acid)	T (threonine)
		S (serine)	T (threonine)
	Bw6	G (glycine)	N (asparagine)	none
		S (serine)	N (asparagine)
HLA-C	C1		N (asparagine)	KIR2DL2
	C2		K (lysine)	KIR2DL1

KIR-ligand assignment with discrepancies based on low-resolution HLA-typing

low resolution HLA-type	main KIR-ligand assignment	exceptions (assigned to opposite group)	unclassified alleles
B*14, 42, 45, 46, 48, 50, 54, 67, 73, 78, 81, 82, 83	Bw6
B*38, 49, 51, 57, 58, 59	Bw4
B*07  B*08	Bw6 Bw6	*0727, 0736, 0738 *0802, 0803	*0711 *0806, 0817
B*13	Bw4	*1309
B*15 and *95	Bw6	*1513, 1516, 15170101, 15170102, 151702, 1523, 1524, 1536, 1543, 1567, 1589, 1595	*15010102N, 1557, 1587, 1594N
B*18	Bw6	*1809
B*27	Bw4	*2708, 2712, 2718, 2726, 2733
B*35	Bw6		*3527, 3552, 3556
B*37	Bw4	*3711	*3705
B*39	Bw6		*3920
B*40  B*41	Bw6 Bw6	*4013, 4019, 4047	*4037 *4105
B*44	Bw4	*4409, 4446
B*47	Bw4	*4702, 4703
B*52	Bw4		*5209
B*53	Bw4		*5305
B*55	Bw6		*5512
B*56	Bw6	*5607
Cw*01, 14	C1
Cw*02, 05, 17, 18	C2
Cw*03	C1	*0307, 0310, 0315
Cw*04	C2	*0411
Cw*06	C2	*0611
Cw*07	C1	*0707, 0709
Cw*08	C1	*0810
Cw*12	C1	*120401, 120402, 1205, 1209
Cw*15	C2	*1507
Cw*16	C1	*1602

• KIR ligand calculator (search for mismatches between KIR ligands)

Minor histocompatibility antigens (mHA) :

chromosome	minor histocompatibility antigen (mHA)	restriction molecule	tissue distribution	reference	clinical significance
autosome	HA-1/2	HLA-A2	restricted : hematopoietic/solid tumor cells	ref	HA-1 cytotoxic and regulatory T cells are found in tolerant kidney transplantation patientsref HA-1 mismatch associated with chronic allograft nephropathyref
	HA-1/B60	HLA-B60	restricted : hematopoietic cells	ref
	HA-2	HLA-A2	restricted : hematopoietic cells	ref
	HA-3	HLA-A1	broad	ref
	HA-8	HLA-A2	broad	ref
	HB-1	HLA-B44	restricted : hematopoietic cells	ref
	ACC-1	HLA-A24	restricted : hematopoietic/solid tumor cells	ref
	ACC-2	HLA-B44	restricted : hematopoietic/solid tumor cells	ref
	UGT2B17/A29	HLA-A29	restricted : hematopoietic cells	ref
	UGT2B17/B44	HLA-B44	restricted : hematopoietic cells	ref
	LRH-1	HLA-B7	restricted : hematopoietic/solid tumor cells	ref
	SP110/HwA9	HLA-A3	restricted : hematopoietic cells	ref
	PANE1/HwA10	HLA-A3	restricted : hematopoietic cells	ref
	C19Orf48/HwA11	HLA-A2	restricted : solid tumor cells	ref
	LB-ECGF-1	HLA-B7	restricted : solid tumor cells	ref
	CTSH/A31	HLA-A31	restricted : hematopoietic cells	ref
	CTSH/A33	HLA-A33	restricted : hematopoietic cells	ref
	LB-ADIR	HLA-A2	restricted : hematopoietic/solid tumor cells	ref
	ACC-6	HLA-B44	broad	ref
	CD19	HLA-DQA1*05/B1*02	restricted : hematopoietic cells	ref
H-Y is a transplantation antigen that can lead to rejection of male organ and bone marrow grafts by female recipients	A1/HY (DFFRY)	HLA-A1	broad : the male-specific form of the peptide differs from its X chromosomal counterpart by the substitution of serine for the C* residue in the sequence IVDC*LTEMY, where C* represents a cysteine disulfide bonded to a second cysteine residue. Both peptides are expressed on the cell surface at < 30 copies per cell	ref1, ref2	mismatching results in reduced cornea survivalref
	A2/HY	HLA-A2	broad	ref	reduced graft survival of male kidneys in female HLA-A2 recipientsref HY cytotoxicity in acute rejection in HLA-identical sibling kidney transplantationref No effect of HY in completely HLA-matched living donor kidney transplantationref
	A33/HY (encoded in the 5'-UTR of the TMSB4Y gene)	HLA-A33	broad	ref
	B7/HY	HLA-B7	broad	ref
	B8/HY	HLA-B8	restricted : hematopoietic cells	ref
	B52/HY	HLA-B52	restricted : hematopoietic/solid tumor cells	ref
	B60/HY	HLA-B60	broad	ref
	DQ5/HY	HLA-DQ5	broad	ref
	DRB1*1501/HY (the specificity for recipient male cells was mediated by the B cell response and not by donor T cells; the first mHA identified in the context of cGvHD)	HLA-DRB1*1501	broad	ref
	DRB3*0301/HY	HLA-DRB3*0301	broad	ref

Web resources : dbMinor at Leiden University

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