HLA-DR

関

主要組織適合複合体　major histocompatibility complex MHC

• クラスIIの主要組織適合複合体(MHC)を構成する

MHC class II

• DRα鎖とDRβ鎖からなるヘテロダイマーからなる膜糖タンパク質

WordNet

1. the 4th letter of the Roman alphabet (同)d
2. the 8th letter of the Roman alphabet (同)h

PrepTutorEJDIC

1. deuteriumの化学記号
2. hydrogenの化学記号
3. 鉛筆の硬度 / 《俗》heroin

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/03/14 05:31:01」(JST)

wiki en

[Wiki en表示]

MHC class II, DR (heterodimer)
Illustration of DR with bound ligand (yellow)
−
Protein type		cell surface receptor
Function		Immune recognition and antigen presentation
−
Subunit name	Gene	Chromosomal locus
α	HLA-DRA	Chromosome 6p21.31
β1	HLA-DRB1	" "
β3	HLA-DRB3	" "
β4	HLA-DRB4	" "
β5	HLA-DRB5	" "

HLA-DR is an MHC class II cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 region 6p21.31. The complex of HLA-DR (Human Leukocyte Antigen - antigen D Related) and its ligand, a peptide of 9 amino acids in length or longer, constitutes a ligand for the T-cell receptor (TCR). HLA (human leukocyte antigens) were originally defined as cell surface antigens that mediate graft-versus-host disease, which resulted in the rejection of tissue transplants in HLA-mismatched donors. Identification of these antigens has led to greater success and longevity in organ transplant.

HLA-DR is also involved in several autoimmune conditions, disease susceptibility and disease resistance. It is also closely linked to HLA-DQ and this linkage often makes it difficult to resolve the more causative factor in disease.

HLA-DR molecules are upregulated in response to signalling. In the instance of an infection, the peptide (such as the staphylococcal enterotoxin I peptide) is bound into a DR molecule and presented to a few of a great many T-cell receptors found on T-helper cells. These cells then bind to antigens on the surface of B-cells stimulating B-cell proliferation.

Function

Illustration of DR receptor presenting antigen to TCR on T-helper cell

The primary function of HLA-DR is to present peptide antigens, potentially foreign in origin, to the immune system for the purpose of eliciting or suppressing T-(helper)-cell responses that eventually lead to the production of antibodies against the same peptide antigen. Antigen presenting cells (macrophages, B-cells and dendritic cells) are the cells in which DR are typically found. Increased abundance of DR 'antigen' on the cell surface is often in response to stimulation, and, therefore, DR is also a marker for immune stimulation.

Structure

HLA-DR is a αβ heterodimer, cell surface receptor, each subunit of which contains two extracellular domains, a membrane-spanning domain and a cytoplasmic tail. Both α and β chains are anchored in the membrane. The N-terminal domain of the mature protein forms an alpha-helix that constitutes the exposed part of the binding groove, the C-terminal cytoplasmic region interact with the other chain forming a beta-sheet under the binding groove spanning to the cell membrane. The majority of the peptide contact positions are in the first 80 residues of each chain.

Genetics

The genetics of HLA-DR is complex. HLA-DR is encoded by several loci and several 'genes' of different function at each locus. The DR α-chain is encoded by the HLA-DRA locus. Unlike the other DR loci functional variation in mature DRA gene products is absent. (Note: see table Number of Variant Alleles HLA-DR Loci- reduces the potential functional combinations from ~1400 to ~400 ([table is not exact because new alleles are continually being added; not all new alleles are functional variants of the mature subunits]).

28 (of 75) Most common DR-DQ haplotypes in Americans of European descent

DR	DR-DQ	DR	DQ		Freq
Serotype	haplotype	B1	A1	B1	%
DR1	DR1-DQ5	01:01	01:01	05:01	9.	1
		01:02	01:01	05:01	1.	4
		01:03	01:01	05:01	0.	5
DR3	DR3-DQ2	03:01	05:01	02:01	13.	1
DR4	DR4-DQ7	04:01	0300	03:01	5.	4
		04:07	0300	03:01	0.	9
	DR4-DQ8	04:01	0300	03:02	5.	0
		04:02	0300	03:02	1.	0
		04:03	0300	03:02	0.	4
		04:04	0300	03:02	3.	9
		04:05	0300	03:02	0.	3
DR7	DR7-DQ2	07:01	02:01	02:02	11.	1
	DR7-DQ9	07:01	02:01	03:03	3.	7
DR8	DR8-DQ4	08:01	04:01	04:02	2.	2
	DR8-DQ7	08:03	06:01	03:01	0.	1
DR9	DR9-DQ9	09:01	0300	03:03	0.	8
DR10	DR10-DQ5	10:01	01:04	05:01	0.	7
DR11	DR11-DQ7	11:01	05:05	03:01	5.	6
		11:03	05:05	03:01	0.	3
		11:04	05:05	03:01	2.	7
DR12	DR12-DQ7	12:01	05:05	03:01	1.	1
DR13	DR13-DQ6	13:01	01:03	06:03	5.	6
		13:02	01:02	06:04	3.	4
		13:02	01:02	06:09	0.	7
	DR13-DQ7	13:03	05:05	03:01	0.	7
DR14	DR14-DQ5	14:01	01:04	05:03	2.	0
DR15	DR15-DQ6	15:01	01:02	06:02	14.	2
		15:02	01:03	06:02	0.	7
DR16	DR16-DQ5	16:01	01:02	05:02	1.	0

The DR β-chain is encoded by 4 loci, however no more than 3 functional loci are present in a single individual, and no more than two on a single chromosome. Sometimes an individual may only possess 2 copies of the same locus, DRB1*. The HLA-DRB1 locus is ubiquitous and encodes a very large number of functionally variable gene products (HLA-DR1 to HLA-DR17). The HLA-DRB3 locus encodes the HLA-DR52 specificity, is moderately variable and is variably associated with certain HLA-DRB1 types. The HLA-DRB4 locus encodes the HLA-DR53 specificity, has some variation, and is associated with certain HLA-DRB1 types. The HLA-DRB5 locus encodes the HLA-DR51 specificity, which is typically invariable, and is linked to the HLA-DR2 types.

• linkage (See Table)
  • DQA1 and DQB1
    • Linkage disequilibrium exists for many DR-DQ types.
  • Nomenclature issues. Some older studies may refer to DR15 or 16 as DR2 and DQ5 and DQ6 as DQ1 therefore a haplotype DR2-DQ1 is usually referring to DR15-DQ6 but could be referring to DR16-DQ5. DR5 is used to refer to DR11 and DR12, in which case DQ3 might be used. In these instances DQ3 almost always can be interpreted as DQ7, but DR5 is most often DR11 and less frequently DR12. Similar issues exist for DR6 versus DR13 and DR14. DR6-DQ1 can refer to either DR13-DQ6 or less frequently DR14-DQ5, but DR6-DQ3 or DR6-DQ7 generally refers to DR13-DQ7. Even older literature has more confusing designations. By looking at the change of disease association with improved testing we can see how science has evolved over time.

Number of Variant Alleles HLA-DR Loci

HLA-DR
HLA	-A1	-B1	-B3 to -B51	Potential
Locus	#	#	#	Combinations
Alleles	3	463	74	1635
Unique Polypeptide	2	394	57	902
Contact Variant	1	~300	~30	~330
1DRB3, DRB4, DRB5 have variable presence in humans

Evolution and Allele Frequencies

There is a high level of allelic diversity at HLA DRB1, it is second only to HLA-B locus in number of allelic variants. These two loci are highest sequence variation rate within human genome. This means HLA-DRB1 is rapidly evolving, much more rapidly than almost all other protein encoding loci. Much of the variation at HLA DRB1 occurs at peptide contact positions in the binding groove, as a result many of the alleles alter the way the DR binds peptide ligands and changes the repertoire each receptor can bind. This means that most of the changes are functional in nature, and therefore are under selection. In the HLA region, genes are under heterozygous or balancing selection, although certain alleles appear to be under positive or negative selection, either in the past or present

HLA generally evolve through a process of gene conversion, which is a form of short distance or 'abortive' genetic recombination. Functional motifs in genes are exchanged to form new alleles, and frequently new, functionally different DR isoforms. HLA-DR represents an extreme example of this. A survey of X-linked loci reveals that most human loci have undergone fixation within the last 600,000 years, and diploid loci have undergone significant proportion of fixation in that period of time.

The level of deep branching at X-linked loci indicates loci were close to fixation or fixed at the end of the human population bottleneck 100,000 to 150,000 years ago. The HLA-DR locus represents a major exception to this observation. Based on distribution of major groupings in the human population it is possible to assert that more than a dozen major variants survived the population bottleneck. This observation is supported by the concept of a heterozygous selection coefficient operating on the HLA-DR, and at the HLA-DRB1 locus to a greater degree relative to HLA-DQB1 and HLA-DPB1. Most of the HLA alleles currently present in the human population can be explained by gene conversion between these ancient ancestral types, some that persist into the extant population.

Serogroups

Subpages for DR serotypes

Serotypes of HLA-DRB1 gene products
	Split antigens
HLA-DR1
HLA-DR2	HLA-DR15	HLA-DR16
HLA-DR3	HLA-DR17	HLA-DR18
HLA-DR4
HLA-DR5	HLA-DR11	HLA-DR12
HLA-DR6	HLA-DR13	HLA-DR14
HLA-DR7
HLA-DR8
HLA-DR9
HLA-DR10

The table below provides links to subpages with information about distribution, genetic linkage and disease association for the HLA-DR serogroups.

Interlocus DRB Linkage

DRB1 is linked with other DRB loci in 4 ways

DR1 to D17 genetic linkage to DR51, DR52, and DR53

non-DRB1	linked DRB1 antigens
antigens	antigens
None	DR1	DR8	DR10
DR51	DR2	DR15	DR16
DR52	DR3	DR17	DR18
	DR5	DR11	DR12
	DR6	DR13	DR14
DR53	DR4	DR7	DR8	DR9

Diseases associated with HLA-DR and links to DR subpages(V - T)

Class	Disease	Associated DR	2	3	4
	alopecia areata	DR5
anemia	pernicious	DR15
	antiphospholipid syndrome, primary	DR5	DR12
aneurysm	coronary artery	DR16
arteritis	Takayasu's	DR16
arthritis, rheumatoid	juvenile	DR4	DR5	DR14	DR15
	pauciarticular, juv.	DR8
	Still's disease	DR12
	iritis w/juv. arthritis	DR12
	seropositive	DR1	DR4	DR10
	w/systemic sclerosis	DR1
	lyme disease induced	DR4
	tiopronin intolerance	DR5	DR11	DR12
cardiomyopathy	hypertrophic	DR4	DR17
	T. cruzi induced	DR4	DR7	DR15
colitis	Crohn's	DR1
	ulcerative	DR1
diabetes	juvenile (type 1)	DR3	DR4	DR17	DR18
	fatty liver (type 2)	DR8
encephalomyelitis	rabies vaccine-induced	DR17
encephalopathy	acute necrotizing	DR52
epilepsy	childhood	DR5
	infantile/spasm	DR17
heart disease	rheumatic	DR16
hepatitis	autoimmune	DR2	DR4	DR17
	primary biliary cirrhosis	DR2	DR8
	chronic type C	DR11
	lichen planus	DR1	DR10
lupus,	systemic	DR3	DR4	DR52
	hydralazine-induced	DR4
	with Sjögren's syndrome	DR15
lymphadenopathy	generalized	DR5
lymphoma,	mycosis fungoides	DR5
	melioidosis	DR16
myasthenia	gravis	DR3	DR6	DR13	DR14
	penicillamine-induced	DR1
myositis	inflammatory inclusion body	DR17	DR18	DR52
	narcolepsy	DR2	DR12
nephritis,	tubulointerstitial	DR1
nephropathy	IgA-mediated	DR4
	polyglandular deficiency syndrome	DR5
pemphigus	foliaceous	DR1
	vulgaris	DR4
psoriasis	vulgaris	DR1	DR7
papillomatosis,	respiratory	DR1
sarcoidosis	non-chronic	DR17	DR52
sclerosis,	multiple	DR2	DR15	DR53
	"bout onset" multiple	DR3
	systemic	DR4	DR11	DR16	DR52
	vulval lichen	DR12
schizophrenia		DR1
susceptibility	leprosy	DR2
	tuberculosis	DR2
	ragweed Ra6 allergy	DR5
	asthma, mite sensitive	DR11
	2ndary infection, AIDS	DR3
	aspergillosis	DR15
	Kaposi's sarcoma	DR5
	thyroid carcinomas	DR8	DR11
	ovarian/cervical cancer	DR10	DR11	DR15
	grape induced anaphylaxis	DR11
	Chlamydia pneumoniae	DR52
thyroiditis	Hashimoto's	DR3	DR5
	Grave's	DR3	DR17	DR52
uveitis	tubulointerstitial	DR1
*references are provided on linked subpages

References

Further reading

• Bénichou S, Benmerah A (2003). "The HIV nef and the Kaposi-sarcoma-associated virus K3/K5 proteins: "parasites"of the endocytosis pathway". Med Sci (Paris) 19 (1): 100–6. doi:10.1051/medsci/2003191100. PMID 12836198. 
• Tolstrup M, Ostergaard L, Laursen AL, et al. (2004). "HIV/SIV escape from immune surveillance: focus on Nef.". Curr. HIV Res. 2 (2): 141–51. doi:10.2174/1570162043484924. PMID 15078178. 
• Anderson JL, Hope TJ (2005). "HIV accessory proteins and surviving the host cell.". Current HIV/AIDS reports 1 (1): 47–53. doi:10.1007/s11904-004-0007-x. PMID 16091223. 
• Li L, Li HS, Pauza CD, et al. (2006). "Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions.". Cell Res. 15 (11-12): 923–34. doi:10.1038/sj.cr.7290370. PMID 16354571. 
• Stove V, Verhasselt B (2006). "Modelling thymic HIV-1 Nef effects.". Curr. HIV Res. 4 (1): 57–64. doi:10.2174/157016206775197583. PMID 16454711. 
• Matsushima GK, Itoh-Lindstrom Y, Ting JP (1992). "Activation of the HLA-DRA gene in primary human T lymphocytes: novel usage of TATA and the X and Y promoter elements.". Mol. Cell. Biol. 12 (12): 5610–9. PMC 360500. PMID 1448091. 
• Schaiff WT, Hruska KA, McCourt DW, et al. (1992). "HLA-DR associates with specific stress proteins and is retained in the endoplasmic reticulum in invariant chain negative cells.". J. Exp. Med. 176 (3): 657–66. doi:10.1084/jem.176.3.657. PMC 2119345. PMID 1512535. 
• Piatier-Tonneau D, Gastinel LN, Amblard F, et al. (1991). "Interaction of CD4 with HLA class II antigens and HIV gp120.". Immunogenetics 34 (2): 121–8. doi:10.1007/BF00211424. PMID 1869305. 
• Nong Y, Kandil O, Tobin EH, et al. (1991). "The HIV core protein p24 inhibits interferon-gamma-induced increase of HLA-DR and cytochrome b heavy chain mRNA levels in the human monocyte-like cell line THP1.". Cell. Immunol. 132 (1): 10–6. doi:10.1016/0008-8749(91)90002-S. PMID 1905983. 
• Rosenstein Y, Burakoff SJ, Herrmann SH (1990). "HIV-gp120 can block CD4-class II MHC-mediated adhesion.". J. Immunol. 144 (2): 526–31. PMID 1967269. 
• Callahan KM, Fort MM, Obah EA, et al. (1990). "Genetic variability in HIV-1 gp120 affects interactions with HLA molecules and T cell receptor.". J. Immunol. 144 (9): 3341–6. PMID 1970352. 
• Bowman MR, MacFerrin KD, Schreiber SL, Burakoff SJ (1991). "Identification and structural analysis of residues in the V1 region of CD4 involved in interaction with human immunodeficiency virus envelope glycoprotein gp120 and class II major histocompatibility complex molecules.". Proc. Natl. Acad. Sci. U.S.A. 87 (22): 9052–6. doi:10.1073/pnas.87.22.9052. PMC 55099. PMID 1978941. 
• Koppelman B, Cresswell P (1990). "Rapid nonlysosomal degradation of assembled HLA class II glycoproteins incorporating a mutant DR alpha-chain.". J. Immunol. 145 (8): 2730–6. PMID 2212658. 
• Clayton LK, Sieh M, Pious DA, Reinherz EL (1989). "Identification of human CD4 residues affecting class II MHC versus HIV-1 gp120 binding.". Nature 339 (6225): 548–51. doi:10.1038/339548a0. PMID 2543930. 
• Diamond DC, Sleckman BP, Gregory T, et al. (1988). "Inhibition of CD4+ T cell function by the HIV envelope protein, gp120.". J. Immunol. 141 (11): 3715–7. PMID 2846691. 
• Tjernlund U, Scheynius A, Johansson C, et al. (1989). "T-cell response to purified protein derivative after removal of Langerhans' cells from epidermal cell suspensions containing keratinocytes expressing class II transplantation antigens.". Scand. J. Immunol. 28 (6): 667–73. doi:10.1111/j.1365-3083.1988.tb01500.x. PMID 3266023. 
• Andrieu JM, Even P, Venet A (1986). "AIDS and related syndromes as a viral-induced autoimmune disease of the immune system: an anti-MHC II disorder. Therapeutic implications.". AIDS research 2 (3): 163–74. doi:10.1089/aid.1.1986.2.163. PMID 3489470. 
• Das HK, Lawrance SK, Weissman SM (1983). "Structure and nucleotide sequence of the heavy chain gene of HLA-DR.". Proc. Natl. Acad. Sci. U.S.A. 80 (12): 3543–7. doi:10.1073/pnas.80.12.3543. PMC 394085. PMID 6304715. 
• Schamboeck A, Korman AJ, Kamb A, Strominger JL (1984). "Organization of the transcriptional unit of a human class II histocompatibility antigen: HLA-DR heavy chain.". Nucleic Acids Res. 11 (24): 8663–75. doi:10.1093/nar/11.24.8663. PMC 326615. PMID 6324094. 
• Das HK, Biro PA, Cohen SN, et al. (1983). "Use of synthetic oligonucleotide probes complementary to genes for human HLA-DR alpha and beta as extension primers for the isolation of 5'-specific genomic clones.". Proc. Natl. Acad. Sci. U.S.A. 80 (6): 1531–5. doi:10.1073/pnas.80.6.1531. PMC 393635. PMID 6403940. 

External links

• HLA-DR antigens at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. ヒト白血球抗原（HLA）：ロードマップ human leukocyte antigens hla a roadmap
• 2. 腎移植におけるHLAマッチングと移植片生着率 hla matching and graft survival in kidney transplantation
• 3. 若年性特発性関節炎：疫学と免疫病態学 juvenile idiopathic arthritis epidemiology and immunopathogenesis
• 4. シェーグレン症候群の病因 pathogenesis of sjogrens syndrome
• 5. 研究用生物学的マーカーによる関節リウマチの診断および評価ま investigational biologic markers in the diagnosis and assessment of rheumatoid arthritis

English Journal

• Pathology and classification of urticaria.

• Greaves MW.Author information Cutaneous Allergy Clinic, St John's Institute of Dermatology, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK; The London Allergy Clinic, 66 New Cavendish Street, London W1G 8TD, UK. Electronic address: mwatsong@hotmail.com.AbstractChronic urticaria is defined as daily or almost daily urticaria for more than 6 weeks. Chronic urticaria is normally subdivided into physical urticaria (wheals evoked by a physical stimulus such as pressure friction or cold contact) and spontaneous urticaria. A patient with a history of less than 6 weeks is traditionally designated as having acute urticaria. Patients with chronic spontaneous urticaria have an increased frequency of HLA-DR and HLA-DQ alleles characteristically associated with autoimmune disease. Some of these patients have functional anti-FceR1 and/or anti-IgE autoantibodies which are considered to be the cause of the urticaria.
• Immunology and allergy clinics of North America.Immunol Allergy Clin North Am.2014 Feb;34(1):1-9. doi: 10.1016/j.iac.2013.07.009. Epub 2013 Aug 31.
• Chronic urticaria is defined as daily or almost daily urticaria for more than 6 weeks. Chronic urticaria is normally subdivided into physical urticaria (wheals evoked by a physical stimulus such as pressure friction or cold contact) and spontaneous urticaria. A patient with a history of less than 6
• PMID 24262685

• Immunological characteristics of human umbilical cord mesenchymal stem cells and the therapeutic effects of their transplantion on hyperglycemia in diabetic rats.

• Wang H1, Qiu X1, Ni P2, Qiu X1, Lin X1, Wu W1, Xie L1, Lin L1, Min J3, Lai X1, Chen Y4, Ho G1, Ma L1.Author information 1Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China.2Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China.3Department of Obstetrics and Gynecology, Shenzhen Pingshan Women's And Children's Hospital, Shenzhen, Guangdong 518118, P.R. China.4Transformation Medical Center, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China.AbstractIslet transplantation involves the transplantation of pancreatic islets from the pancreas of a donor to another individual. It has proven to be an effective method for the treatment of type 1 diabetes. However, islet transplantation is hampered by immune rejection, as well as the shortage of donor islets. Human umbilical cord Wharton's jelly-derived mesenchymal stem cells (HUMSCs) are an ideal cell source for use in transplantation due to their biological characteristics and their use does not provoke any ethical issues. In this study, we investigated the immunological characteristics of HUMSCs and their effects on lymphocyte proliferation and the secretion of interferon (IFN)-γ, and explored whether direct cell-to-cell interactions and soluble factors, such as IFN-γ were important for balancing HUMSC-mediated immune regulation. We transplanted HUMSCs into diabetic rats to investigate whether these cells can colonize in vivo and differentiate into pancreatic β-cells, and whether the hyperglycemia of diabetic rats can be improved by transplantation. Our results revealed that HUMSCs did not stimulate the proliferation of lymphocytes and did not induce allogeneic or xenogeneic immune cell responses. qRT-PCR demonstrated that the HUMSCs produced an immunosuppressive isoform of human leukocyte antigen (HLA-I) and did not express HLA-DR. Flow cytometry revealed that the HUMSCs did not express immune response-related surface antigens such as, CD40, CD40L, CD80 and CD86. IFN-γ secretion by human peripheral blood lymphocytes was reduced when the cells were co-cultured with HUMSCs. These results suggest that HUMSCs are tolerated by the host in an allogeneic transplant. We transplanted HUMSCs into diabetic rats, and the cells survived in the liver and pancreas. Hyperglycemia of the diabetic rats was improved and the destruction of pancreatic cells was partly repaired by HUMSC transplantation. Hyperglycemic improvement may be related to the immunomodulatory effects of HUMSCs. However, the exact mechanisms involved remain to be further clarified.
• International journal of molecular medicine.Int J Mol Med.2014 Feb;33(2):263-70. doi: 10.3892/ijmm.2013.1572. Epub 2013 Nov 28.
• Islet transplantation involves the transplantation of pancreatic islets from the pancreas of a donor to another individual. It has proven to be an effective method for the treatment of type 1 diabetes. However, islet transplantation is hampered by immune rejection, as well as the shortage of donor
• PMID 24297321

• Reduced frequency of T lymphocytes expressing CTLA-4 in frontotemporal dementia compared to Alzheimer's disease.

• Santos RR, Torres KC, Lima GS, Fiamoncini CM, Mapa FC, Pereira PA, Rezende VB, Martins LC, Bicalho MA, Moraes EN, Reis HJ, Teixeira AL, Romano-Silva MA.Author information Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Avenida Alfredo Balena, 190, Belo Horizonte, MG, CEP 30130-100, Brazil. Electronic address: rodrsantos@gmail.com.AbstractStudies suggest that inflammation is involved in the neurodegenerative cascade of dementias. Immunological mechanisms may be part of the pathophysiological process in frontotemporal dementia (FTD), but up till now only vague evidence of such mechanisms has been presented. The B7- CD28/CTLA-4 pathway is an important immunological signaling pathway involved in modulation of T cell activation. The aim of this study was to compare the expression of molecules associated with co-stimulatory signaling in peripheral blood mononuclear cells (PBMC) of FTD to Alzheimer disease (AD) and control groups. Our results confirm the previous demonstrated increased expression of CD80 in CD14+ Alzheimer patients T cells but show, for the first time, a reduction in the expression of CTLA-4 in CD4+ FTD cells. As CTLA-4 is the most potent negative regulators of T-cell activation we speculated that peripheral T lymphocytes in FTD are more activated and this could be involved in the neurodegeneration observed in this dementia.
• Progress in neuro-psychopharmacology & biological psychiatry.Prog Neuropsychopharmacol Biol Psychiatry.2014 Jan 3;48:1-5. doi: 10.1016/j.pnpbp.2013.06.019. Epub 2013 Jul 25.
• Studies suggest that inflammation is involved in the neurodegenerative cascade of dementias. Immunological mechanisms may be part of the pathophysiological process in frontotemporal dementia (FTD), but up till now only vague evidence of such mechanisms has been presented. The B7- CD28/CTLA-4 pathway
• PMID 23891730

Japanese Journal

• Increased B7-H1 and B7-H4 Expressions on Circulating Monocytes and Tumor-Associated Macrophages are Involved in Immune Evasion in Patients with Gastric Cancer

• Matsunaga Tomoyuki,Saito Hiroaki,Ikeguchi Masahide
• Yonago Acta medica 54(1), 1-10, 2011-03
• … There were significant correlations between B7-H4 expression and B7-H1 or HLA-DR expression on monocytes/macrophages in gastric cancer patients. …
• NAID 120002854450

• 急性膵炎における全身性免疫応答の解析 (特集 重症急性膵炎の病態解明と治療の新展開)

• 佐藤 晃彦,廣田 衛久,下瀬川 徹
• 消化器内科 52(2), 219-224, 2011-02
• NAID 40018768283

Related Links

• HLAをより深く知る | HLAについて | HLA研究所

白血球抗原型として出発したHLAですが、その多型性は血液型の範疇をはるかに超える特徴をもっています。血液型とは次元の異なる多型として理解すべきでしょう。 血液型は偶然の突然変異がたまたま定着して「型」になったものが ...

• HLA-DR - エスアールエル 医療従事者向けサイト ご利用の皆様へ

HLA-DRはMHCクラスⅡ抗原で,34kDaのαポリペプチドと29kDaのβポリペプチドで構成される膜貫通型糖タンパクです。この分子は抗原提示細胞(APC)であるB細胞,単球,マクロファージ,樹状細胞などに存在します。活性化したT細胞にも存在する ...

Related Pictures

---

★リンクテーブル★

リンク元	「主要組織適合複合体」「悪性リンパ腫」「成人T細胞白血病」「急性前骨髄球性白血病」「ランゲルハンス細胞」
拡張検索	「HLA-DR2 antigen」「HLA-DR3 antigen」「HLA-DR5 antigen」
関連記事	「D」「HL」「DR」「H」「HLA」

「主要組織適合複合体」

　　[★]

英

major histocompatibility complex, MHC

同

ヒト白血球抗原 human leucocyte antigen, HLA　←　LHA/MHCの疾患との遺伝的関係についてはここを参照、MHC分子、主要組織適合遺伝子複合体

関

MHCのクラスと特徴 (出典不明)

	MHC class I	*MHC class II
MHC発現組織	全ての有核細胞(×赤血球)	CD4陽性T細胞
		CD8陽性T細胞
		抗原提示細胞(マクロファージ、樹状細胞、 ランゲルハンス細胞、クッパー細胞、ミクログリア、B細胞)
抗原認識するリンパ球	Tc細胞	Th細胞
ドメイン構造	α鎖(α1,2,3を持つ分子)とβ2-microgloblin	α鎖(α1,α2を持つ分子)とβ鎖(β1,β2を持つ分子)
遺伝子座	HLA-A,B,C,	HLA-DP,DQ,DR
提示されるペプチド	内在抗原	外来抗原
抗原ペプチドの長さ	9残基	12-30残基
抗原ペプチドとMHCとの相互作用部位	2残基	3(免疫学授業プリント) 4(IMM.131)

MHC分子の発現 (IMM.136)

		MHC class I	MHC class II
リンパ組織	T細胞	＋＋＋	＋
	B細胞	＋＋＋	＋＋＋
	マクロファージ	＋＋＋	＋＋
	樹状細胞	＋＋＋	＋＋＋
	胸腺上皮細胞	＋	＋＋＋
有核細胞	好中球	＋＋＋	－
	肝細胞	＋	－
	腎臓	＋	－
	脳	＋	－
無核細胞	赤血球	－	－

---

　　主要組織適合遺伝子複合体
　　　　移植抗原として発見された抗原系
　　　　応答免疫(抗原提示)に関与する
　　ヒト(HLA complex) human leucocyte antigen
　　　HLA
　　　ドメイン構造
　　　　クラスI		A	B	C
　　　　クラスII	DP	DQ	DR
　　　多型性がある
　　　12種類のHLAを発現(父由来、母由来)
　　マウス(H2 complex) Histcompatibility-2
　　　ドメイン構造
　　　　クラスI		K	D
　　　　クラスII	A	E
　　MHCの歴史
　　　G.Snell		マウスH2が移植の正否を左右する
　　　J.Dausset		HLAが抗原
　　　B.Benaceraf	MHC遺伝子を明らかにし、MHCが免疫応答に関与していることを証明

(1)分子構造

　クラスI　H鎖　β2-microglobulin
　クラスII　α鎖　β鎖
　細胞外領域　膜貫通領域　細胞内領域
　ドメイン
　Igスーパーファミリー
　クリスタログラフィー　crystallography

(2) MHC分子の生合成

　抗原処理
　抗原提示
　クラスI (proteasome TAP)
　　クラスI抗原提示(内在性抗原)
　　①ほとんどの細胞が提示
　　　ただし赤血球には発現していない
　　②細胞内：内在抗原をプロテアソーム(LMP複合体)が分子切断→ERに移動
　　③ERI TAPトランスポーターによりER内に移動
　　　クラスI+ペプチド複合体形成
　　④細胞表面に移動
　　⑤Tc(CD8+ T細胞)細胞が認識：標的細胞を障害
　クラスII (Ii=invariant chain, HLA-DM)
　　クラスII抗原提示(外来抗原)
　　①抗原提示細胞：貪食、飲食による取り込み
　　②ファゴリソゾーム：ペプチドに分解
　　③小胞体(ER)：(MHC class II + Ii鎖)複合
　　④ファゴリソゾーム：HLA-DMがIi鎖を解離
　　　ペプチドを提示→(MHC class II + ペプチド)複合体
　　⑤細胞表面に移動
　　⑥Th(CD4+T)細胞が認識

(3) MHC遺伝子

• MHC遺伝子座

• クラスI：HLA-A,HLA-B,HLA-C(古典的)

→全ての有核細胞が発現

　　　最近、E,F,Gが発見された→E,FはT細胞、Gは胎盤トロホブラストが発現(妊娠免疫に重要)

• クラスII：HLA-DP,HLA-DQ,HLA-DR

→限定された細胞が発現(マクロファージ、樹状細胞、ランゲルハンス細胞、クッパー細胞)

亜領域A1,A2,およびB1,B2を有し、いずれかしか発現しない。ちなみに、Aはα鎖、Bはβ鎖をコードしている。

HLA-DM、LMP、TAP遺伝子座がDP-DQ間に発現していることが明らかとなった

• クラスIII：補体成分：C2,C4,Bf

　　　　　　　　サイトカイン：TNPet,C,
　　　　　　　　酵素：21-hydroxylase
　クラス(領域　亜領域)
　遺伝的多塑性　polymorphism
　対立遺伝子頻度

-MHC

同

主要組織適合遺伝子複合体

「悪性リンパ腫」

　　[★]

英

malignant lymphoma

ラ

lymphoma malignum

関

悪性リンパ腫とマーカー

悪性リンパ腫.xls

sIg

CD5

CD10

CD19

CD20

CD23

CD43

bcl

cyclin

TdT

その他

転座

小リンパ性リンパ腫 small lymphocytic lymphoma 慢性リンパ性白血病 chronic lymphocytic leukemia

＋

＋

＋

＋

＋

－

－

－

濾胞性リンパ腫 FL

＋

－

＋

＋

bcl2　＋

－

MALTリンパ腫

－

－

＋

マントル細胞リンパ腫 MCL

＋

＋

－

＋

＋

びまん性大細胞性B細胞リンパ腫 DLBL

＋

－

＋／－

＋

＋

bcl6　＋

前駆Bリンパ芽球性リンパ腫 急性Bリンパ球性白血病 LBL/ALL

－

＋

＋

バーキットリンパ腫 BL

＋

－

＋

＋

＋

Myc, Ki-67

ｔ（8,14)Myc；IgH　～80% t(2,8)κ；Myc　～15%

ホジキンリンパ腫

CD15, CD30, CD45 -

t(8,22)Myc；λ　～10%

成人T細胞白血病 ATL

CD2, CD3, CD4, CD25, HLA-DR, CD8 -

病期

• Ann Arbor分類

参考

• 1.

http://www.rinpashu.com/inspection/

国試

• 100D031

「成人T細胞白血病」

　　[★]

英

adult T cell leukemia, adult T-cell leukemia ATL

同

成人T細胞白血病リンパ腫 adult T-cell leukemia/lymphoma ATLL

関

ヒトTリンパ球向性ウイルス

特徴

• CD4陽性Tリンパ球に感染して白血病/リンパ腫を起こす　　→　　成熟したT細胞に感染し、それが腫瘍性に増殖

(CD2⁺, CD3⁺, CD4⁺, CD25⁺, HLA-DR⁺, CD8^-)

病型

• 急性型、慢性型、くすぶり型、リンパ腫型

	急性型	リンパ腫型	慢性型	くすぶり型
典型的な症状	腫瘍随伴症状(腫瘍熱、高カルシウム血症(意識障害・脱水・腎機能障害) (50%で認められる))が初発症状であることが多い。 臓器浸潤による症状(消化管浸潤(下痢・腹痛)、肝臓浸潤(黄疸)、 肺浸潤(呼吸困難)、中枢神経浸潤(脳神経症状))	リンパ節腫大は全例で認められる。 腫瘍熱、高カルシウム血症を初発症状とする場合もある。 末梢血中の形態的異常細胞は1%以下	多くの場合、自覚症状を欠き、健康診断などで偶然診断される。 日和見感染症や腫瘍の浸潤に伴う皮膚症状(皮疹、皮膚腫瘤)、 肺病変(労作時息切れ、咳嗽)が診断の発端となる場合もある。	リンパ球増多を伴わないため、血液検査では診断に至らない。 無症候キャリアーと同様、多くの患者では症状を欠く。
PS>1	67.6％	45.4％	27.2％	22.7％
感染性併発症	26.9％	10.9％	35.5％	35.6％
皮膚病変	40.2％	25％	46.1％	48.9％
肺病変	20.2％	10.9％	15.1％	15.6％
肝腫大	35.9％	16％	13.8％	0％
脾腫大	29.9％	15.4％	11.2％	0％
4個以上の腫大リンパ節	80.7％	62.2％	54％	6.7％
高カルシウム血症	50.3％	16.7％	0％	0％
貧血(Hb<10g/dl)	10.1％	4.5％	4％	0％
血小板減少(10万/ul)	19.4％	4.5％	2％	6.7％

疫学

• 日本に約120万人の感染者
• 男性に多い。
• 1000-2000人に1。50歳以上で発症(平均58歳)。

病原体

• ヒトTリンパ球向性ウイルス HTLV-1

感染経路

• 母乳感染　←　哺乳の停止・人工乳による感染防止
• 輸血
• 性交

病理

参考1

• 末梢血、骨髄：花弁状、脳回転状に分葉した異型細胞　→　ATL細胞：CD4陽性、CD8陰性

[show details]

• リンパ節
• その他：(皮膚)皮膚T細胞リンパ腫のように表皮向性をもち、ポートリエ微小膿瘍を伴って皮膚に浸潤することがある。このばあい、緩徐進行型の経過をたどる
• 免疫表現型
• 遺伝子：決まった核型異常や遺伝子異常はない。

病態

• ATL細胞はPTHrP、IL-1α、TNF-βを産生　→　高カルシウム血症、全身症状？(発熱、全身倦怠感など)
• 正常T細胞の減少　→　易感染性

症状

• 初発症状は皮膚症状、リンパ節腫脹、肝脾腫、高カルシウム血症など。貧血や出血症状の頻度は少ない。
• 皮膚症状 → PMID: 24438140 [1]
• リンパ節腫脹
• 肝脾腫
• 高カルシウム血症：ATL細胞の産生する副甲状腺ホルモン関連蛋白質(PTHrP)により破骨細胞の活性化が起こるため。

検査

• 血液塗沫

• 花弁状の腫瘍細胞

合併症

• HTLV-1 associated myelopath(HAM) = tropical spastic paraparesis(TSP) →まとめて「HAM/TSP」と呼ばれることがある。

治療

• 慢性(進行型を除く)・くすぶり型

• 経過観察

• 急性・リンパ腫型・慢性進行型

予後

• 急性型とリンパ腫型は予後不良
• LDH、血清Ca濃度が予後と関連(PMID 16122659)

参考

• 1. [charged] Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma - uptodate [2]

国試

• 103I007

「急性前骨髄球性白血病」

　　[★]

英

acute promyelocytic leukemia, APL

同

M3。急性前骨髄芽球性白血病？

関

急性骨髄性白血病 AML、白血病。前骨髄球

概念

• 急性骨髄性白血病の一病型
• 白血病細胞が前骨髄球の段階で成熟停止を起こした型
• FAB分類：M3
• アウエル小体が多く認められる。アウエル小体が集積した細胞(鳥の巣細胞、ファゴット細胞)がみられる。
• 免疫組織化学：MPO陽性(*ミエロペルオキシダーゼ活性はほぼ100%陽性)
• 異型前骨髄球がみられる。
• 染色体異常

• 95%以上の症例：t(15;17)(q22;q21)
• 全症例：PML遺伝子(chr.15)とRAR-α遺伝子(chr.17)の融合遺伝子の存在

M3と他のAMLを区別するポイント

• 免疫表現型：CD13(+), CD33(+), HLA-DR(-)。(micro granular cariantの時は)CD34(+), CD2(+)

検査

• 急性白血病に特徴的：高尿酸血症、LDH上昇
• 染色体異常：全例にt(15;17)を認め、PML遺伝子とRAR-α遺伝子が誘導したPML-RARA遺伝子を認める。

[show details]

合併症

• 播種性血管内凝固症候群(DIC)

• Auer顆粒を豊富に含み、この中にはトロンボプラスチン類似物質を含む。この物質の逸脱により凝固が亢進しDICにつながる
• 線溶亢進型DICを引きおこし、臓器障害より出血症状が前面にてくる。フィブリノゲン減少、Dダイマー・FDP増加が見られる。

治療

• レチノイン酸(ATRA, all-trans retinoic acid)の経口投与で高い確率で寛解する
• 白血球や前骨髄球が多い場合には化学療法を併用する：レチノイン酸　＋　アントラサイクリン系抗悪性腫瘍薬(イダルビシン、ダウノルビシン, DNA二本鎖の間にintercalateしでDNA,RNAの合成を阻害)　＋　シタラビン(Ara-C, シトシンアナログ, 代謝拮抗薬)

国試

• 105D048

「ランゲルハンス細胞」

　　[★]

英

Langerhans cell, Langerhans cells

同

Langerhans細胞

関

[[]]

• 骨髄由来の樹状細胞
• 抗原提示能あり

• 表皮にあって抗原を捕獲しリンパ節に遊走して抗原提示を行う
• 接触アレルギーに関与

• 有棘層に存在
• 紫外線放射により機能が抑制される。ステロイドによりランゲルハンス細胞の数が減る
• 気道粘膜上にも存在する？
• 表皮、食道粘膜以外の骨髄由来の抗原提示細胞であって、ランゲルハンス細胞と同じと考えられる細胞は樹状細胞とよばれる？

組織学

• 細胞質内に特徴的なランゲルハンス細胞顆粒(バーベック顆粒)

細胞マーカー

• HLA-DR
• CD1a
• S-100

臨床関連

• ランゲルハンス細胞組織球症

---

「HLA-DR2 antigen」

　　[★]

• HLA-DR2抗原

関

HLA-DR2

「HLA-DR3 antigen」

　　[★]

• HLA-DR3抗原

関

HLA-DR3

「HLA-DR5 antigen」

　　[★]

• HLA-DR5抗原

関

HLA-DR5

「D」

　　[★]

• アスパラギン酸
• ジヒドロウリジン
• 遠位の distal,
• うつ病 depression
• 下行結腸 descending colon(大腸内視鏡検査の結果を記載するときに用いる)

　 　

「HL」

　　[★]

• ホジキンリンパ腫 Hodgkin's lymphoma
• 高脂質血症 hyperlipidemia
• high lateral branch

「DR」

　　[★]

• デジタルラジオグラフィ
• 糖尿病網膜症 diabetic retinopathy

「H」

　　[★]

• 食道裂孔
• ヒスチジン
• 水素

　 　 　

「HLA」

　　[★] ヒト白血球抗原 human leukocyte antigen