hla-typing dr opoola a.o. registrar,luth. outline definition of terms classification of hla types ...
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OutlineDefinition of termsClassification of HLA types functionsCharacteristicsClinical significanceReferences
Definition
The HLA system is a group of tissue antigens termed Human Leukocyte Antigens governed by a chromosomal region bearing a number of genetic Loci, each with multiple alleles that have relevance to transplantation rejection reactions and that mark the prevalence of
several diseases. This group of genes resides on the short
arm of Chromosome 6 and encodes Cell-Surface antigen-presenting proteins and many other genes.
Definition of terms CHROMOSOME: One of the threadlike
structures in a cell nucleus that carry the genetic information in the form of gene.
ALLELES: Variants of a single genetic locus.
MAJOR HISTOCOMPATIBILITY COMPLEX: A cluster of genes located in close proximity e.g. on human chromosome 6, that encode the histocompatibility antigens (MHC Molecules).
Definition of terms HISTOCOMPATIBLE: Sharing similar
antigens i.e in transplantation
ANTIBODY: A protein produced as a result of interaction with an antigen. The protein has the ability to combine with the antigen that stimulated its production.
ANTIGEN: A substance that can react with antibody. Not all antigens can induce antibody production; those that can are also called immunogens.
Definition of terms B LYMPHOCYTES: Strictly, a bursa-
derived cell in avian species and by analogy, a cell derived from the equivalent of the bursa in non-avian species. B Cells are the precursors of plasma cells that produce antibody.
T LYMPHOCYTE: A thymus – derived cell that participates in a variety of cell-mediated immune reactions.
ANTIGEN PRESENTING CELLS: Chiefly Macrophages or B Cells that process and present antigens to T Cells.
Definition of terms MACROPHAGES: A phagocytic
mononuclear cells derived from bone monocytes and found in tissues and at the site of inflammation.
Macrophages serve accessory roles
in immunity, particularly as APCs
COMPLEMENT: A set of plasma proteins that is the primary mediator of antigen – antibody reactions.
Functions The HLA System (MHC MOLECULES) bind
peptide antigens and present them to T-Cells.
Thus these transplantation antigens are responsible for antigen recognition by the T-Cell receptor.
While antibody molecules interact with antigens directly, the T-Cell receptor
only recognizes antigen presented by MHC molecules on an antigen presenting cells .
Function The T Cell receptor is also specific
for the MHC molecule.
If the antigen is presented by another allelic form of the MHC molecule there is no recognition by the T Cell receptor.
This phenomenon is known as MHC
RESTRICTION
ClassificationThe HLA system is classified into 3 based on their location on the chromosome and cell distribution. These are:-
1.Class 1: 3 major and 3minor
2.Class 2: 3major and 2 minor
3.Class 3: Complement proteins and several cytokines
Class 1MHC Proteins These major class I genes are encoded by
the HLA-A, - B, - C genes.
These proteins are made up of two chains:
(i) A transmembrane glycoprotein of MW 45,000, non-covalently associated with a non-MHC encoded polypeptide of MW 12,000 that is known as B2 – macroglobulin.
Class 1 molecules are to be found on virtually all nucleated cells in the body.
Minor genes are HLA – E, HLA – F and HLA-G.
Class 2 MHC proteinsMajor are HLA-DP,DQ and DR and
minor are HLA-DM and DO.
The genes of the Class II combine to form heterodimeric (αβ) protein receptors that are typically expressed on the surface of antigen presenting cells.
Class 2 MHC proteins1. HLA-DP α- chain encoded by HLA-DPA1 locus β-chain encoded by HLA-DPB1 locus
2. HLA-DQ α-chain encoded by HLA-DQA1 locus β-chain encoded by HLA-DQB1 locus
3. HLA-DR α-chain encoded by HLA-DRA locus 4 β-chains (only 3 possible per person) encoded by HLA-DRB1, DRB3, DRB4, DRB5 loci
Class 2 MHC proteinsDM and DO are used in the internal
processing of antigens, loading the antigenic peptides generated from pathogens onto the HLA molecules of antigen-presenting cell.
The HLA – D Locus encoded proteins are made up of non-covalently associated transmembrane glycoprotein of about MW 33,000 and MW 29,000
Class 2 MHC proteins Unlike Class I proteins, they have a
restricted tissue distribution and are chiefly found on macrophages, B-Cells, and other APCs.
Their expression on the other Cells – e.g., endothelial cells can be induced by interferon-gamma.
CLASS 1 CLASS 11
GENETIC LOCI (PARTIAL LIST)
HLA – A, - B, - C HLA-DP, - DQ, - DR
POLYPEPTIDE COMPOSITION
MW 45,000 + B2 M (MW 12,000)
α CHAIN (MW 33,000)β CHAIN (MW 29,000)
CELL DISTRIBUTION ALL NUCLEATED CELLS (SOMATIC)
APCs (Macrophages, B-Cells etc) Activated human T-Cells
PRESENT ANTIGENS TO
CD8 T CELLS CD4 T CELLS
SIZE OF PEPTIDE BOUND
8 – 11 RESIDUES 10 – 30 OR MORE RESIDUES
TABLE SHOWING FEATURES OF CLASS I AND CLASS II PROTEINS
CHARACTERISTICS OF HLA THEY ARE POLYGENIC: There are
several genes for each class of molecule.
THEY ARE POLYMORPHIC: They have a large number of alleles in the population for each of the genes.
THEY ARE HAPLOTYPIC: Genes tend to be inherited as a block as there are relatively in-frequent cross-over events at the Locus.
CHARACTERISTICS OF HLA LINKAGE DISEQUILLIBRIUM: This is defined
as a deviation from Hardy – Weinberg equilibrium for alleles at linked loci. One consequence of this has been the resulting deficiency in assigning HLA- disease associations to a single allele at a single Locus.
Characteristics The proteins encoded by the HLAs are the
proteins on the outerpart of body cells that are unique to that person.
The immune system uses the HLAs to
differentiate self cells and non-self cells.
Any cell displaying that persons HLA type belongs to that person
Clinical Significance 1. In DISEASE DEFENSE
2. AGENTS OF HUMAN DISEASE IN AUTOIMMUNITY: Known to mediate many autoimmune diseases
3. AS ANTIGENS: Responsible for organ transplant rejection
4. IN REPRODUCTION – may be involved in male selection
5. IN CANCER – may be protective or fail to protect.
Clinical Significance IN INFECTIOUS DISEASE: When a foreign pathogen enters the body, specific cells called antigen-presenting cells (APCs) engulf the pathogen through a process called phagocytosis.
Proteins from the pathogen are digested into small peptides and loaded onto HLA antigens (Specifically MHC Class II).
They are then displayed by the APCs for the T Cells to produce a variety of effects to eliminate the pathogen.
Clinical Significance Through a similar process, proteins (both
native and foreign, such as the protein of viruses) produced inside most cells are displayed on HLA antigens (specifically MHC Class I) on the cell surface.
Infected cells can be recognised and destroyed by components of the immune system (Specifically CD8+ T Cells).
Clinical Significance IN AUTOIMMUNITYHLA types are inherited, and some of them are connected with autoimmune disorders and other diseases.
People with certain HLA antigens are more likely to develop certain autoimmune diseases such as Type 1 Diabetes, Ankylosing Spondylitis, celiac disease, SLE, myasthenia Gravis, inclusion body myositis and Sjogren’s syndrome.
Clinical significance HLA typing in autoimmunity is being
increasingly used as a tool in diagnosis.
In Gluten Sensitive Enteropathy (GSE), it is the only effective means of discriminating between first degree relatives who are at risk from those who are not at risk, prior to the appearance of sometimes irreversible symptoms such as allergies and secondary autoimmune disease.
Diseases Marker
Gene
Spondyloarthropathies Ankylosing spondylitis,Reiter’s syndrome, Acute anterior uveitis, Reactive arthritis(Yersinia, Salmonella, Shigella, Chlamydia), Psoriatic Spondylitis
B27 B*2702, –04, –05
Collagen-Vascular Diseases Juvenile arthritis, pauciarticular DR8,DR5
Rheumatoid arthritis DR4 DRB1*0401, –04, –05
Sjögren's syndrome DR3 Systemic lupus erythematosus White DR3 Japanese DR2
Disease Marker Gene
Autoimmune Gut and Skin
Gluten-sensitive enteropathy (celiac disease)
DQ2 DQA1*0501
DQB1*0201
Chronic active hepatitis DR3
Dermatitis herpetiformis DR3
Psoriasis vulgaris Cw6
Pemphigus vulgaris DR4 DRB1*0402
DQ1 DQB1*0503
Bullous pemphigoid variant DQ7 DQB1*0301
Disease Marker Gene
Autoimmune Endocrine
Type 1 diabetes mellitus DQ8 DQB1*0302 DR4 DRB1*0401, –
04 DR3 DR2 DQB1 *0602Hyperthyroidism (Graves') B8, DR3
Hyperthyroidism (Japanese) B35
Adrenal insufficiency DR3 Autoimmune Neurologic
Myasthenia gravis B8, DR3
Multiple sclerosis DR2 DRB1*1501
DRB5*0101
Miscellaneous Diseases Markers
Gene
Behçet's disease B51
Congenital adrenal hyperplasia B47 21·OH (Cyp21B)
Narcolepsy DR2 DQB1*0602
Goodpasture's syndrome (anti-GBM)
DR2
Abacavir hypersensitivity B57 B*5701
HLA and autoimmunity diseases diseasesHLA allele Diseases with increased risk
HLA-B27Ankylosing spondylitis, post gonococcal arthritis, anterior uveitis
HLA-B47 21-hydroxylase deficiency
HLA-DR2 Systemic Lupus Erythematosus
HLA-DR3Autoimmune Hepatitis, Primary Sjogren syndrome, Diabetes mellitus type 1, SLE
HLA-DR4Rheumatoid Arthritis, Diabetes mellitus type 1
Clinical SignificanceIN GRAFT REJECTION Any cell displaying some other HLA type is “non-self” and is an invader resulting in the rejection of the tissue bearing those cells.
Because of the importance of HLA in transplantation, the HLA Loci are among the most frequent typed by serology or PCR relative to any other autosomal alleles.
HLA-A,B &DR-Important in Kidney transplant
HLA/TISSUE TYPING1.HLA- A1*,A2,B8*,B44,DR4*,DR152.HLA-A1*,A3,B7,B8*,DR4*,DR121A, 1B, 1DR mismatch 1.HLA- A2 - ; B27, B13, DR17, DR42.HLA- A2 A3, B8, B14, DR17 -
Once there is double DR mismatch-No transplant*
Clinical Significance IN CANCER:Some HLA mediated diseases are directly involved in the promotion of cancer.
Gluten sensitive enteropathy is associated with increased prevalence of enteritis associated T-Cell Lymphoma and DR3 – DQ2 homozygotes are within the highest risk group with close to 80% of gluten sensitive EATL cases.
Clinical Significance More often; however, HLA molecules play a
protective role, recognizing the increase in antigens that were not tolerated.
Abnormal cells may be targeted for apoptosis mediating many cancers before clinical diagnosis.
Prevention of cancer may be a portion of heterozygous selection acting on HLA