HLA System AND RA

Dr. Abdulrahman Abdullah Algassim

Objectives:

Definition

Classification

Function

Nomenclature

HLA and RA

What is the HLA ?

HLA is MHC in humans

What is MHC? It is a tetramer (I) or Dimer (II) antigen presenting protein

in all nucleated cells, they present the epitope to TCR

Chromosome 6p21.3 (most variable loci in Humans)

4 major loci in each haplotype. ( loci are much more than 4, HLA DR alone have more than 6 loci)

MHC-binding peptides

Each human usually expresses:3 types of MHC class I (A, B, C) and3 types of MHC class II (DR, DP,DQ)

The number of different T cell antigen receptors is estimated to be

1,000,000,000,000,000Each of which may potentially recognise a different peptide antigen

How can 6 invariant molecules have the capacity tobind to 1,000,000,000,000,000 different peptides?

Classification:

HLA A, B, C FUCTION AS MHC l

HLA DP,DQ,DR FUCTION AS MHC ll

MHC l present to CD8+ T cell

MHC ll present to CD4+ T helper T cell

Inheritance of MHC haplotypes

B C ADP DQ DR

B C ADP DQ DR

B C ADP DQ DR

B C ADP DQ DR

X

ParentsDP-1,2DQ-3,4DR-5,6B-7,8C-9,10A-11,12

DP-9,8DQ-7,6DR-5,4B-3,2C-1,8A-9,10

DP-1,8DQ-3,6DR-5,4B-7,2C-9,8A-11,10

DP-1,9DQ-3,7DR-5,5B-7,3C-9,1A-11,9

DP-2,8DQ-4,6DR-6,4B-8,2C-10,8A-12,10

DP-2,9DQ-4,7DR-6,5B-8,3C-10,10A-12,9

B C ADP DQ DR

B C ADP DQ DR

B C ADP DQ DR

B C ADP DQ DR

B C ADP DQ DR

B C ADP DQ DR

B C ADP DQ DR

B C ADP DQ DR

Children

Antigen processing: Endogenous pathwayAntigen processing: Endogenous pathway

All nucleated cells can process endogenous proteins and

present fragments on their class I MHC.

Endoplasmic reticulum

Nucleus

Cytoplasmicproteins

degradation

Vesicle carryingMHC I-peptide

Processing in E.R. and complexing with MHC I

Display of MHC I + peptideon cell surface

Antigen processing: Exogenous pathwayAntigen processing: Exogenous pathwayProfessional antigen presenting cells ingest microbes and free

particles, degrade them in lysozomes, and present fragments to CD4+ T cells on MHC II.

Endoplasmic reticulum

Nucleus

Vesicle carryingMHC II

MHC II is assembled in ER

Display of MHC II + peptideon cell surface

Ingestion of microbe

Degradtion in lysozome

Vesicle fusion, assembly of

peptide/MHC II

Nomenclature: History lesion

1- HL A1-A15.

2- new specifies appeared HLA7 HLA B7 etc.

3- HLA Aw AND HLA Bw HLA C

4- HLA4 HLA DP, DQ, DR

THEN HLA DRw.

DRB1*, DRB3, DRB4 and DRB5

NOW IT’S NUMERICAL

http://hla.alleles.org/nomenclature/index.html

Reference

Adapted from Kuby’s Immunology 7th edition

HLA And RA

Disease susceptibility

Disease activity

RA AND HLA: disease susceptibility

A genetic link between HLA-DR and RA was initially described in the 1976 (Stastny P. et al.)1

HLA-DR4 occurred in 70% of RA patients compared with about 30% of controls, giving a relative risk of having RA of approximately 4 to 5 to individuals with HLA-DR4. (Nepom G T et al.)2.

Critiques:

A considerable proportion of RA occurs in individuals who lack any of the genes that comprise the DR4 haplotype.

DR4 also confers risk for certain autoimmune, diseases that are not generally associated with RA.

In RA patients who lack DR4 haplotypes, certain other DR alleles, are associated with susceptibility to RA, although at lower relative risks than DR4.

OTHER HLA DRB1 Patterns:

HLA DR1 (Schiff B et al.)

HLA DR 10 (Oilier WER et al.)

And many others (racial variance)

HLA-DR Pattern in Saudi RA Pt.:

(Alarfaj AS, 2001) found that the HLA DR10 is associated with RA in Saudi pupation .

The results of his study showed that the most prevalent HLA antigen in the study group was HLA-DR3, followed by DR2 and DR4, then DR7 and DR10. However, when compared to the control group, there was a significant rise in the HLA-DR10.3

Shared Epitope theory:

When so many HLA DRB1 subtypes have been implicated in RA susceptibility AND on the assumption that MHC ll are directly involved in the etiology and pathogenesis of rheumatoid arthritis.

it suggest that there are something in common between those antigen. (QKRAA/QRRAA/RRRAA on the single letter amino acid code). (Gregersen PK, et al.)4

Critiques:

1- Based on the crystal structure of HLA-DR molecules, the region associated with RA (QKRAA) primarily faces away from the antigen-binding cleft of the DR molecule that determines the specificity of peptides presented to CD4 + helper T cells.

2- Other genes must be involved because many healthy individuals carry the SE motif and do not develop RA.

3-the simplicity of this theory, meaning that each SE allele carry the same risk.

The Learning continues:

THE LATEST UPDATES ARE: SE alleles are reclassified high (*0103, *0401/2 etc. ) , intermediate ( *1001, *0404/5 ) and protective( *07, *08 *1401/4) (Michou L, et al.

2006) 5

Questions to be answered ?

How are these SE affect the T cell response, despite the antigen presented ?

and those who are SE negative ??????

AND if so, what is the trigger ? Is it ………. ?

(there is an inflammation and we still don’t know why)

HLA and RA severity:

Controversy some studies prove and some neglect.

most articles are pro ( multi racial ) only some against.

HLA AND erosive RA:

In1989 ( Calin A. et al.) concluded that Those who are SE+ve have more erosion.

Many other studies conquered.

(Weyand CM. et al. ) concluded Nodular disease was present in 100% of patients typed as HLA-DRB1*04/04 and in 59% of patients typed as HLA-DRB1*04.

HLA AND RA SEVERTIY IN OTHER RACES:

Korean: (Ho Youn K. et al.) Found that exRA (not nodules) and bony erosion are significantly increased in those who are positive for SE alleles. Plus they found the dose of the alleles are associated with severity of RA.

Japan7 and china8 , showed same significance

Saudi Arabian:(Alarfaj AS. Feb 2001) found an association between HLA DR10 and the severity of:1- joint involvement at presentation 2- HGB and WBC level.

Argentinean:(Citera G. et al. Jul 2001) subtype *1001 is correlated with the severity of RA( radiographically)

HLA AND exRA, a cohort study discussion (Turesson C. et al) :

The association of SEs with ExRA + homozygosity of SEs on exRA

Combined data:1. 88 pt with exRA ( MAYO clinic RETRO cohort)

2. 35 pt with exRA(Malmö University Hospital PRO cohort)

CONTROLS: pt with RA no exRA

matched demographics

SE GENOTYPED

HLA-DRB1*0401 was significantly associated with Felty's syndrome (allele frequency 0.475; P = 0.003).

HLA-DRB1*04 alleles encoding the SE (DRB1*0401, *0404, or *0405) was present in 105 out of 151 ExRA patients as compared with 96 out of 178 non-ExRA patients (OR 1.77, 95% CI 1.13–2.77).

Questions to be answered

How or by which mean SEs increase the immune response toward RA self antigen, i.e RA severity?

Do you think, on the bases of the studies above that DR screening at the time of diagnosis might help in predicting a certain prognostic value ? ( meta analysis )

and if so, do we need more aggressive treatment for those who are unfortunate to have the SE alleles?

THANK YOU

References

1-Stastny P: Mixed lymphocyte cultures in rheumatoid arthritis. J Clin Invest 57: 1148-1 157, 1976

2- Nepom G T , Byers P , Seyfried C, et al: HLA genes associated with rheumatoid arthritis: Identification of susceptibility alleles using specific oligonucleotide probes . Arthritis Rheum 32 : 15 ,1989.

3- Al-Arfaj AS. HLA-DR pattern of rheumatoid arthritis in Saudi Arabia. Annals of Saudi Medicine 2001; 21: 92-93.

4- Gregerson PK, Silver J, Winchester RJ (1987) The shared epitope hypothesis: an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 30:1205–1213

5- Michou L, Croiseau P, Petit-Teixeira E, du Montcel ST, Lemaire I, Pierlot C, Osorio J, Frigui W, Lasbleiz S, Quillet P, et al: Validation of the reshaped shared epitope HLA-DRB1 classification in rheumatoid arthritis. Arthritis Res Ther 2006, 8:R79.

6- Calin A, Elswood J, Klouda PT. Destructive arthritis, rheumatoid factor, and HLA-DR4. Susceptibility versus severity, a case-control study. Arthritis Rheum. 1989 Oct;32(10):1221-5.

7-Tsuchiya K. Immunogenetic analysis of rheumatoid arthritis in the Japanese population. Fukuoka Acta Med 1993;84:69-78

8-Molkentin J, Gregersen PK, Lin X et al. Molecular analysis of HLA!DRB and DQB polymorphisms in Chinese with rheumatoid arthritis. Ann Rheum Dis 1993;52:610-2