HLA System AND RA Dr Abdulrahman Abdullah Algassim

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 6 p 21. 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)

Classification: � HLA A, B, C FUCTION AS MHC l � HLA DP, DQ, DR FUCTION AS MHC ll � MHC l present to CD 8+ T cell � MHC ll present to CD 4+ T helper T cell

Nomenclature: History lesion 1 - HL A 1 -A 15. 2 - new specifies appeared HLA 7 HLA B 7 etc. 3 - HLA Aw AND HLA Bw HLA C 4 - HLA 4 HLA DP, DQ, DR THEN HLA DRw. DRB 1*, DRB 3, DRB 4 and DRB 5 NOW IT’S NUMERICAL

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

Reference � Adapted from Kuby’s Immunology 7 th 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-DR 4 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-DR 4. (Nepom G T et al. )2.

Critiques: � A considerable proportion of RA occurs in individuals who lack any of the genes that comprise the DR 4 haplotype. � DR 4 also confers risk for certain autoimmune, diseases that are not generally associated with RA. � In RA patients who lack DR 4 haplotypes, certain other DR alleles, are associated with susceptibility to RA, although at lower relative risks than DR 4.

OTHER HLA DRB 1 Patterns: HLA DR 1 (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 DR 10 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-DR 3, followed by DR 2 and DR 4, then DR 7 and DR 10. However, when compared to the control group, there was a significant rise in the HLA-DR 10. 3

Shared Epitope theory: � When so many HLA DRB 1 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 CD 4 + 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: � In 1989 ( 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-DRB 1*04/04 and in 59% of patients typed as HLA-DRB 1*04.

HLA AND RA SEVERTIY IN OTHER RACES: � Korean: (Ho Youn K. et al. ) Found that ex. RA (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. � Japan 7 and china 8 , showed same significance � Saudi Arabian: (Alarfaj AS. Feb 2001) found an association between HLA DR 10 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 ex. RA, a cohort study discussion (Turesson C. et al) : � The association of SEs with Ex. RA + homozygosity of SEs on ex. RA � Combined data: 1. 2. 88 pt with ex. RA ( MAYO clinic RETRO cohort) 35 pt with ex. RA(Malmö University Hospital PRO cohort) CONTROLS: pt with RA no ex. RA matched demographics SE GENOTYPED

� HLA-DRB 1*0401 was significantly associated with Felty's syndrome (allele frequency 0. 475; P = 0. 003). � HLA-DRB 1*04 alleles encoding the SE (DRB 1*0401, *0404, or *0405) was present in 105 out of 151 Ex. RA patients as compared with 96 out of 178 non-Ex. RA 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-DRB 1 classification in rheumatoid arthritis. Arthritis Res Ther 2006, 8: R 79.

6 - Calin A, Elswood J, Klouda PT. Destructive arthritis, rheumatoid factor, and HLA-DR 4. 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