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Anti-TRIM21 Xavier Bossuyt
Anti-TRIM21
Xavier Bossuyt
SS-A / Ro
Structure: snRNP – hY (human cytoplasmic) RNA – Protein
BACKGROUND
SS-A / Ro 52 ?? Ben Chetrit et al. JEM 1988; 167:1560-71
Majority of SS-A/Ro sera
(identified by ID) from Sjögren’s patients have a band at 60 kDa and 52 kDa when tested by WB
SS-A/Ro52
SS-A / Ro 52 ?? Reymond et al. EMBO J 2001;20:2140-51
• Identification of Ro52
• TRIM21:
(TRIpartite Motive proteins)
• Structural and genetic differences with SS-A/Ro60
• No co-purification of TRIM21 and SSA/Ro60
• Anti-TRIM does not co-precipitate Ro60
• TRIM does not have consensus sequence for RNA binding
Tripartite Motif
RING B B coiled coil variable C terminal
CLINICAL ASSOCIATIONS
SS-A / Ro 60 – Sjögren’s syndrome (60-70%)
– SLE (35 %) – Cutaneous lupus (majority) – Neonatal lupus
Bossuyt X. Clin Chem. 2004;50:2361-9
SS-A / Ro 52
Dijon: fréquence des Ac anti-TRIM 21
0
50
100
150
200
250
300
Nombre de sérums 209 158 75 16 42 30 2 288 59
Nombre de patients 132 98 49 7 24 15 2 144 47
Ac anti-TRIM 21
Ac anti-SS-A60
Ac anti-SS-B
Ac anti-Sm
Ac anti-RNP
Ac anti-Scl-70
Ac anti-Jo-1
Ac anti-ADNn
Ac anti-CENP-B
NO Olsson, G Renier GEAI 2008 / Lakomy et al. Revue Francophone des laboratoires 2008
Les Ac anti-TRIM 21 font partie des ANA les plus fréquents
2231 ANA(+) sera 9.4% anti-TRIM21 2.1% anti-TRIM21 isolés
Dijon: maladies associées aux Ac anti-TRIM 21
0
5
10
15
20
25
30N
ombr
e de
pat
ient
s
Ac anti-TRIM 21 isolés 5 2 3 0 7 7 12
Ac anti-TRIM 21associés 23 30 8 2 4 3 13
LES GS SCL SHARP Autres MAI AVCAutres
pathologies
Pas d’association avec une MAI particulière
Pas toujours associés à une MAI
NO Olsson, G Renier GEAI 2008 / Lakomy et al. Revue Francophone des laboratoires 2008
Angers: maladies associées
Ac anti-TRIM 21 et Ac anti-SS-A/Ro60
43%
32%
3%
6%
16%
Lupus érythémateux disséminé Syndrome de Gougerot Sjogren
Polyarthrite rhumatoïde Associations
Autres
Ac anti-TRIM 21 sans Ac anti-SS-A/Ro60
11%
14%6%6%11%
20%
6%
3%
23%
Lupus érythémateux disséminé Syndrome de Gougerot Sjogren
Sclérodermie Polyarthrite rhumatoïde
Cirrhose biliaire primitive Myosite
autres associations
Syndrome de Raynaud
NO Olsson, G Renier GEAI 2008 / Lakomy et al. Revue Francophone des laboratoires 2008
Schulte-Pelkum , M. Fritzler , M. Mahler Latest update on the Ro/SS-A autoantibody system Autoimmunity Reviews. 2009; 8: 632 - 637
Target of anti-Ro52 associated auto-antibodies (detected by BioPlex).
P. Ghillani , C. André , C. Toly , A.M. Rouquette , D. Bengoufa , P. Nicaise , C. Goulvestre , A. Gleizes , M.A....
Clinical significance of anti-Ro52 (TRIM21) antibodies non-associated with anti-SSA 60<ce:hsp sp="0.25"/>kDa antibodies: Results of a multicentric study
Autoimmunity Reviews, Volume 10, Issue 9, 2011, 509 - 513
Main diseases or clinical manifestations associated with anti-Ro52 antibodies.
P. Ghillani , C. André , C. Toly , A.M. Rouquette , D. Bengoufa , P. Nicaise , C. Goulvestre , A. Gleizes , M.A....
Clinical significance of anti-Ro52 (TRIM21) antibodies non-associated with anti-SSA 60<ce:hsp sp="0.25"/>kDa antibodies: Results of a multicentric study
Autoimmunity Reviews, Volume 10, Issue 9, 2011, 509 - 513
Clinical significance of antibodies to Ro52/TRIM21 in systemic sclerosis. Hudson M, Pope J, Mahler M, Tatibouet S, Steele R, Baron M; Canadian Scleroderma Research Group (CSRG), Fritzler MJ. Arthritis Res Ther. 2012;14:R50.
Frequency of selected autoantibodies in the CSRG cohort n %
CENP-B 285 36%
Centromere by IIF 334 35%
CENP-A 275 34% Ro52/TRIM21 194 20%
RNA polymerase III 144 19%
Topoisomerase I 150 16% PM/Scl 53 7% Ro60 53 6% U1 RNP 59 6% Chromatin 44 5% Sm 39 4% SS-B/La 26 3% Jo-I 6 1% Ribosomal P 14 1%
N = 963. CENP, centromere protein; IIF, indirect immunofluorescence; PM/Scl, polymyositis/scleroderma (exosome) autoantigen; RNP, ribonucleoprotein; Sm, Smith autoantigen; SS-B, Sjögren syndrome antigen B or La.
Anti-TRIM21 associated with * other antibodies * interstitial lung disease
(n) Anti-U1 snRNP (25)
Anti-La (21)
Anti-Ro52 (106)
Anti-Ro60 (17)
Anti-Mas (8) Anti-PM/Scl (23) Anti-Mi-2
(58) Anti-SRP (20)
(85) Anti-synthetase 3 7 56 3 3 0 4 2
(20) Anti-SRP 1 0 6 1 0 0 0
(58) Anti-Mi-2 3 2 12 3 0 2
(23) Anti-PM/Scl 2 2 3 1 0
(8) Anti-Mas 0 0 2 0
(17) Anti-Ro60 2 8 12
(106) Anti-Ro52 11 12
(21) Anti-La 1
Autoantibody profiles in the sera of European patients with myositis. Brouwer et al. Ann Rheum Dis. 2001;60:116-23.
Associations of myositis specific autoantibodies and myositis associated autoantibodies in 417 serum samples from European patients with myositis
Disease Anti-Ro52 frequency, % Sjögren’s syndrom 67, 75
Systemic lupus erythematosus (SLE) 27, 43
mothers to infants with CHB 95
Infants with cutaneous NLE 81
Cutaneous LE (CLE) (Data only on Ro/SSA) 71
Chronic CLE (discoid LE) 9
Idiopathic inflammatory myopathies 20, 31, 35
Dermatomyositis 17, 22 Polymyositis 19 , 29
Antisynthtase syndrome 58
Overlap myositis 37 Systemic sclerosis 19
Primary biliary cirrhosis 28
Autoimmune hepatitis type 1 38
Oke V and Wahren-Herlenius J Autoimmunity 2012; 39:77-82
Disease Anti-Ro52 frequency, % Sjögren’s syndrom 67, 75
Systemic lupus erythematosus (SLE) 27, 43
mothers to infants with CHB 95
Infants with cutaneous NLE 81
Cutaneous LE (CLE) (Data only on Ro/SSA) 71
Chronic CLE (discoid LE) 9
Idiopathic inflammatory myopathies 20, 31, 35
Dermatomyositis 17, 22 Polymyositis 19 , 29
Antisynthtase syndrome 58
Overlap myositis 37 Systemic sclerosis 19
Primary biliary cirrhosis 28
Autoimmune hepatitis type 1 38
Oke V and Wahren-Herlenius J Autoimmunity 2012; 39:77-82
Disease Anti-Ro52 frequency, % Sjögren’s syndrom 67, 75
Systemic lupus erythematosus (SLE) 27, 43
mothers to infants with CHB 95
Infants with cutaneous NLE 81
Cutaneous LE (CLE) (Data only on Ro/SSA) 71
Chronic CLE (discoid LE) 9
Idiopathic inflammatory myopathies 20, 31, 35
Dermatomyositis 17, 22 Polymyositis 19 , 29
Antisynthtase syndrome 58
Overlap myositis 37 Systemic sclerosis 19
Primary biliary cirrhosis 28
Autoimmune hepatitis type 1 38
Oke V and Wahren-Herlenius J Autoimmunity 2012; 39:77-82
Disease Anti-Ro52 frequency, % Sjögren’s syndrom 67, 75
Systemic lupus erythematosus (SLE) 27, 43
mothers to infants with CHB 95
Infants with cutaneous NLE 81
Cutaneous LE (CLE) (Data only on Ro/SSA) 71
Chronic CLE (discoid LE) 9
Idiopathic inflammatory myopathies 20, 31, 35
Dermatomyositis 17, 22 Polymyositis 19 , 29
Antisynthtase syndrome 58
Overlap myositis 37 Systemic sclerosis 19
Primary biliary cirrhosis 28
Autoimmune hepatitis type 1 38
Oke V and Wahren-Herlenius J Autoimmunity 2012; 39:77-82
STRUCTURE - FUNCTION
SS-A / Ro60
• Structure: snRNP – hY (human cytoplasmic) RNA – Protein SSA 60
• Function:
– binds to misfolded, noncoding RNAs – misfolded RNAs are recognized and then
tagged by Ro60 for degradation
TRIM-21
• Structure
• Function: – Fc receptor – E3 ubiquitin ligase
Tripartite Motif
RING B B coiled coil variable C terminal
Tripartite Motif
RING B B coiled coil variable C terminal
• Ubiquitin : – 8,5 kDa, 76 AA – Covalent linkage: C-terminal glycine linked to lysine of target protein – 7 lysines : K6, K11, K23, K27, K33, K48, K63 polyUb with # functions – Post-translational modification
• Degradation • Regulation
– Linkage of Ub or polyUb to self-protein or non-self (e.g. virale)
• Innate immunity
Watkinson, McEwan, James. J. Clin Immunol 2014;34:S30-S34
TLR4
TLR3 TLR7/8/9
TRAF3
IRF3/5/7
NUCLEUS GENE TRANSCRIPTION
PROINFLAMMATORY CYTOKINES AND TYPE 1 INTERFERONS
MDA-5
CELL
TLR1/2 TLR5 TLR6/2 IL-1R
MyD88
TRAF 6
IRF7/1 MAPK NEMO
IKK
IKBA
NF-KB
AP-1 IKBA
NF-KB
TLR4
TLR3 TLR7/8/9
TRAF3
IRF3/5/7
NUCLEUS GENE TRANSCRIPTION
PROINFLAMMATORY CYTOKINES AND TYPE 1 INTERFERONS
MDA-5
CELL
TLR1/2 TLR5 TLR6/2 IL-1R
MyD88
TRAF 6
IRF7/1 MAPK NEMO
IKK
IKBA
NF-KB
AP-1 IKBA
NF-KB
TRIM21 TRIM21
TRIM21
CONCLUSIONS
• Ro60 (SS-A) and Ro52 (TRIM-21) are different (genetic, structure, function)
• Anti-Ro60 (SS-A) and anti-Ro52 (TRIM-21) represent two distinct autoantibody systems
• Separate detection is desirable in a clinical diagnostic setting.
