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
• Structural and genetic differences with SS-A/Ro60 • No co-purification of TRIM21 and SSA/Ro60
• TRIM21: (TRIpartite Motive proteins)
• Anti-TRIM does not coprecipitate Ro60
Tripartite Motif
RING
B B
coiled coil
variable C terminal
• TRIM does not have consensus sequence for RNA binding
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
2231 ANA(+) sera 9.4% anti-TRIM21 2.1% anti-TRIM21 isolés
300 250 200 150 100 50 0
Ac anti- Ac anti- Ac anti- Ac anti- Ac anti- Ac anti- Ac anti- Ac anti- Ac antiTRIM 21 SS-A60 SS-B Sm RNP Scl-70 Jo-1 ADNn CENP-B
Nombre de sérums
209
158
75
16
42
30
2
288
59
Nombre de patients
132
98
49
7
24
15
2
144
47
Les Ac anti-TRIM 21 font partie des ANA les plus fréquents
NO Olsson, G Renier GEAI 2008 / Lakomy et al. Revue Francophone des laboratoires 2008
Dijon: maladies associées aux Ac antiTRIM 21
Nombre de patients
30 25 20 15 10 5 0 LES
GS
SCL
SHARP
Autres MAI
AVC
Autres pathologies
Ac anti-TRIM 21 isolés
5
2
3
0
7
7
12
Ac anti-TRIM 21associés
23
30
8
2
4
3
13
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 sans Ac anti-SS-A/Ro60
Ac anti-TRIM 21 et Ac anti-SS-A/Ro60
3% 16%
6%
23%
20% 6%
43%
11%
3%
11% 6% 6%
32%
Lupus érythémateux disséminé
Syndrome de Gougerot Sjogren
Polyarthrite rhumatoïde
Associations
Autres
14%
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 60kDa 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 60kDa 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 Ro52/TRIM21
275 194
34% 20%
RNA polymerase III 144
19%
Topoisomerase I PM/Scl Ro60 U1 RNP Chromatin Sm SS-B/La Jo-I Ribosomal P
16% 7% 6% 6% 5% 4% 3% 1% 1%
150 53 53 59 44 39 26 6 14
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
Autoantibody profiles in the sera of European patients with myositis. Brouwer et al. Ann Rheum Dis. 2001;60:116-23.
(n)
Anti-U1 snRNP (25)
Anti-La Anti-Ro52 (21) (106)
Anti-Ro60 Anti-Mas Anti-Mi-2 Anti-SRP Anti-PM/Scl (23) (17) (8) (58) (20)
(85) Anti-synthetase
3
7
56
3
3
0
4
(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
2
1
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) Chronic CLE (discoid LE)
(Data only on Ro/SSA) 71 9
Idiopathic inflammatory myopathies 20, 31, 35 Dermatomyositis Polymyositis
17, 22 19 , 29
Antisynthtase syndrome
58
Overlap myositis Systemic sclerosis
37 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) Chronic CLE (discoid LE)
(Data only on Ro/SSA) 71 9
Idiopathic inflammatory myopathies 20, 31, 35 Dermatomyositis Polymyositis
17, 22 19 , 29
Antisynthtase syndrome
58
Overlap myositis Systemic sclerosis
37 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) Chronic CLE (discoid LE)
(Data only on Ro/SSA) 71 9
Idiopathic inflammatory myopathies 20, 31, 35 Dermatomyositis Polymyositis
17, 22 19 , 29
Antisynthtase syndrome
58
Overlap myositis Systemic sclerosis
37 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) Chronic CLE (discoid LE)
(Data only on Ro/SSA) 71 9
Idiopathic inflammatory myopathies 20, 31, 35 Dermatomyositis Polymyositis
17, 22 19 , 29
Antisynthtase syndrome
58
Overlap myositis Systemic sclerosis
37 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
TRIM-21 Tripartite Motif
RING
•
Structure: snRNP – –
•
– –
•
Structure
•
Function:
hY (human cytoplasmic) RNA Protein SSA 60
Function:
binds to misfolded, noncoding RNAs misfolded RNAs are recognized and then tagged by Ro60 for degradation
B B
– –
coiled coil
Fc receptor E3 ubiquitin ligase
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
TLR1/2
TLR6/2
TLR5
IL-1R
TLR4
CELL MyD88
TLR7/8/9
TLR3 MDA-5
TRAF 6
MAPK
TRAF3
IRF7/1
NEMO IKK
AP-1
IKBA
IKBA
NF-KB
NF-KB
IRF3/5/7
NUCLEUS GENE TRANSCRIPTION PROINFLAMMATORY CYTOKINES AND TYPE 1 INTERFERONS
TLR1/2
TLR6/2
TLR5
IL-1R
TLR4
CELL MyD88
TLR7/8/9
TLR3 MDA-5
TRAF 6
MAPK
TRAF3
IRF7/1
NEMO IKK
TRIM21 AP-1
TRIM21
IKBA
IKBA
NF-KB
NF-KB
TRIM21
IRF3/5/7
NUCLEUS GENE TRANSCRIPTION PROINFLAMMATORY CYTOKINES AND TYPE 1 INTERFERONS
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.
