Collagen type II (peptide 261-273) TCR specific clonotypes confirmed in a subset of DRB1-04+ early rheumatoid arthritis patients.
Maria De Santis, Catholic University
25 January 2010
Sir, In 2008 we reported the BV-BJ (immunoscope) of the response to human collagen II 261-273 in peripheral blood of DR4+ subjects affected Rheumatoid Arthritis (1). Two of these rearrangements were frequently used; a BV13b-BJ2.3 of 199b length (BV13b) and a BV11-BJ2.2 of 139b length (BV11). Both rearrangements associated with acute presentation of disease, and we suggested a common CDR3 motif for BV13b and two for BV11. Several papers (2,3) have shown a skewing of the repertoire of T cells infiltrating the synovia. The possibility to monitor T cells associate with disease status in peripheral blood would be valuable for management of patients. To assess the predictive ability of rearrangements BV13b and BV11, we examined PBMC from 31 consecutive patients attending our outpatient early arthritis clinic. Patients were examined as described, blind with respect to DRB1 haplotype and disease status. Nine patients were DR4+, 8 in disease remission (DAS44 < 1.6) and 1 in an acute disease state (DAS44 >3.7). None of them belonged to the cohort previously reported (1). Of the 22 DR4- subjects, 16 were in disease remission and 6 in active disease. Overall, out of 50 samples, BV13b was detected in 5/8 samples obtained from DR4+ patient in active RA, in 1/14 samples obtained from DR4+ RA patients in remission and in 1/23 samples obtained from DR4- RA patients (p<10-8 in all cases). Samples from 5 DR4+ healthy subjects were negative. Thus, detection of BV13b in PBMC is highly indicative of a DR4+ subject in active disease status. Also detection of BV11 (tested in 58 samples) is associated with DR4 and active disease, but its potency is lower than that of BV13b (p=0.049 versus healthy DR4+ donors, p=0.001 vs DR4+ patients in remission and p<10-5 vs DR4- patients). Three of the 5 positive samples obtained from DR4+ patients at remission of disease had been obtained in proximity of an acute episode (<3 months after (1 sample) or before (2 samples)). A total of 114 new sequences for BV11 were obtained, 37 of length 139b. Between the two motives proposed for BV11, the SEPR consistently associated with DR4+ subjects in acute or proximity to disease (p=0.0003 vs DR4- patients and p=0.045 vs DR4+ healthy donors). In conclusion these data support the possibility to monitor T cells specific for human collagen in peripheral blood of DR4+ RA patients, and should prove useful for the clinical management of patients.
Francesco Ria*, Romina Penitente*, Maria De Santis**, Gianfranco Ferraccioli** Institute of General Pathology * - Department of Rheumatology** -School of Medicine-Catholic University of the Sacred Heart-Via Moscati 31, 00168 Rome, Italy
References. 1. Ria F, Penitente R , De Santis M, Nicolò C, Di Sante G, Orsini M, Arzani D, Fattorossi A, Battaglia A, Ferraccioli G: Collagen-specific T-cell repertoire in blood and synovial fluid varies with disease activity in early rheumatoid arthritis. Arthritis Research & Therapy 2008, 10:R135 2. Backlund J, Carlsen S, Hoger T, Holm B, Fugger L, Kihlberg J, Burkhardt H, Holmdahl R: Predominant selection of T cells specific for the glycosylated collagen type II epitope (263-270) in humanized transgenic mice and in rheumatoid arthritis. Proc Natl Acad Sci U S A 2002, 99(15):9960-9965 3. Sekine T, Kato T, Masuko-Hongo K, Nakamura H, Yoshino S, Nishioka K, Yamamoto K: Type II collagen is a target antigen of clonally expanded T cells in the synovium of patients with rheumatoid arthritis. Ann Rheum Dis 1999, 58(7):446-450.
Competing interests
national patent RM2007A000429 and international PCT: PCT/IB2008/053152
Collagen type II (peptide 261-273) TCR specific clonotypes confirmed in a subset of DRB1-04+ early rheumatoid arthritis patients.
25 January 2010
Sir,
In 2008 we reported the BV-BJ (immunoscope) of the response to human collagen II 261-273 in peripheral blood of DR4+ subjects affected Rheumatoid Arthritis (1). Two of these rearrangements were frequently used; a BV13b-BJ2.3 of 199b length (BV13b) and a BV11-BJ2.2 of 139b length (BV11). Both rearrangements associated with acute presentation of disease, and we suggested a common CDR3 motif for BV13b and two for BV11. Several papers (2,3) have shown a skewing of the repertoire of T cells infiltrating the synovia. The possibility to monitor T cells associate with disease status in peripheral blood would be valuable for management of patients.
To assess the predictive ability of rearrangements BV13b and BV11, we examined PBMC from 31 consecutive patients attending our outpatient early arthritis clinic. Patients were examined as described, blind with respect to DRB1 haplotype and disease status. Nine patients were DR4+, 8 in disease remission (DAS44 < 1.6) and 1 in an acute disease state (DAS44 >3.7). None of them belonged to the cohort previously reported (1). Of the 22 DR4- subjects, 16 were in disease remission and 6 in active disease. Overall, out of 50 samples, BV13b was detected in 5/8 samples obtained from DR4+ patient in active RA, in 1/14 samples obtained from DR4+ RA patients in remission and in 1/23 samples obtained from DR4- RA patients (p<10-8 in all cases). Samples from 5 DR4+ healthy subjects were negative. Thus, detection of BV13b in PBMC is highly indicative of a DR4+ subject in active disease status.
Also detection of BV11 (tested in 58 samples) is associated with DR4 and active disease, but its potency is lower than that of BV13b (p=0.049 versus healthy DR4+ donors, p=0.001 vs DR4+ patients in remission and p<10-5 vs DR4- patients). Three of the 5 positive samples obtained from DR4+ patients at remission of disease had been obtained in proximity of an acute episode (<3 months after (1 sample) or before (2 samples)).
A total of 114 new sequences for BV11 were obtained, 37 of length 139b. Between the two motives proposed for BV11, the SEPR consistently associated with DR4+ subjects in acute or proximity to disease (p=0.0003 vs DR4- patients and p=0.045 vs DR4+ healthy donors).
In conclusion these data support the possibility to monitor T cells specific for human collagen in peripheral blood of DR4+ RA patients, and should prove useful for the clinical management of patients.
Francesco Ria*, Romina Penitente*, Maria De Santis**, Gianfranco Ferraccioli**
Institute of General Pathology * - Department of Rheumatology** -School of Medicine-Catholic University of the Sacred Heart-Via Moscati 31, 00168 Rome, Italy
References.
1. Ria F, Penitente R , De Santis M, Nicolò C, Di Sante G, Orsini M, Arzani D, Fattorossi A, Battaglia A, Ferraccioli G: Collagen-specific T-cell repertoire in blood and synovial fluid varies with disease activity in early rheumatoid arthritis. Arthritis Research & Therapy 2008, 10:R135
2. Backlund J, Carlsen S, Hoger T, Holm B, Fugger L, Kihlberg J, Burkhardt H, Holmdahl R: Predominant selection of T cells specific for the glycosylated collagen type II epitope (263-270) in humanized transgenic mice and in rheumatoid arthritis. Proc Natl Acad Sci U S A 2002, 99(15):9960-9965
3. Sekine T, Kato T, Masuko-Hongo K, Nakamura H, Yoshino S, Nishioka K, Yamamoto K: Type II collagen is a target antigen of clonally expanded T cells in the synovium of patients with rheumatoid arthritis. Ann Rheum Dis 1999, 58(7):446-450.
Competing interests
national patent RM2007A000429 and international PCT: PCT/IB2008/053152