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Immunological characteristics and T-cell receptor clonal diversity in children with systemic juvenile idiopathic arthritis undergoing T-cell-depleted autologous stem cell transplantation.

Wu Q, Pesenacker AM, Stansfield A, King D, Barge D, Foster HE, Abinun M, Wedderburn LR - Immunology (2014)

Bottom Line: Children with systemic Juvenile Idiopathic Arthritis (sJIA), the most severe subtype of JIA, are at risk from destructive polyarthritis and growth failure, and corticosteroids as part of conventional treatment can result in osteoporosis and growth delay.At present, the immunological basis underlying remission after ASCT is unknown.Immune reconstitution of T cells, B cells, natural killer cells, natural killer T cells and monocytes, in parallel with T-cell receptor (TCR) diversity by analysis of the β variable region (TCRVb) complementarity determining region-3 (CDR3) using spectratyping and sequencing, were studied in five children with sJIA before and after ASCT.

View Article: PubMed Central - PubMed

Affiliation: Rheumatology Unit, UCL Institute of Child Health, University College London, London, UK.

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Highly oligoclonal CD8+ T-cell receptor β variable region (TCRVb) repertoire early in immune reconstitution in patients, who were in remission after autologous stem cell transplantation (ASCT), (Patterns A and B) compared with high TCRVb diversity in the patient who relapsed (Pattern C). Patient 1 (a) and patient 2 (b) TCRVb CDR3 length spectratyping for respective TCRVb falling into pattern A (left) and pattern B (right); TCRVb as labelled; samples tested for patient 1: before and 1 and 12 months after ASCT and for patient 2: before and 23·5 months after ASCT. (c) TCRVb CDR3 length spectratyping in same Vb families before and 3 months after ASCT in patient 3 (pattern C).
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fig03: Highly oligoclonal CD8+ T-cell receptor β variable region (TCRVb) repertoire early in immune reconstitution in patients, who were in remission after autologous stem cell transplantation (ASCT), (Patterns A and B) compared with high TCRVb diversity in the patient who relapsed (Pattern C). Patient 1 (a) and patient 2 (b) TCRVb CDR3 length spectratyping for respective TCRVb falling into pattern A (left) and pattern B (right); TCRVb as labelled; samples tested for patient 1: before and 1 and 12 months after ASCT and for patient 2: before and 23·5 months after ASCT. (c) TCRVb CDR3 length spectratyping in same Vb families before and 3 months after ASCT in patient 3 (pattern C).

Mentions: We observed different patterns in the clonality of TCRVb, when comparing diversity before, immediately after, and at later time-points after ASCT. In Fig. 3, TCRVb diversity of the CD4-negative T-cell subset (representing CD8+ T cells) is shown for three patients before and after transplant; patient 1 (Fig. 3a) and patient 2 (Fig. 3b) had successful ASCT, whereas patient 3 (Fig. 3c) relapsed after ASCT. For patient 1, at baseline, in all Vb families other than Vb15 and Vb21, TCRVb CDR3 distribution was normally diverse (representative examples shown in Fig. 3a, top). One month after transplant, TCRVb CDR3 distribution was highly skewed in every Vb family, suggesting that a highly oligoclonal T-cell repertoire was generated early in immune reconstitution. Twelve months post transplant, full CDR3 length diversity was re-established in five out of 24 families, namely TCRVb Vb1, 5, 8, 17 and 23 (Fig. 3a, pattern A). Increased T-cell clonal diversity in these instances might suggest that de novo T-cell development and TCR rearrangement occurs after ASCT and this may contribute to remission from autoimmune disease. In comparison, however, CDR3 length distribution remained skewed at 12 months post transplant in 13 of 24 families (Vb2, 3, 4, 6a, 6b, 9, 11, 13a, 13b, 14, 15, 18 and 21). Of interest, in some families, in addition to dominant peaks at different lengths, a re-emergence of some dominant peaks from pre-ASCT was observed (Fig. 3a, pattern B). This might suggest that in certain instances, some T cells, bearing specific TCRVb CDR3 expression, could persist through immunosuppressive conditioning and have a proliferative advantage over T-cell clones that are newly generated post transplant.


Immunological characteristics and T-cell receptor clonal diversity in children with systemic juvenile idiopathic arthritis undergoing T-cell-depleted autologous stem cell transplantation.

Wu Q, Pesenacker AM, Stansfield A, King D, Barge D, Foster HE, Abinun M, Wedderburn LR - Immunology (2014)

Highly oligoclonal CD8+ T-cell receptor β variable region (TCRVb) repertoire early in immune reconstitution in patients, who were in remission after autologous stem cell transplantation (ASCT), (Patterns A and B) compared with high TCRVb diversity in the patient who relapsed (Pattern C). Patient 1 (a) and patient 2 (b) TCRVb CDR3 length spectratyping for respective TCRVb falling into pattern A (left) and pattern B (right); TCRVb as labelled; samples tested for patient 1: before and 1 and 12 months after ASCT and for patient 2: before and 23·5 months after ASCT. (c) TCRVb CDR3 length spectratyping in same Vb families before and 3 months after ASCT in patient 3 (pattern C).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4008230&req=5

fig03: Highly oligoclonal CD8+ T-cell receptor β variable region (TCRVb) repertoire early in immune reconstitution in patients, who were in remission after autologous stem cell transplantation (ASCT), (Patterns A and B) compared with high TCRVb diversity in the patient who relapsed (Pattern C). Patient 1 (a) and patient 2 (b) TCRVb CDR3 length spectratyping for respective TCRVb falling into pattern A (left) and pattern B (right); TCRVb as labelled; samples tested for patient 1: before and 1 and 12 months after ASCT and for patient 2: before and 23·5 months after ASCT. (c) TCRVb CDR3 length spectratyping in same Vb families before and 3 months after ASCT in patient 3 (pattern C).
Mentions: We observed different patterns in the clonality of TCRVb, when comparing diversity before, immediately after, and at later time-points after ASCT. In Fig. 3, TCRVb diversity of the CD4-negative T-cell subset (representing CD8+ T cells) is shown for three patients before and after transplant; patient 1 (Fig. 3a) and patient 2 (Fig. 3b) had successful ASCT, whereas patient 3 (Fig. 3c) relapsed after ASCT. For patient 1, at baseline, in all Vb families other than Vb15 and Vb21, TCRVb CDR3 distribution was normally diverse (representative examples shown in Fig. 3a, top). One month after transplant, TCRVb CDR3 distribution was highly skewed in every Vb family, suggesting that a highly oligoclonal T-cell repertoire was generated early in immune reconstitution. Twelve months post transplant, full CDR3 length diversity was re-established in five out of 24 families, namely TCRVb Vb1, 5, 8, 17 and 23 (Fig. 3a, pattern A). Increased T-cell clonal diversity in these instances might suggest that de novo T-cell development and TCR rearrangement occurs after ASCT and this may contribute to remission from autoimmune disease. In comparison, however, CDR3 length distribution remained skewed at 12 months post transplant in 13 of 24 families (Vb2, 3, 4, 6a, 6b, 9, 11, 13a, 13b, 14, 15, 18 and 21). Of interest, in some families, in addition to dominant peaks at different lengths, a re-emergence of some dominant peaks from pre-ASCT was observed (Fig. 3a, pattern B). This might suggest that in certain instances, some T cells, bearing specific TCRVb CDR3 expression, could persist through immunosuppressive conditioning and have a proliferative advantage over T-cell clones that are newly generated post transplant.

Bottom Line: Children with systemic Juvenile Idiopathic Arthritis (sJIA), the most severe subtype of JIA, are at risk from destructive polyarthritis and growth failure, and corticosteroids as part of conventional treatment can result in osteoporosis and growth delay.At present, the immunological basis underlying remission after ASCT is unknown.Immune reconstitution of T cells, B cells, natural killer cells, natural killer T cells and monocytes, in parallel with T-cell receptor (TCR) diversity by analysis of the β variable region (TCRVb) complementarity determining region-3 (CDR3) using spectratyping and sequencing, were studied in five children with sJIA before and after ASCT.

View Article: PubMed Central - PubMed

Affiliation: Rheumatology Unit, UCL Institute of Child Health, University College London, London, UK.

Show MeSH
Related in: MedlinePlus