Contributions
Abstract: 71
Type: Oral
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: Results from phase II and III trials showed that treatment with anti-CD52 is significantly more efficacious than interferon β-1a in reducing the relapse rate in patients with active RR-MS. Unfortunately, treatment with this drug is associated with a 30% incidence of development of secondary autoimmune thyroid disease (AITD). A biomarker of increased risk for development of AITD might enable stratification of patients to avoid this risk. We have previously reported that in new onset type 1 diabetics (T1D) and a proportion of their first-degree relatives, high affinity anergic insulin-reactive B cells that are normally resident in peripheral blood are lost, but accumulate in the pancreas where they participate in T1D development. Thus loss of anergic insulin-reactive B cells may serve as a biomarker for increased risk for T1D. We hypothesized that anergic thyroglobulin (TG) and/or thyroid peroxidase (TPO)-reactive B cell departure from peripheral blood may mark subjects at risk of AITD, for whom anti-CD52 therapy should be avoided.
Goals of study: Determine whether anergic TG and TPO-reactive B cells are lost in new onset AITD patients and, if so, whether this loss is an indicator of high risk of development of AITD in healthy subjects.
Methods: Using magnetic particles to enrich for TG and TPO-reactive B cells from peripheral blood of AITD subjects and healthy controls, we analyzed the frequency and phenotype of various B cell populations.
Results: We observed a significant loss of TG and TPO+ anergic B cells in the peripheral blood of new onset AITD subjects compared to healthy controls. In addition, healthy controls maintained a higher frequency of these cells in the anergic state compared to non-reactive B cells, indicating enhanced anergy of these autoreactive cells. In addition, in AITD subjects TG+ B cells exhibited a significant increase in expression of the activation marker CD86 compared to healthy controls, indicating early activation of these cells. Consistent with activation and autoantibody production by these cells, loss of anergic TG/TPO+ B cells was inversely correlated to patients' anti-TG/TPO titers.
Conclusions: Loss of anergic TG/TPO+ B cells from peripheral blood occurs early in AITD and is associated with activation of these cells and autoantibody production. These findings justify expansion of this study to analyze anergic B cell status in first degree relatives of AITD patients and longitudinal analysis of risk.
Disclosure: This study was funded by Sanofi Genzyme.
Abstract: 71
Type: Oral
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: Results from phase II and III trials showed that treatment with anti-CD52 is significantly more efficacious than interferon β-1a in reducing the relapse rate in patients with active RR-MS. Unfortunately, treatment with this drug is associated with a 30% incidence of development of secondary autoimmune thyroid disease (AITD). A biomarker of increased risk for development of AITD might enable stratification of patients to avoid this risk. We have previously reported that in new onset type 1 diabetics (T1D) and a proportion of their first-degree relatives, high affinity anergic insulin-reactive B cells that are normally resident in peripheral blood are lost, but accumulate in the pancreas where they participate in T1D development. Thus loss of anergic insulin-reactive B cells may serve as a biomarker for increased risk for T1D. We hypothesized that anergic thyroglobulin (TG) and/or thyroid peroxidase (TPO)-reactive B cell departure from peripheral blood may mark subjects at risk of AITD, for whom anti-CD52 therapy should be avoided.
Goals of study: Determine whether anergic TG and TPO-reactive B cells are lost in new onset AITD patients and, if so, whether this loss is an indicator of high risk of development of AITD in healthy subjects.
Methods: Using magnetic particles to enrich for TG and TPO-reactive B cells from peripheral blood of AITD subjects and healthy controls, we analyzed the frequency and phenotype of various B cell populations.
Results: We observed a significant loss of TG and TPO+ anergic B cells in the peripheral blood of new onset AITD subjects compared to healthy controls. In addition, healthy controls maintained a higher frequency of these cells in the anergic state compared to non-reactive B cells, indicating enhanced anergy of these autoreactive cells. In addition, in AITD subjects TG+ B cells exhibited a significant increase in expression of the activation marker CD86 compared to healthy controls, indicating early activation of these cells. Consistent with activation and autoantibody production by these cells, loss of anergic TG/TPO+ B cells was inversely correlated to patients' anti-TG/TPO titers.
Conclusions: Loss of anergic TG/TPO+ B cells from peripheral blood occurs early in AITD and is associated with activation of these cells and autoantibody production. These findings justify expansion of this study to analyze anergic B cell status in first degree relatives of AITD patients and longitudinal analysis of risk.
Disclosure: This study was funded by Sanofi Genzyme.