Why does alemtuzumab cause secondary autoimmunity? If we knew we could do something about it? It would make alemtuzumab use safer.
We have reported that memory B cells and memory T cells are depleted for a long time after alemtuzumab and there are naive cells returning when there is limited regulatory cell activity and that may allow break though of autoimmunity. Others argue differently. However , we have made the point that following immune depletion there are stereotyped repopulation approachesthat following depletion naive B cells expand to fill the space, whereas in the T cell compartment, there is an early expansion of remaining memory cells and then naive T cells slowly appear. In this study they look for differences between people who develop autoimmunityand those that do not…The don’t really find anything compelling in terms of celltypes. I am not surprised because they are looking for a needle in a haystack. Based on studies in animalswhere you know what the disease causing cells are, if you look in tissues they are a very small population of the the cells present, but they did find evidence that some cells persisted. In contrast with stem cell transplantation the repertoire was essentially completely different . In people developing autoimmunity they found persistent clones and when they looked at cell clones they found expansions in after the occurrence of autoimmunity.
In conclusion, our data demonstrate that
- (i) peripheral immunological alterations following alemtuzumab are mirrored by longitudinal changes in the CSF;
- (ii) incomplete T-cell repertoire renewal and reduced thymopoiesis contribute to a proautoimmune state after alemtuzumab;
- (iii) proteomics and surface immunological phenotyping do not identify patients at risk for secondary autoimmune disorders;
- (iv) homeostatic proliferation with disparate dynamics of clonal T- and B-cell expansions are associated with secondary autoimmunity; and
- (v) hyperexpanded T-cell clones at baseline and Month 12 may be used as a biomarker for the risk of alemtuzumab-induced autoimmunity.