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Haematopoietic stem cell transplantation (HSCT) is an effective treatment for severe autoimmune diseases such as systemic lupus erythematosus (SLE).1 However, it is increasingly recognised that these patients have an added propensity to develop secondary autoimmune disorders.2 ,3
Here, we report on a 21-year-old male patient who received a CD34-selected autologous HSCT following conditioning with antithymocyte-globulin and cyclophosphamide (CYC) after written informed consent for refractory, severe SLE with renal, haematological, mucocutaneous and musculoskeletal manifestations (SLEDAI 19).1 Clinical remission was achieved for SLE within 3 months after HSCT and anti-double-stranded DNA (anti-dsDNA) antibodies disappeared despite immunosuppressive drug withdrawal. Eight months after HSCT, the patient presented with spontaneous joint and skin bleeding and was diagnosed with factor VIII (FVIII) inhibitor haemophilia with an activated partial thromboplastin time >100 s, FVIII activity <1% and a FVIII inhibitor titre of 435 Bethesda units (figure 1A). At that time point, flow cytometric analyses revealed a drastic increase in B cell numbers, expansion of circulating plasmablasts and a predominance of CD45RO memory CD4 T cells with oligoclonal T cell receptor Vβ expression (table 1), but clinical and laboratory tests showed no evidence of lupus activity. FVIII haemophilia was refractory to methylprednisolone, plasmapheresis, intravenous immunoglobulin (IVIG), intravenous CYC, rituximab and extracorporeal apheresis in combination with IVIG and oral CYC, but later resolved spontaneously during a relapse of SLE 36 months post-transplantation (with similar disease manifestations compared with pre-HSCT) while the patient was on low-dose prednisolone (5 mg/day).
Secondary autoimmunity typically arises during reconstitution of the immune repertoire, where, in genetically susceptible individuals, T cells regenerated into the lymphopenic environment may be skewed towards autoreactivity4 ,5 and promote the development of plasma cells (PCs) secreting autoantibodies, for example, against clotting FVIII inhibitor, as described earlier.3 ,6 These PCs can be extremely resistant to immunosuppressive and B cell depletion therapy,3 which reflects their longevity in bone marrow survival niches that are abundantly available after immunoablation.7 In our patient, acquired FVIII inhibitor persisted despite these therapies but surprisingly disappeared from serum when the SLE relapsed. Since lupus reactivation was accompanied by PC formation and lupus-specific autoantibody production several months before the flare, we assume that the resolution of FVIII haemophilia was mediated by FVIII-specific PCs being displaced by the vast number of recurring lupus-specific PCs competing for survival niches.7 ,8 Although PC competition occurs in the bone marrow, it is mirrored by an increase in HLA-DRlow mature PCs in peripheral blood, as indicated by vaccination studies.9 Accordingly, during the period when autoantibodies switched from being FVIII specific to lupus specific, we observed increased frequencies of circulating HLA-DRlow PCs, which may represent displaced FVIII-specific PCs. At the time of lupus reactivation, most PCs were dsDNA specific (figure 1C) and had an HLA-DRhigh phenotype representing newly generated PCs – a typical feature of active SLE.10
Although it is obviously difficult to prove in humans, our data may suggest a model in which development and resolution of secondary autoimmunity after autologous HSCT may be mediated by competition of PCs for survival niches in the bone marrow or inflamed tissues. Collectively, these findings support our concept of PC competition for survival niches as such,7 indicate a role for long-lived PCs in the maintenance of secondary autoimmunity and suggest a rationale for therapeutic PC targeting in refractory secondary autoimmune disorders.
Handling editor Tore K Kvien
Contributors TA, SS, BH, QC and SZ carried out most of the experiments; FH, RA, AT and AHR made substantial contributions to the conception and design of the study; TA, G-RB, RA and FH conducted the clinical trial; and TA, SS, AHR and FH wrote the manuscript. All authors read and approved the final manuscript.
Funding This work was supported by the Deutsche Forschungsgemeinschaft (SFB650 TP12 and TP17).
Competing interests None.
Patient consent Obtained.
Ethics approval Local IRB Berlin.
Provenance and peer review Not commissioned; externally peer reviewed.