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Development and resolution of secondary autoimmunity after autologous haematopoietic stem cell transplantation for systemic lupus erythematosus: competition of plasma cells for survival niches?
  1. Tobias Alexander1,2,
  2. Sandra Schneider1,2,
  3. Bimba Hoyer1,2,
  4. Qingyu Cheng1,2,
  5. Andreas Thiel2,3,
  6. Sabine Ziemer4,
  7. Gerd-Rüdiger Burmester1,
  8. Renate Arnold5,
  9. Andreas Radbruch2,
  10. Falk Hiepe1,2
  1. 1 Department of Medicine, Division of Rheumatology and Clinical Immunology, Charité – University Medicine Berlin, Berlin, Germany
  2. 2 German Rheumatism Research Center (DRFZ), Berlin, Germany
  3. 3 Regenerative Immunology and Aging, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité – University Medicine Berlin, Berlin, Germany
  4. 4 Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité – University Medicine Berlin, Berlin, Germany
  5. 5 Medical Department, Division of Hematology, Oncology and Tumor Immunology, Charité – University Medicine Berlin, Berlin, Germany
  1. Correspondence to Dr Falk Hiepe, Department of Medicine, Division of Rheumatology and Clinical Immunology, Charité – University Medicine Berlin, Charitéplatz 1, Berlin 10117, Germany; falk.hiepe{at}

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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).

Table 1

Significantly expanded T cell receptor (TCR) Vβ-expressing CD4 T cells at baseline (pre-Tx) and during follow-up after haematopoietic stem-cell transplantation (after Tx), analysed with 22 TCR Vβ-specific mononuclear antibodies (IOTest Beta Mark, Beckman Coulter Immunotech) and flow cytometry

Figure 1

Haemostaseology, serologic and immunophenotypic findings after CD34-selected autologous haematopoietic stem cell transplantation (HSCT) for systemic lupus erythematosus (SLE). (A) The association between clinical events (including onset of factor VIII (FVIII) haemophilia and relapse of SLE), levels of coagulation factors for activated partial thromboplastin time (aPTT), FVIII activity, FVIII-specific (FVIII inhibitor) and lupus-specific autoantibody titres, including antinuclear antibodies (ANA), anti-double-stranded DNA (anti-dsDNA), anti-ribonucleoprotein (anti-RNP) and anti-Smith (anti-Sm) antibodies and the number of circulating CD27 naive and CD27 memory CD20 B cells, respectively, CD19 CD20 CD27high plasma cells (PCs), CD45RA CD31 thymic naive and CD45RO memory CD4 T cells. Normal ranges are as follows: aPTT, 26–40 s; FVIII, 50%–150%; FVIII inhibitor, <1 Bethesda units (BUs) per millilitre; ANA, <1 : 320; anti-dsDNA, anti-RNP and anti-Sm, <1.5 relative units (RUs) (Dr Fooke Laboratories, Germany); CD27 naive B cells, 101–396/µl; CD27 memory B cells, 30–294/µl; CD19 CD20 CD27high PCs, 1.6–10.6/µl; CD31 CD45RA naive CD4 T cells, 91–411/µl; CD45RO memory CD4 T cells, 232–765/µl. The dashed lines indicate time points of treatments. (B) The phenotype of circulating CD19 B cells with respect to surface expression of CD20 (clone L27) and CD27 (clone 2E4) to assess levels of CD27 naive and CD27 memory CD20 B cells, respectively, and CD19 CD20 CD27high PCs (left row). Surface expression analysis of HLA-DR (clone LN3) on gated CD20 CD27high PCs (red histograms) was performed to discriminate between short-lived (HLA-DRhigh) and long-lived (HLA-DRlow) PCs (right row). Filled histograms are gated on CD20 B cells as controls. (C) The number of antibody-secreting cells using Enzyme-Linked Immuno Spot assay after magnetic enrichment of CD27 cells from peripheral blood mononuclear cells during SLE flare 36 months after HSCT. The purity of the isolated cells was >95%. The bars show the total number of peripheral blood antibody-secreting cells (per 1×106 CD27 cells) for IgM, IgG and IgA (left rows) and anti-dsDNA specific (right rows). AZA, azathioprine; CYC, cyclophosphamide; HLA, human leucocyte antigen; HQL, hydroxychloroquine; IVIG, intravenous immunoglobulin therapy; IA, immunoadsorption; MP, methylprednisolone; PP, plasmapheresis; RTX, Rituximab.

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.


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  • 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.