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Deposition of complement components C5b-9 and MASP2 in tissues is not a feature of GVHD and may assist in discriminating GVHD from thrombotic microangiopathy following allogenic transplantation

Bone Marrow Transplantation volume 58, pages 1270–1274 (2023)Cite this article

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Graft-versus-host disease (GVHD) affects 40–60% of individuals with post-allogenic hematopoietic stem cell transplantation (alloHSCT) and accounts for 15% of alloHSCT-related mortality [1]. The pathophysiology of GVHD is complex, involving pro-inflammatory cytokines and complement activation [2, 3]. Our group recently reported that deposition of terminal complement component C5b-9 and lectin pathway of complement enzyme mannose-binding lectin–associated serine protease 2 (MASP2) in cutaneous microvasculature of normal-appearing skin is characteristic of patients with transplant-associated thrombotic microangiopathy (TA-TMA) [4]. However, GVHD has been implicated in confounding the ability to diagnose a complement-mediated TA-TMA clinically [5], including the use of complement deposition in tissues as an adjunct to the differential diagnosis. C5b-9 is deposited in the skin of mice developing GVHD following administration of allogenic T lymphocytes [6], but there are sparse clinical data related to complement deposition in GVHD lesions. Tosi et al. reported C3 in lesional skin from 70% of patients with acute or chronic GVHD following alloHSCT [7], but the majority were scored as low intensity occurring in conjunction with IgM, which can promote non-specific C3 adsorption. Ma et al. did report more compelling C3 staining of skin and lip in GVHD [8], and endovascular deposition of C4d has been observed in the skin of some 70% of GVHD patients, but it was “minimal” in almost one-half of cases and was complicated by high background staining attributed to non-specific collagen deposition [2].

We conducted a single-center retrospective analysis to evaluate the presence of C5b-9 and MASP2 in punch skin biopsies of lesions from 20 individuals developing cutaneous GVHD, both acute (n = 10) and chronic (n = 10), post-alloHSCT. Two of these individuals had concurrent TA-TMA. Biopsies were obtained with a median of 3 days (range 0–21 days) post-recognition of cutaneous lesions suspicious for GVHD (Table 1). The majority of individuals were not receiving steroids at the time of GVHD recognition. Currently accepted clinical criteria for the diagnosis and grading of acute [9] and chronic [10] GVHD were used. Steroid-refractory GVHD was defined as progression after 3 days, or lack of improvement after 7 days, of treatment with methylprednisolone 2 mg/kg per day equivalent [11].

Table 1 Demographics and disease characteristics in patients developing acute or chronic GVHD (with and without TA-TMA) post-alloHSCT.
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Fig. 1: Complement components C5b-9 and MASP2 deposition in skin and gut characterize TA-TMA but not GVHD.

Data availability

Data used and/or analyzed during this submission are original and they are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Stephanie Ceneus for expert technical work and Bing He for performing some of the staining. We also thank Dr Sonia Elhadad for help with statistical analysis. This work was supported by funds from Omeros Corporation and the Angelo Donghia Foundation (JL).

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  1. Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medicine/New York Presbyterian Hospital, New York, NY, USA

    Mohammad Alhomoud, Alexandra Gomez-Arteaga, Nora Chokr, Samuel Yamshon, Adrienne Phillips, Sebastian Mayer, Tsiporah Shore & Jeffrey Laurence

  2. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA

    Cynthia Magro, Surya Seshan & Taotao Zhang

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Contributions

MA and JL conceived the study and wrote the paper with critical insight from CM. CM performed the skin biopsy analyses. TZ provided the protocol and performed some of the staining. TS, SM, AP, AG, NC, and SY provided important insights and treated these patients. All authors reviewed and approved the final manuscript.

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Correspondence to Mohammad Alhomoud.

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Competing interests

JL has received research grants and speaker fees from Jazz Pharmaceuticals, Alexion, and Omeros Corporation. These entities did not have input in the study design, analysis, manuscript preparation, or decision to submit for publication. The remaining authors declare no competing financial interests.

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Alhomoud, M., Magro, C., Seshan, S. et al. Deposition of complement components C5b-9 and MASP2 in tissues is not a feature of GVHD and may assist in discriminating GVHD from thrombotic microangiopathy following allogenic transplantation. Bone Marrow Transplant 58, 1270–1274 (2023). https://doi.org/10.1038/s41409-023-02089-y

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