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Development of PBC/SSc overlap syndrome in chronic GVHD patient: immunological implications in the presence of mitochondrial, nucleolar and spindle midzone autoantigens

Roberto Assandri, Federico Serana, Alessandro Montanelli




Chronic Graft versus Host Disease (cGVHD) is a complex disease resulting from donor T-cell recognition of a genetically disparate recipient that is unable to reject donor cells after allogeneic Stem Cell Transplantation (HSCT). cGVHD has some features resembling to autoimmune diseases (AD) such as Sjögren syndrome, primary biliary cirrhosis (PBC) and scleroderma (SSc). Also patients with cGVHD could develop extensive cGVHD with scleroderma-like skin manifestations and other clinical signs similar to those of patients with scleroderma. We take into consideration a patient with GVHD that developed PBC/SSc overlap syndrome with a complex and particular autoantibodies profile. Indirect immunofluorescence (IIF) with double coloration showed a cytoplasmic mitochondrial-like pattern, a clumpy nucleolar staining pattern, and a cell-cycle related staining pattern. Following anaphase onset, proteins regulator of cytokinesis localizes to the overlap zone on the ends of midzone microtubules and becomes compacted during furrow ingression to form the midbody. Second level tests confirmed the presence of anti-mitochondrial antibodies M2-subunit but no other autoantibodies were found. We performed a home-made immunoblot analysis that identified a 37 kDa fibrillarin band, and not identify 47 kDa, 31KDa and 18/20 kDa bands. After literature review of these possible cellular localizations, the proteins recognized by our patient’s serum seem likely to be Aab to core midzone organizer components. However, due to the unavailability of the proper techniques in our laboratory, we were not able to further characterize them.  The pathogenesis and morbidity of cGVHD after HSCT remains enigmatic, but the presence of specific autoantibodies are the hallmark of AD and represent a possibility of differential diagnosis. Standard techniques combined with the use of non-routinely laboratory techniques are a usefully and complementary method for studying difficult and particular cases. In fact, these autoantibodies will be considered as ‘‘diagnostic’’ and not as ‘‘esoteric’’ antibodies. In conclusion, a re-assessment of the diagnostic protocols in cGVHD together with a precise observation of the clinical and laboratory picture will ultimately help us clarify the disease and could provide a better understanding of the immune network deregulation.

Keywords: GVHD, Immunological implications, Treatment.


Chronic Graft versus Host Disease (cGVHD), Stem Cell Trasplantation (SCT) ,primary biliary cirrhosis (PBC), scleroderma (SSc)


Copelan EA Hematopoietic stem-cell transplantation. N Engl J Med. 2006 Apr 27;354(17):1813-26

Szyska M, Na IK Bone Marrow GvHD after Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol. 2016 Mar 30;7:118

Morales-Cárdenas A, Pérez-Madrid C, Arias L, Ojeda P, Mahecha MP, Rojas-Villarraga A, Pulmonary involvement in systemic sclerosis. Autoimmun Rev. 2016 Nov;15(11):1094-1108

Socié G, Ritz J Current issues in chronic graft-versus-host disease. Blood. 2014 Jul 17;124(3):374-84

Sarantopoulos S, Stevenson KE, Kim HT, et al. Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease. Blood. 2009;113(16):3865-3874.

Corre E, Carmagnat M, Busson M, et al. Long-term immune deficiency after allogeneic stem cell transplantation: B-cell deficiency is associated with late infections. Haematologica. 2010;95(6):1025-1029.

Kuzmina Z, Krenn K, Petkov V, et al. CD19(1) CD21(low) B cells and patients at risk for NIHdefined chronic graft-versus-host disease with bronchiolitis obliterans syndrome. Blood. 2013; 121(10):1886-1895.

Kuzmina Z, Greinix HT, Weigl R, et al. Significant differences in B-cell subpopulations characterize patients with chronic graft-versus-host diseaseassociated dysgammaglobulinemia. Blood. 2011;117(7):2265-2274

Zheng B, Vincent C, Fritzler MJ, Senécal JL, Koenig M, Joyal F. Prevalence of Systemic Sclerosis in Primary Biliary Cholangitis Using the New ACR/EULAR Classification Criteria. J Rheumatol. 2016 Oct 15

Assandri R, Monari M, Montanelli A. Development of systemic sclerosis in patients with autoimmune hepatitis: an emerging overlap syndrome. Gastroenterol Hepatol Bed Bench. 2016 Summer;9(3):211-9.

Gabbiani G (2003) The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 200: 500–503. 36.

Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH, Fauci AS (1986) Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA 83: 4167–4171

Zhang Y, McCormick LL, Desai SR, Wu C, Gilliam AC (2002) Murine sclerodermatous graft-versus-host disease, a model for human scleroderma: cutaneous cytokines, chemokines, and immune cell activation. J Immunol 168:3088–3098

Leask A, Abraham DJ, Finlay DR, Holmes A, Pennington D, Shi-Wen X et al.(2002) Dysregulation of transforming growth factor beta signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts. Arthritis Rheum 46: 1857–1865.

Miklos DB, Kim HT, Zorn E, et al. Antibody response to DBY minor histocompatibility antigen is induced after allogeneic stem cell transplantation and in healthy female donors. Blood. 2004;103(1):353-359

Miklos DB, Kim HT, Miller KH, et al. Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission. Blood. 2005; 105(7):2973-2978

Baroni SS, Santillo M, Bevilacqua F, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med. 2006; 354(25):2667-2676.

Svegliati S, Olivieri A, Campelli N, et al. Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease. Blood. 2007;110(1):237-241

Mehra S, Walker J, Patterson K, Fritzler MJ. Autoantibodies in systemic sclerosis. Autoimmun Rev. 2013 Jan;12(3):340-5

Yang JM, Hildebrandt B, Luderschmidt C, Pollard KM. Human scleroderma sera contain autoantibodies to protein components specific to the U3 small nucleolar RNP complex. Arthritis Rheum 2003;48:210–7.

Gershwin ME, Rowley M, Davis PA, Leung P, Coppel R, Mackay IR. Molecular biology of the 2-oxo-acid dehydrogenase complexes and anti-mitochondrial antibodies. Prog Liver Dis. 1992;10:47–61

Fritzler MJ, Ayer LM, Gohill J, O’Connor C, Laxer RM, Humbel RL. An antigen in metaphase chromatin and the midbody of mammalian cells binds to scleroderma sera. J Rheumatol 1986;14:291–4

Hizlan, D., Mishima, M., Tittmann, P., Gross, H., Glotzer, M. and Hoenger, A. (2006). Structural analysis of the ZEN-4/CeMKLP1 motor domain and its interaction with microtubules. J. Struct. Biol. 153, 73-84

Ruchaud, S., Carmena, M. and Earnshaw, W. C. (2007). Chromosomal passengers: conducting cell division. Nat. Rev. Mol. Cell Biol. 8, 798-812.

Akhmanova, A. and Steinmetz, M. O. (2008). Tracking the ends: a dynamic protein network controls the fate of microtubule tips. Nat. Rev. Mol. Cell Biol. 9, 309-322

DOI: https://doi.org/10.22037/ghfbb.v0i0.1182