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IgG4-related disease in autoimmune lymphoproliferative syndrome
Clinical Immunology 180 (2017) 97–99
Contents lists available at ScienceDirect
Clinical Immunology journal homepage: www.elsevier.com/locate/yclim
Letter to the Editor IgG4-related disease in autoimmune lymphoproliferative syndrome Keywords: IgG4-related disease ALPS Pancreatitis IgG4 Hypergammaglobulinemia
1. Introduction Autoimmune lymphoproliferative syndrome (ALPS) is a rare disease in which the Fas/FasL-mediated apoptosis of lymphocytes is disturbed. Increased CD3+ TCRα/β+ CD4− CD8− ‘double negative’ T cells (DNT) are the hallmark of disease, but many patients also display alterations in the B cell compartment. Impaired lymphocyte homeostasis predisposes patients to autoimmune cytopenia, lymphoproliferative disease and hematologic malignancies. 2. Case report and additional case series A 26-year-old male presented in 2011 with generalized lymphadenopathy, splenomegaly, and multiple masses up to 4 cm in the renal cortex. Renal biopsy showed a further undifferentiated monomorphic infiltration of CD3+ T lymphocytes. Laboratory investigations revealed polyclonal hypergammaglobulinemia (IgG 4010 mg/dL, ref. 700–1600) and increased serum concentrations of cobalamin (3178 pg/mL, ref. 191–663), soluble interleukin-2 (IL-2) receptor (6871 U/mL, ref. 158– 623), IL-10, and soluble Fas ligand (FasL) (631.40 pg/mL, ref. b200). DNT were increased (8.6%, ref. b 1), and in vitro T lymphocyte apoptosis was reduced (19.8%, ref. N80). These findings fulfilled the revised diagnostic criteria of ALPS [1]. The diagnosis ALPS-FAS was confirmed by detection of a missense mutation in exon 9 of the FAS/CD95/APO-1/TNFRSF6 gene. Repeated renal biopsy showed a mixed form of tubular damage, without infiltration of DNT or lymphoproliferation. Immunosuppressive therapy with rapamycin was initiated, reducing lymphadenopathy, renal masses and ALPS-associated biomarkers. Two years later, the patient developed acute pancreatitis. Discontinuation of rapamycin did not improve the clinical symptoms. Computed tomography had shown nodular changes of the pancreatic head, suggestive of lymphocytic infiltration, and the patient was referred to our clinic. IgG subclass measurements revealed a drastic polyclonal IgG4 elevation of 6500 mg/dl (ref. b135). Peripheral blood T cell receptor (TCR) and IgH
Abbreviations: CTL, cytotoxic T lymphocytes; DNT, CD3+ TCRα/β+ CD4− CD8− double negative T cells; FasL, Fas ligand; GC, germinal center. 1 Present address: Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, The Netherlands.
http://dx.doi.org/10.1016/j.clim.2017.05.003 1521-6616/© 2017 Elsevier Inc. All rights reserved.
clonality testing revealed polyclonality. Pancreas biopsy showed lobular fibrosis and infiltrates containing eosinophilic granulocytes, CD4+ T lymphocytes, and plasma cells. The majority of pancreatic plasma cells were IgG4+ (N 10 cells/hpf), consistent with the diagnosis of IgG4related disease (Fig. 1, B, D, F) [2]. Glucocorticoids were successfully administered. IgG4-related disease is a multi-organ disease of uncertain pathogenesis, affecting preferentially exocrine glands [3]. Serum IgG4 levels are of limited diagnostic value; elevated plasmablasts are potential disease biomarkers. In retrospect, the patient's serum from 2011 already showed elevated IgG4 (5540 mg/dL) and CD20− CD38++ CD27+ plasmablasts (11.8%, ref. 0.4–3.6), several years before the onset of pancreatitis. IgE levels were increased up to 7750 IE/mL (ref. 10–100) with neither eosinophilia nor allergic symptoms. Revision of a lymph node biopsy from 2010 showed a relative increase of IgG4+ plasma cells (Fig. 1, A, C, E), but further criteria of an IgG4-related disease were not yet matched. Revision of the residual kidney biopsy material showed CD38+ plasma cells without glomerular immune complex depositions, which does not meet the criteria for IgG4-related disease. To determine whether IgG4-related disease could be common in ALPS, we screened eighteen further patients with a genetic diagnosis of ALPS-FAS, lymphoproliferative disease, and elevated total IgG. Hypergammaglobulinemia is present in 80% of ALPS-FAS patients. According to the diagnostic criteria of IgG4-related diseases, four of eighteen patients (22%) showed elevated IgG4, but at much lower levels than the index patient and without associated organ pathology [2].
3. Discussion To our knowledge, this is the second case describing a link between IgG4-related disease and ALPS [4]. A common pathogenesis for ALPS and IgG4-related disease has not been described. Recently, clonally expanded CD4+ granzyme A+(GZMA+) cytotoxic T cells (CTL) were detected in blood [5] and affected organs [6] of IgG4-related disease patients. These cells act in concert with B cells and plasmablasts and produce high levels of IL-1 and interferon-gamma, presumably driving the development of fibrosis by activating macrophages and fibroblasts. Fas deficiency in murine B cells causes intrinsic B cell differentiation defects and aberrant elimination of self-reactive B cells, leading to an unconventional “rogue” population of germinal center B cells which develop in IgE- and IgG autoantibody-producing plasmablasts [7]. Possibly, the absence of Fas in both B and T lymphocytes of our patient allowed for the development of comparable rogue B cells and/or for clonal expansion of CD4+ GZMA+ CTL. Thus, IgG4-related disease may be favored by the pathophysiological consequences of Fas deficiency. Screening of IgG4 levels and clinical hints for IgG4-related disease may be justified in ALPS patients. As they generally present at a younger age than patients with IgG4-related disease, overt disease might eventually develop in those with high IgG4. Screening of IgG4-related disease cohorts
98
Letter to the Editor
Fig. 1. Histopathologic manifestations of IgG4-related disease. Lymph node (A, C, E) and pancreatic biopsies (B, D, F). A. T-zone expansion (arrowheads) while secondary follicles (dotted line) are well-preserved (H&E). C, E. Immunolabelling for IgG (C) and IgG4 (E) reveals abundant plasma cells throughout the paracortex and germinal centers; IgG4:IgG ratio ~ 20%. D. Partial pancreatic scarring with intermingled eosinophils and intramural lymphocytes in a small venous vessel (arrowheads). E. IgG + plasma cells (brown; 36/HPF) between glandular lobuli. F. IgG4+ (32/HPF) plasma cells. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
for ALPS-associated mutations would provide further information on whether this disease could be a late-onset atypical presentation of ALPS. In conclusion, IgG4-related disease should be considered in ALPS patients, especially when manifesting lymphocytic organ infiltration, hypergammaglobulinemia, or symptoms refractory to rapamycin.
References [1] J.B. Oliveira, J.J. Bleesing, U. Dianzani, T.A. Fleisher, E.S. Jaffe, M.J. Lenardo, et al., Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop, Blood 116 (14) (2010) e35–e40. [2] H. Umehara, K. Okazaki, Y. Masaki, M. Kawano, M. Yamamoto, T. Saeki, et al., Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011, Mod. Rheumatol. 22 (1) (2012) 21–30. [3] T. Kamisawa, Y. Zen, S. Pillai, J.H. Stone, IgG4-related disease, Lancet 385 (9976) (2015) 1460–1471. [4] R.C. Langan, F. Gill, M.T. Raiji, J.E. Mullinax, S. Pittaluga, P. Pandalai, et al., Autoimmune pancreatitis in the autoimmune lymphoproliferative syndrome (ALPS): a sheep in wolves' clothing? Pancreas 42 (2) (2013) 363–366. [5] H. Mattoo, V.S. Mahajan, T. Maehara, V. Deshpande, E. Della-Torre, Z.S. Wallace, et al., Clonal expansion of CD4(+) cytotoxic T lymphocytes in patients with IgG4-related disease, J. Allergy Clin. Immunol. 138 (3) (2016) 825–838.
[6] T. Maehara, H. Mattoo, M. Ohta, V.S. Mahajan, M. Moriyama, M. Yamauchi, et al., Lesional CD4+ IFN-gamma+ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis, Ann. Rheum. Dis. (2016). [7] D. Butt, T.D. Chan, K. Bourne, J.R. Hermes, A. Nguyen, A. Statham, et al., FAS inactivation releases unconventional germinal center B cells that escape antigen control and drive IgE and autoantibody production, Immunity 42 (5) (2015) 890–902.
Annick A.J.M. van de Ven Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Maximilian Seidl Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Institute of Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Vanessa Drendel Annette Schmitt-Graeff Institute of Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Letter to the Editor
Reinhard E. Voll Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Department of Rheumatology and Clinical Immunology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Anne Rensing-Ehl Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Carsten Speckmann Stephan Ehl Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Center for Pediatrics and Adolescent Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
99
Klaus Warnatz Florian Kollert* Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Department of Rheumatology and Clinical Immunology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany ⁎Corresponding author at: Department of Rheumatology and Clinical Immunology Center of Chronic Immunodeficiency University Medical Center Freiburg, Faculty of Medicine University of Freiburg, Germany. E-mail address: fl[email protected]. 16 January 2017 Available online 3 May 2017
Contents lists available at ScienceDirect
Clinical Immunology journal homepage: www.elsevier.com/locate/yclim
Letter to the Editor IgG4-related disease in autoimmune lymphoproliferative syndrome Keywords: IgG4-related disease ALPS Pancreatitis IgG4 Hypergammaglobulinemia
1. Introduction Autoimmune lymphoproliferative syndrome (ALPS) is a rare disease in which the Fas/FasL-mediated apoptosis of lymphocytes is disturbed. Increased CD3+ TCRα/β+ CD4− CD8− ‘double negative’ T cells (DNT) are the hallmark of disease, but many patients also display alterations in the B cell compartment. Impaired lymphocyte homeostasis predisposes patients to autoimmune cytopenia, lymphoproliferative disease and hematologic malignancies. 2. Case report and additional case series A 26-year-old male presented in 2011 with generalized lymphadenopathy, splenomegaly, and multiple masses up to 4 cm in the renal cortex. Renal biopsy showed a further undifferentiated monomorphic infiltration of CD3+ T lymphocytes. Laboratory investigations revealed polyclonal hypergammaglobulinemia (IgG 4010 mg/dL, ref. 700–1600) and increased serum concentrations of cobalamin (3178 pg/mL, ref. 191–663), soluble interleukin-2 (IL-2) receptor (6871 U/mL, ref. 158– 623), IL-10, and soluble Fas ligand (FasL) (631.40 pg/mL, ref. b200). DNT were increased (8.6%, ref. b 1), and in vitro T lymphocyte apoptosis was reduced (19.8%, ref. N80). These findings fulfilled the revised diagnostic criteria of ALPS [1]. The diagnosis ALPS-FAS was confirmed by detection of a missense mutation in exon 9 of the FAS/CD95/APO-1/TNFRSF6 gene. Repeated renal biopsy showed a mixed form of tubular damage, without infiltration of DNT or lymphoproliferation. Immunosuppressive therapy with rapamycin was initiated, reducing lymphadenopathy, renal masses and ALPS-associated biomarkers. Two years later, the patient developed acute pancreatitis. Discontinuation of rapamycin did not improve the clinical symptoms. Computed tomography had shown nodular changes of the pancreatic head, suggestive of lymphocytic infiltration, and the patient was referred to our clinic. IgG subclass measurements revealed a drastic polyclonal IgG4 elevation of 6500 mg/dl (ref. b135). Peripheral blood T cell receptor (TCR) and IgH
Abbreviations: CTL, cytotoxic T lymphocytes; DNT, CD3+ TCRα/β+ CD4− CD8− double negative T cells; FasL, Fas ligand; GC, germinal center. 1 Present address: Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, The Netherlands.
http://dx.doi.org/10.1016/j.clim.2017.05.003 1521-6616/© 2017 Elsevier Inc. All rights reserved.
clonality testing revealed polyclonality. Pancreas biopsy showed lobular fibrosis and infiltrates containing eosinophilic granulocytes, CD4+ T lymphocytes, and plasma cells. The majority of pancreatic plasma cells were IgG4+ (N 10 cells/hpf), consistent with the diagnosis of IgG4related disease (Fig. 1, B, D, F) [2]. Glucocorticoids were successfully administered. IgG4-related disease is a multi-organ disease of uncertain pathogenesis, affecting preferentially exocrine glands [3]. Serum IgG4 levels are of limited diagnostic value; elevated plasmablasts are potential disease biomarkers. In retrospect, the patient's serum from 2011 already showed elevated IgG4 (5540 mg/dL) and CD20− CD38++ CD27+ plasmablasts (11.8%, ref. 0.4–3.6), several years before the onset of pancreatitis. IgE levels were increased up to 7750 IE/mL (ref. 10–100) with neither eosinophilia nor allergic symptoms. Revision of a lymph node biopsy from 2010 showed a relative increase of IgG4+ plasma cells (Fig. 1, A, C, E), but further criteria of an IgG4-related disease were not yet matched. Revision of the residual kidney biopsy material showed CD38+ plasma cells without glomerular immune complex depositions, which does not meet the criteria for IgG4-related disease. To determine whether IgG4-related disease could be common in ALPS, we screened eighteen further patients with a genetic diagnosis of ALPS-FAS, lymphoproliferative disease, and elevated total IgG. Hypergammaglobulinemia is present in 80% of ALPS-FAS patients. According to the diagnostic criteria of IgG4-related diseases, four of eighteen patients (22%) showed elevated IgG4, but at much lower levels than the index patient and without associated organ pathology [2].
3. Discussion To our knowledge, this is the second case describing a link between IgG4-related disease and ALPS [4]. A common pathogenesis for ALPS and IgG4-related disease has not been described. Recently, clonally expanded CD4+ granzyme A+(GZMA+) cytotoxic T cells (CTL) were detected in blood [5] and affected organs [6] of IgG4-related disease patients. These cells act in concert with B cells and plasmablasts and produce high levels of IL-1 and interferon-gamma, presumably driving the development of fibrosis by activating macrophages and fibroblasts. Fas deficiency in murine B cells causes intrinsic B cell differentiation defects and aberrant elimination of self-reactive B cells, leading to an unconventional “rogue” population of germinal center B cells which develop in IgE- and IgG autoantibody-producing plasmablasts [7]. Possibly, the absence of Fas in both B and T lymphocytes of our patient allowed for the development of comparable rogue B cells and/or for clonal expansion of CD4+ GZMA+ CTL. Thus, IgG4-related disease may be favored by the pathophysiological consequences of Fas deficiency. Screening of IgG4 levels and clinical hints for IgG4-related disease may be justified in ALPS patients. As they generally present at a younger age than patients with IgG4-related disease, overt disease might eventually develop in those with high IgG4. Screening of IgG4-related disease cohorts
98
Letter to the Editor
Fig. 1. Histopathologic manifestations of IgG4-related disease. Lymph node (A, C, E) and pancreatic biopsies (B, D, F). A. T-zone expansion (arrowheads) while secondary follicles (dotted line) are well-preserved (H&E). C, E. Immunolabelling for IgG (C) and IgG4 (E) reveals abundant plasma cells throughout the paracortex and germinal centers; IgG4:IgG ratio ~ 20%. D. Partial pancreatic scarring with intermingled eosinophils and intramural lymphocytes in a small venous vessel (arrowheads). E. IgG + plasma cells (brown; 36/HPF) between glandular lobuli. F. IgG4+ (32/HPF) plasma cells. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
for ALPS-associated mutations would provide further information on whether this disease could be a late-onset atypical presentation of ALPS. In conclusion, IgG4-related disease should be considered in ALPS patients, especially when manifesting lymphocytic organ infiltration, hypergammaglobulinemia, or symptoms refractory to rapamycin.
References [1] J.B. Oliveira, J.J. Bleesing, U. Dianzani, T.A. Fleisher, E.S. Jaffe, M.J. Lenardo, et al., Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop, Blood 116 (14) (2010) e35–e40. [2] H. Umehara, K. Okazaki, Y. Masaki, M. Kawano, M. Yamamoto, T. Saeki, et al., Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011, Mod. Rheumatol. 22 (1) (2012) 21–30. [3] T. Kamisawa, Y. Zen, S. Pillai, J.H. Stone, IgG4-related disease, Lancet 385 (9976) (2015) 1460–1471. [4] R.C. Langan, F. Gill, M.T. Raiji, J.E. Mullinax, S. Pittaluga, P. Pandalai, et al., Autoimmune pancreatitis in the autoimmune lymphoproliferative syndrome (ALPS): a sheep in wolves' clothing? Pancreas 42 (2) (2013) 363–366. [5] H. Mattoo, V.S. Mahajan, T. Maehara, V. Deshpande, E. Della-Torre, Z.S. Wallace, et al., Clonal expansion of CD4(+) cytotoxic T lymphocytes in patients with IgG4-related disease, J. Allergy Clin. Immunol. 138 (3) (2016) 825–838.
[6] T. Maehara, H. Mattoo, M. Ohta, V.S. Mahajan, M. Moriyama, M. Yamauchi, et al., Lesional CD4+ IFN-gamma+ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis, Ann. Rheum. Dis. (2016). [7] D. Butt, T.D. Chan, K. Bourne, J.R. Hermes, A. Nguyen, A. Statham, et al., FAS inactivation releases unconventional germinal center B cells that escape antigen control and drive IgE and autoantibody production, Immunity 42 (5) (2015) 890–902.
Annick A.J.M. van de Ven Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Maximilian Seidl Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Institute of Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Vanessa Drendel Annette Schmitt-Graeff Institute of Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Letter to the Editor
Reinhard E. Voll Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Department of Rheumatology and Clinical Immunology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Anne Rensing-Ehl Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Carsten Speckmann Stephan Ehl Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Center for Pediatrics and Adolescent Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
99
Klaus Warnatz Florian Kollert* Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Department of Rheumatology and Clinical Immunology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany ⁎Corresponding author at: Department of Rheumatology and Clinical Immunology Center of Chronic Immunodeficiency University Medical Center Freiburg, Faculty of Medicine University of Freiburg, Germany. E-mail address: fl[email protected]. 16 January 2017 Available online 3 May 2017