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Bone marrow T-cell infiltrates in viral
infections and autoimmune diseases
Alexander Tzankov
Institute of Pathology, University Hospital Basel
Bone marrow T-cell infiltrates
• Physiological roles of mature bone marrow T-cells
• Bone marrow T-cells in viral infections
• Bone marrow T-cells in (auto)immune conditions
• Bone marrow T-cells and drug reactions
• Paraneoplastic bone marrow T-cell expansions
• Summary
Bone marrow T-cell infiltrates
• Physiological roles of mature bone marrow T-cells
• Bone marrow T-cells in viral infections
• Bone marrow T-cells in (auto)immune conditions
• Bone marrow T-cells and drug reactions
• Paraneoplastic bone marrow T-cell expansions
• Summary
Bone marrow T-cells, physiology
• 7-9% B-cells
• 20-25% T-cells
8-9% CD4+ T-cells
14-18% CD8+ T-cells
CD4/CD8 = 0.5-0.7
2-5% NK-cells
• Higher & less CD8-skewed in aspirates
Clark et al. Blood 1986;67:1660
Bone marrow T-cells, physiology
Dean et al. Immunol Let 2005;99:94
Di Rosa. Immunol Cell Biol 2009;87:20
• >50% of bone marrow T-cells express
CD69, early activation marker
HLA-DR, late activation marker
• Only 25% CD45RA+/RO- naïve T-cells
• Major source of CD8+ long-lived memory T-cells
• Region-specific regulative/protective function?
Bone marrow T-cells, physiology
Herndler-Brandstetter et al. J Leuk Biol 2012;91:197
Herndler-Brandstetter et al. J Immunol 2011;186;6965
Feuerer et al. Nat Med 2003;9:1151
• Bone marrow T-cells stimulated in situ by dendritic cells
• Cytotoxic defense against systemic blood-borne antigens
Bone marrow T-cells, physiology
Lord et al. Blood 1973; 42:395
Trainin et al. Nature 1969;221:1154
Ilstad et al. J Immunol 1984;136:28
Monteiro et al. Blood 2005; 15:105
Lee et al. J Immunol 2009;10:6377
Schwarzenberger et al. J Immunol 2000;164:4783
• Thymectomized mice become anemic
• T-cell infusion aid hematopoietic reconstitution
• Attributable to CD4+ bone marrow T-cells
• Dependent on MHC matching
• Major source of GM-CSF, IL3-6 & 13
• Granulopoiesis Th17/Treg dependent
Bone marrow T-cell infiltrates
• Physiological roles of mature bone marrow T-cells
• Bone marrow T-cells in viral infections
• Bone marrow T-cells in (auto)immune conditions
• Bone marrow T-cells and drug reactions
• Paraneoplastic bone marrow T-cell expansions
• Summary
Epstein-Barr virus
• Atypical peripheral T-cell lymphocytosis (CD8 skewed)
• Bone marrow T-cell lymphocytosis (CD8 skewed)
Occasional antigenic loss for CD5 or CD7
Occasionally T-cell clonality
• Plasmacytosis (more prominent in immunocompromized)
• PTLD
• Hemophagocytosis/Hemophagocytic syndrome
Epstein-Barr virus
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CD8
Cytomegalovirus
• (T-LGL) atypical peripheral lymphocytosis
Occasionally T-cell clonality
• Bone marrow T-cell lymphocytosis (CD8 skewed)
• Fibrin ring granulomas
• Hypoplasia in immunocompromized
Human herpes virus 8
• Lympho-follicular hyperplasia
Occasionally with Castleman features
• Plasmacytosis
• T-cell increase
Bacon et al. Br J Haematol 2005; 127:585
Bone marrow T-cell infiltrates
• Physiological roles of mature bone marrow T-cells
• Bone marrow T-cells in viral infections
• Bone marrow T-cells in (auto)immune conditions
• Bone marrow T-cells and drug reactions
• Paraneoplastic bone marrow T-cell expansions
• Summary
Marrow T-cells and autoimmunity
• T-cell (T-LGL skewed) lymphocytosis
• Erythro- and megakaryopoietic changes
Hemolysis (AIHA) & peripheral platelet consumption
“Anemia of chronic disease”
• Plasmacytosis
• (Autoimmune) myelofibrosis
• Pure red cell aplasia
• Aplastic anemia
Rizzi et al. Leuk & Lymphoma 2004;45:561
Bass et al. AJCP 2001;116:211
Voulgarelis et al. Am J Hematol 2006;81:590
Prochorec-Sobieszek et al. Arthritis Res Ther 2008;10:R55
Aplastic anemia as a collateral
damage of immunosurveillance?
Maciejewski et al. Folia Histochem Cytobiol 2007;45:5
Bone marrow T-cell infiltrates
• Physiological roles of mature bone marrow T-cells
• Bone marrow T-cells in viral infections
• Bone marrow T-cells in (auto)immune conditions
• Bone marrow T-cells and drug reactions
• Paraneoplastic bone marrow T-cell expansions
• Summary
Marrow T-cells and drug reactions
• Drugs commonly associated with T-cell increase Allopurinol
Phenytoin
Rituximab (Alemtuzumab)
Imatinib
HBV immunization
• Histopathology T-cell infiltration
Occasionally clonal
CD4 skewed, occasionally PD-1 increase
Eosinophilia
Myelopoietic maturation arrest
Granulomas
Villard et al. Br J Haematol 2000;110:230
Braziel et al. Blood 2002;100:435
Raynaud et al. Hum Pathol 2008;39:194
Johns et al. MJHID 2010;6207
Bone marrow T-cell infiltrates
• Physiological roles of mature bone marrow T-cells
• Bone marrow T-cells in viral infections
• Bone marrow T-cells in (auto)immune conditions
• Bone marrow T-cells and drug reactions
• Paraneoplastic bone marrow T-cell expansions
• Summary
Paraneoplastic T-cell expansions
• B-cell lymphomas
Marginal zone B-cell lymphoma
Lymphoplasmacytic lymphoma
Follicular lymphoma
• AML, particularly MLL rearranged
• MDS
• MPN
• Thymomas
• Systemic mastocytosis
Horny et al. J Clin Pathol 2003;56:575
Magalhães et al. Leuk Res 2002;26:525
Smith et al. AJCP 1994;102:447
Cervantes et al. Br J Haematol 1988;70:279
Bone marrow T-cell infiltrates
• Physiological roles of mature bone marrow T-cells
• Bone marrow T-cells in viral infections
• Bone marrow T-cells in (auto)immune conditions
• Bone marrow T-cells and drug reactions
• Paraneoplastic bone marrow T-cell expansions
• Summary
Summary
• Important physiological role of T-cells in the bone marrow
• Rise and CD8 skewing in viral and autoimmune diseases
Look for viropathic effects and ask for clinics, serology & PCR
• Rise and CD4 skewing in adverse drug reactions
Ask for
• Attack, mask or accompany neoplastic diseases
Look for