A novel thymoma-associated immunodeficiency with increased naive T cells and reduced CD247 expression.
The mechanisms underlying thymoma-associated immunodeficiency are largely unknown, and the significance of increased blood γδ Τ cells often remains elusive. In this study we address these questions based on an index patient with thymoma, chronic visceral leishmaniasis, myasthenia gravis, and a marked increase of rare γδ T cell subsets in the peripheral blood. This patient showed cutaneous anergy, even though he had normal numbers of peripheral blood total lymphocytes as well as CD4(+) and CD8(+) T cells. Despite his chronic infection, analyses of immunophenotypes and spectratyping of his lymphocytes revealed an unusual accumulation of naive γδ and αβ T cells, suggesting a generalized T cell activation defect. Functional studies in vitro demonstrated substantially diminished IL-2 and IFN-γ production following TCR stimulation of his "untouched" naive CD4(+) T cells. Biochemical analysis revealed that his γδ and αβ T cells carried an altered TCR complex with reduced amounts of the ζ-chain (CD247). No mutations were found in the CD247 gene that encodes the homodimeric ζ protein. The diminished presence of CD247 and increased numbers of γδ T cells were also observed in thymocyte populations obtained from three other thymoma patients. Thus, our findings describe a novel type of a clinically relevant acquired T cell immunodeficiency in thymoma patients that is distinct from Good's syndrome. Its characteristics are an accumulation of CD247-deficient, hyporresponsive naive γδ and αβ T cells and an increased susceptibility to infections.
Department of Pathology, University of Freiburg Medical Center, 79106 Freiburg, Germany;
Petros
P
Christopoulos
Department of Molecular Immunology, BIOSS Centre for Biological Signalling Studies, Faculty of Biology, University of Freiburg Medical Center, 79106 Freiburg, Germany; Center for Chronic Immunodeficiency CCI, University of Freiburg Medical Center, 79106 Freiburg, Germany; Max-Planck-Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany;
Elaine P
EP
Dopfer
Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726;
Miroslav
M
Malkovsky
Department of Dermatology and Venereology (Allergy Research Group), University of Freiburg Medical Center, 79106 Freiburg, Germany;
Philipp R
PR
Esser
Department of Pathology, University of Freiburg Medical Center, 79106 Freiburg, Germany;
Hans-Eckart
HE
Schaefer
Institute of Pathology, University Medical Center Mannheim, 68167 Mannheim, Germany;
Alexander
A
Marx
Department of Pathology, University of Freiburg Medical Center, 79106 Freiburg, Germany;
Sylvia
S
Kock
Department of Pathology, University of Freiburg Medical Center, 79106 Freiburg, Germany;
Nicole
N
Rupp
Institute for Transfusion Medicine, University Ulm, 89081 Ulm, Germany;
Myriam R
MR
Lorenz
Institute for Transfusion Medicine, University Ulm, 89081 Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service, Baden-Württemberg-Hessen, 89081 Ulm, Germany;
Klaus
K
Schwarz
Department of Gastroenterology, University of Freiburg Medical Center, 79106 Freiburg, Germany; and.
Jan
J
Harder
Department of Dermatology and Venereology (Allergy Research Group), University of Freiburg Medical Center, 79106 Freiburg, Germany;
Stefan F
SF
Martin
Department of Pathology, University of Freiburg Medical Center, 79106 Freiburg, Germany;
Martin
M
Werner
Institute of Clinical Microbiology, Immunology and Hygiene, Friedrich Alexander University Erlangen-Nuremberg and University Hospital Erlangen, 91054 Erlangen, Germany.
Christian
C
Bogdan
Department of Molecular Immunology, BIOSS Centre for Biological Signalling Studies, Faculty of Biology, University of Freiburg Medical Center, 79106 Freiburg, Germany; Center for Chronic Immunodeficiency CCI, University of Freiburg Medical Center, 79106 Freiburg, Germany; Max-Planck-Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany;
Wolfgang W A
WW
Schamel
Department of Pathology, University of Freiburg Medical Center, 79106 Freiburg, Germany; paul.fisch@uniklinik-freiburg.de.
Paul
P
Fisch
D000328:Adult; D000953:Antigens, Protozoan / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology*; D007156:Immunologic Memory; D016130:Immunophenotyping; D007891:Leishmania / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D010641:Phenotype; D000081207:Primary Immunodeficiency Diseases; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D017422:Sequence Analysis, DNA; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D013945:Thymoma / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology*
D000953:Antigens, Protozoan; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D016207:Cytokines; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta