{"id":{"repo_id":"freiburg-diss","oai_identifier":"oai:freidok.uni-freiburg.de:1604"},"canonical_url":"https://search.dev.ndltd.org/etd/freiburg-diss/oai:freidok.uni-freiburg.de:1604","repository":{"repo_id":"freiburg-diss","name":"University of Freiburg","base_url":"https://freidok.uni-freiburg.de/oai/oai2.php"},"display":{"title":"Changes in peripheral B cell subsets under immunosuppressive therapy","abstract":"Normal homeostasis of the immune system is critical for the maintenance of immunological tolerance and immunocompetence. Failure of self-tolerance results in autoimmune reactions which may progress to chronic autoimmune diseases. B cells play an important role in the pathogenesis of autoimmune diseases and influence autoimmunity through multiple pathways. With the availability of informative B cell surface markers it is now possible to identify within the circulating B cell compartment (CD19+) at least 4 subsets: naive B cells (CD27-), IgM memory B cells (CD27+IgM/D+), switched memory B cells (CD27+IgM/D-) and plasma cells (CD27+CD38+CD24-). For the first time this B cell subset analysis was performed in three established autoimmune conditions (systemic lupus erythematosus (SLE), wegener's granulomatosis (WG), chronic graft versus host disease (GvHD)) with special emphasis on changes induced by immunosuppressive therapy (disease modifying antirheumatic drugs (DMARDs)) and cyclophosphamide (CYC) treatment. There was a significant impact of immunosuppressive treatment on peripheral B cell subsets in SLE and WG patients. Absolute lymphocyte numbers and CD19+ B cell counts were significantly decreased, as were naive B cells and switched memory B cells. Plasma cells tended to show a relative but not an absolute increase. In SLE patients the most significant decrease was observed for IgM memory B cells after CYC and DMARD therapy: absolute and relative cell counts were very low and remained so for a mean period of over 3 years after the last CYC treatment. Untreated SLE patients showed no significant decrease of IgM memory B cells. It is suggested that remission inducing therapy with CYC has a profound and long-lasting impact on total lymphocytes and peripheral B cell subsets in SLE and WG patients. Notably the IgM memory B cells are seriously hit. In contrast, plasma cells which can hide in protected niches of bone marrow and lamina propria intestini appear to be quite resistant to conventional immunosuppressive therapy. As IgM memory B cells provide the first T cell independent humoral immune response to bacterial polysaccharides from Streptococcus pneumoniae and Hemophilus influenzae it may be predicted that primary immune responses against these bacterial antigens are severely compromised in CYC and DMARD treated patients. It has recently been shown that splenectomy and congenital asplenia cause a profound and long-lasting loss of IgM memory B cells together with an impairment of the immune response to pneumococcal polysaccharides. As successful allogeneic stem cell transplantation (allo-SCT) patients with stable chimerism often show signs of functional asplenia with appearance of Howell-Jolly bodies in erythrocytes we were interested to study B cell subsets in those patients. After a mean follow-up of 4.7 years 12 clinically stable allo-SCT recipients (five with positive Howell-Jolly bodies) exhibited a profound decrease of IgM memory B cells similar to splenectomized or CYC treated SLE and WG patients. There was no difference in IgM memory B cells numbers between allo-SCT recipients with and without functional asplenia as evidenced by the occurence of Howell-Jolly bodies. Ten of the 12 patients have an ongoing mild to moderate GvHD, suggesting that this process may impede IgM memory formation in the spleen. In any case the presented findings underline that the generation of IgM memory B cells is critically dependent on a functional spleen and is highly susceptible to CYC and DMARD treatment.","abstract_html":"Normal homeostasis of the immune system is critical for the maintenance of immunological tolerance and immunocompetence. Failure of self-tolerance results in autoimmune reactions which may progress to chronic autoimmune diseases. B cells play an important role in the pathogenesis of autoimmune diseases and influence autoimmunity through multiple pathways. With the availability of informative B cell surface markers it is now possible to identify within the circulating B cell compartment (CD19+) at least 4 subsets: naive B cells (CD27-), IgM memory B cells (CD27+IgM/D+), switched memory B cells (CD27+IgM/D-) and plasma cells (CD27+CD38+CD24-). For the first time this B cell subset analysis was performed in three established autoimmune conditions (systemic lupus erythematosus (SLE), wegener&#x27;s granulomatosis (WG), chronic graft versus host disease (GvHD)) with special emphasis on changes induced by immunosuppressive therapy (disease modifying antirheumatic drugs (DMARDs)) and cyclophosphamide (CYC) treatment. There was a significant impact of immunosuppressive treatment on peripheral B cell subsets in SLE and WG patients. Absolute lymphocyte numbers and CD19+ B cell counts were significantly decreased, as were naive B cells and switched memory B cells. Plasma cells tended to show a relative but not an absolute increase. In SLE patients the most significant decrease was observed for IgM memory B cells after CYC and DMARD therapy: absolute and relative cell counts were very low and remained so for a mean period of over 3 years after the last CYC treatment. Untreated SLE patients showed no significant decrease of IgM memory B cells. It is suggested that remission inducing therapy with CYC has a profound and long-lasting impact on total lymphocytes and peripheral B cell subsets in SLE and WG patients. Notably the IgM memory B cells are seriously hit. In contrast, plasma cells which can hide in protected niches of bone marrow and lamina propria intestini appear to be quite resistant to conventional immunosuppressive therapy. As IgM memory B cells provide the first T cell independent humoral immune response to bacterial polysaccharides from Streptococcus pneumoniae and Hemophilus influenzae it may be predicted that primary immune responses against these bacterial antigens are severely compromised in CYC and DMARD treated patients. It has recently been shown that splenectomy and congenital asplenia cause a profound and long-lasting loss of IgM memory B cells together with an impairment of the immune response to pneumococcal polysaccharides. As successful allogeneic stem cell transplantation (allo-SCT) patients with stable chimerism often show signs of functional asplenia with appearance of Howell-Jolly bodies in erythrocytes we were interested to study B cell subsets in those patients. After a mean follow-up of 4.7 years 12 clinically stable allo-SCT recipients (five with positive Howell-Jolly bodies) exhibited a profound decrease of IgM memory B cells similar to splenectomized or CYC treated SLE and WG patients. There was no difference in IgM memory B cells numbers between allo-SCT recipients with and without functional asplenia as evidenced by the occurence of Howell-Jolly bodies. Ten of the 12 patients have an ongoing mild to moderate GvHD, suggesting that this process may impede IgM memory formation in the spleen. In any case the presented findings underline that the generation of IgM memory B cells is critically dependent on a functional spleen and is highly susceptible to CYC and DMARD treatment.","abstract_has_math":false,"creators":["Hu, Shaoxian"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Peter, Hans-Hartmut"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":null,"date_issued":"","date_published":null,"updated_at":"2026-07-24T02:22:22Z","subjects":["systemische Lupus erythematodes (SLE)","Wegener-Granulomatose (WG)","chronische Transplantat-gegen-Wirt -Reaktion (GvHD)","systemic lupus erythematosus (SLE)","Wegener's granulomatosis (WG)","chronic graft versus host disease (GvHD)"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://freidok.uni-freiburg.de/data/1604","outbound_label":"Repository record","outbound_source":"source_url"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Peter, Hans-Hartmut"]},{"key":"dc:creator","label":"Author","values":["Hu, Shaoxian"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:type","label":"Dc Type","values":["DoctoralThesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["systemische Lupus erythematodes (SLE)","Wegener-Granulomatose (WG)","chronische Transplantat-gegen-Wirt -Reaktion (GvHD)","systemic lupus erythematosus (SLE)","Wegener's granulomatosis (WG)","chronic graft versus host disease (GvHD)"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Normal homeostasis of the immune system is critical for the maintenance of immunological tolerance and immunocompetence. Failure of self-tolerance results in autoimmune reactions which may progress to chronic autoimmune diseases. B cells play an important role in the pathogenesis of autoimmune diseases and influence autoimmunity through multiple pathways. With the availability of informative B cell surface markers it is now possible to identify within the circulating B cell compartment (CD19+) at least 4 subsets: naive B cells (CD27-), IgM memory B cells (CD27+IgM/D+), switched memory B cells (CD27+IgM/D-) and plasma cells (CD27+CD38+CD24-). For the first time this B cell subset analysis was performed in three established autoimmune conditions (systemic lupus erythematosus (SLE), wegener's granulomatosis (WG), chronic graft versus host disease (GvHD)) with special emphasis on changes induced by immunosuppressive therapy (disease modifying antirheumatic drugs (DMARDs)) and cyclophosphamide (CYC) treatment. There was a significant impact of immunosuppressive treatment on peripheral B cell subsets in SLE and WG patients. Absolute lymphocyte numbers and CD19+ B cell counts were significantly decreased, as were naive B cells and switched memory B cells. Plasma cells tended to show a relative but not an absolute increase. In SLE patients the most significant decrease was observed for IgM memory B cells after CYC and DMARD therapy: absolute and relative cell counts were very low and remained so for a mean period of over 3 years after the last CYC treatment. Untreated SLE patients showed no significant decrease of IgM memory B cells. It is suggested that remission inducing therapy with CYC has a profound and long-lasting impact on total lymphocytes and peripheral B cell subsets in SLE and WG patients. Notably the IgM memory B cells are seriously hit. In contrast, plasma cells which can hide in protected niches of bone marrow and lamina propria intestini appear to be quite resistant to conventional immunosuppressive therapy. As IgM memory B cells provide the first T cell independent humoral immune response to bacterial polysaccharides from Streptococcus pneumoniae and Hemophilus influenzae it may be predicted that primary immune responses against these bacterial antigens are severely compromised in CYC and DMARD treated patients. It has recently been shown that splenectomy and congenital asplenia cause a profound and long-lasting loss of IgM memory B cells together with an impairment of the immune response to pneumococcal polysaccharides. As successful allogeneic stem cell transplantation (allo-SCT) patients with stable chimerism often show signs of functional asplenia with appearance of Howell-Jolly bodies in erythrocytes we were interested to study B cell subsets in those patients. After a mean follow-up of 4.7 years 12 clinically stable allo-SCT recipients (five with positive Howell-Jolly bodies) exhibited a profound decrease of IgM memory B cells similar to splenectomized or CYC treated SLE and WG patients. There was no difference in IgM memory B cells numbers between allo-SCT recipients with and without functional asplenia as evidenced by the occurence of Howell-Jolly bodies. Ten of the 12 patients have an ongoing mild to moderate GvHD, suggesting that this process may impede IgM memory formation in the spleen. In any case the presented findings underline that the generation of IgM memory B cells is critically dependent on a functional spleen and is highly susceptible to CYC and DMARD treatment.","Die normale Homöostase des Immunsystems entscheidet über den Erhalt der immunologischen Toleranz und der Immunkompetenz. Störungen der Selbsttoleranz führen zu Autoimmunreaktionen, aus denen chronische Autoimmunkrankheiten entstehen können. B-Zellen spielen dabei eine wichtige pathogenetische Rolle. Mittels Zytofluorimetrie können heute im peripheren B-Zell-Kompartiment (CD19+) mindestens 4 B-Zell-Untergruppen identifiziert werden: Naive B-Zellen (CD27-), IgM Gedächtnis B- Zellen (CD27+IgM/D+), klassengewechselte Gedächtnis B-Zellen (CD27+IgM/D-) und Plasmazellen (CD27+CD38+CD24-). Die vorliegende Arbeit beschreibt die erstmalige Anwendung einer detaillierten B-Zell- Subset Analyse auf drei klinische Autoimmunkrankheiten (systemische Lupus erythematodes (SLE), Wegener-Granulomatose (WG), chronische Transplantat-gegen-Wirt -Reaktion (GvHD)) unter besonderer Berücksichtigung der Einflüsse von Immunsuppressiva (krankheitsmodifizierende Antirheumamittel (DMARDs)) und Cyclophosphamid (CYC). Immunsuppressive Therapie mit DMARDs oder CYC führte zu einer signifikanten und lang anhaltenden Reduktion der absoluten Lymphozyten- und B-Zellzahlen im Blut von SLE und WG Patienten. Neben den CD19+ B-Zellen waren auch naive B-Zellen und Gedächtnis B-Zellen reduziert, wohingegen die Plasmazellen bei unveränderter Absolutzahl relativ anstiegen. Die drastischste Absenkung erfuhren die IgM Gedächtniszellen nach Therapie mit CYC oder DMARDs. Unbehandelte SLE Patienten zeigten keine Reduktion der IgM Gedächtnis B-Zellen gegenüber Kontrollen. Die erhobenen Befunde zeigen, dass nach Remissionsinduktion mit CYC, ein ausgeprägter, mehrjähriger Abfall von Gesamtlymphozyten und peripheren B-Zellen bei SLE and WG Patienten auftritt. Die IgM Gedächtnis-B-Zellen sind besonders betroffen, während die Plasmazellen recht resistent gegenüber immunsuppressiver Therapie sind. Ausgehend von der Tatsache, da IgM Gedächtniszellen T-Zell unabhängige Antikörper gegen neu eingedrungenen Erreger bilden, z.B. Streptococcus pneumoniae and Hemophilus influenzae, zeigen unsere Ergebnisse, dass unter immunsuppressiver Therapie vorwiegend die primäre humorale Immunantwort und weniger die anamnestische Antikörperbildung durch Plasmazellen beeinträchtigt wird. Kürzlich wurde gezeigt, dass Splenektomie oder congentiale Asplenie zu einem profunden und lang anhaltenden Verlust von IgM Gedächtnis B-Zellen führen und einhergehend damit eine Störung der Antikörperantwort gegen Pneumokokken-Polysaccharide zu beobachten ist. Da Patienten nach einer erfolgreichen allogene Stammzelltransplantation (Allo-SCT) vielfach Zeichen einer funktionellen Asplenie mit Auftreten von Howell-Jolly Körperchen in Erythrozyten aufweisen, war es interessant bei diesen Patienten B-Zell-Subsets zu analysieren. Bei 12 Allo-SCT Patienten mit stabilem Chimerismus (5 davon mit positiven Howell-Jolly Körperchen) wurden B-Zell-Subset-Analysen im Durchschnitt 4,7 Jahre nach der Allo-SCT durchgeführt. Alle Patienten zeigten eine hochgradige Verminderung der IgM Gedächtnis-B-Zellen unabhängig vom Vorhandensein von Howell-Jolly Körperchen. Da 10 der 12 Patienten Zeichen einer milden bis moderaten chronischen GvHD aufwiesen, legen diese Befunde nahe, dass eine GvHD die Bildung von IgM Gedächtnis-Zellen in der Milz behindert. Ferner zeigen diese Befunde, dass die Bildung von IgM Gedächtnis B-Zellen in kritischer Weise von einer intakten Milz abhängt und hoch empfindlich auf <br>Immunsuppressiva und CYC reagiert."]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Changes in peripheral B cell subsets under immunosuppressive therapy","Die Einflüsse von Immunsuppressive Therapie im peripheren B-Zell-Untergruppen"]}]}],"canonical_facts":{"dc:contributor":["Peter, Hans-Hartmut"],"dc:creator":["Hu, Shaoxian"],"dc:description.abstract":["Normal homeostasis of the immune system is critical for the maintenance of immunological tolerance and immunocompetence. Failure of self-tolerance results in autoimmune reactions which may progress to chronic autoimmune diseases. B cells play an important role in the pathogenesis of autoimmune diseases and influence autoimmunity through multiple pathways. With the availability of informative B cell surface markers it is now possible to identify within the circulating B cell compartment (CD19+) at least 4 subsets: naive B cells (CD27-), IgM memory B cells (CD27+IgM/D+), switched memory B cells (CD27+IgM/D-) and plasma cells (CD27+CD38+CD24-). For the first time this B cell subset analysis was performed in three established autoimmune conditions (systemic lupus erythematosus (SLE), wegener's granulomatosis (WG), chronic graft versus host disease (GvHD)) with special emphasis on changes induced by immunosuppressive therapy (disease modifying antirheumatic drugs (DMARDs)) and cyclophosphamide (CYC) treatment. There was a significant impact of immunosuppressive treatment on peripheral B cell subsets in SLE and WG patients. Absolute lymphocyte numbers and CD19+ B cell counts were significantly decreased, as were naive B cells and switched memory B cells. Plasma cells tended to show a relative but not an absolute increase. In SLE patients the most significant decrease was observed for IgM memory B cells after CYC and DMARD therapy: absolute and relative cell counts were very low and remained so for a mean period of over 3 years after the last CYC treatment. Untreated SLE patients showed no significant decrease of IgM memory B cells. It is suggested that remission inducing therapy with CYC has a profound and long-lasting impact on total lymphocytes and peripheral B cell subsets in SLE and WG patients. Notably the IgM memory B cells are seriously hit. In contrast, plasma cells which can hide in protected niches of bone marrow and lamina propria intestini appear to be quite resistant to conventional immunosuppressive therapy. As IgM memory B cells provide the first T cell independent humoral immune response to bacterial polysaccharides from Streptococcus pneumoniae and Hemophilus influenzae it may be predicted that primary immune responses against these bacterial antigens are severely compromised in CYC and DMARD treated patients. It has recently been shown that splenectomy and congenital asplenia cause a profound and long-lasting loss of IgM memory B cells together with an impairment of the immune response to pneumococcal polysaccharides. As successful allogeneic stem cell transplantation (allo-SCT) patients with stable chimerism often show signs of functional asplenia with appearance of Howell-Jolly bodies in erythrocytes we were interested to study B cell subsets in those patients. After a mean follow-up of 4.7 years 12 clinically stable allo-SCT recipients (five with positive Howell-Jolly bodies) exhibited a profound decrease of IgM memory B cells similar to splenectomized or CYC treated SLE and WG patients. There was no difference in IgM memory B cells numbers between allo-SCT recipients with and without functional asplenia as evidenced by the occurence of Howell-Jolly bodies. Ten of the 12 patients have an ongoing mild to moderate GvHD, suggesting that this process may impede IgM memory formation in the spleen. In any case the presented findings underline that the generation of IgM memory B cells is critically dependent on a functional spleen and is highly susceptible to CYC and DMARD treatment.","Die normale Homöostase des Immunsystems entscheidet über den Erhalt der immunologischen Toleranz und der Immunkompetenz. Störungen der Selbsttoleranz führen zu Autoimmunreaktionen, aus denen chronische Autoimmunkrankheiten entstehen können. B-Zellen spielen dabei eine wichtige pathogenetische Rolle. Mittels Zytofluorimetrie können heute im peripheren B-Zell-Kompartiment (CD19+) mindestens 4 B-Zell-Untergruppen identifiziert werden: Naive B-Zellen (CD27-), IgM Gedächtnis B- Zellen (CD27+IgM/D+), klassengewechselte Gedächtnis B-Zellen (CD27+IgM/D-) und Plasmazellen (CD27+CD38+CD24-). Die vorliegende Arbeit beschreibt die erstmalige Anwendung einer detaillierten B-Zell- Subset Analyse auf drei klinische Autoimmunkrankheiten (systemische Lupus erythematodes (SLE), Wegener-Granulomatose (WG), chronische Transplantat-gegen-Wirt -Reaktion (GvHD)) unter besonderer Berücksichtigung der Einflüsse von Immunsuppressiva (krankheitsmodifizierende Antirheumamittel (DMARDs)) und Cyclophosphamid (CYC). Immunsuppressive Therapie mit DMARDs oder CYC führte zu einer signifikanten und lang anhaltenden Reduktion der absoluten Lymphozyten- und B-Zellzahlen im Blut von SLE und WG Patienten. Neben den CD19+ B-Zellen waren auch naive B-Zellen und Gedächtnis B-Zellen reduziert, wohingegen die Plasmazellen bei unveränderter Absolutzahl relativ anstiegen. Die drastischste Absenkung erfuhren die IgM Gedächtniszellen nach Therapie mit CYC oder DMARDs. Unbehandelte SLE Patienten zeigten keine Reduktion der IgM Gedächtnis B-Zellen gegenüber Kontrollen. Die erhobenen Befunde zeigen, dass nach Remissionsinduktion mit CYC, ein ausgeprägter, mehrjähriger Abfall von Gesamtlymphozyten und peripheren B-Zellen bei SLE and WG Patienten auftritt. Die IgM Gedächtnis-B-Zellen sind besonders betroffen, während die Plasmazellen recht resistent gegenüber immunsuppressiver Therapie sind. Ausgehend von der Tatsache, da IgM Gedächtniszellen T-Zell unabhängige Antikörper gegen neu eingedrungenen Erreger bilden, z.B. Streptococcus pneumoniae and Hemophilus influenzae, zeigen unsere Ergebnisse, dass unter immunsuppressiver Therapie vorwiegend die primäre humorale Immunantwort und weniger die anamnestische Antikörperbildung durch Plasmazellen beeinträchtigt wird. Kürzlich wurde gezeigt, dass Splenektomie oder congentiale Asplenie zu einem profunden und lang anhaltenden Verlust von IgM Gedächtnis B-Zellen führen und einhergehend damit eine Störung der Antikörperantwort gegen Pneumokokken-Polysaccharide zu beobachten ist. Da Patienten nach einer erfolgreichen allogene Stammzelltransplantation (Allo-SCT) vielfach Zeichen einer funktionellen Asplenie mit Auftreten von Howell-Jolly Körperchen in Erythrozyten aufweisen, war es interessant bei diesen Patienten B-Zell-Subsets zu analysieren. Bei 12 Allo-SCT Patienten mit stabilem Chimerismus (5 davon mit positiven Howell-Jolly Körperchen) wurden B-Zell-Subset-Analysen im Durchschnitt 4,7 Jahre nach der Allo-SCT durchgeführt. Alle Patienten zeigten eine hochgradige Verminderung der IgM Gedächtnis-B-Zellen unabhängig vom Vorhandensein von Howell-Jolly Körperchen. Da 10 der 12 Patienten Zeichen einer milden bis moderaten chronischen GvHD aufwiesen, legen diese Befunde nahe, dass eine GvHD die Bildung von IgM Gedächtnis-Zellen in der Milz behindert. Ferner zeigen diese Befunde, dass die Bildung von IgM Gedächtnis B-Zellen in kritischer Weise von einer intakten Milz abhängt und hoch empfindlich auf <br>Immunsuppressiva und CYC reagiert."],"dc:format.medium":["application/pdf"],"dc:subject":["systemische Lupus erythematodes (SLE)","Wegener-Granulomatose (WG)","chronische Transplantat-gegen-Wirt -Reaktion (GvHD)","systemic lupus erythematosus (SLE)","Wegener's granulomatosis (WG)","chronic graft versus host disease (GvHD)"],"dc:title":["Changes in peripheral B cell subsets under immunosuppressive therapy","Die Einflüsse von Immunsuppressive Therapie im peripheren B-Zell-Untergruppen"],"dc:type":["DoctoralThesis"]},"updated_at":"2026-07-24T02:22:22Z"}