Hypomorphic Mutations in the BCR Signalosome Lead to Selective Immunoglobulin M Deficiency and Impaired B-cell Homeostasis
B cell activation via the B cell receptor (BCR) signalosome involves participation of signaling molecules such as BTK and BLNK. Genetic defects in these molecules are known to impair B cell differentiation and subsequently lead to agammaglobulinemia. Here we identified novel mutations in BTK and BLN...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.02984/full |
| _version_ | 1811195445556281344 |
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| author | Christoph B. Geier Kai M. T. Sauerwein Alexander Leiss-Piller Isabella Zmek Michael B. Fischer Michael B. Fischer Martha M. Eibl Martha M. Eibl Hermann M. Wolf Hermann M. Wolf |
| author_facet | Christoph B. Geier Kai M. T. Sauerwein Alexander Leiss-Piller Isabella Zmek Michael B. Fischer Michael B. Fischer Martha M. Eibl Martha M. Eibl Hermann M. Wolf Hermann M. Wolf |
| author_sort | Christoph B. Geier |
| collection | DOAJ |
| description | B cell activation via the B cell receptor (BCR) signalosome involves participation of signaling molecules such as BTK and BLNK. Genetic defects in these molecules are known to impair B cell differentiation and subsequently lead to agammaglobulinemia. Here we identified novel mutations in BTK and BLNK in two unrelated patients that perturb the intrinsic B-cell receptor signaling pathway and lead to selective IgM deficiency, whereas production of other immunoglobulin isotypes and IgG antibody response remain intact. Currently it is unknown how BCR signaling strength affects mature B cell development in humans. Both patients show reduced levels of BCR signalosome phosphorylation as well as impaired BCR-dependent Ca2+ influx, which was accompanied by a marked decrease in IgD+IgM+CD27+ MZ-like B-cells. We further describe reduced expression of essential B cell differentiation factors such as BAFF-R and T-Bet in the patients' B-cells, which might contribute to the observed deficiency of MZ-like B cells. MZ-like B cells are known to produce natural IgM antibodies that play an essential role in immune homeostasis. By using surface plasmon resonance (SPR) technology and a synthetic blood group A trisaccharide as antigen we were able to show that both patients lack the presence of anti-blood group A IgM considered to be prototypical natural antibodies whereas IgG levels were normal. Antibody binding dynamics and binding affinity of anti-blood group A IgG were comparable between patients and healthy controls. These results indicate that human IgM deficiency can be associated with signaling defects in the BCR signalosome, defective production of natural IgM antibodies in the blood group A/B/0 system and abnormalities in B cell development. |
| first_indexed | 2024-04-12T00:43:25Z |
| format | Article |
| id | doaj.art-f8f0c62524f34c26822bffbdec8a3f16 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T00:43:25Z |
| publishDate | 2018-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-f8f0c62524f34c26822bffbdec8a3f162022-12-22T03:54:57ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-12-01910.3389/fimmu.2018.02984417487Hypomorphic Mutations in the BCR Signalosome Lead to Selective Immunoglobulin M Deficiency and Impaired B-cell HomeostasisChristoph B. Geier0Kai M. T. Sauerwein1Alexander Leiss-Piller2Isabella Zmek3Michael B. Fischer4Michael B. Fischer5Martha M. Eibl6Martha M. Eibl7Hermann M. Wolf8Hermann M. Wolf9Immunology Outpatient Clinic, Vienna, AustriaImmunology Outpatient Clinic, Vienna, AustriaImmunology Outpatient Clinic, Vienna, AustriaImmunology Outpatient Clinic, Vienna, AustriaClinic for Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, AustriaDepartment for Health Science and Biomedicine, Danube University Krems, Krems, AustriaImmunology Outpatient Clinic, Vienna, AustriaBiomedizinische Forschungs GmbH, Vienna, AustriaImmunology Outpatient Clinic, Vienna, AustriaMedical School, Sigmund Freud Private University, Vienna, AustriaB cell activation via the B cell receptor (BCR) signalosome involves participation of signaling molecules such as BTK and BLNK. Genetic defects in these molecules are known to impair B cell differentiation and subsequently lead to agammaglobulinemia. Here we identified novel mutations in BTK and BLNK in two unrelated patients that perturb the intrinsic B-cell receptor signaling pathway and lead to selective IgM deficiency, whereas production of other immunoglobulin isotypes and IgG antibody response remain intact. Currently it is unknown how BCR signaling strength affects mature B cell development in humans. Both patients show reduced levels of BCR signalosome phosphorylation as well as impaired BCR-dependent Ca2+ influx, which was accompanied by a marked decrease in IgD+IgM+CD27+ MZ-like B-cells. We further describe reduced expression of essential B cell differentiation factors such as BAFF-R and T-Bet in the patients' B-cells, which might contribute to the observed deficiency of MZ-like B cells. MZ-like B cells are known to produce natural IgM antibodies that play an essential role in immune homeostasis. By using surface plasmon resonance (SPR) technology and a synthetic blood group A trisaccharide as antigen we were able to show that both patients lack the presence of anti-blood group A IgM considered to be prototypical natural antibodies whereas IgG levels were normal. Antibody binding dynamics and binding affinity of anti-blood group A IgG were comparable between patients and healthy controls. These results indicate that human IgM deficiency can be associated with signaling defects in the BCR signalosome, defective production of natural IgM antibodies in the blood group A/B/0 system and abnormalities in B cell development.https://www.frontiersin.org/article/10.3389/fimmu.2018.02984/fullprimary immunodeficiencyB-cell defectsselective IgM deficiencyBTKBLNKmarginal-zone B cells |
| spellingShingle | Christoph B. Geier Kai M. T. Sauerwein Alexander Leiss-Piller Isabella Zmek Michael B. Fischer Michael B. Fischer Martha M. Eibl Martha M. Eibl Hermann M. Wolf Hermann M. Wolf Hypomorphic Mutations in the BCR Signalosome Lead to Selective Immunoglobulin M Deficiency and Impaired B-cell Homeostasis Frontiers in Immunology primary immunodeficiency B-cell defects selective IgM deficiency BTK BLNK marginal-zone B cells |
| title | Hypomorphic Mutations in the BCR Signalosome Lead to Selective Immunoglobulin M Deficiency and Impaired B-cell Homeostasis |
| title_full | Hypomorphic Mutations in the BCR Signalosome Lead to Selective Immunoglobulin M Deficiency and Impaired B-cell Homeostasis |
| title_fullStr | Hypomorphic Mutations in the BCR Signalosome Lead to Selective Immunoglobulin M Deficiency and Impaired B-cell Homeostasis |
| title_full_unstemmed | Hypomorphic Mutations in the BCR Signalosome Lead to Selective Immunoglobulin M Deficiency and Impaired B-cell Homeostasis |
| title_short | Hypomorphic Mutations in the BCR Signalosome Lead to Selective Immunoglobulin M Deficiency and Impaired B-cell Homeostasis |
| title_sort | hypomorphic mutations in the bcr signalosome lead to selective immunoglobulin m deficiency and impaired b cell homeostasis |
| topic | primary immunodeficiency B-cell defects selective IgM deficiency BTK BLNK marginal-zone B cells |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.02984/full |
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