Defective B cell development and function in Btk-deficient mice (original) (raw)
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The Role of Bruton's Tyrosine Kinase in B-Cell Development and Function in Mice and Mana
Annals of the New York Academy of Sciences, 2008
X-linked agammaglobulinemia (XLA)' is an inherited humoral immunodeficiency disease caused by an intrinsic B-cell defect as demonstrated by the unilateral inactivation of the X chromosome in the female carriers. The affected males suffer from recurrent bacterial infections.2 Typical XLA is characterized by a severe deficiency of mature B cells (less than 1%: 5-15% in normal) and very low levels of serum immunoglobulins of all isotypes (about 10% of normal). T cell dependent immune responses are undetectable, and germinal follicles in the lymph nodes are not found (reviewed in Conley3 and Rosen et Numbers of pre-B cells in the bone marrow are normal or decreased. The pro-B to pre-B cell ratio in the bone marrow is inverted as reflected by increased numbers of TdT+/CD34+ B cell^^.^ and severe deficiency of surface IgM+ B cells. The XLA defect may reflect an inefficient differentiation to the pre-B stage or inefficient expansion of pre B and to mature B cells (FIG. 1). X-linked immunodeficient (xid) mice (FIG. I , Refs. 7, 11) share features with XLA; however, the defect is milder. In xid mice, numbers of B cells are only slightly reduced, and they show an immature phenotype (IgMl0/IgDhi population is reduced or The CD5+ cells are absent, and there is a selective Ig deficiency; that is, levels of IgM and IgG3 are very Xid mice do not respond to TI-I1 and show reduced response to some TD antigens.I2.l3 In vitro studies showed that xid B cells do not proliferate in response to antigen receptor ligation14 and showed a defective response to mitogenic activity of LPS." a This work was supported by the Howard Hughes Medical Institute and by National Institutes of Health Grants A120047 and POlAI35714. W. N. Khan is a fellow of the Swedish Natural Science Research Council. 27 28 ANNALS NEW YORK ACADEMY OF SCIENCES IgMIIgD DJ XLA BI cells Memory cell Pro B Pre 0 Immature B Mature B Antigen independent, Stromal cell dependent Antigen dependent, stromal cell independent
Journal of Experimental Medicine, 1975
A study of the composition and functional properties of spleen cells from the immune deficient CBA/HN mice and their F1 progeny is reported. While abnormalities were seen in both the numbers and function of thymus-independent (B) lymphocytes, all studies involving thymus-dependent (T) lymphocytes were normal. The X-linked nature of the immune defect in these mice was therefore attributed to abnormal or absent B lymphocytes. The possible nature of this defect and the similarity of the immune defect in these mice to certain human X-linked immunodeficiency diseases are discussed.
Development of Ly-1+ B Cells in immunodeficient CBA/N mice
Developmental analyses of B cell differentiation are consistent with the existence of at least two distinct lineages . Thus, adult bone marrow solely regenerates the commonest (Ly-1 -) lineage, while Ly-1 + B cells reconstitute the Ly-1 + B cell lineage (1). CBA/N mice carrying the X-linked immunodeficiency gene (xid) show a defective differentiation of B lymphocytes (2) . They lack all Ly-1 + B cells as well as the normally predominant subpopulation within the Ly-1lineage . Functional studies (4) indicated that Ly-1 + B cells are responsible for the production of most of the autoantibodies, while those B cells in the Ly-1 -lineage participate in the conventional responses to "foreign" antigens . These observations may account for both the protection conferred against autoimmune disease, when the xid genetic defect is bred into lupus-prone strains, and the CBA/N mice unresponsiveness to many bacterial antigens (5, 6) .
The Journal of Experimental Medicine, 2000
The B cell receptor (BCR) regulates B cell development and function through immunoglobulin (Ig)α and Igβ, a pair of membrane-bound Ig superfamily proteins, each of which contains a single cytoplasmic immunoreceptor tyrosine activation motif (ITAM). To determine the function of Igβ, we produced mice that carry a deletion of the cytoplasmic domain of Igβ (IgβΔC mice) and compared them to mice that carry a similar mutation in Igα (MB1ΔC, herein referred to as IgαΔC mice). IgβΔC mice differ from IgαΔC mice in that they show little impairment in early B cell development and they produce immature B cells that respond normally to BCR cross-linking as determined by Ca2+ flux. However, IgβΔC B cells are arrested at the immature stage of B cell development in the bone marrow and die by apoptosis. We conclude that the cytoplasmic domain Igβ is required for B cell development beyond the immature B cell stage and that Igα and Igβ have distinct biologic activities in vivo.
Journal of Experimental Medicine, 2000
The B cell receptor (BCR) regulates B cell development and function through immunoglobulin (Ig)α and Igβ, a pair of membrane-bound Ig superfamily proteins, each of which contains a single cytoplasmic immunoreceptor tyrosine activation motif (ITAM). To determine the function of Igβ, we produced mice that carry a deletion of the cytoplasmic domain of Igβ (IgβΔC mice) and compared them to mice that carry a similar mutation in Igα (MB1ΔC, herein referred to as IgαΔC mice). IgβΔC mice differ from IgαΔC mice in that they show little impairment in early B cell development and they produce immature B cells that respond normally to BCR cross-linking as determined by Ca2+ flux. However, IgβΔC B cells are arrested at the immature stage of B cell development in the bone marrow and die by apoptosis. We conclude that the cytoplasmic domain Igβ is required for B cell development beyond the immature B cell stage and that Igα and Igβ have distinct biologic activities in vivo.