acid-phosphatase and Agammaglobulinemia

Mutations in Bruton's tyrosine kinase (Btk) cause the B-cell disorder X-linked agammaglobulinaemia (XLA) in humans, but the effect of Btk deficiency in human bone health has not been investigated previously. In this study, we show that human Btk-deficient osteoclasts are defective at resorption activity in vitro owing to a dysregulation of the actin cytoskeletal function. Contrary to expectation, XLA patients did not exhibit increased bone density or alterations in serum markers of bone turnover, indicating that a potential compensation mechanism normalizes bone homeostasis. In contrast to the bone turnover markers, the levels of inflammatory cytokines interleukin 6 (IL-6), IL-1β, and tumor necrosis factor α (TNF-α) were significantly elevated in XLA patients' serum compared with control individuals. Supplementation of osteoclast cultures from normal and XLA subjects with serum from XLA patients or recombinant inflammatory cytokines IL-6, IL-1β, and TNF-α resulted in a stimulation of osteoclast activity in vitro, whereas the addition of cytokine-neutralizing antibodies inhibited this stimulatory effect, confirming that elevated inflammatory cytokines in XLA serum heightened osteoclast activity in vitro. This study provides novel evidence that Btk signaling is crucial for optimal actin cytoskeletal organization and lacunar resorption in isolated osteoclasts. In XLA patients, however, these inherent osteoclast defects are corrected by increased inflammatory cytokine levels, restoring osteoclast activity and leading to the normalization of bone density.

Topics: Acid Phosphatase; Actins; Adult; Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; Biomarkers; Bone Density; Bone Resorption; Cells, Cultured; Cytokines; Dentin; Genetic Diseases, X-Linked; Humans; Inflammation Mediators; Isoenzymes; Middle Aged; Osteoclasts; Protein-Tyrosine Kinases; Tartrate-Resistant Acid Phosphatase

Autosomal-Recessive Osteopetrosis (ARO) comprises a heterogeneous group of bone diseases for which mutations in five genes are known as causative. Most ARO are classified as osteoclast-rich, but recently a subset of osteoclast-poor ARO has been recognized as due to a defect in TNFSF11 (also called RANKL or TRANCE, coding for the RANKL protein), a master gene driving osteoclast differentiation along the RANKL-RANK axis. RANKL and RANK (coded for by the TNFRSF11A gene) also play a role in the immune system, which raises the possibility that defects in this pathway might cause osteopetrosis with immunodeficiency. From a large series of ARO patients we selected a Turkish consanguineous family with two siblings affected by ARO and hypogammaglobulinemia with no defects in known osteopetrosis genes. Sequencing of genes involved in the RANKL downstream pathway identified a homozygous mutation in the TNFRSF11A gene in both siblings. Their monocytes failed to differentiate in vitro into osteoclasts upon exposure to M-CSF and RANKL, in keeping with an osteoclast-intrinsic defect. Immunological analysis showed that their hypogammaglobulinemia was associated with impairment in immunoglobulin-secreting B cells. Investigation of other patients revealed a defect in both TNFRSF11A alleles in six additional, unrelated families. Our results indicate that TNFRSF11A mutations can cause a clinical condition in which severe ARO is associated with an immunoglobulin-production defect.

Topics: Acid Phosphatase; Actins; Agammaglobulinemia; Amino Acid Sequence; Amino Acid Substitution; Argentina; Arginine; Biopsy; Case-Control Studies; Cell Line, Transformed; Cell Proliferation; Cell Transformation, Viral; Cells, Cultured; Cohort Studies; Consanguinity; Cysteine; Dendrites; DNA Mutational Analysis; Female; Genes, Recessive; Herpesvirus 4, Human; Heterozygote; Homozygote; Humans; Ilium; Isoenzymes; Leukocyte Common Antigens; Leukocytes, Mononuclear; Lipopolysaccharides; Macrophage Colony-Stimulating Factor; Male; Models, Immunological; Molecular Sequence Data; Mutation, Missense; Osteoclasts; Osteopetrosis; Osteoprotegerin; Pakistan; Pedigree; Polymorphism, Genetic; Protein Structure, Tertiary; Radiography, Thoracic; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Vitronectin; Sequence Homology, Amino Acid; Tartrate-Resistant Acid Phosphatase; Turkey

Large granular lymphocytes (LGL) are nonadherent cells with cytoplasmic azurophilic granules, avid receptors for the Fc portion of IgG, and a paranuclear localization of alpha-naphthyl acid esterase or acid phosphatase. LGL constitute the bulk of TG cells (cells with receptors for sheep erythrocytes and for IgG molecules) and null cells (non-T, non-B cells). In the present study we demonstrate that 20-33% of the circulating human LGL express receptors for the third complement component (C3R). When TG cell or null cell fractions from normal individuals or non-T cells from a patient with infantile agammaglobulinaemia (which contained almost exclusively LGL) were rosetted with erythrocytes coated with antibody and complement, a variable number of C3R-bearing cells were detected. Such cells were isolated and analysed further; the great majority of them displayed the cytochemical and ultrastructural features of LGL.

Topics: Acid Phosphatase; Agammaglobulinemia; Cell Separation; Complement C3; Cytoplasmic Granules; Humans; Lymphocytes; Lymphocytes, Null; Naphthol AS D Esterase; Receptors, Complement; T-Lymphocytes

Topics: Acid Phosphatase; Adenosine Triphosphatases; Adult; Agammaglobulinemia; Esterases; Ganglia, Autonomic; Glucuronidase; Glycoproteins; Histocytochemistry; Humans; Ileum; Immunoelectrophoresis; Immunoglobulin Fragments; Intestinal Mucosa; Isocitrate Dehydrogenase; Jejunum; Malabsorption Syndromes; Male; Staining and Labeling

Topics: Acid Phosphatase; Agammaglobulinemia; Aged; Anemia, Myelophthisic; Blood Platelet Disorders; Bone Marrow Diseases; Diethylstilbestrol; Erythrocytes; Erythropoiesis; Half-Life; Humans; Iron; Iron Isotopes; L-Lactate Dehydrogenase; Leukocytes; Male; Neoplasm Metastasis; Osmotic Fragility; Prostatic Neoplasms; Remission, Spontaneous; Time Factors

Topics: Acid Phosphatase; Agammaglobulinemia; Anemia, Myelophthisic; Bone Marrow; Humans; Immunoglobulin G; Isoenzymes; L-Lactate Dehydrogenase; Male; Neoplasm Metastasis; Prostatic Neoplasms