Moreover, selective responses to serotypes 3, 4, and 9 were also abnormal when separately determined (Table2). in CD20-deficient mice. Our study therefore identifies what we believe to be a novel type of humoral immunodeficiency caused by CD20 deficiency and characterized by normal development of antigen-independent B cells, along with a reduced capacity to mount proper antibody responses. == Introduction == Main antibody deficiencies are associated with an increased susceptibility to infections by encapsulated bacteria. In recent years, a variety of genetic defects have been recognized that explain these disorders (1). Agammaglobulinemia is usually accompanied by a strong reduction or even complete absence of mature circulating B cells and results from a block of antigen-independent B cell development in the bone marrow. Frequently, this block is usually caused by mutations in the components of the preB cell receptor (pre-BCR) or associated signaling molecules such as Brutons tyrosine kinase (27). In disorders associated with defects in the responsiveness of mature B cells, normal numbers of circulating mature B cells are found with deficiencies of some but not all immunoglobulin classes. These disorders fall into 2 groups. In the first of these, hyper-IgM syndromes, genetic defects impair immunoglobulin-class switching (e.g., IgM to IgG) and somatic mutation of immunoglobulin genes in response to antigens (810). The second and most frequently occurring category is usually common variable immunodeficiency (CVID), a syndrome involving hypogammaglobulinemia, a lack of antibody production in response to vaccination and Tafenoquine Succinate sometimes autoimmune phenomena or granulomatous inflammation. Genetic mutations have been found in some CVID patients that can either be B cell intrinsic (CD19) or extrinsic (ICOS, TACI) (1114). Still, for the majority of patients, the molecular basis for antibody deficiencies have yet to be unraveled. CD20 was one of the first B cellspecific differentiation antigens recognized (15). Nowadays, CD20 immunotherapy using chimeric mAbs is used for the treatment of B cell neoplasia, Tafenoquine Succinate EBV-associated immunopathology, and a growing list of diseases with presumed autoimmune origin (16,17). CD20 Tafenoquine Succinate belongs to the MS4A family of molecules with multiple membrane spanning domains (18,19) and is expressed on pre-B and mature B cells but is usually lost upon differentiation into plasma cells (20). CD20 is unlikely to have a natural ligand, but in vitro studies with CD20 mAbs have demonstrated its involvement in the regulation of B cell activation and proliferation (21,22). Moreover, CD20 is a component of a multimeric cell surface complex that regulates Ca2+transport across the plasma membrane (23,24). Although CD20 mAb immunotherapy depletes normal and malignant B cells in vivo by antibody-dependent activation of the innate monocytic network (25), mAb crosslinking of CD20 alters Ca2+homeostasis, which influences cell cycle progression and can lead to apoptosis of normal and leukemic B cells in vitro (23,26). TheCD20gene structure and expression pattern is strongly conserved between mouse and human (2729) and CD20-deficient mice have been independently generated by 2 groups (29,30).CD20/B cells develop and function normally, but spleen B cells exhibit demonstrable alterations in BCR- and CD19-induced Ca2+responses (29). The importance of CD20 for the generation and function of human B cells has yet to be clarified. We describe here a patient that completely lacked surface CD20 expression on B cells as a result of a homozygous mutation in theCD20gene (28). The patient had a prolonged hypogammaglobulinemia, normal B Rabbit Polyclonal to OR52D1 cell figures, and a strong reduction in circulating memory B cells. A decreased frequency of somatic hypermutations in IgG heavy chain genes was found. After repeated vaccinations the patient mounted proper responses to recall antigens but displayed a strongly reduced ability to respond to Tafenoquine Succinate pneumococcal polysaccharides. In agreement with a conserved role of CD20 in the generation of T cellindependent (TI) antibody responses, we found that CD20-deficient mice have a reduced ability to respond to TI.