The most essential function of B-lineage cells is the production and secretion of antibodies, or immunoglobulins (Ig), capable of binding noncovalently to foreign proteins, carbohydrates, and glycolipids. In many respects, the differentiation of B cells revolves around the formation of this remarkable protein. The most relevant of the innumerable antigens of the environment in terms of survival are found on pathogenic bacteria and viruses. Their recognition is made possible by the tremendous variety of amino terminal sequences of the variable (V) regions of heavy (H) and light (L) chains expressed by millions of B cells, each of which expresses one of the many possible antibody structures. Antigen is identified by the V region of a secreted Ig, whereas its constant (C) domains mediate lysis of the antigen by complement proteins or cytotoxic cells, or its phagocytosis by macrophages or neutrophils. On the other hand, recognition of antigen by Ig expressed on B-cell membranes (surfaces Ig, sIg) can trigger cell division and differentiation. By immunofluorescence staining, three important phases in B-lineage differentiation are recognized: (1) bone marrow pre-B cells expressing μ heavy chains in cytoplasm (c) and lacking surface immunoglobulin (sIg - cμ + ); (2) circulating B cells expressing both heavy and light chains assembled into a complete surface Ig molecule (sIg + , cIg + / - ); and (3) secretory plasma cells with abundant cytoplasmic Ig (sIg + / - , cIg + ). The pre-B cells, blinded to antigens by lack of sIg, thus appear to be governed solely by their own genetic 'judgment' in selecting and modifying germline V(H) and V(L) gene segments to form a preliminary antibody repertoire. Of the many newly formed B-cell clones, only those cells that have, or acquire by mutation, sIg matching the antigenic environment can survive to express vital growth-factor receptors, proliferate, become plasma cells, and secrete Ig. In parallel with the refinement in V region specificity by genetic and antigenic forces, a similar evolution shapes the choice of heavy chain constant regions, or isotypes. All B cells are initially sIgM + , and in order to switch C(H) expression to one of the other seven isotypes (excluding δ), cells must actually delete unwanted C(H) genes. Despite total switching of the Ig constant region, the molecule retains the same variable region characteristic of that cell clone. External forces may favor growth of cells bearing a particular isotype, an important effect considering the specialized functions of the various isotypes (IgM, complement lysis, and phagocytosis; IgG, phagocytosis, and placental transfer; IgA gastrointestinal and biliary secretion; IgE, eosinophil and basophil triggering). Formation of pentameric IgM and dimeric IgA is mediated by the J chain, a small glycoprotein that binds to the carboxyterminal end of μ and α chains and whose expression is up-regulated during B-cell differentiation.