Thymusindependentbcell Activation

Many immunogens can directly cross-link the BCR-mlgMcomplex. Generally, these immunogens have multiple identical epitopes or repeating subunits and are not normally processed in the antigen presentation pathways.

With some exceptions, these immunogens fall into two groups. The first group consists of polysaccharides, glycolipids, and nucleic acids. The second group consists of various lipopolysaccharides (LPS) liberated from the cell walls of gram-negative bacteria.

Using an alternate nomenclature, these immunogens are designated TI type 1 or 2 depending onthe necessity for second signals inB-cell activation. Type 1 TI immunogens such as LPS, neisserial porin proteins, and bacterial DNA do not need a second signal to initiate antibody production (Snapper and Mond, 1996). With the type 1 antigens, the nature of the response is dose dependent. For example, low concentrations of LPS initiate production of anti-LPS antibody. At high doses, LPS is a polyclonal B-cell stimulator producing antibodies to a variety of antigens.

Type 2 polysaccharides and glycolipids stimulate B cells but require a small number of macrophages and NK cells producing IL-12 and IL-15. These cytokines direct the differentiation and recruitment of Thl cells that secrete IL-2. In addition, polysaccharide-activated NK cells secretelRJ-'v and GM-CSF. These cytokines directly stimulate proliferation of B cells. Antibodies resulting from type 2 immunogen stimulation are usually low-affinity, anticarbohydrate antibodies called natural antibodies (Snapper and Mond, 1996).

Often TI immunogens have attached complement components. When complement is part of the complex reacting with the BCR, other molecules can associate with the BCR and assist in the signaling process. CD19, CD81 (receptor for complement fragment C3d), TAPA-1, and Leu-13 form multimolecular complexes with the BCR (Fig. 3). The CD19, CD81, Leu-13 complex functions as a signal transduction complex for the complement receptor (Tedder et al., 1994). Phosphorylation of serine kinase is the major signaling pathway. Alternatively spliced forms of the src kinase lyn form stable complexes with CD19 initiating intracellular signaling (van Noesel et al., 1993). The CD19-CD21-TAPA-1 mechanism is distinct from the BCR signaling. Signaling does not require the syc protein for activation and, by virtue of nine tyrosine residues in the CD19 tail, it can bind similar and related kinases (Fig. 4).

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