Myelodysplastic syndromes (MDS) are age-dependent stem cell malignancies that share biological features of activated adaptive immune response and ineffective hematopoiesis. Here we report that myeloid-derived suppressor cells (MDSC), which are classically linked to immunosuppression, inflammation, and cancer, were markedly expanded in the bone marrow of MDS patients and played a pathogenetic role in the development of ineffective hematopoiesis. These clonally distinct MDSC overproduce hematopoietic suppressive cytokines and function as potent apoptotic effectors targeting autologous hematopoietic progenitors. Using multiple transfected cell models, we found that MDSC expansion is driven by the interaction of the proinflammatory molecule S100A9 with CD33. These 2 proteins formed a functional ligand/receptor pair that recruited components to CD33's immunoreceptor tyrosine-based inhibition motif (ITIM), inducing secretion of the suppressive cytokines IL-10 and TGF-β by immature myeloid cells. S100A9 transgenic mice displayed bone marrow accumulation of MDSC accompanied by development of progressive multilineage cytopenias and cytological dysplasia. Importantly, early forced maturation of MDSC by either all-trans-retinoic acid treatment or active immunoreceptor tyrosine-based activation motif-bearing (ITAM-bearing) adapter protein (DAP12) interruption of CD33 signaling rescued the hematologic phenotype. These findings indicate that primary bone marrow expansion of MDSC driven by the S100A9/CD33 pathway perturbs hematopoiesis and contributes to the development of MDS.

Generation of the B cell recall response appears to involve interaction of Ag, in the form of an immune complex (IC) trapped on follicular dendritic cells (FDCs), with germinal center (GC) B cells. Thus, the expression of receptors on FDC and B cells that interact with ICs could be critical to the induction of an optimal recall response. FDCs in GCs, but not in primary follicles, express high levels of the IgG Fc receptor FcγRIIB. This regulated expression of FcγRIIB on FDC and its relation to recall Ab responses were examined both in vitro and in vivo. Trapping of IC in spleen and lymph nodes of FcγRII−/− mice was significantly reduced compared with that in wild-type controls. Addition of ICs to cultures of Ag-specific T and B cells elicited pronounced Ab responses only in the presence of FDCs. However, FDCs derived from FcγRIIB−/− mice supported only low level Ab production in this situation. Similarly, when FcγRIIB−/− mice were transplanted with wild-type Ag-specific T and B cells and challenged with specific Ag, the recall responses were significantly depressed compared with those of controls with wild-type FDC. These results substantiate the hypothesis that FcγRIIB expression on FDCs in GCs is important for FDCs to retain ICs and to mediate the conversion of ICs to a highly immunogenic form and for the generation of strong recall responses.

This review focuses on how immunogens trapped by FDC in the form of Ag-Ab complexes productively signal B cells. In vitro. Ag-Ab complexes are poorly immunogenic but in vivo immune complexes elicit potent recall responses. FDC trap Ag-Ab complexes and make immune complex coated bodies or "iccosomes". B cells endocytose iccosomes, the Ag is processed, and T-cell help is elicited. In vitro, addition of FDC bearing appropriate Ag-Ab complex to memory T and B cells provoke potent recall responses (IgG and IgE). FDC also provide nonspecific costimulatory signals which augment B-cell proliferation and Ab production. B cell-FDC contact is important and interference with ICAM-1-LFA-1 interactions reduces FDC-mediated costimulation. Preliminary data suggest that a costimulatory signal may be delivered via CR2L on FDC binding CR2 on B cells. FDC can also stimulate B cells to become chemotactically active and can protect lymphocytes from apoptosis. FDC also appear to be rich in thiol groups and may replace reducing compounds such as 2 mercaptoethanol in cultures. In short, FDC-Ag specifically signals B cells through BCR, and FDC provide B cells with iccosomal-Ag necessary for processing to elicit T-cell help. In addition, FDC provide nonspecific signals that are important to promote B-cell proliferation, maintain viability, and induce chemotactic responsiveness.

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Locally advanced or high-grade salivary gland carcinomas follow an aggressive clinical course. Based on our limited experience, postoperative chemoradiation with a platinum-based regimen seems to be effective in selected patients and warrants further investigation.