Chemokine expression and regulation of angiogenesis in rheumatoid arthritis.

Regulation of angiogenesis occurs in the context of particular microenvironments and is governed by a sensitive balance between angiogenic and anti-angiogenic mediators. Under normal physiologic conditions, the expansion of existing blood vessels is held in check suggesting that homeostasis is maintained by a predominance of angiostatic factors. In the rheumatoid arthritis joint, it is probable that the expansive and tumor-like synovial pannus that invades cartilage requires additional nutrients and oxygen. In the face of these demands, there is likely a shift in the balance such that angiogenic mediators predominate leading to neovascularization, a hallmark of rheumatoid arthritis. Chemokines are a subset of cytokines that primarily mediate physiologic and pathophysiologic leukocyte trafficking during inflammation and immune cell differentiation. Chemokines are also fundamental participants, along with a variety of other factors, which regulate angiogenesis. Within the CXC family of chemokines, there is functional discrepancy, where some family members are angiogenic and others are angiostatic. Moreover, the expression of several chemokines has been well documented in rheumatoid arthritis synovial tissues and fluids. This review will discuss what is known about the role of specific chemokines in the regulation of angiogenesis with particular emphasis on those chemokines likely to participate in rheumatoid arthritis.

In vitro and in vivo expression of a nephritogenic Ig heavy chain determinant: pathogenic autoreactivity requires permissive light chains.

Lymphocyte antigen receptors are promising targets for immune intervention strategies in disorders marked by repertoire skewing or expansion of lymphocyte subsets. Appropriate application of immune receptor modulation is predicated on understanding the role of a particular receptor in pathogenesis and disease regulation. The VHB/W16 gene, restricted to mice carrying the j haplotype for the J558 family, is overexpressed by murine lupus anti-DNA Ig. This gene is also expressed recurrently among nephritogenic anti-DNA Ig recovered from several autoimmune strains, suggesting that cells expressing this pathogenic receptor are positively selected during disease progression. To explore the extent and mechanisms by which Ig H chains expressing this gene contribute to autoimmunity, an Ig H chain gene was engineered for in vitro and in vivo recombination studies. Site-directed mutagenesis generated unique restriction sites to link PCR-amplified V region (VDJ) cDNA to previously isolated genomic fragments containing Ig regulatory and signal sequences. The new 3 kb VDJ gene was then ligated to a 9 kb fragment encoding the IgM constant region. Transfection of H chain loss variant myeloma with the complete 12 kb construct, termed 238H-Cmicro, resulted in secretion of intact Ig pairing 238H-Cmicro, with a lambda L chain; however, transfectant Ig lacked autoreactivity and pathogenicity. Introduction of the 238H-Cmicro H chain as a transgene onto the non-autoimmune C57BL/6 background resulted in abundant B cell surface expression of 238H-Cmicro, however, four transgenic Ig recovered by fusion of LPS-stimulated splenocytes and formed by combination of 238H-Cmicro, with endogenous kappa chains do not bind DNA or laminin. These results indicate that the antigen binding sites encoded by this disease-associated gene and/or H chain must associate with permissive L chains to specify autoimmunity. The 238H-Cmicro, transgenic model should prove useful in dissecting the in vivo fate of 238H-Cmicro, L combinations that produce pathogenic autoreactive receptors and in evaluating receptor-targeted interventions.