John A. Hardin

The Impact of Vitamin D on Dendritic Cell Function in Patients with Systemic Lupus Erythematosus

Background Excessive activity of dendritic cells (DCs) is postulated as a central disease mechanism in Systemic Lupus Erythematosus (SLE). Vitamin D is known to reduce responsiveness of healthy donor DCs to the stimulatory effects of Type I IFN. As vitamin D deficiency is reportedly common in SLE, we hypothesized that vitamin D might play a regulatory role in the IFNα amplification loop in SLE. Our goals were to investigate the relationship between vitamin D levels and disease activity in SLE patients and to investigate the effects of vitamin D on DC activation and expression of IFNα-regulated genes in vitro. Methodology/Principal Findings In this study, 25-OH vitamin D (25-D) levels were measured in 198 consecutively recruited SLE patients. Respectively, 29.3% and 11.8% of African American and Hispanic SLE patient had 25-D levels <10 ng/ml. The degree of vitamin D deficiency correlated inversely with disease activity; R = −.234, p = .002. In 19 SLE patients stratified by 25-D levels, there were no differences between circulating DC number and phenotype. Monocyte-derived DCs (MDDCs) of SLE patients were normally responsive to the regulatory effects of vitamin D in vitro as evidenced by decreased activation in response to LPS stimulation in the presence of 1,25-D. Additionally, vitamin D conditioning reduced expression of IFNα-regulated genes by healthy donor and SLE MDDCs in response to factors in activating SLE plasma. Conclusions/Significance We report on severe 25-D deficiency in a substantial percentage of SLE patients tested and demonstrate an inverse correlation with disease activity. Our results suggest that vitamin D supplementation will contribute to restoring immune homeostasis in SLE patients through its inhibitory effects on DC maturation and activation. We are encouraged to support the importance of adequate vitamin D supplementation and the need for a clinical trial to assess whether vitamin D supplementation affects IFNα activity in vivo and, most importantly, improves clinical outcome.

Tissue Factor Activity in Lymphocyte Cultures from Normal Individuals and Patients with Hemophilia A

The procoagulant material of lymphocytes has been characterized as tissue factor. Lymphocytes stimulated with phytohemagglutinin or the purified protein derivative of the tubercle bacillus developed procoagulant activity with incubation in tissue culture. While this material corrected the prolonged clotting time of factor VIII (AHF) deficient plasma, we have shown, utilizing a sensitive radioimmunoassay, that no AHF antigen was present in the cell cultures. Further, we have demonstrated this material to be tissue factor by coagulation techniques and immunological cross-reactivity. The published data regarding factor VIII synthesis is reviewed in light of these observations and comments are made regarding the role of the lymphocyte procoagulant.

Increased IL-12 inhibits B cells' differentiation to germinal center cells and promotes differentiation to short-lived plasmablasts

B cells activated by antigen in T cell–dependent immune responses can become short-lived plasma cells, which remain in the spleen, or germinal center–derived memory or plasma cells, which show evidence of affinity maturation and, in the case of plasma cells, migrate to the bone marrow. We show that this cell fate decision can be governed by the cytokine environment engendered by activated dendritic cells (DCs). DCs from mice lacking the Fc receptor γ chain exhibited an activated phenotype in vitro. They secreted more of the proinflammatory cytokine IL-12, which led to the preferential generation of short-lived splenic plasma cells, with ensuing low affinity antibodies and a diminished recall response. Understanding the factors that regulate antigen-activated B cell differentiation and memory cell formation has implications for both antibody-mediated autoimmune disease and protective antibody responses.

Multiple Heavy-Chain Determinants on Individual B Lymphocytes in the Peripheral Blood of Patients with Sjögren's Syndrome

Abstract Surface markers on peripheral blood lymphocytes were studied in Sjogrens syndrome. Cells bearing IgG, IgA, IgM and IgD were identified with monospecific fluorescent antiserums. In five of seven patients the frequency of cells identified with at least two anti-heavy-chain reagents was elevated. In two of these patients striking elevations were seen in the frequency of lymphocytes bearing each of the heavy-chain classes, the sum of the number of cells binding individual anti-heavy-chain serums being about four times greater than the apparent number of B lymphocytes as identified both with an anti-Fab reagent and by the binding of aggregated γ-globulin. The cells binding anti-heavy-chain serums were identified as B lymphocytes by doubling labeling procedures. These data indicate that individual B lymphocytes in some patients with Sjogrens syndrome bear multiple classes of heavy chains, an abnormality that has been noted by others in some patients with lymphoma. This association is of interest sinc...

Case 23-1975

Presentation of Case A 59-year-old woman was admitted to the hospital because of dyspnea. In her youth she had had multiple attacks of pneumonia. For many years she had been treated intermittently ...