Total Immunoglobulin Synthesis Research Articles

Systemic PPARγ Ligation Inhibits Allergic Immune Response in the Skin

We have shown previously that specific ligands of the peroxisome proliferator-activated receptor-gamma (PPARgamma) inhibit the systemic allergic immune response. The objective of this study was to investigate the impact of PPARgamma-ligand treatment on the local allergic immune response. We established a murine model exhibiting clinical and histological features of AD-like skin lesions with high reproducibility. In this model, the PPARgamma ligand was applied in an either preventive or therapeutic manner via systemic and local routes. The affected skin areas were assessed by standardized skin score, histological analyses, and immunohistochemical examinations. Our data show that systemic application of PPARgamma ligand by a preventive protocol led to significantly reduced onset of eczematous skin lesions. This was confirmed by histology, showing decreased skin thickness accompanied by significantly reduced infiltrations of CD4+ and CD8+ lymphocytes but also mast cells. Additionally, early allergen-specific IgE and IgG1 responses were reduced (day 21/35), whereas IgG2a levels remained unchanged. In conclusion, our results demonstrate that PPARgamma-ligand treatment inhibits not only systemic allergic immune response, but also local allergen-mediated dermatitis. Our findings point to therapeutic strategies, including a PPARgamma-ligand-based treatment.

Human colonic intraepithelial lymphocytes suppress in vitro immunoglobulin synthesis by autologous peripheral blood lymphocytes and lamina propria lymphocytes.

Human colonic intraepithelial lymphocytes have been shown to suppress the proliferation of autologous lamina propria lymphocytes and allogeneic peripheral blood mononuclear cells. This study has shown that, in vitro, intraepithelial lymphocytes suppress IgA and total immunoglobulin synthesis (but not IgG or IgM production) by autologous peripheral blood and lamina propria lymphocytes. This down regulation of IgA production is mediated by a soluble factor secreted by the intraepithelial lymphocytes. There is no difference in immunoglobulin down regulation by intraepithelial lymphocytes of control subjects and patients with inflammatory bowel disease.

Effect of fibronectin on antigen-induced lymphoproliferation and antibody synthesis in rats.

Macrophages are important positive and negative regulators of both primary and secondary antibody responses, and their activity may, in turn, be controlled by soluble mediators secreted by other cells. Fibronectin is a 440,000 dalton normal constituent of plasma and extracellular membranes that acts through macrophages to inhibit mitogen- and alloantigen-stimulated lymphoproliferation. We examined the effect of Fn on the antigen-stimulated lymphoproliferative and antibody responses in cells from trinitrophenol-derivitized keyhole limpet hemocyanin (TNP-KHL) primed rats. Fn in concentrations equivalent to normal plasma levels inhibited TNP-KLH-stimulated lymphoproliferation by unseparated lymph node leukocytes. When the experiment was repeated using purified lymph node T cells and added thioglycollate-induced peritoneal exudate macrophages or splenic adherent macrophages, Fn alone and TNP-KLH alone stimulated lymphoproliferation, but in combination they were strongly inhibitory. The effect was not due to decreased lymphocyte viability in the presence of both TNP-KLH and Fn. Nor was it due to complexes between TNP-KLH and Fn or to a simple alteration in the kinetics of lymphoproliferation. Fn had to be present with the TNP-KLH within the 1st hour of incubation. If macrophages were coincubated with TNP-KLH and Fn for 24 h, washed, and added to enriched T cells, inhibition was equivalent to that seen with continuous coculture. Similarly, coculture of TNP-KLH and Fn inhibited both total immunoglobulin and TNP-KLH-specific antibody synthesis at optimal concentrations of splenic adherent cells. However, at suboptimal levels of splenic macrophages, the combination was synergistic, stimulating more total immunoglobulin synthesis than either TNP-KLH or Fn alone. These data suggest that the inhibitory effect was dependent upon the concentration and phenotype of macrophages present in culture.

Distribution of anti-histone-antibody-secreting cells in NZB/NZW mice

Using a histone-specific plaque assay, we examined anti-histone-antibody (AHA) production at the organ level in the autoimmune NZB/NZW strain. The spleen had the highest absolute numbers of AHA-secreting cells. High percentages of immunoglobulin-secreting cells producing AHA were characteristic of spleen and bone marrow but not lymph node. AHA-secreting cells were detected in NZB/NZW mice with elevated serum activity but not in mice with normal serum levels. Serum AHA activity correlated with the number of AHA-secreting cells in the spleen but not with the total number of immunoglobulin-secreting cells in the spleen nor with the total serum immunoglobulin level. These findings concerning the organ distribution of AHA-secreting cells contrast with results of other investigators studying autoantibodies of other specificities. Furthermore, our results suggest that AHA production does not solely result from a generalized increase in total immunoglobulin synthesis present in NZB/NZW mice.

AN IMMUNOTOXIN OF RICIN A CHAIN CONJUGATED TO THYROGLOBULIN SELECTIVELY SUPPRESSES THE ANTI-THYROGLOBULIN AUTOANTIBODY RESPONSE

The autoantigen thyroglobulin has been conjugated with the A chain of the toxin ricin. In vitro this conjugated "immunotoxin" specifically suppressed the thyroglobulin autoantibody response of lymphocytes from patients with Hashimoto's thyroiditis. Neither total immunoglobulin synthesis nor the synthesis of autoantibody to thyroid microsomes by these lymphocytes was affected by the immunotoxin. The demonstration that an autoantigen coupled to a toxin can induce specific immunological unresponsiveness suggests that such immunotoxins could provide a novel and highly selective means for deleting autoantibody-secreting lymphocyte clones in patients with autoimmune disease.

Lipopolysaccharide induction of immunoglobulin synthesis in irradiated lymphocytes

Normal or heavily irradiated mouse spleen cells were stimulated to immunoglobulin synthesis by lipopolysaccharides (LPS). Total immunoglobulin synthesis was measured at the cellular level by plaque formation. It was found that only a subpopulation of lymphocytes is inducible after irradiation. Lymphocytes in that subpopulation are larger than small lymphocytes and do not adhere to plastic; their resistance to irradiation appears to be related to their cycling state, not to their differentiation stage.

QUANTITATICN OF LYMPHOCYTE IMMUNOGLOBULIN BIOSYNTHESIS

Quantitaticn of peripheral blood lymphocyte immunoglobulin biosynthesis was evaluated as a method for detection of humoral immunodeficiency. Lymphocytes isolated from 3-15 cc of heparinized blood, using Ficoll-Hypaque gradients, were incubated in leucine free medium (1×106 cells/cc) with tritiated leucine for 48 and 72 hrs. Newly synthesized secreted IgG and total immunoalobulins were measured using specific anti-immunoglobulin antibodies coupled to insoluble bromacetylcellulose. Synthesis was readily detected in newborn infants as young as 28 wks gestation. The normal range (6 individuals) for total immunoglobulin synthesis and IgG synthesis was 1.3-5.5%, and 0.3-1.6%, respectively, of total secreted proteins. The lymphocytes of a patient with X-linked agammaglobulinemia synthesized no immunoglobulins. In a patient with non-X-linked agammaglobulinemia (with B-cells), total immunoglobulin and IgG synthesis was 0.20% and 0.13%, respectively. A patient with common variable hypogammaglobulinemia (normal IgM, low IgG, absent IgA) also showed depressed synthesis (total immunoglobulins 0.70%, IgG 0.40%). Quantitation of lymphocyte immunoglobulin biosynthesis appears to be a useful technique for the early diagnosis of humoral immunodeficiency and may be of potential value for the detection of immunodeficiency disease carriers.