Intravenous immunoglobulin abrogates dendritic cell differentiation induced by interferon‐α present in serum from patients with systemic lupus erythematosus

Objective

Alterations in the function of dendritic cells (DCs) may explain the systemic autoimmune responses that characterize systemic lupus erythematosus (SLE). Even though several reports have documented the beneficial effect of intravenous immunoglobulin (IVIG) in SLE, the underlying mechanisms of action remain poorly understood. Considering the effect of serum factors, including interferon‐α (IFNα), on the activity of DCs, we investigated the effects of IVIG on the differentiation of DCs mediated by serum from SLE patients.

Methods

DCs were differentiated from peripheral blood monocytes obtained from SLE patients and from healthy blood donors, in the presence of SLE serum. IVIG was used at a concentration of 0.15 mM. A functional assay was performed to assess the inhibitory effect of IVIG on the uptake of nucleosomes by DCs.

Results

IVIG interfered with the differentiation of DCs from SLE patients and healthy donors cultured in the presence of SLE serum. Treatment of DCs with IVIG inhibited the ingestion of nucleosomes by immature DCs, by up to 36%.

Conclusion

The present findings indicate that IVIG, by down‐regulating the IFNα‐mediated differentiation of DCs and by inhibiting uptake of nucleosomes, may exert an essential immunoregulatory effect in SLE patients at the onset of the immune response, at the DC level. Given the critical role of HLA molecules and the costimulatory signals delivered by CD80 and CD86 in optimal antigen presentation and T cell activation, inhibition of expression of HLA and CD80/CD86 on DCs by IVIG offers a plausible explanation for the efficacy of IVIG in SLE and other immune‐mediated inflammatory conditions.

     

Mathematical Model of Diffusion-Limited Gas Bubble Dynamics in Unstirred Tissue with Finite Volume

Models of gas bubble dynamics for studying decompression sickness have been developed by considering the bubble to be immersed in an extravascular tissue with diffusion-limited gas exchange between the bubble and the surrounding unstirred tissue. In previous versions of this two-region model, the tissue volume must be theoretically infinite, which renders the model inapplicable to analysis of bubble growth in a finite-sized tissue. We herein present a new two-region model that is applicable to problems involving finite tissue volumes. By introducing radial deviations to gas tension in the diffusion region surrounding the bubble, the concentration gradient can be zero at a finite distance from the bubble, thus limiting the tissue volume that participates in bubble–tissue gas exchange. It is shown that these deviations account for the effects of heterogeneous perfusion on gas bubble dynamics, and are required for the tissue volume to be finite. The bubble growth results from a difference between the bubble gas pressure and an average gas tension in the surrounding diffusion region that explicitly depends on gas uptake and release by the bubble. For any given decompression, the diffusion region volume must stay above a certain minimum in order to sustain bubble growth. © 2002 Biomedical Engineering Society. PAC2002: 8719Tt, 8719Uv, 8710+e     

Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis

The clinical use of intravenous immunoglobulin (IVIg) based on its immunomodulatory and anti-inflammatory potential remains an ongoing challenge. Fcgamma receptor-mediated effects of IVIg, although well elucidated in certain pathologies, cannot entirely account for its proven benefit in several autoimmune disorders mediated by autoreactive T cells. In this study, we show that prophylactic infusion of IVIg prevents the development of experimental autoimmune encephalomyelitis (EAE), an accepted animal model for multiple sclerosis (MS). The protection was associated with peripheral increase in CD4+CD25+Foxp3+ regulatory T cell (Treg) numbers and function. The protection was Treg-mediated because IVIg failed to protect against EAE in mice that were depleted of the Treg population. Rather than inducing de novo generation from conventional T cells, IVIg had a direct effect on proliferation of natural Treg. In conclusion, our results highlight a novel mechanism of action of IVIg and provide a rationale to test the use of IVIg as an immunomodulatory tool to enhance Treg in early onset MS and other autoimmune and inflammatory conditions.     

Genetic portrait of North-West Indian population based on X chromosome Alu insertion markers

International Journal of Legal Medicine - In the present study, allele frequencies and forensic parameters of four ethnic groups (Brahmin, Khatri, Jat Sikh, and Scheduled Caste) of Punjab, India,...     

Protein destabilizing agents induce polyreactivity and enhanced immunomodulatory activity in IVIg preparations

Normal pooled human IVIg are produced using various blood protein fractionation technologies and as a result they may well differ in their biological properties. We have demonstrated that exposure of IVIg, for a period as short as 15 min, to protein-destabilizing agents like acidic pH, ROS or pro-oxidative ferrous ions dramatically increases the panel of recognized Ag including pro-inflammatory cytokines. We now show that exposure of IVIg to ferrous ions modifies some IgG molecules without denaturating them and enhances the protective activity of the preparation in experimental septic shock.     

Defective functions of polymorphonuclear neutrophils in patients with common variable immunodeficiency

Common variable immunodeficiency (CVID) is a heterogeneous antibody deficiency condition with alterations in T cell regulation and function, dendritic and B-cell compartment and represents the most frequent cause of symptomatic primary immunodeficiency. We addressed whether CVID is associated with abnormalities in the polymorphonuclear neutrophil (PMN) compartment, an important component of innate immunity and plays a key role in host defenses against invading microorganisms. We used flow cytometry to examine PMN phenotypic and functional abnormalities in CVID patients, using whole-blood conditions in order to avoid artifacts due to isolation procedures. We demonstrated that PMN from CVID patients displays, at resting state, a decreased expression of CD15, CD11b and CD16b, which might be related to an abnormality in neutrophil maturation. In addition, these neutrophils exhibit a decrease in degranulation, phagocytosis and reactive oxygen species production, as well as an increased death by apoptosis. These PMN abnormalities observed in CVID patients could result in an increased risk for recurrent bacterial infections.