The influence of intravenous immunoglobulins on dendritic cells in immune (idiopathic) thrombocytopenic purpura

Childhood immune (idiopathic) thrombocytopenic purpura (ITP) is an autoimmune disease defined by isolated thrombocytopenia. 70-80% of the ITP patients recover within a few months, while the remaining 20-30% develop chronic ITP. ITP is a heterogeneous disease. In the majority of patients the increased platelet destruction is caused by autoantibodies directed against platelets. However, not in all patients autoantibodies are found. In these patients other disease mechanisms are likely to be involved, however, these are poorly defined. In addition, the cause of the production of autoantibodies against platelets in ITP is largely unknown. The treatment of ITP is aimed at increasing the platelet count in order to prevent bleedings. One of the therapies is intravenous immunoglobulin (IVIg), which consists of pooled human immunoglobulin G. There are indications that treatment with IVIg decreases the risk on developing chronic ITP. Therefore, IVIg needs to have additional immune modulatory effect that can change the outcome of disease. However, it is unknown how IVIg achieves this anti-inflammatory effect. It is important to unravel its working mechanism in order to develop a recombinant product to replace IVIg therapy. Replacement of IVIg is desirable, since there is a threat of shortage of IVIg availability and to limit safety issues as IVIg is a primary blood product. In this essay is focussed on the effect of IVIg on dendritic cells (DCs), since DCs play a key role in the amplification of the auto-immune response as antigen presenting cell. In order to influence DCs, IVIg need to interact with DCs. IgG molecules consist of a variable region and a constant region and for both parts interaction partners are suggested in literature. There is some in vitro evidence that the variable region influences DCs, possibly via interactions with CD40. Several articles provide both in vitro and in vivo evidence for a role of the constant part of IgG molecules in the working mechanism of IVIg. Suggested interaction partners of the constant region are the activatory FcγRs and DC-SIGN. However, contradictory results are found on the role of DC-SIGN. Inhibitory FcγRs do play a role in the anti-inflammatory effect, but not as direct interaction partner of IVIg. These interactions can change the DC in such a way that this result in an anti-inflammatory effect. It is reported that IVIg can inhibit DC maturation, differentiation and antigen presentation. This leads to an impaired T cell activation and an inhibition of the auto-immune response. In addition, IVIg changes the cytokine secretion of DCs, which might shift the T cell response into a more Th2 like phenotype. Since patients with chronic ITP have a higher Th1/Th2 ratio, IVIg might restore the balance of the T cell response and in this way prevent development of chronic ITP. IVIg primed DCs can also influence other cell types, like macrophages and platelets. It is suggested that IVIg treated DCs higher the expression of FcγRIIB, the inhibitory FcγR, on macrophages. This effect is reached via a change in the cytokine expression of DCs. An increased FcγRIIB expression can contribute to the anti-inflammatory effect of IVIg, since this alters the activatory/inhibitory FcγR ratio, resulting in a higher threshold for immune activation. Platelets are also changed by IVIg treated DCs. It is reported that platelets of mice treated with IVIg primed DCs engage less with leukocytes compared to platelets of untreated mice. When platelets engage less with leukocytes, the degradation and antigen presentation will decrease, resulting in an inhibition of the auto-immune response. So, different interactions partners and effects of IVIg are proposed in literature. It is possible that different mechanisms act at the same time. Since contradictory results are published and since it is not clear which mechanisms are most important in vivo, it is not possible to conclude exactly in which way IVIg reaches his anti-inflammatory effect