Wednesday, December 18, 2013

The Role of CD40–CD154 Interactions in Autoimmunity and the Benefit of Disrupting this Pathway

Autoimmune disease is associated with adaptive immune component dysfunction such as the B cells and T cells. The cells somehow pass through peripheral tolerance and cause a self reaction. Autoimmunity is determined by genetics, environmental, and hormonal effects that contribute to the disease. Many autoimmune diseases have been studied and examined but the biology behind them are not completely understood.

A major pathway is the CD40-CD40 ligand (CD154) because it is needed to activate many adaptive immune cells such as DC's, B cells, and T cells. This interaction has multiple functions and as costimulatory molecules, they are upregulated in several autoimmune diseases for example SLE (systemic lupus ertyhematosus). It was thought that disabling this interaction could be a new avenue of therapy for autoimmunity.

Caption: The image to the left shows the basic interactions between immune cells in the body when trying to get rid of an antigen. The same interactions occur in autoimmune diseases where the body is attacking self antigens. In this picture, we can see the CD40-CD40L (CD154) interaction described above between a dendritic cell presents antigens and a CD4+ T cell which aims to help the immune response by releasing cytokines.

CD40 provides a help signal to dendritic cells to maturation. The duration of the signal assists in determining the function of the dendritic cells which is displayed in this study. There are various other proteins that can trigger dendritic cells to become activated and thus spark an autoimmune response such as heat shock proteins. These can skew a response using cytokines, interleukins, and different factors. In a mouse model, diabetes was induced when CD40 expression on bone marrow was necessary for heat shock protein induced activation. 

This reaction of CD40-CD154 is not only found in dendritic cells but it also impacts T cells by priming them, polarizing T cells to a certain response.

Caption: The basic polarization of T cells is shown in the following image with different cytokines determining the Th cell developed. 

Th (T helper) cells only express CD154 after they have been stimulated by an antigen which allow them to have this interaction of CD40-CD154; unfortunately over expression of CD154 can lead to autoimmune diseases. This not only occurs in T cells but in B cells as well. The CD40-CD154 interaction enhances CD86 expression on B cells in autoimmunity specifically SLE disease which is a hypersensitive reaction. CD86 contributes to the presentation of self-antigens to T cells thus inducing a negative immune response by the body. 

Even soluble CD154 was studied and was increased in the plasma of autoimmune diseased patients versus the control showing that they contribute to inflammation of targeting self tissues to a degree. This reaction plays a role in allograft rejection. They have conducted multiple studies with treatments of mAb anti-CD154 and the transplant was more successful. 

This leads us to believe that it could be a possible form of therapy for autoimmune diseases as it is a pro-inflammatory pathway and appears to have many effects. If this pathway was blocked then it would lead to cells being tolerized or apoptisized instead of self attacking. Since this is a popular option, they tested whether the initiating it at the onset of the disease/transplant or further along would relieve symptoms more and it was found that at initiation was best. There was a study performed with efficacy and safeness but due to some developing thromboembolic effects there was an early end although many had shown improvement up to 50%. 

CD154 was thought to be acting through co-stimulation blockade but they actually determined that it was Fc dependent decreasing T cells that are alloreactive with excess CD154. They are still investigating this mechanism and how it affects Tregs as well as other cells that express CD154. It is thought that vascular tissue expressing CD154 may be a target in the thromboembolic effects but it is still unknown.  

Works Cited




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