SCARF1: A Novel Receptor for Apoptotic Clearance

            Autoimmunity is one of the most difficult to treat and unfathomable types of disease, because we are not fighting a virus, bacterium, or parasite: we are fighting our own body. Usually, doctors can count on the immune system to help them out when their patients are sick; it is the job of this system to ensure that any foreign threat to the body is eliminated. But the nature of autoimmunity is such that the biggest ally we have in the quest to keep ourselves healthy turns against us and begins attacking that which it has evolved to protect.

There are many classes of autoimmune disease, each with a very different cause. The immune system is so diverse and complicated that a mutation in one of its parts can affect the entire system and ultimately manifest in disease. There are myriad ways in which this can happen, but the result is what is called “breaking tolerance”. When tolerance is broken, the immune system recognizes some small component of the body as a foreign object and mounts an immune response against it. This can cause differing amounts of damage, depending on how prevalent the component is, and if its recognition and destruction leads to the labeling of more self proteins as targets. There is the danger of a phenomenon called epitope spreading, which happens when a cell is targeted and destroyed, releasing its contents into the body. The immune system has not been desensitized, or “tolerized” to the proteins inside a cell, as it should have no need to recognize them in a healthy body. When this happens in the context of an already active self-targeted immune response, immune cells may further target the otherwise normal contents of the dying cells, leading to a more serious attack throughout the body.

            One important safeguard against autoimmunity is the safe breakdown clearance of apoptotic cells. An apoptotic cell is one that is infected, compromised, or simply too old and losing effective function. These cells are marked for uptake by phagocytes, which are a class of cell types that uptake and destroy their targets, breaking down anything in the cell that could be toxic if released into the body. It is known how and when phagocytes such as macrophages and dendritic cells destroy their targets, but the specifics of their identification are little investigated. In their paper “The scavenger receptor SCARF1 mediates the clearance of apoptotic cells and prevents autoimmunity”, Zaida G. Ramirez-Ortiz et al identify and characterize the receptor SCARF1 which, allows phagocytes to recognize their targets for destruction. SCARF1 is a transmembrane protein which has homologs even in the simple research model C. elegans, and acts by binding to a C1q and phosphatidylserine complex. Phosphatidylserine is a part of the inside of the cell membrane, and becomes exposed on the exterior portion of the membrane only when the cell needs to be phagocytosed. SCARF1, the researchers found, cannot recognize and destroy cells without this component bound to C1q, a peptide which also plays a role in the complement system. High concentrations of this peptide near a cell marked with phosphatidylserine cause a complex to form, which binds to SCARF1 and results in successful phagocytosis. 

   

1. Macrophage Engulfing Apoptotic Cells

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. 

Stopping Autoimmunity at its Roots: New Advances in the Treatment of Lupus Nephritis

Autoimmune diseases are the result of our own immune systems turning against us. There are various mechanisms through which autoimmunity can develop, most of which involve the breakdown in peripheral tolerance, which are the mechanisms our body puts in place to keep autotreactive T and B cells from damaging self tissue. If an autoreactive lymphocyte escapes central tolerance and finds its way to the periphery, it becomes the job of regulatory T cells (Treg cells) or tolerogenic DCs to anergize or delete the autoreactive lymphocyte. If there are abnormalities in regulatory T cells, then peripheral tolerance is hindered and an autoimmune disease could develop. Other conditions could result if problems exist in compliment deposition since C3b is responsible for helping immune complexes remain soluble when they pass through narrow channels in the body’s periphery. When cells are destroyed during an autoimmune attack, internal cell contents can be leaked and then work as antigens for the activation of additional lymphocytes. This occurrence may perpetuate an autoimmune response. Regardless of the mechanism, these responses are damaging to the host and require the development of effective treatments.

One damaging autoimmune disease, systemic lupus erythematosus (SLE), is caused by the production of “antinuclear” antibodies which target internal cell components such as DNA when these molecules are released from cells. This disease can affect the skin, joints, kidney, lung, heart, and brain. Since SLE’s symptoms are often varied, the disease can be mistaken for other illnesses. The mechanism of action of SLE has been linked to abnormal B cell development and activation. These B cells are also more sensitive to cytokines than would normally be expected. Furthermore, the fact that an increase in IL-10, a B-cell stimulating molecule, has been associated with SLE patients provides additional evidence that this disease is caused by B cells. This observation is interesting because typically we associate IL-10 as an immunosuppressive cytokine, however in the case of SLE patients, the immunostimulatory effects of IL-10 on B cells appear to outweigh its immunosuppressive value (1). SLE is considered to be a type-III hypersensitivity because these activated B cells produce autoantibodies that can form insoluble immune complexes that basically “clog up” narrow capillaries or other parts of the body such as the glomerulus, a spherical structure in the kidneys which filters blood. As a result, many SLE patients manifest the serious disorder called lupus nephritis. Lupus nephritis is a major cause of morbidity and mortality among SLE patients (2). It results when immune complexes interfere or cause damage to structures in the kidney, such as the glomerulus, and can rapidly worsen to kidney failure. Treatment for lupus nephritis typically focuses on the use of medications to suppress the immune system in order to improve kidney function. Dialysis, to control symptoms of kidney failure, and kidney transplantation are other treatments that may be recommended.

Recent research by K. Ichinose and several colleagues at Beth Israel Deaconess Medical Center and Harvard Medical School has been focusing on the cause of lupus nephritis rather than on new treatments for the malady. The researchers are hoping that their efforts will lead to the development of a more targeted drug which can do more for patients than the current drugs that work by suppressing the immune system on a large scale. They chose to study mesangial cells (MC’s) in the glomerulus because they proliferate during lupus nephritis, a phenomenon that could link MC’s to the cause of this autoimmune disease. Typically, the function of these specialized cells is related to support, filtration, and phagocytosis of immunoglobulin. These cells can also produce the proinflammatory cytokine IL (interleukin)-6, found during glomerular inflammation. The researchers also looked at calcium/calmodulin-dependent kinase type IV (CaMKIV). This kinase belongs to a family of kinases that regulates autoimmunity and cell proliferation. CaMKIV is a multifunctional protein that is highly expressed in the central nervous system. Because increased expression of CaMKIV has been linked to certain cancers, some researchers see this as evidence that it is involved in cell proliferation (3). This observation led them to perform tests to ascertain whether CaMKIV could be deleted or its actions blocked, possibly leading to decreased MC proliferation and IL-6 production that could in theory alleviate an autoimmune response.

CaMKIV: A Potential Target for a Treatment for Lupus Nephritis

Systemic lupus erythematosus (SLE) is an autoimmune disorder that currently has no cure (PubMed Health, 2011). SLE may result in abnormal deposits in kidney cells, which leads to complications in the kidneys. This results in the condition lupus nephritis, in which extensive damage to the kidney occurs and ultimately results in kidney failure (PubMed Health, 2011). There has been much speculation that Calcium/calmodulin-dependent protein kinases (CaMKs) is a factor in the progression of SLE, for it has previously been demonstrated that CaMKIV contributes to decreased IL-2 production in SLE T cells (Karin, 1995). CaMKIV may also play a role in the production of IL-6, for it has been demonstrated that just before the age when lupus nephritis is developed, spleen cells of mice contain a subpopulation of Th cells that selectively induced their B cells in vitro to produce highly cationic IgG autoantibodies to both single-stranded DNA and double-stranded DNA (Datta, 1987). This may be of critical importance, for it has also been shown that IL-6 is a feed forward process in which macrophages respond to IgG to support further B-cell production of IgG (Maeda, 2010).

It has previously been demonstrated that inhibiting CaMKIV in lupus-prone MRL/lpr mice mitigates disease pathology (Karin, 1995). Ichinose et al. have recently elaborated on the cellular abnormalities that may be controlled by CaMKIV (2011). These results have helped to clarify the cellular processes that result in the damage of kidneys in lupus nephritis by producing large amounts of autoimmune mesangial cells and increasing production of IL-6 and have shown that CaMKIV may be a critical target in developing treatments for lupus nephritis.