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.

In testing to determine whether CaMKIV plays a significant role in causing lupus nephritis, researchers used an inhibitor of CaMKIV, KN-93, as well as genetic depletion of CaMKIV in a mouse model of lupus. It has been previously shown that KN-93 mitigates disease in lupus prone mice by suppressing cytokine production and costimulatory molecule expression in lymphocytes. Thus the remaining question is what happened as a result of this inhibition that alleviated the disease? It makes sense that the researchers used flow cytometry to measure the amount of MCs progressing through the cell cycle since it is known that this receptor be connected with cell proliferation. When the testing was completed the results showed that the uninhibited presence of CaMKIV led to cell progression but when blocked or altogether deleted, the cells tended to be stuck in earlier phases of the cell cycle. These results provide strong evidence that CaMKIV plays a role in MC proliferation which itself is associated with disease.

In addition to the above findings, the researchers observed that mesangial IL-6 production was suppressed by KN-93 treatment. This finding demonstrates a direct link between CaMKIV activity and IL-6, a known mediator of the autoimmune response in the kidneys. It was also discovered that kidney damage was significantly diminished when CaMKIV was either deleted or blocked.

In summary, the important research performed by Ichinose and his associates reveals that CaMKIV is major receptor in mediating the autoimmunity which causes lupus nephritis. It then follows that the inhibitor KN-93 could prove to be of direct therapeutic value to patients suffering from this medical condition since by inhibiting CaMKIV the mesangial cells in the patients’ glomeruli would stop proliferating and halt the production of the damaging IL-6 that appears to cause the disease. As a result I suspect that this inhibitor could soon be tested in clinical trials. Hopefully, this would treat one of the root causes of lupus nephritis, a major illnesses associated with systemic lupus erythematosus (SLE).

Reference: Ichinose K., Juang, Y. T., Crispin, J. C., Kis-Toth, K., Tsokos, G. C. (2011). Suppression of Autoimmunity and Organ Pathology in Lupus-prone Mice Upon Inhibition of Calcium/Calmodulin-dependent Protein Kinase Type IV. Arthritis Rheum. 63: 523-529.

Other Citations:
1. Blenman, K.R., Duan, B., Xu, Z., Wan, S., Atkinson, M.A., Flotte, T.R., Croker, B.P., Morel, L. (2006). IL-10 regulation of lupus in NZM2410 murine model. Laboratory Investigation. 86: 1136-1148.

2. Danila, M.I., Pons-Estel, G.J., Zhang, J., Vila, L.M., Reveille, J.D., Alarcon, G.S. (2009). Renal damage is the most important predictor of mortality within the damage index: data from LUMINALXIV, a multiethnic US cohort. Rheumatology (Oxford). 48(5): 542-5.

3. Shang, S., Takai, N., Nishida, M., Miyazaki, T., Nasu, K., Miyakawa, I. (2003). CaMKIV expression is associated with clinical stage and PCNA-labeling index in endometrial carcinoma. Int J Mol Med. 11(2):181-6.