Jun. 01, 2010

Animal Study Sheds Light on Development of Lupus Nephritis

Proliferative lesions and metalloproteinase activity in murine lupus nephritis mediated by type I interferons and macrophages. 
Authors: Triantafyllopoulou A, Franzke CW, Seshan SV, Perino G, Kalliolias GD, Ramanujam M, van Rooijen N, Davidson A, and Ivashkiv LB. (2010).  
Proc Natl Acad Sci USA 107: 3012-3017.

What is the topic?
Kidney involvement is one of the most challenging features of lupus. However, knowledge about how kidney damage occurs in people with lupus is limited. Studies have looked at lupus-related kidney inflammation under a microscope. In one type of kidney involvement, cells are literally growing and multiplying in those inflamed areas, expanding and distributing the kidney tissue and interfering with it doing its job (which is to be a sensitive membrane that filters out waste). This is called “proliferative lupus nephritis.” When this kind of inflammation becomes particularly severe, you can see a major buildup of these inflamed tissues inside the kidney’s filtering area, which often has a crescent shape. This is called “crescentic” because of the shape. 

Researchers hope to learn more about human lupus by figuring out how to make it develop in animals. A drug called polycytidylic acid (PCA) causes increased activity of immune system proteins called interferons (IFNs), which seem to play a role in the development of lupus. In mice that are already bred to be somewhat prone to lupus, the appearance of some features that look like the human disease, including lupus nephritis, are accelerated by giving PCA.     

What did the researchers hope to learn?
The researchers hoped to learn about the role of IFNs and macrophages (white blood cells) in the development of experimental lupus nephritis. 

Who was studied?
Nineteen week-old female mice (the breed is called NZB/W) were purchased from Jackson Laboratory, a special company that creates mouse “models” for human diseases. 

How was the study conducted?
Some of the mice were injected with PCA three times per week for four weeks. Another group of mice got a single dose of a kind of IFN known to be associated with lupus, called type I IFN. A third group of mice served as the comparison group (control group) and were injected with only salt water. The researchers started these treatments when the lupus-prone mice were usually too young to develop kidney disease on their own, but had some lupus antibodies found in blood tests. 

The mice were monitored for the development of protein in the urine, which is a fairly reliable sign of kidney involvement. The kidney tissues were studied over time to see whether certain genes were being used as blueprints for making inflammatory proteins. The inflammatory genes included genes which are known to be turned on by IFNs, and other genes which are known to become activated in human lupus-related kidney inflammation.    

What did the researchers find?
After two weeks, PCA-treated mice, but not the control mice, developed protein in the urine. The kidneys of the PCA-treated mice had evidence of proliferative and crescentic lupus nephritis. PCA treatment caused increased activity of genes known to be switched on by IFN and this was detectable in the kidney at six hours and at two weeks after drug treatment. This drug treatment also caused an increase in levels of an activated white blood cell, called a macrophage, in the kidney. These macrophages were of a special kind involved in repair of tissues. When PCA-treated mice were given a substance to deplete the body of macrophages before they got the PCA, it blocked these changes. 

Treatment with PCA caused an increase in gene activity of inflammatory proteins known to be involved in human lupus nephritis. However, all of these changes were blocked in the mice that were depleted of macrophages. 

Mice treated directly with IFN also developed proliferative lupus nephritis and increases in kidney macrophages. These effects were also reduced in mice depleted of macrophages.    

What were the limitations of the study?
People are not mice. There are many known differences between the immune systems of humans and mice and probably many as yet unknown differences as well. Also, mouse “models” are all genetically identical, so what you find in one mouse will be relevant to all the other mice of that type. This is not true for humans. Even two sisters with lupus might have very different immune system imbalances from each other. Nevertheless, there are some common immune imbalances that are found in large percentages of people with lupus. Animal models are essential to figure out what types of imbalances might be causing human lupus, and to find new targets for fine-tuning treatments at the microscopic level. Still, these findings need to be proven in humans, step by step, after being tested in the mice, and figuring out which people might benefit from various insights from mouse studies is a whole additional step after that. 

What do the results mean for you?
The findings do confirm some other studies which suggest that IFNs and macrophages may be important in the development of lupus nephritis, at least in some subsets of people. This could provide some encouragement for future studies aimed at seeing whether treatments that target these things might become useful as treatments for human lupus-related kidney inflammation. 

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