Immune Cell Dysfunction and Altered Apoptosis in Systemic Juvenile Idiopathic Arthritis

Elizabeth Mellins, M.D.

Stanford University School of Medicine

Funded in March, 2007: $300000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Two Types of Immune Cell Dysfunctions May Produce Autoimmune Arthritis in Children

This study will explore whether a form of autoimmune arthritis that occurs in children is produced when innate immune white blood cells remain activated and resist the normal processes of cell death, while regulatory immune cells fail to intercede. If so, the findings may lead to improved means to diagnose and treat this autoimmune disorder.

Systemic juvenile idiopathic arthritis (SJIA) is a chronic inflammatory disease of childhood. Not only does the inflammation damage the membrane surrounding joints, producing arthritis, but it also damages the membrane surrounding the heart and lungs.  About 25,000 children in this country have SJIA, and about five percent of them die of complications. The Stanford researchers hypothesize that this autoimmune disease is produced by two factors.  First, innate immune white blood cells, called “monocytes,” remain activated for a prolonged time and stimulate inflammation, while managing to avoid the normal process (called “apoptosis”) that leads to the death of activated cells. Second, regulatory immune T cells fail to prevent or curtail activation of the monocytes. 

The investigators will test this hypothesis in serial blood samples from 45 children with SJIA in different stages of the disease: those on medication who are having disease flare-ups, those on medication whose disease is in a quiet stage, and those patients who are in remission—a temporary lessening of symptoms or even disappearance of the disease—without medication.  Findings will be compared to 35 children with a related arthritic condition that affects multiple joints but not the heart and lung membranes and to 30 healthy volunteers.  Through this comparison, the researchers would identify monocyte and regulatory T cell abnormalities that not only occur during active SJIA disease but also persist in patients who are in remission, suggesting that these are the abnormalities responsible for the disease.

Significance:  This study may identify specific defects in immune white blood cells and regulatory T cells that underlie susceptibility to this systemic autoimmune disease of childhood, providing targets for immunotherapies designed to prevent or treat this autoimmune disease. 

ABSTRACT

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Immune Cell Dysfunction and Altered Apoptosis in Systemic Juvenile Idiopathic Arthritis

Systemic juvenile idiopathic arthritis is (SJIA) is a chronic inflammatory disease of childhood characterized by a combination of systemic features (fever, rash, serositis [e.g., pericarditis, pleuritis]) and arthritis. The pathogenic mechanisms in SJIA remain poorly understood.  kPCR-validated data from microarray analyses of SJIA PBMC have led us to hypothesize that dysregulation and prolonged activation of monocytes represents a key aspect of the pathobiology of SJIA.

Here we propose to test this hypothesis in the following aims: 1) to determine whether/which signal transduction pathways are altered in circulating monocytes and whether changes in monocyte signal transduction pathways are cell autonomous; 2) to test whether a dysregulated state is maintained by reduced susceptibility of monocytes to apoptosis, a physiologic mechanism for removal of activated cells, and whether resistance to apoptosis is cell autonomous; and 3) to test whether altered apoptosis and prolonged activation are maintained by lack of counter-regulatory cell function, specifically, regulatory T cell (Treg) function. We will test samples from SJIA subjects at disease flare, quiescence (on therapy), and remission (off therapy) and from polyJIA and healthy controls for comparison with SJIA.

Our results may suggest new therapeutic targets for SJIA. Phenotypic abnormalities that persist in SJIA remission samples will suggest that these represent intrinsic defects that may underlie susceptibility to this inflammatory disorder.  In addition, our findings may have implications for other disorders, including RA, which share features of SJIA.

INVESTIGATOR BIOGRAPHIES

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Elizabeth Mellins, M.D.

Elizabeth Mellins, M.D., received her doctorate from Harvard Medical School before doing a pediatric residency at the University of Colorado and the University of Washington, where she also did a pediatric rheumatology fellowship. Currently she is an Associate Professor of Pediatrics at Stanford University.

Dr. Mellins’ laboratory has had a long-term interest in MHC class II molecules. This interest was motivated initially by the still-unexplained role of these molecules as inherited risk factors for rheumatic disease.  Her lab has studied the cell biology and biochemistry of these molecules and has contributed to the current understanding of how MHC class II molecules get loaded with peptides, including the roles of the co-factors invariant chain and HLA-DM. This interest has also lead them to related issues in primary human antigen presenting cells, including dendritic cells and monocytes, such as how certain pathogens subvert the class II antigen presentation pathway.

Several years ago they began a new line of work, investigating the pathophysiology of the pediatric disease systemic juvenile idiopathic arthritis (SJIA). Clinical aspects of this disease suggested that dysregulated antigen presenting cells might be involved and their initial studies are consistent with this idea.  Dr. Mellins’ lab is currently studying monocyte dysfunction in this disease and is also interested in the possibility that cells that regulate monocyte action are involved in SJIA pathobiology.