Department of Pediatrics Research Profile

Polly Ferguson, MD
Research Profile

Research Interests

Chronic Recurrent Multifocal Osteomyelitis (CRMO)
CRMO is a chronic inflammatory disease of unknown etiology. It primarily affects children and results in recurrent fever and the development of multiple inflammatory bone lesions. It is frequently seen in association with other, more common, inflammatory disorders such as psoriasis, inflammatory bowel disease and cutaneous pustulosis making it a particularly interesting disorder to study. There are reports of affected siblings in the literature and published evidence for a susceptibility locus for CRMO on human chromosome 18q suggesting a genetic component to its etiology. In addition, there is a syndromic, autosomal recessive disorder, called Majeed syndrome, in which CRMO is a major clinical feature. The genetic basis of CRMO is further supported by the existence of a similar disorder in the mouse (cmo, chronic multifocal osteomyelitis) resulting from a spontaneous mutation that is inherited as an autosomal recessive trait. In collaboration with Dr. Hatem El-Shanti in the Division of Medical Genetics, we are in the process of dissecting the genetic basis of CRMO utilizing all 3 available models. First, the El-Shanti lab has recently demonstrated that Majeed Syndrome, a syndromic form of CRMO, is caused by defects in the LPIN2 gene. Second, my laboratory has recently identified the gene defect in the cmo mouse and are currently performing experiments to determine the immunologic abnormalities in these mice. Third, we (El-Shanti and Ferguson) are collecting DNA from patients with sporadic (non-syndromic) CRMO to see if we can determine the gene defect(s) in these patients. The goal of this research is to understand the genetic basis of chronic, non-infectious osteomyelitis. Knowledge about the gene defect(s) present in CRMO may aid in the understanding of the pathways of inflammation involved, not only in CRMO, but also in the inflammatory disorders that frequently accompany this disorder such as psoriasis and inflammatory bowel disease.

Systemic Lupus Erythematosus (SLE)
SLE is a phenotypically diverse, multi-system autoimmune disorder that is caused by ill-defined interaction(s) between environmental and genetic factors. Genome wide linkage analysis of SLE multiplex families suggests there is significant racial and genetic heterogeneity, further complicating the genetic dissection of this disorder. Fortunately, there are phenotypically similar mouse models of lupus; including genetically engineered and spontaneous models. Most of the investigative work in the field has focused on identifying disease susceptibility loci; however, there are experimental data that suggest disease resistance genes are also important, The non-autoimmune New Zealand White (NZW) mouse does not develop lupus despite harboring the best characterized lupus susceptibility intervals and a disease permissive major histocompatibility locus H-2z/z suggesting that the NZW genome contains allelic polymorphisms that negatively regulate the phenotypic expression of lupus susceptibility gene(s). We hypothesize that experimental crosses between NZW and C57BL/6.FcgammaRIIB-deficient mice will allow the identification of NZW-derived intervals that attenuate the lupus phenotypes in this genetically engineered murine model of lupus. We are 1) mapping quantitative trait loci (QTL) that modulate the FcgammaRIIB-/- lupus phenotype in order to identify NZW-derived intervals that are associated with suppression of the phenotype and 2) we will then construct chromosome substitution strains (CSS) in order to dissect the genetic contribution of these individual QTL. Identification of QTL that modulate the lupus phenotype and the subsequent development of QTL containing CSS will lay the foundation for the future functional assessment of the lupus-attenuating QTL and for candidate gene analysis. Understanding the genetic basis of disease resistance could facilitate the development of novel therapeutic approaches for treating this devastating disease.

For more information on how to participate in our study, please contact us via e-mail at polly-ferguson@uiowa.edu or call 319-356-1608.

Lab Members: Xinyu Bing, RA

Collaborative Projects With: Hatem El-Shanti, Tom Waldschmidt

Affiliations:

• Department of Pediatrics

Model System: Murine & human

Recent Publications or Creative Works:

1. Su K, Wu J, Edberg JC, Li X, Ferguson P, Cooper GS, Langefeld CD, Kimberly RP: promoter haplotype of the ITIM-bearing FcγRIIb alters receptor expression and associates with autoimmunity. I. Regulatory FCGR2B polymorphisms and their association with systemic lupus erythematosus. J Immunol 172:7186, 2004.
2. Su K, Li X, Edberg JC, Wu J, Ferguson P, Kimberly RP: A promoter haplotype of the ITIM-bearing FcγRIIb alters receptor expression and associates with autoimmunity. II. Differential binding of GATA4 and YY1 transcription factors and correlated receptor expression and function. J Immunol 172:7192, 2004.
3. DiMeo DE, Ferguson PJ, Bishop WP: An unusual intestinal presentation of c-ANCA/PR-3 positive vasculitis in a child. J Pediatr Gastro Nutr 40:368, 2005.
4. Ferguson PJ, Chen S, Tayeh MK, Ochoa L, Leal SM, Pelet A, Munnich A, Lyonnet S, Majeed HA, El-Shanti H: Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia. J Med Genet 42:551, 2005.
5. Ferguson PJ, Bing X, Vasef M, Ochoa L, Mahgoub A, Waldschmidt T, Tygrett L, Schlueter A, El-Shanti, H: A missense mutation in pstpip2 is associated with the murine autoinflammatory disorder chronic multifocal osteomyelitis. [e-published 23 Aug 2005]. Bone 38:41, 2006.
6. Ferguson PJ, Weinberger M: Shrinking Lung Syndrome in a 14 Year Old Boy With Systemic Lupus Erythematosus. [e-published 15 Dec 2005]. Pediatr Pulmonol. 41:194-197, 2006.
7. Khanna G and Ferguson P: MR Imaging of Diabetic Cheiroarthropathy. Accepted. Amer J Roent/AJRonline.org, manuscript # 06-0672.

Submitted Manuscripts

1. Al-Musawi ZS, Al-Saad KK, Ijadi-Magsoodi R, El-Shanti H, Ferguson PJ: A splice site mutation confirms the role of LPIN2 in Majeed Syndrome. Resubmitted with requested revisions Oct 2006.