Molecular and Experimental Medicine
Division of Rheumatology Research
Impact of Innate Immunity in Allergy
and Infectious Diseases
B.L. Zuraw, S.C. Christiansen,
J. Eddleston, A. Kiemer, S. Mattsson
Inflammation
plays a critical role in the pathogenesis of many allergic and infectious diseases. We focus on
how components of the innate immune system modulate inflammatory responses and influence the
course of several allergic and infectious diseases.
Airway Epithelial Cells and Asthmatic Inflammation
Delineation of the parameters that control
the initiation and propagation of airway inflammation may provide new therapeutic targets for
the treatment of asthma. Using in vitro and in vivo challenge models, we are studying the short-term
consequences of exposure to allergens and viruses on activation of transcription factors and
expression of genes in human airway epithelial cells. Glucocorticoid-induced leucine zipper
interferes with activation of the transcription factors NF-κB
and activator protein 1 in myeloid cells. We have shown that glucocorticoid-induced leucine zipper
is expressed in airway epithelial cells, and we are studying how it participates in airway inflammation,
particularly after rhinovirus infection.
In recent studies, we found that a variety
of soluble mediators generated in the airway, including kinins and cytokines, can activate SMADs
in airway epithelial cells. SMADs are transcription factors involved in airway remodeling; they
stimulate collagen synthesis in part by increasing expression of connective tissue growth factor
(CTGF). We found a corresponding rapid increase in CTGF mRNA and protein in stimulated airway epithelial
cells. We are addressing the effects of airway epithelial cell CTGF on activation of lung fibroblasts
and production of collagen.
C1 Inhibitor Mutations
in Hereditary Angioedema
Hereditary angioedema is an autosomal
dominant disease caused by a mutation of the gene for C1 inhibitor and characterized by recurrent
angioedema. Bradykinin, a mediator of the effector arm of the innate immune system, is a potent
mediator of increased vascular permeability. Our studies have implicated activation of the plasma
contact system with subsequent generation of bradykinin as the causal factor in angioedema associated
with deficiency in C1 inhibitor. We identified a variety of new mutations and polymorphisms of
the gene for C1 inhibitor in patients with hereditary angioedema, and we are characterizing the
transcriptional and posttranscriptional control of mutant and wild-type C1 inhibitor expression
to define the genotype-phenotype relationships in this disease. Currently, we are focusing on
interventions that may increase the synthesis and secretion of functional C1 inhibitor in patients
with hereditary angioedema, changes that might decrease the severity of the disease in these patients.
Activation of Alveolar
Macrophages and the Outcome of Infection
Alveolar macrophages are exploited by
several important human pathogens, including Mycobacterium tuberculosis and Bacillus
anthracis endospores. We are studying the interactions between these microorganisms and
human macrophages. Alveolar macrophages play a critical role in the pathogenesis of inhalational
anthrax, phagocytosing B anthracis endospores and transporting them to the mediastinal
lymph nodes where the spores germinate and release toxins. We are assessing the efficiency of killing
of ingested B anthracis endospores by alveolar macrophage to elucidate environmental
and genetic factors that may determine whether the spores survive and lead to outgrowth of B
anthracis.
We are also interested in how the innate
response of alveolar macrophages influences the pathogenesis of tuberculosis. Morbidity and
mortality in patients with tuberculosis are due to the ability of M tuberculosis to establish
prolonged infection of macrophages. We propose that the intensity of the macrophage response
to M tuberculosis may determine whether the infection becomes chronic, and we are focusing
on the ability of mycobacterial DNA to activate macrophages through signaling via Toll-like receptor
9.
In collaboration with H. Herwald, Lund
University, Lund, Sweden, we showed that Staphylococcus aureus proteins activate blood
monocytes and induce B1 receptors for bradykinin in bystander cells. Kinins, generated in plasma
by S aureus proteins, enhance the expression of B1 receptors. In ongoing experiments,
we are examining how these effects may contribute to the regulation of vascular permeability and
shock in patients with systemic infections.
Publications
Chen, L.Y., Zuraw, B.L., Ye, R.D.,
Pan, Z.K. A Rho exchange factor mediates fMet-Leu-Phe-induced
NF-κB activation in
human peripheral blood monocytes. J. Biol. Chem. 279:7208, 2004.
Dosanjh, A., Zuraw, B.
Endothelin-1 (ET-1) decreases human bronchial epithelial cell migration and proliferation:
implications for airway remodeling in asthma. J. Asthma 40:883, 2003.
Stevenson, D.D., Simon, R.A., Zuraw,
B.L. Sensitivity to aspirin and nonsteroidal anti-inflammatory
drugs. In: Middleton’s Allergy Principles and Practice, 6th ed. Adkinson, N.F.,
Jr., et al. (Eds.). Mosby, St. Louis, 2003, p. 1695.
Stevenson, D.D., Zuraw, B.L.
Pathogenesis of aspirin-exacerbated respiratory disease. Clin. Rev. Allergy Immunol. 24:169,
2003.
Zuraw, B.L.
Diagnosis and management of hereditary angioedema: an American approach. Transfus. Apheresis
Sci. 29:239, 2003.
Zuraw, B.L.
Urticaria and angioedema. In: Pediatric Allergy: Principles and Practice. Leung, D.Y.M.,
et al., (Eds.). Mosby, St. Louis, 2003, p. 574.
|
