Toll-like Receptor 2 Gene Polymorphism, Serum Cytokines and Susceptibility to Disease Severity or Treatment Response of Pulmonary Tuberculosis

NCT00772408 | Completed DMC

• 1 other identifier: NSC 95-2314-B-182A-030
• Study Type: observational
• Target: 300
• Locations: 1 country
• Sites: 2

Brief Summary

Infection with Mycobacterium tuberculosis remains at epidemic levels globally. Innate and adaptive immune responses evolve as protective mechanisms against mycobacterial infection in humans. Toll-like receptors (TLRs) are transmembrane proteins characterized by an extracellular leucine-rich domain that participates in ligand recognition and an intracellular tail. TLRs are the first defense system to detect potential pathogens, initiate immune responses and form the crucial link between innate and adaptive immune systems. Stimulation of TLR initiates a signaling cascade that involves a number of proteins, such as MyD88 and IL-1 receptor-associated kinase. This signal cascade leads to NF-κB activation, which induce the secretion of pro-inflammatory cytokines. TLR2 is a family of TLR family and has been reported to be the principle mediator of macrophage activation in response to mycobacterium. Growing amounts of data suggest that the ability of certain individuals to respond properly to TLR ligands may be impaired by single nucleotide polymorphisms (SNPs) within TLR genes, resulting in an altered susceptibility to, or course of, infectious disease. The genetic polymorphism of TLR2 (arginine to glutamine substitution at residue 753 (Arg753Gln)) has been associated with a negative influence on TLR2 function, which may, in turn, determine the innate host response to mycobacteria. In addition, another polymorphism (Arg677Trp) of the TLR2 was reported to be associated with susceptibility to tuberculosis in Tunisian patients. Moreover, in Mycobacterium leprosy patients with TLR2 mutation (Arg677Trp), production of IL-2, IL-12, IFN-gamma, and TNF-alpha by M. leprae-stimulated peripheral blood mononuclear cell were decreased compared with that in groups with wild-type TLR2. To date, there have been no studies of the association of SNPs of TLR2 with cytokine profiles and clinical outcomes on M. tuberculosis. We hypothesize that polymorphisms in the TLR2 are associated with :

1. 1.increased prevalence of active pulmonary TB infection,
2. 2.altered levels of pro-inflammatory and anti-inflammatory cytokines in serum,
3. 3.clinical outcomes and presentations. We thus design a prospective case-control study to test this hypothesis. The frequency of TLR2 polymorphisms in both pulmonary TB patients and healthy controls will be determined by polymerase chain reaction-restriction fragment length polymorphism. Serial serum levels of IL-12, IFN-γ, and IL-10 in pulmonary TB patients with or without TLR2 polymorphisms will be measured by enzyme linked immunosorbent assay. Relationships between TLR2 polymorphisms and serum cytokines dynamics or clinical outcomes will be analyzed.

Conditions

Pulmonary Tuberculosis; Genetic Variants of Host; Immune Response of Host

Keywords

pulmonary tuberculosis; Toll-like receptor 2 gene polymorphisms; blood lymphocyte subsets; systemic symptoms; pleural effusion

Outcome Measures

Primary Outcomes (1)

• susceptibility of pulmonary tuberculosis

  At diagnosis

Secondary Outcomes (1)

• clinical presentation of pulmonary TB

  at diagnosis

Study Arms (2)

TB

patients with pulmonary TB

control

healthy controls

Eligibility Criteria

• Age: 20 Years - 90 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Case: patients visiting the Pulmonary department of Chang Gung Memorial Hospital, Kaohsiung, Taiwan Control:healthy subjects visiting the Center of health examination at Chang Gung Memorial Hospital, Kaohsiung, Taiwan

You may qualify if:

• a) findings on CXR that are compatible with presentations of Mycobacterium tuberculosis b) clinical symptoms, such as fever, body weight loss, night sweating, chest pain and chronic cough, that indicate active infection of pulmonary tuberculosis (TB) c) microbiological diagnosis by sputum smear and culture, bronchoalveolar lavage fluid culture, or DNA probe examination.
• d) Resolution on CXR with anti-TB regimens e) Written informed consent form prior to participation into this study

You may not qualify if:

• a) concurrent active disease of other chronic illnesses, such as lung cancer, chronic bronchitis and bronchial asthma b) poor physical conditions that make any examination infeasible c) participation in another trial with use of an investigated drug within on month d) use of corticosteroid or immunosuppressant drugs

Sponsors & Collaborators

• Chang Gung Memorial Hospital: lead

Study Sites (2)

Kaohsiung Chang Gung Memorial Hospital

Kaohsiung Hsien, Taiwan, 886, Taiwan

Location

Kaohsiung Chang Gung Memorial Hospital

Kaohsiung, Taiwan, 886, Taiwan

Location

Biospecimen

Retention: SAMPLES WITH DNA

peripheral blood leukocyte DNA and plasma

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Pleural Effusion

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Pleural Diseases

Study Officials

• Meng-Chih Lin, MD

  Chang Gung Memorial Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 13, 2008
• First Posted: October 15, 2008
• Study Start: August 1, 2006
• Primary Completion: November 1, 2009
• Study Completion: November 1, 2009
• Last Updated: February 28, 2013

Record last verified: 2008-10

Locations

TW (2)