TUBERCULOSIS: Immunopathology: The Neglected Role of Extracellular Matrix Destruction

Sci Transl Med 23 February 2011: Vol. 3, Issue 71, p. 71ps6 : DOI: 10.1126/scitranslmed.3001847
Paul T. Elkington1,*, Jeanine M. D’Armiento2 and Jon S. Friedland1


Abstract
The extracellular matrix in the lung must be destroyed for Mycobacterium tuberculosis—the agent that causes tuberculosis (TB)—to spread. The current paradigm proposes that this destruction occurs as a result of the action of proinflammatory cytokines, chemokines, immune cells, and lipids that mediate TB-associated necrosis in the lung. However, this view neglects the fact that lung matrix can only be degraded by proteases. We propose an original conceptual framework of TB immunopathology that may lead directly to treatments that involve inhibition of matrix metalloproteinase activity to hinder matrix destruction and reduce the morbidity and mortality associated with TB.

Citation: P. T. Elkington, J. M. D’Armiento, J. S. Friedland, Tuberculosis Immunopathology: The Neglected Role of Extracellular Matrix Destruction. Sci. Transl. Med. 3, 71ps6 (2011).

http://stm.sciencemag.org/content/3/71/71ps6.abstract

TUBERCULOSIS: THE PATHOGENESIS OF TUBERCULOSIS

Tuberculosis patients relapse if treatment is not continued for 6 months, because chemotherapy fails to convert the patients' response from the necrotizing pattern characteristic of disease (Koch phenomenon) to the nonnecrotizing bactericidal function required for optimal immunity. We need to understand the nature of these two immunological states and how to convert one to the other. Studies in mice and humans implicate differences in cytokine profiles and in metabolism of adrenal steroids. Either enhanced susceptibility or protection can be evoked in mice with appropriate doses of a killed environmental saprophyte. This emphasizes the importance of shared epitopes and may explain the geographically variable efficacy of Mycobacterium bovis Bacillus Calmette Guérin vaccination. Unlike soluble antigens of M. tuberculosis itself, which tend to evoke necrosis, the shared mycobacterial epitopes evoke little skin-test reactivity in patients. Preparations of these epitopes show potential as immunotherapeutic agents to convert the response from necrotic to bactericidal mode
http://www.annualreviews.org/doi/abs/10.1146/annurev.micro.50.1.259

TUBERCULOSIS & MALARIA: genetic susceptibility

Five single-nucleotide polymorphisms in the cytokine-inducible SRC homology 2 (SH2) domain protein (CISH) are associated with greater susceptibility to bacteremia, tuberculosis (TB) and malaria, according to research published online May 19 in the New England Journal of Medicine.
Chiea C. Khor, MB, BS, DPhil, of the Genome Institute of Singapore, and colleagues analyzed data from 8,402 people from Gambia, Hong Kong, Kenya, Malawi, and Vietnam participating in case-control series concerning bacteremia, TB and malaria. CISH appears critical for T-cell proliferation and survival following infection, the authors write.
The researchers found an association between CISH genetic variants and susceptibility to these diseases. People with one CISH risk allele had an 18 percent higher overall risk of one of these diseases, and the risk increased to 81 percent in people with four or more risk alleles.
"Our findings implicate CISH in multiple-pathogen susceptibility and raise the possibility that pharmacologic manipulation of the SOCS (suppressor of cytokine signaling) pathway may have an effect on the treatment of multiple, diverse infectious diseases. CISH variants may also influence responses to existing immunotherapies such as interleukin-2 therapy in renal-cell cancer, which is associated with wide and largely unexplained variations in interindividual response rates," the authors write.
http://www.modernmedicine.com/modernmedicine/Modern+Medicine+Now/iCISHi-Variants-Associated-With-Infectious-Disease/ArticleNewsFeed/Article/detail/670862?contextCategoryId=40137

TUBERCULOSIS: test to distinguish active from dorrmant

A rapid test that could tell the difference between latent and active tuberculosis would be a major step forward," said Dr. Jason Stout of Duke University Medical Center who presented his findings at the American Thoracic Society meeting in New Orleans.
Doctors could more quickly treat active infections, helping to limit the spread of the disease, Stout said.
Current blood tests can distinguish between people who are infected with TB and those who are not but they cannot tell whether an infection is active or dormant. It takes a culture test that grows the TB bacilli to show if it is active or not, and that can take weeks.
Stout and colleagues collected blood samples from 71 people with active TB, latent TB or no infection at all.
They added a bit of TB bacteria to the blood samples to stimulate an immune response, then measured the activity of 25 immune signaling chemicals called cytokines to try to identify a pattern that could be used as a signature of active TB infection.
"We found that a pattern of two cytokines, called MCP-1 and IL-15, was reasonably good at differentiating between persons sick with TB and persons infected but not sick," Stout said.
A third cytokine called IP-10 also showed promise at sorting between people who are infected and those who are not.
Stout said other studies have pointed to these three cytokines individually as possible TB markers, but his is the first to put all three together as a possible TB test.
"These findings could lead to earlier diagnosis of active tuberculosis, which could be beneficial for both the sick person and others around her or him who might be spared from infection," Stout said in a statement.
Tuberculosis killed 1.8 million people in 2008, or nearly 5,000 people a day. It is caused by the Mycobacterium tuberculosis bacteria. More than 2 billion people, or about a third of the world's population, are thought to be infected.
It is not only a scourge in poor countries but also in the West, where it has flared anew in the last 20 years because of AIDS, which weakens the immune system.
TB can be cured with antibiotics, but they need to be taken daily for months to be effective. Because people often skip doses, multiple drug resistant forms are spreading and the World Health Organization says the hard-to-treat infection is spreading.
http://www.reuters.com/article/idUSTRE64F23P20100516