Tuberculosis 2

MYCOBACTERIAL LIPIDS AND PROTEINS Lipids have been involved in mycobacterial recognition by the innate immune system, and lipoproteins (such as 19-kDa lipoprotein) have been proven to trigger potent signals through Toll-like receptors present in blood ?

dendritic cells.

These activated macrophages aggregate around the lesion's center and effectively neutralize tubercle bacilli without causing further tissue ?

destruction.

SKIN TEST REACTIVITY Coincident with the appearance of immunity, DTH to M. tuberculosis ?

develops.

It is possible that an immune response capable of eradicating early infection may sometimes develop as a consequence, for instance, of disabling mutations in mycobacterial genomes rendering their replication?

ineffective.

The ability to predict, through systemic biomarkers, which affected individuals will progress toward disease would be of immense value in devising prophylactic ?

interventions.

Studies of mouse genetics identified a novel host resistance gene, ipr1, which is encoded within the ?;

sst1 locus

MACROPHAGE-ACTIVATING RESPONSE CMI is critical at this early ?

stage.

Recent work also describes the involvement of neutrophils in the host response, although the timing of their appearance and their effectiveness remain ?

uncertain.

Even when healing takes place, viable bacilli may remain dormant within macrophages or in the necrotic material for many ?

years.

About 2-4 weeks after infection, two host responses to M. tuberculosis develop:

1. a macrophage-activating CMI response and 2. a tissue-damaging response.

In addition, macrophages can undergo apoptosis—a defensive mechanism to prevent release of cytokines and bacilli via their sequestration in the ?

apoptotic cell.

Among the antigens that may play a protective role are the ?

30-kDa (or 85B) and ESAT-6 antigens.

ROLE OF T LYMPHOCYTES Alveolar macrophages, monocytes, and dendritic cells are also critical in processing and presenting antigens to T lymphocytes, primarily ?

CD4+ and CD8+ T cells;

These initial stages of infection are usually ?

asymptomatic.

CD8+ T cells have been associated with protective activities via cytotoxic responses and lysis of infected cells as well as with production of ?

IFN-γ and TNF-α

In the case of CMI, two types of cells are essential: macrophages, which directly phagocytose tubercle bacilli, and T cells (mainly CD4+ T lymphocytes), which induce protection through the production of cytokines, especially ?

IFN-γ.

TH1 cells produce?

IFN-γ—an activator of macrophages and monocytes—and IL-2.

TH2 cells produce ?

IL-4, IL-5, IL-10, and IL-13 and may also promote humoral immunity.

ipr1 encodes an interferon (IFN)-inducible nuclear protein that interacts with other nuclear proteins in macrophages primed with IFNs or infected by ?

M. tuberculosis.

the result is the activation and proliferation of CD4+ T lymphocytes, which are crucial to the host's defense against ?

M. tuberculosis.

these cells migrate to the draining lymph nodes and present mycobacterial antigens to?

T lymphocytes.

The human homologue NRAMP1, which maps to chromosome 2q, may play a role in determining susceptibility to TB, as is suggested by a study among ?

West Africans.

In addition, polymorphisms in multiple genes, such as those encoding for various major histocompatibility complex (MHC) alleles, IFN-γ, T cell growth factor β, interleukin (IL) 10, mannose-binding protein, IFN-γ receptor, Toll-like receptor 2, vitamin D receptor, and IL-1, have been associated with susceptibility to?

TB.

Activated CD4+ T lymphocytes can differentiate into cytokine-producing ?

TH1 or TH2 cells.

Their primary mechanism is probably related to production of oxidants (such as reactive oxygen intermediates or nitric oxide) that have ?

antimycobacterial activity

The tissue-damaging response is the result of a delayed-type hypersensitivity (DTH) reaction to various bacillary ?

antigens

Protective immunity is probably the result of reactivity to many different mycobacterial ?

antigens.

Ultimately, the chemoattractants and bacterial products released during the repeated rounds of cell lysis and infection of newly arriving macrophages enable dendritic cells to access ?

bacilli;

IFN-γ may induce the generation of reactive nitrogen intermediates and regulate genes involved in ?

bactericidal effects.

At this point, the development of CMI and humoral immunity ?

begins.

The liquefied caseous material, containing large numbers of bacilli, is drained through ?

bronchi.

These "healed" lesions in the lung parenchyma and hilar lymph nodes may later undergo ?

calcification.

Individual granulomas that are formed during this phase of infection can vary in size and cell composition; some can contain the spread of mycobacteria, while others ?

cannot.

ROLE OF MACROPHAGES AND MONOCYTES While CMI confers partial protection against M. tuberculosis, humoral immunity plays a less well-defined role in protection (although evidence is accumulating on the existence of antibodies to lipoarabinomannan, which may prevent dissemination of infection in ?

children).

Some observations have challenged the traditional view that any encounter between mycobacteria and macrophages results in ?

chronic infection.

Within the cavity, tubercle bacilli multiply, spill into the airways, and are discharged into the environment through expiratory maneuvers such as ?

coughing and talking.

There, they proliferate and produce ?

cytokines.

This evidence underscores the fact that previous latent or active TB may not confer fully protective ?

immunity.

The lesion tends to enlarge further, and the surrounding tissue is progressively ?

damaged.

INNATE RESISTANCE TO INFECTION Several observations suggest that genetic factors play a key role in innate nonimmune resistance to infection with M. tuberculosis and the development of ?

disease.

There is also evidence of reinfection with a new strain of M. tuberculosis in patients previously treated for active ?

disease.

Studies suggest that M. tuberculosis uses specific virulence mechanisms to subvert host cellular signaling and to elicit an early regulated proinflammatory response that promotes granuloma expansion and bacterial growth during this key ?

early phase.

The role of cytokines in promoting intracellular killing of mycobacteria, however, has not been entirely ?

elucidated.

After infection with M. tuberculosis, alveolar macrophages secrete various cytokines responsible for a number of events (e.g., the formation of granulomas) as well as systemic effects (e.g., ?

fever and weight loss).

Bronchial walls and blood vessels are invaded and destroyed, and cavities are ?

formed.

With the development of specific immunity and the accumulation of large numbers of activated macrophages at the site of the primary lesion, granulomatous lesions (tubercles) are ?

formed.

It is important to recognize that latent infection and disease represent not a binary state but rather a continuum along which infection will eventually move in the direction of ?

full containment or disease.

A study of M. marinum infection in zebrafish has delineated one molecular mechanism by which mycobacteria induce ?

granuloma formation.

additional naïve macrophages are recruited to the early ?

granuloma.

Disruption of MMP9 function results in reduced bacterial ?

growth.

MMP9 in turn stimulates recruitment of naïve macrophages, thus inducing granuloma maturation and bacterial ?

growth.

The resulting extrapulmonary lesions may undergo the same evolution as those in the lungs, although most tend to ?

heal.

According to recent developments, latency may not be an accurate term because bacilli may remain active during this "latent" stage, forming biofilms in necrotic areas within which they temporarily ?

hide.

Finally, natural killer cells act as co-regulators of CD8+ T cell lytic activities, and γδ T cells are increasingly thought to be involved in protective responses in ?

humans.

New monocytes and macrophages attracted to the site are key components of the ?

immune response.

The macrophage-activating response is a T cell-mediated phenomenon resulting in the activation of macrophages that are capable of ?

killing and digesting tubercle bacilli.

At this point, some lesions may heal by fibrosis, with subsequent calcification, whereas inflammation and necrosis occur in other ?

lesions.

At the center of the lesion, the caseous material ?

liquefies.

DELAYED-TYPE HYPERSENSITIVITY In a minority of cases, the macrophage-activating response is weak, and mycobacterial growth can be inhibited only by intensified DTH reactions, which lead to ?

lung tissue destruction.

In the majority of infected individuals, local macrophages are activated when bacillary antigens processed by macrophages stimulate T lymphocytes to release a variety of ?

lymphokines.

Initially, the tissue-damaging response can limit mycobacterial growth within ?

macrophages.

The mycobacterial protein ESAT-6 induces secretion of matrix metalloproteinase 9 (MMP9) by nearby epithelial cells that are in contact with infected ?

macrophages.

LTBI ensues as a result of this dynamic balance between the?

microorganism and the host.

In young children with poor natural immunity, hematogenous dissemination may result in highly fatal ?

miliary TB or tuberculous meningitis.

These lesions consist of accumulations of lymphocytes and activated macrophages that evolve toward epithelioid and giant cell ?

morphologies.

In mice, a gene called Nramp1 (natural resistance-associated macrophage protein 1) plays a regulatory role in resistance/susceptibility to?

mycobacteria.

That the latter are more important in eliciting a T lymphocyte response is suggested by experiments documenting the appearance of protective immunity in animals after immunization with live, protein-secreting ?

mycobacteria.

Qualitative and quantitative defects of CD4+ T cells explain the inability of HIV-infected individuals to contain ?

mycobacterial proliferation.

THE HOST RESPONSE, GRANULOMA FORMATION, AND "LATENCY" In the initial stage of host-bacterium interaction, prior to the onset of an acquired CMI response, M. tuberculosis disseminates widely through the lymph vessels, spreading to other sites in the lungs and other organs, and undergoes a period of extensive growth within ?

naïve unactivated macrophages;

In the central part of the lesion, the necrotic material resembles soft cheese (caseous necrosis)—a phenomenon that may also be observed in other conditions, such as ?

neoplasms.

Although M. tuberculosis can survive, its growth is inhibited within this necrotic environment by low oxygen tension and low ?

pH.

Thus, the term persister is probably more accurate to indicate the behavior of the bacilli in this ?

phase.

These antigens are being incorporated into newly designed vaccines on various ?

platforms.

The existence of this resistance, which is polygenic in nature, is suggested by the differing degrees of susceptibility to TB in different ?

populations.

In fact, cases of active TB are often accompanied by strongly positive skin-test ?

reactions.

Although DTH is associated with protective immunity (TST-positive persons are less susceptible to a new M. tuberculosis infection than TST-negative persons), it by no means guarantees protection against ?

reactivation.

and increase the synthesis of cytokines such as TNF-α and IL-1, which in turn regulate the release of ?

reactive oxygen intermediates and reactive nitrogen intermediates.

Another study has shown that M. tuberculosis-derived cyclic AMP is secreted from the phagosome into host macrophages, subverting the cell's signal transduction pathways and stimulating an elevation in the secretion of tumor necrosis factor α (TNF-α) as well as further proinflammatory cell ?

recruitment.

The interplay of these various cytokines and their cross-regulation determine the host's ?

response.

TNF-α also seems to be important. Observations made originally in transgenic knockout mice and more recently in humans suggest that other T cell subsets, especially CD8+ T cells, may play an important ?

role.

M. tuberculosis possesses various protein antigens. Some are present in the cytoplasm and cell wall; others are ?

secreted.

The cellular mechanisms responsible for TST reactivity are related mainly to previously sensitized CD4+ T lymphocytes, which are attracted to the ?

skin-test site.

Although both of these responses can inhibit mycobacterial growth, it is the balance between the two that determines the forms of TB that will develop ?

subsequently.

However, alternatively activated alveolar macrophages may be particularly susceptible to M. tuberculosis growth early on, given their more limited proinflammatory and bactericidal activity, which is related in part to being bathed in ?

surfactant.

This reactivity is the basis of the TST, which is used primarily for the detection of M. tuberculosis infection in persons without ?

symptoms

In the early stages of infection, bacilli are usually transported by macrophages to regional lymph nodes, from which they gain access to the central venous return; from there they reseed the lungs and may also disseminate beyond the pulmonary vasculature throughout the body via the ?

systemic circulation.

it destroys unactivated macrophages that contain multiplying bacilli but also causes caseous necrosis of the involved ?

tissues

As stated above, this response, mediated by various bacterial products, not only destroys macrophages but also produces early solid necrosis in the center of the?

tubercle.