**4. The tuberculous granuloma**

It was thought that the CD4+T cell is the omnipotent determinant of the adaptive immune response in TB. However, lately it became clear that more T-cell subsets, including CD8+ and TH17 cells and even B cells participate in the process [1,7,28]. The induction phase seems to be delayed relatively to the response to more common pathogens. It is initiated by signaling and presentation of the microbial peptides by the macrophages and DCs to the CD4+ cells via MHC class II molecules, while mycobacterial membranal lipids are presented through MHC-I molecules of the CD-1 family [29]. The presentation of mycobacterial antigens occurs within the draining lung lymph-nodes to which the macrophages have migrated, followed by the activation of CD4+ and other T cells. These T cells use various receptors, such as TLRs, NODlike receptors and C-type lectins, for this purpose. The peptides considered as potentially immunodominant are the already mentioned ESAT-6 and CFP10 and others, such as Rv2031c, Rv2654c and Rv1038c. The T cell response to these antigens is not homogenous, various T cell epitopes being engaged during the different phases of the infection [30]. Other Rv proteins are binding to T cells mainly during the latent phase [31]. T cell activation, by the recognition of these antigens in the initiating phase, results in the secretion of numerous cytokines, mostly proinflammatory, such as IL-1β, IL-6, IL-21 and IL-12p40. The later activates CD4+TH1 cells, but p40 is also a subunit of IL-23, which induces the TH17 cell lineage, which secretes IL-17, IL-21 and IL-22. These cytokines are considered to be essential for anti-microbial protection and IL-17 is thought to have a major role in granuloma formation [32], as well as TNFα, which is also secreted by CD4+ cells and promotes intra-phagosomal killing of the bacteria in macrophages. During an acute mycobacterial infection γδ T cells secrete much IL-17 [33], which also promotes the secretion of IL-12, thus a self-enhancing inflammatory loop is being formed. This is balanced by the secretion of TGFβ, the role of which is to dampen an over‐ reactive inflammatory response, partly so by inducing T-reg cells. The later may inhibit TH1 responses, thus potentially facilitating mycobacterial replication within macrophages [34]. A

22 Tuberculosis - Current Issues in Diagnosis and Management

high incidence of T reg Foxp3 cells has been found in extra-pulmonary TB [35].

ous mycobacterial and sometimes salmonellar infections.

The activated T cells undergo clonal expansion and migrate out of the lymph nodes into the site of the infection in the lung, as effector T cells. This process is driven by chemo‐ kines, secreted by various inflammatory cells. Upon arrival to the battle ground they se‐ crete interferon gamma (IFNγ), which is a key cytokine in the ensuing confrontation, by further activating the microbicidal machinery of the macrophage and causing it to se‐ crete IL-18, amongst other cytokines, which seems to be part of the protective TH1 type response. IFNγ also induces the production of toxic NO via inducible NO synthase (iNOS). Casanova et al [36,37,38] have described in detail the importance of the IFNγ-IL-12 cytokines loop, including their receptors, for TB immunity. Furthermore they have described rare Mendelian genetic defects in this system, resulting in susceptibility to seri‐

CD8+ T cells also participate in the immune reaction, as they have been found in the me‐ diastinal lymph nodes, mixed with CD4+ cells and later at the infection site in the lungs. Most evidence about them has been collected in mouse and primate models and their role in human infections has not been fully elucidated [7].It has been demonstrated in vi‐ tro that CD8+ cells recognize bacterial peptides and lipids through the MHC-I CD-1 mol‐ The formation of granuloma is the host's containment effort in response to an infection which he can not eradicate. In most cases it results in a state of latency, with dormant, but viable, bacteria residing in it [7, 45, 47]. Therefore the granuloma benefits also the bacteria, who may emerge from dormancy, proliferate again and cause an active disease, if the host's immune system is weakened due to any reason. HIV coinfection, with its damage to T cells, has become the most prominent example of this situation.

The granuloma contains a nucleus of necrotic lung tissue and intraphagosomal bacteriacontaining macrophages, surrounded by fibroblasts, DCs, neutrophils, B cells and various subsets of T cells, all of those secreting cytokines, mainly IFNγ and TNFα, and chemokines which ensure a continuous mobilization of granulocytes to the granuloma. TNFα activates adhesion molecules on the immunocytes [48]. Thus the granuloma is a dynamic and continu‐ ous battlefield balancing the bacteria against the immune system. Occasionally, as described before, the bacteria may damage the phagosomal membrane and escape, inducing an apoptotic or necrotic death of the macrophage. This enables the bacteria to proliferate with enhancement of tissue damaging inflammation, which may result in cavity formation.

DCs and AMa, which recognize the bacterial PAMPs with their PRRs, such as surface TLRs. This recognition triggers DC and macrophage activation, which results in the phagocytosis and internalization of the bacteria in the phagolysosome, where they are submitted to toxic lysis. Meanwhile the macrophages emigrate to the mediastinal lymph nodes, where the bacterial lip‐ id and peptide molecules are presented to CD4+ and CD8+ T cells via MHC-I and MHC-II, caus‐ ing T cell activation and clonal proliferation. The later return to the battlefield at the site of the lung infection and try to complete bacterial elimination, by intensifying local inflammation. To achieve that, the T cells and the macrophages secrete a series of cytokines, such as IFNγ, IL-12

The Immune Response to *Mycobacterium tuberculosis* Infection in Humans

http://dx.doi.org/10.5772/54986

25

Nevertheless, 90% of infected persons, who remain clinically asymptomatic, enter the stage of latency, in which they continue to harbor dormant, albeit viable, bacteria in their macrophages and 10% develop active clinical disease. This is due to numerous evasion tactics from the immune system, that MTB has developed during its long cohabitation with the human host. The bacterium may damage the phagosomal membrane and escape into the macrophage cytosol, inducing necrotic cell death. It may interfere with the signaling to T cells via MHC molecules, downregulate the secretion of IFNγ, promote the secretion of IL-10 and the activity of CD4+Foxp3 T reg cells, thus dampening the protective inflammatory response. A hallmark of the latency stage is granuloma formation, which is a complex structure, containing a core of dormant bacteria in necrotic tissue, surrounded by neutrophils, macrophages, DCs and T cells. This precarious balance may be easily disrupted, if, for whatever reason, immune

So far, BCG is the only antituberculous vaccine widely available, which does confer a measure of protection in children, but failed to arrest the spread of the infection in adult populations. Many centers around the world are trying to identify immunodominant bacterial epitopes, which could form the basis of a universal efficacious vaccine. So far, the 85A and 85B antigens, in various constructs, seem to be presently the most promising, at least in animal models and limited clinical trials. In addition, since the beginning of the 20th century, many mycobacterial formulations and lately also cytokines, have been tried as specific immune stimulants. In most cases they did induce generalized inflammation with significant side-effects, but with little clinical benefit. However, recent technological developments, such as recombinant prepara‐ tions and DNA extracts, may obtain better results. To those have to be added numerous

One may estimate that within a decade, or so, better anti-tuberculous vaccines and treatments

Pediatric Research Laboratory, Pediatric Division, Kaplan Medical Center, Associated with

and TNFα. Secreted chemokines attract more inflammatory cells, such as neutrophils.

surveillance is weakened, causing bacterial breakthrough and clinical relapse.

projects trying to unravel the immunogenetic susceptibility or resistance factors.

will be developed, possibly targeted to specific populations.

the Hadassah and Hebrew University-Jerusalem, Rehovot, Israel

**Author details**

Zeev Theodor Handzel
