**3. The role of adaptive immunity in the outcome of the Infection**

In the previous section the importance of the host innate immune response in the encounter with MTB was described. However, it is generally accepted that the long-term outcome of the primary infection is determined by the effective mobilization of the adaptive immune re‐ sponse. Active TB patients, as well as latently infected carriers, do not suffer from a general innate or adaptive immune defect. On the contrary, ex-vivo studies of their immunocyte function demonstrate increased lymphocyte proliferation and the secretion of numerous cytokines [27]. Thus the disease, in people generally healthy, is a result of a very specific immune failure in face of MTB, or other mycobacteria.

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

ecules, which induce a cytotoxic response toward the bacteria and to the phagocytes in which they reside. They also secrete IFNγ and TNFα. Humans with latent TB develop a

The Immune Response to *Mycobacterium tuberculosis* Infection in Humans

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

23

From all the above it is clear that the dominant protective response in TB is Th1 type. However in multiple-drug resistant (MDR) [40] and in young children [41] there is a skewing towards a Th2 type response, with greater secretion of IL-4. This may explain why children tend to develop pulmonary milliary and extrapulmonary disease. In addition it seems that the disease in children tends to have a Mendelian heritability of specific defects, while in adults there is no such background, rather some discrete polymorphisms may be found in different popula‐ tions, such as in the natural resistance-associated macrophage protein 1 (NRAMP1) [42].

For a long time it was generally accepted that B-cells and specific antibodies have no protective role against TB. However monoclonal antibodies against some mycobacterial antigens have shown a clear protective effect in mice [43]. It has been postulated that the unique phenomenon of BCG protection against pediatric TB meningitis may be due in part to specific antibodies.

Similarly to the innate immune system, mycobacteria have also developed evasion tactics from the adaptive immune system [44]. They may interfere with the antigen presentation process, promote the secretion of IL-10 by T cells, thereby polarizing them toward a TH2 type response, in which the essential IFNγ secretion is inhibited [7]. They may also attract more T-reg cells to the infection site, thereby further dampening the protective inflammatory response. It was demonstrated in a tuberculosis rabbit model, that mycobacteria may delay the macrophage and T-cells activation process, thereby enabling them to form a permanent infection and damaging pulmonary tissue [45]. More specifically, the bacteria possess a set of genes- rpf, which code for the regulatory Rpf proteins, which are believed to be responsible for activating bacteria from a dormant state in latency. In addition the bacteria have also a set of "anti-

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 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‐

Presently the exact role of B-cells in human TB remains to be determined.

dormancy genes"-DosR, which induce bacterial growth, when appropriate [46].

**4. The tuberculous granuloma**

the most prominent example of this situation.

high level of mycobacteria-specific CD8+ T cells [39].

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‐ ous mycobacterial and sometimes salmonellar infections.

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‐ ecules, which induce a cytotoxic response toward the bacteria and to the phagocytes in which they reside. They also secrete IFNγ and TNFα. Humans with latent TB develop a high level of mycobacteria-specific CD8+ T cells [39].

From all the above it is clear that the dominant protective response in TB is Th1 type. However in multiple-drug resistant (MDR) [40] and in young children [41] there is a skewing towards a Th2 type response, with greater secretion of IL-4. This may explain why children tend to develop pulmonary milliary and extrapulmonary disease. In addition it seems that the disease in children tends to have a Mendelian heritability of specific defects, while in adults there is no such background, rather some discrete polymorphisms may be found in different popula‐ tions, such as in the natural resistance-associated macrophage protein 1 (NRAMP1) [42].

For a long time it was generally accepted that B-cells and specific antibodies have no protective role against TB. However monoclonal antibodies against some mycobacterial antigens have shown a clear protective effect in mice [43]. It has been postulated that the unique phenomenon of BCG protection against pediatric TB meningitis may be due in part to specific antibodies. Presently the exact role of B-cells in human TB remains to be determined.

Similarly to the innate immune system, mycobacteria have also developed evasion tactics from the adaptive immune system [44]. They may interfere with the antigen presentation process, promote the secretion of IL-10 by T cells, thereby polarizing them toward a TH2 type response, in which the essential IFNγ secretion is inhibited [7]. They may also attract more T-reg cells to the infection site, thereby further dampening the protective inflammatory response. It was demonstrated in a tuberculosis rabbit model, that mycobacteria may delay the macrophage and T-cells activation process, thereby enabling them to form a permanent infection and damaging pulmonary tissue [45]. More specifically, the bacteria possess a set of genes- rpf, which code for the regulatory Rpf proteins, which are believed to be responsible for activating bacteria from a dormant state in latency. In addition the bacteria have also a set of "antidormancy genes"-DosR, which induce bacterial growth, when appropriate [46].
