Box 4-3.
The Th1/Th2 Response and the Outcome of Leprosy and Tuberculosis
Some people who contract tuberculosis, caused by Mycobacterium tuberculosis, or leprosy, caused by Mycobacterium leprae, develop a systemic form of the disease. In the case of tuberculosis this is called miliary tuberculosis, while in the case of leprosy this is called lepromatous leprosy. Other people develop a more localized form of the disease and, although there is damage in the area of infection, bacteria do not spread so readily to internal organs. What causes some people to develop the localized type of infection and others to develop the more dangerous systemic form of infection? What both M. tuberculosis and M. leprae have in common is that they enter and replicate in macrophages. An explanation based on the Th1/Th2 response has been proposed and seems to be supported by the evidence so far.
In people who are able to elicit a robust Th1-type immune response that leads to generation of activated macrophages, the numbers of invading bacteria are greatly reduced and the infection tends to be localized. In people who do not mount a strong Th1-type immune response, but instead mount a Th2-type response, which does not contribute to activation of macrophages but rather to production of antibodies, the bacteria reach high numbers in macrophages and subsequently disseminate throughout the body. Thus, balance between the Th1- and Th2-initiated paths of immune response to infection has critical practical implications for patients. This is one of many reasons why immunologists are trying to understand the complex interplay of cytokines that controls this crucial decision. Obviously, understanding this decision is crucial to the development of effective vaccines and therapies. Indeed, in cases for which a vaccine might not be available, development of pharmaceutical drugs capable of directing the Th1-Th2 decision branching could potentially manipulate the immune response to favor the more effective one against a particular infection. Recent evidence suggests that Treg and Th17 cells play important roles in directing the Th1-Th2 decision branching.
Source:
Modlin RL. 1994. Th1-Th2 paradigm: insights from leprosy. J Invest Dermatol 102:828–832.[PubMed][CrossRef]
Sadhu S, Khaitan BK, Joshi B, Sengupta U, Nautiyal AK, Mitra DK. 2016. Reciprocity between regulatory T cells and Th17 cells: relevance to polarized immunity in leprosy. PLoS Negl Trop Dis 10:e0004338.
A fourth pathway that contributes to T cell regulation, the so-called Treg pathway (or Th3 pathway), has now been identified. The Treg cells produce additional regulatory compounds that control the differentiation of Th0 cells. Treg cells maintain tolerance to self-antigens and modulate autoimmune responses and serve to suppress other immune cells, particularly once invading pathogens have been cleared from the body. Cytokines produced by Treg cells can direct the outcome of an immune response, tipping the balance between one dominated by a Th1 or a Th2 pathway (as in Box 4-3).
Production of Antibodies by B Cells
Two signals are required to activate B cells to differentiate into plasma cells and produce antibodies (Figure 4-10). This failsafe costimulatory mechanism makes sense, considering the dire consequences of not strictly controlling antibody production. One mechanism that activates B cells is the associated Th cells that mature in the thymus gland (thymus-dependent antigens). Resting B cells are not dividing, but they do express a single type of membrane immunoglobulin (mIg) on their surfaces. There are an enormous number (>1010) of resting B cells displaying mIg molecules with different antigen specificities on their surfaces! The mIg molecules interact with a membrane-bound transducer protein to form the B cell receptor (BCR). When an antigen binds to the Fab regions of two mIg molecules, linking them together, a signal is sent to the B cell that can lead to cell proliferation, if a second signal is detected. The second signal is generated by endocytosis and presentation of the antigen on the MHC II-antigen complexes on the surface of the same B cell. The use of MHC II helps B cells find the activated Th cells that are displaying TCRs specific to the displayed antigen, which ensures specific responses to a particular antigen. Binding of a Th cell to the B cell involves a set of multiprotein contacts similar to those that occur between other APCs and T cells (Figure 4-10). This binding causes the Th cell to produce additional surface receptors that lead to even tighter binding between the antigen-stimulated B cell and the Th cell. This tight binding stimulates the B cell to produce and display cytokine receptors and the Th cell to produce cytokines, which in turn stimulate the B cell to proliferate and differentiate into the mature form of B cells, called plasma cells, that secrete antibodies.
Figure 4-10. The Th2 cell binds and activates B cells presenting the same epitope on their MHC II. The B cell receptor complex is comprised of membrane-bound immunoglobulin (mIg), which can be of isotype IgM, IgD, IgA, IgG2, or IgE, the signaling mediator proteins Igα and Igβ, and the CD21 complement receptor that recognizes iC3b and promotes B cell activation. For simplicity, many of the other proteins involved in binding and activating the B cell (e.g., CD54, CD11a/CD18, CD2, CD58, CD80/70, CD28) are omitted. Stimulation of B cells through interactions of CD40 on the B cells with CD40 ligand expressed by Th cells and through cytokines produced by Th cells results in proliferation of the B cells and conversion into antibody producing cells, called plasma cells. A fraction of the activated B cells become memory B cells.
A fraction of activated B cells become quiescent memory B cells. In subsequent encounters with the same antigen and again with memory Th cells against that same antigen, the memory B cells respond with a much shorter lag period and produce more antibodies for a longer period of time than in the primary response of the naïve Th and B cells. In addition, this secondary response produces antibodies with higher affinity, primarily of the IgG isotype.
Links between the Innate and Adaptive Defense Systems
Treating the innate and adaptive defense systems as separate subjects in separate chapters makes pedagogical sense because it is generally easier to understand complex systems by first separating them into their constituent components. However, it is important to note that for the human body to have the innate defenses acting independently of the adaptive defenses would be counterproductive, because the two types of defense need to act synergistically. Some examples of links are cytokines and chemokines, which are produced by and act on both types of immune responses; PMNs that serve as first responders and contribute through cytokine production to the Th1/Th2 decision-making process; DCs that opsonize pathogens and present the processed antigens to the adaptive immune cells; and antibodies that are made as an adaptive response but, when bound to bacterial cells, activate one arm of the complement cascade (i.e., the classical pathway).
We now add yet another link: the interaction between natural killer cells and B cells. It may be simply a coincidence that natural killer (NK) cells have a number of similarities, morphologically and cytokinologically, to T cells. Because T cells interact with B cells on other planes of existence, it is somewhat satisfying to learn that NK cells interact with B cells, too. Briefly, NK cells can stimulate B cells to proliferate (as T helper cells do) but by some factor that is not one of the known cytokines. B cells in turn induce NK cells to secrete more IFN-γ, which, as we have already seen, is an important factor in macrophage activation.
T-Cell-Independent Antibody Responses
In addition to the CD1-dependent T cell pathway discussed earlier (Figure 4-6C), nonpeptide antigens such as polysaccharides (e.g., bacterial capsule components), nucleic acids (e.g., bacterial DNA or RNA), and to a lesser extent lipids and glycolipids (e.g., bacterial membrane components) can also stimulate T-cell-independent antibody responses. T-cell-independent antigens provoke an antibody response by directly interacting with B cells (