A specific immune response to invading microbes is conveniently divided into humoral and cellular immunity. The importance of each arm of the specific response varies from infection to infection. Experimental animal models and naturally occurring immunodeficiency states clearly demonstrate that certain components of the immune response are crucial for con-trolling a particular infection.
For example, individuals with anti-body deficiencies are particularly prone to repeated infections with pyrogenic bacte-ria. Yet, replacement therapy with immu-noglobulin greatly reduces the number of infections. Interestingly, these individu-als can mount a normal response to most viruses (varicella, measles, mumps, etc.). Yet the absence of mucosal antibody does make them susceptible to some enterovi-ruses.
Although it is clear that innate immu-nity is the first line of defense against invading organisms, the TLRs are also playing a role in adaptive immunity, and the dendritic cell (DC) appears to be play-ing a key role in linking the innate and adaptive immune responses. As immature cells, they are present in the peripheral tissues. However, with the appearance of invading organisms, DCs recognize these pathogens through their TLRs. Fortunately, they express the full repertoire of TLRs. After activation of the TLRs, the DCs are transformed into more mature cells with a high expression of major histocompatibil-ity complex (MHC) and the co-stimulatory molecules CD80 and CD86. The DCs then migrate to the lymph nodes to activate antigen-specific naïve T cells.
The cytokine milieu being
expressed around the cells determines their fate; that is, the produc-tion of
IL-12 drives these cells to TH1 cells, which produce interferon-δ, whereas IL-4 drives them toward
TH2 cells producing IL-4, IL-5, Il-10, and IL-13. These latter
cytokines are of interest as they are also responsible for the development of
allergic diseases such as asthma and account for the regulation of
antigen-specific IgE pro-duction, accumulation of eosinophils, and activation
of mast cells. In this connection, the incidence of allergic disease and atopy
has markedly increased in the industrial-ized countries compared with
developing countries over the past decades, and one hypothesis is that this
increase is linked to the reduction of bacterial infections, which occurs in a
cleaner environment, a hypothesis known as the “hygiene hypoth-esis”. The
discovery that TLR signaling might be crucially involved in the establishment
of TH1/TH2 path-ways opens up the field to look for new
strategies against diseases such as asthma and atopy.
In summary, the fields of both innate and adaptive immunity have experienced a new and rapid growth in interest in the past eight to ten years. Concomitant with this growth, the number of genomes that have been sequenced is expanding, thus enabling researchers to identify and to characterize the receptors and adaptors involved in the recognition.
Although much of the work over the past years has focused on defining ligands for the different TLRs, the molecular basis for this recognition is not known for a sin-gle ligand. Furthermore, the characteriza-tion of TLR-dependent signaling for the instruction of adaptive immune responses has just started to be explored. Because TLRs play such a crucial role in innate and adaptive immune responses to distinct vir-ulence factors, the development of selec-tive inhibitors/activators may be a worth-while endeavor to help manage a number of infectious and immunologic diseases.