Bacteria cause allergic disease because of toxicity, invasiveness, immunopathology, or lends of these three mechanisms. Thus much of the interaction between a given bacterial species and the cellular immune response can be predicted by considering the immunological mechanisms available in relation to the mechanism of pathogenicity, and the structure of the bacterium. For a toxigenic bacterium, neutralizing antigen & antibody may be all that is needed. Otherwise destruction of the organism itself may be required.
Nonspecific Recognition of Common Bacterial Structures and Soluble Antigen
Much of the defense against bacteria depends on pathways which have nothing to do with the specific soluble antigen receptors of either B cells or T cells, and probably antedate these in evolution. Many bacteria are simply excluded by barriers such as skin, acidity in gut and vagina, commensalisms occupying the relevant niche, entrapment by mucus, etc. If not excluded, the organism may be recognized by:
- Acute phase proteins, C-reactive protein and mannose-binding protein which also fix complement.
-Receptors for the formyl peptides released by bacteria which are chemoarrractants and activators of phagocytes.
-Receptors for bacterial cell wall components, glycolipids, glucans and other polysaccharides that nonspecificaLly enhance the cellular immune response, and can be used as immunological adjuvants.
-Complement, activated in the absence of antibody by a wide range of bacterial components.
-Receptors that lead to cytokine release. The bacterial products which do this include endotoxin (lipopolysaccharide, LPS) of gram-negative organisms, lipoteichoic acids of gram-positive cocci, and the lipoarabinomannan of mycobacteria. It is probable that all bacteria contain cytokine triggers.
Nonspecific Recognition and Cellular Immune Response Mechanism
Collectively these nonspecific recognition pathways perform crucial functions. First, the pattern of nonspecific recognition events, cytokines and bacterial products supplies information as to the type of cellular immune response that needs to be activated. This immunoregulatory ‘decision’ is particularly important because activation of inappropriate effectors mechanisms can lead to enhanced susceptibility rather than to protection. These features account for the ‘adjuvant’ properties of bacterial components, which are often used by immunologists to boost or direct responses to other soluble antigens. For example, the adjuvant properties of Bordetella pert ussis and Mycobacterium tuberculosis impose different ba Iances of T1 i to TH2 cyrokines on the T cell response to any simultaneously administered antigen. If the immune system activates a TH2 pattern of response to a mycobacterial pathogen, accelerated disease will result.
Other Factors Influencing THI/TH2 Balance of T Cell Response
Dose and the different handling of soluble antigen versus particulate antigen are also important. Low dose soluble antigen selectively primes T1 2, while low dose particulate antigen selectively primes TH 1. These relationships reverse as dose is increased. The reason appears to be that presentation of Low dose soluble antigen is mostly by B cells, which tend to drive TFI2, while presentation of low dose particulate antigen (such as bacteria, or Leishmania) is mostly by macrophages, which tend to drive TH1.
Local metabolism within lymph nodes of glucocorticoids (cortisol), and of dehydroepiandrosterone (which yields metabolites that oppose some effects of cortisol), also profoundly influences TH1RH2 cytokine balance. Cortisol diverts the response to T112, and is partly responsible for increased susceptibility to certain infections in stressed individuals.
Nonspecific recognition and early defense: the protective role of cytokines. The nonspecific recognition events cause sufficient activation of the immune system to mobilize a ‘holding operation’ that can control bacterial growth while specific immunity develops. The cytokines released have rapid protective effects, but if their release is excessive or prolonged, they can cause severe immunopathology, and even death. Nevertheless tumor necrosis factor a (TNFa) protects mice from M. avium, Legionella pneumophila. Streptococcus pneumoniae and Klebsiella. The mechanisms of protection by cytokines, particularly TNFa, include rapid induction (<5 mm) of increased adhesion of neutrophils to endothelial cells, increased expression of CR3 and other cell adhesion molecules, priming of neutrophils for enhanced production of oxygen reduction products, and activation of macrophages. Cytoki nes also affect ‘nonprofessional’ phagocyres, and exposure of Hep-2 celLs (derived from a human carcinoma of the larynx) to TNFct renders them resistant to invasion by Salmonella typhimurium. Similarly, interferon ‘y (IFNy) derived from natural killer (NK) cells will activate killing mechanisms in macrophages.
Interactions of bacteria with complement Numerous bacterial components cart activate the alternative pathway. This results in three categories of protective function:
Interactions of bacteria with complement numerous bacterial components can activate the alternative pathway. This result in three categories of protective function:
1. Release of the chemotactic products, C3a and CSa. These cause smooth muscle contraction, mast cell degranulation, and neutrophil chemotaxis and activation.
2. Attachment to the organism of derivatives of C3, which play an important role in the subsequent interaction with phagocytes.
3. Killing of some gram-negative organisms if the lytic complex C5b—C9 gains access to the outer lipid bilayer.
Many organisms have devised strategies to resist these effects of complement. Some capsules are very poor activators of the alternative pathway. Alternatively, Long side-chains (0 antigens) on LPS may fix C3b at a distance from the vulnerable lipid bilayer. Similarly, smooth gram-negative organisms (Escherichia coil, Salmonella, Pseudomonas) may fix but then rapidly shed the C5b—C9 membrane complex. Capsules rich in sialic acid (like host cell membranes) promote the inactivation of C3h by interaction with factors H and 1, and Neisseria meningitidis, E. coli K I and group B streptococci resist complement attachment in this way. The M reactive protein of group A streptococci acts as an acceptor for factor H and there is a gene for a C5a protease close to the M reactive protein gene.
Role of Antibody
Antibody clearly plays a crucial role during infections with toxigenic organisms. It neutralizes diphtheria toxin by blocking the attachment of the binding portion of the molecule to its target T cell response. Similarly it may block locally acting toxins, extra-cellular matrix-degrading enzymes which act as spreading factors, and motility due to flagella. An important function on external surfaces, often performed by secretory immunoglobulin A (IgA), is inhibition of binding of bacteria to epithelial cells. It is also likely that some antibodies to the bacterial surface can block functional requirements of the organism such as receptors for iron-chelating compounds or the intake of nutrients. However, the most important role of antibody in immunity to nontoxigenic bacteria is the more efficient targeting of complement so that even organisms that resist the alternative pathway by the mechanisms described in the previous section are damaged by complement, or become coated with C3 products.
Interactions Between Bacteria and Phagocytic Cells
The important consequence of the inflammatory and chemotactic events triggered by bacteria in the tissues is the enhanced exposure of the bacteria to phagocytic cells. The first stage in the intracellular killing is the attachment of the organism to the surface of the phagocyte. This important and complex interaction determines whether uptake occurs, and whether killing mechanisms are triggered. In addition to complement and antibody, this interaction can involve C-reactive protein, lectins on the organisms and on host cell membranes, the family of adhesion-promoting receptors CR3, LFA-l, p150,95 and the integrins. Some organisms are able to enter cells via unconventional receptors, such as integrins, and so avoid triggering killing mechanisms.
