Basis of Acquired Resistance

Specific acquired immunity against infectious diseases may be mediated by antibodies and/or T lymphocytes. Immunity mediated by these two factors may be manifested by a direct effect upon a pathogen, such as (1) antibody-initiated, complement-dependent bacteriolysis or (2) opsonophagocytosis and killing, as occurs for some bacteria, (3) neutralization of viruses or toxins, or (4) by T lymphocytes which will kill a cell parasitized by a microorganism.

Primary vs Opportunistic Pathogens

Among the almost infinite varieties of microorganisms, relatively few are capable of causing a disease in an otherwise normal or healthy individual. These disease-causing microorganisms are conveniently classified as primary pathogens. A disease may also be caused by organisms ordinarily in contact with the host, such as bacteria or fungi in the colon or in the upper respiratory tract (opportunistic pathogens), following an injury (whether mechanical, such as an open fracture, following a disease with immunosuppressive activity, such as measles or malaria, or induced by cytotoxic chemotherapy).

Protective Antigens

In general, specific acquired immunity to human pathogens is directed to only one or a few protective antigens. The immunologic properties of the protective antigen are important determinants of the human protective defense.

Immune Mechanisms

Preventive Immunity

Protein antigens (Also see Ch. 1)

Proteins, in most instances, are defined as T cell dependent antigens by two properties. First, proteins are hydrolyzed to peptides by intracellular proteases. Second, proteins may have multiple but unique specificities (epitopes). These two properties permit recognition by receptors (membrane immunoglobulin) of antibody-producing cells (plasma cells) and internalization and proteolysis by enzymes. Activation requires that the peptide fragment of the protein antigen interact with the plasma cell histocompatibility antigen to form a complex that attracts and activates T cells. The activated antigen-specific T cells release cytokines that cause plasma cells to divide and to increase their secretion of specific antibody.

The same mechanism serves to activate T cells by contact with host cells parasitized by intracellular microorganisms. Proteins secreted by intracellular organisms interact with histocompatibility antigens of the host cell (T cell epitopes) and provide a specific site for T cells that kill the parasitized host cell (cytotoxic T lymphocytes).

Some protective epitopes, especially those of viruses, are expressed only on the intact organism (conformation epitope). An example is the neutralizing epitope of polioviruses (D antigen) that requires the intact capsid to elicit neutralizing antibodies.

The protective protein antigens are highly specific and are unique to each pathogen. Acquisition of antibodies to protein protective antigens either follows infection with the pathogen or vaccination.

Polysaccharide antigens

Surface polysaccharides of pathogens may serve as protective antigens (Table 8-1). These polysaccharides may be capsular polysaccharides, present on either Gram-negative or Gram-positive organisms or the outermost domain of the lipopolysaccharide of Gram-negative organisms. Polysaccharides have simple structures composed of identical repeating units so that each molecule will have relatively fewer epitopes than a protein. But in contrast to a protein, a polysaccharide is multivalent for each epitope. This multivalency explains why a polysaccharide can crosslink the receptors of plasma cells, resulting in activation and multiplication of plasma cells, both of which increase secretion of antibodies.

Table 8-1

The Surface Polysaccharides of Primary Bacterial Pathogens Causing Systemic Infections.

The protective epitopes of polysaccharides, in contrast to proteins, are widely shared in nature, and natural immunity: antibody synthesis in the absence of the homologous organism, occurs in almost every individual during development. Similarly, disease and often asymptomatic carriage will also stimulate serum polysaccharide antibodies. Lastly, because they do not interact with T cells, polysaccharides are designated as T cell independent.

Each bacterial species, such as pneumococci, may have many capsular polysaccharides but only a fraction of these will be associated with a disease. For example, there are now 89 reported types but most systemic pneumococcal infections are caused by about 23 types. In infants and children, most pneumococcal infections are caused by only 8 types. Similarly, of the six types of Haemophilus influenzae, almost all systemic infections, especially meningitis, are caused by type b.

It is important to understand that immunity may be directed towards the intact pathogens such as bacteria, viruses, protozoa, or fungi, or to individual extracellular antigens such as toxins (antitoxin).

Antibody and secondary biologic activities

Serum antibodies are the signal and specific component of a complex inactivation system. Serum IgM and IgG antibodies exert their protective effect directly upon bacteria whose surface polysaccharides or proteins are protective antigens. This signal is generated by the configuration of the non-antibody combining site region of the heavy polypeptide chain after binding of antibody with an epitope. For some pathogens such as meningococci (Gram-negative), the antigen-antibody configuration will activate the serum complement protein cascade with deposition of a C8,9 peptide probe that drills itself through the outer membrane. The resultant lesion causes release of intracellular components and lysis of the meningococci. In addition to bacteriolysis, other Gram-negatives, such as Haemophilus influenzae type b, also may be inactivated by serum antibody, affixed to the polysaccharide of this pathogen, that attracts and activates serum complement proteins to form C3 and C5 complexes. The latter complexes attract and activate phagocytic cells that engulf and digest the pathogen (opsonophagocytosis). This antibody-initiated, complement-dependent phagocytosis and killing are required for Gram-positive bacteria whose cell wall is not susceptible to lysis by complement.

Serum antibodies may confer immunity by binding directly to viral pathogens. The effect of this simple interaction is neutralization or inactivation of the virus. The exact protective mechanism of viral-specific antibodies is not known and may be unique for each pathogen (see Ch. 50). In many cases, antibody binding renders the viral pathogen incapable of infecting a host cell by preventing penetration of cells. As an example, antibodies to the fusion (F) protein of measles prevent the integration of virus with the cell membrane of the host. Experimental proof for this direct antiviral effect is that monovalent fragments of IgG, unable to activate complement, exert similar neutralization activity as the intact antibody. Some larger viral pathogens, coated with specific antibody, may be phagocytized and digested (See Chapter 50).

Antibodies that neutralize bacterial toxins (antitoxins), such as tetanus, diphtheria and pertussis toxins, are protective and therapeutic. The protective effects of antitoxins are varied. Antitoxin does not exert antibacterial action upon Clostridium tetani. Rather, antitoxin inactivates the functions of tetanus toxin that facilitates its migration up the neural sheath to the synapse, and antibodies to the enzymatic region inhibit its alteration of the synapse. The neutralizing activities of diphtheria and pertussis antitoxins, in contrast, exert secondary antibacterial actions upon their respective pathogens. Both toxins serve to condition the respiratory epithelium to permit colonization by Corynebacterium diphtheriae tox⁺ and Bordetella pertussis: the former by its cytotoxicity and the latter by its inactivation of the function of phagocytic cells. Antitoxins block these actions and facilitate the function of phagocytic cells.

Cell-mediated immunity

Antigen-specific activation of T cells has been described (vide supra). The targets for activated T cells are parasitized host cells (also see Ch. 50). The secondary or inactivation mechanisms invoked by activated T cell phagocytic host cell complexes are not clearly understood. One important mechanism is the release of nitrous oxide that results in killing of the host cell and of the pathogen. Cell-mediated immunity is largely, if not exclusively, a curative mechanism.

Disease-acquired immunity

Convalescence from most infectious diseases confers immunity. This immunity, in most instances, may be transferred for a limited period to non-immune individuals by injection of IgG as FDA-licensed immunoglobulin (Table 8-2) or to the newborn by passively acquired maternal serum IgG. There is also evidence that secretory IgA acquired by breast feeding confers immunity to newborns. These findings indicate that critical levels of antibodies are sufficient to prevent infectious diseases. Their preventive action is best explained by antibodies killing or inactivating the inoculum of the pathogen on epithelial surfaces. Herd immunity follows vaccination with Haemophilus type b conjugates, diphtheria toxoid and measles virus vaccines. The resulting immunity causes a decreased transmission of the pathogen. Since there is no animal vector for these pathogens, the incidence of the disease in the entire community is far below that percentage of the population that has been vaccinated (herd immunity). Antibody-mediated inactivation of the inoculum may also occur in the blood stream in the case of pathogens inoculated directly into the tissues or blood stream, such as hepatitis B or malaria. There is yet no evidence in humans that antigen-specific T lymphocytes can prevent infectious diseases.

Table 8-2

U.S. Licensed Immunoglobulin For Passive Immunization.

Natural immunity

Acquisition of serum antibodies to surface polysaccharides of pathogens is age-related and often occurs without the individual encountering the homologous organism. An example is group A meningococci, the cause of epidemic meningitis. Despite the absence of this pathogen in the United States for about 50 years, either as a cause of meningitis or in asymptomatic carriers, most adults have antibodies to this capsular polysaccharide. Antigenic stimuli for Group A meningococcal antibodies are likely due to exposure to several Gram-positive and Gram-negative bacterial species in human stools. Another example is Shigella dysenteriae type 1, the cause of epidemic dysentery. Adults in Sweden and the United States have antibodies to the LPS of S. dysenteriae type 1, despite the virtual absence of this pathogen in these countries during the past 50 years. The stimulus for these natural and protective antibodies is probably cross-reacting polysaccharides of the enteric and respiratory tract floras.

Natural serum antibodies to surface polysaccharides confer specific protection to adults and are transmitted to newborns. The highest attack rate and mortality occur during childhood when these maternally-acquired anti-polysaccharide antibodies have waned and adult levels have not been reached. Acquisition of natural antibodies is not uniform and many adults remain non-immune. Vaccination with polysaccharide-based vaccines increases the percentage of adults with protective levels to almost 100%. These principles are elegantly illustrated by the development of groups A and C meningococcal polysaccharide vaccines during the 1960's when outbreaks of meningitis caused by this pathogen occurred in armed forces recruits during the Vietnam conflict. Introduction of these polysaccharide vaccines rapidly eliminated these outbreaks.

Vaccination-induced active and passive immunity

Vaccines are heterogeneous according to (1) the nature of the immunizing substance, whether they are inert or living, and (2) by the method of their administration. Vaccines include living attenuated strains of viruses (poliovirus) or bacteria (BCG), inactivated viruses (yellow fever) and bacteria (anthrax), purified polysaccharides (pneumococcal 23 valent) or polysaccharide-protein conjugates (Haemophilus type b conjugate). Inert and injected vaccines, such as tetanus toxoid, elicit mostly serum antibodies. Living vaccines, such as attenuated strains of viruses (poliovirus), elicit secretory antibodies and sensitized T cells.

To date, the FDA regulates vaccines and seroepidemiologic studies to assess the immune status of populations by measurement of biologically active antibodies only. Thus, the status of diphtheria immunity is evaluated by the percentage of the population with protective levels of neutralizing antibodies to diphtheria toxin (antitoxin). Similarly, the immune status to measles is evaluated by measurement of the percentage of the population with protective levels of neutralizing antibodies. For some vaccines, such as BCG, there is as yet no measure of immunity to assess their effectiveness.

Some investigational vaccines utilize recombinant DNA technology to mobilize genes governing the synthesis of protective antigens. These specific genes may be inserted into avirulent vectors. Administration of vectors is designed to stimulate the comprehensive immunity that follows disease with the pathogen itself. Naked DNA may be incorporated into plasmids that infect somatic cells and continually induce synthesis of protective antigens that stimulate antibodies and activated T cells.

Curative immunity

Infection with most pathogens does not result in death of the host and the offending organism is ultimately cleared after the symptoms of the disease have waned. The basis of the curative process of patients is not well understood, but it is likely mediated by expansion of both specific immune and effector mechanisms. Quantitative increases of specific antibodies and activated T cells is accompanied by increases in serum complement levels and phagocytic cells. Also, infection increases the levels of cytokines and serum proteins known as acute phase reactants, such as C-reactive protein, alpha 1 trypsin inhibitor, and transferrin, that serve as scavengers or inhibitors of bacterial debris. Cure of infectious diseases is most likely the prolonged interaction of maximal levels of host specific and non-specific (effector) (see Ch. 49) mechanisms with the pathogen.