For S. pneumoniae, N. meningitidis, and H. influenzae, “natural immunity is required to maintain the commensal state” ². Infection by these bacteria is not necessarily dangerous in and of itself, and, in fact, most carriers are afforded protection from a previously developed commensal relationship and, therefore, effective adaptive response against these colonizing bacteria. Therefore, a health carrier should prevent the infection from spreading outside of colonies on the mucosal surface of the nasopharynx. For non-carriers and immune-deficient persons, however, these bacteria have clear pathogenic potential in that these bacteria can survive after invasion of the blood stream, particularly if antibody responses and compliment pathway activation have been somehow deactivated².

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[NON-SPECIFIC DEFENSE MECHANISMS]

Non-specific defense mechanisms are the first response against invading pathogens, such as the bacteria that cause bacterial meningitis, including S. pneumoniae, N. meningitidis, and H. influenzae. These include both mechanical mechanisms and innate, or non-adaptive, immune response mechanisms for both the purpose of preventing infection and for controlling nasopharyngeal colonization to prevent possible invasion of the intravascular space and CNS.

Mechanical

The human body has several non-specific, physical mechanisms for preventing infection of the nasopharynx. These include “laminar airflow across mucous layers that filter inspired air, the guttural reflex, laryngeal disclosure, and the cough reflex”⁶. Additionally, within the respiratory tract hydrogen peroxide is produced and secreted by mucosal epithelial cells as a general bactericide. Interestingly, the middle ear and Eustachian tube are usually immune to bacterial colonization despite their direct connection to the nasopharynx. The mechanism by which this immunity is achieved is not entirely clear; however, it appears that secretions of lysozyme, lactoferrin and β-defensins -1 and -2 play a role. Lysozyme secretions are particularly effective against the invasion of gram-positive bacteria^6,8.

Innate immune response

S. pneumoniae, N. meningitidis, and H. influenzae all are capable of colonizing the human nasopharynx and establishing a comensal relationship with its human host. As such, unrestrained proliferation following initial nasopharyngeal colonization is unlikely in healthy individuals with normal immune responses¹⁰. In general, within the mucosal membrane of the nasopharynx, alveolar macrophages and neutrophils will clear such bacteria following their opsonization by compliment¹⁰. This compliment activation appears to be mediated primarily by C-reactive proteins (CRP) that have bound themselves to phosphatidylcholine found on the surface of bacterial cell walls⁷. Studies have demonstrated that intact compliment-mediated pathways are critical for effective innate immune clearance of these bacteria and, subsequently, for preventing intravascular invasion¹⁰.

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[SPECIFIC DEFENSE MECHANISMS]

S. pneumoniae

The adaptive response to thymus independent antigens
In order for a B-cell to illicit an immune response against thymus independent (TI) antigens, no direct T-cell help is required. The TI antigens of S. pneumoniae include its capsular polysaccharides (CP)⁷. Among adults, anti-CP Ab have the highest protective capacity of any other previously studied antibody against S. pneumoniae antigens. Via TI-2 activation, B-cells produce antibodies against CP—primarily IgM, IgA and IgG2—which then facilitate bacterial opsonization and compliment mediated destruction. The presence of highly specific anti-CP antibodies allow for the rapid clearing of S. pneumoniae from the blood. Specific antibody and functional compliment pathways are also required within the mucosal membranes so that colonization can either be prevented entirely or, at the very least, be carefully regulated within nasopharynx¹.

Because they do not elicit T-cell help, there are several drawbacks to TI antigens, particularly if they are to be used in vaccines. First, poor antibody class switching has been observed. Second, without direct T-cell stimulation of the B-cells, immunologic memory is not elicited. Third, because infants do not produce significant amounts of IgG2, the antibody subclass that is critical for responding to most polysaccharide antigens, infants cannot mount effective immune responses against these antigens¹.

The adaptive response to thymus dependent antigens

In order for B-cells to produce a response to thymus dependent (TD) antigens, they “require direct contact with T-helper cells, not simply exposure to T-helper derived cytokines”⁷. In the case of TD antigens, B-cells need T-cell help to receive signal two, which is critical for the proper differentiation of Ag-specific B-cells to memory cells or Ab-producing plasma cells, and in turn, for mounting an effective immune response against these antigens. The antibodies primarily involved in responding to these antigens include (in order of decreasing importance) IgG1, IgG4, IgM, and IgG2¹.

In S. pneumoniae, TD antigens include pneumococcal proteins, such as neuraminidase, IgA1 protease, pneumolysin, pneumococcal surface protein A (Psp A), and autolysin. Some advantages to utilizing these TD antigens in vaccine development is their ability to induce immunologic memory, as evidenced by studies noting antibody affinity maturation and class-switching following inoculation with a pneumococcal TD antigen¹. Furthermore, a TD response can be elicited in young infants, who are nearly always able to mount an adult-like response against such antigens¹.

N. meningitidis

Innate immune response

N. meningitidis is capable of eliciting an innate immune response via several mechanisms, and this innate response is particularly critical for efficient immune clearance. First, the mannose binding lectin (MBL) pathway is instrumental in activating compliment mediated phagocytosis of the bacteria. Next, the recognition of capsular lipooligosaccharide (LOS) triggers the TLR4 pathway, which initiates a signal transduction process that attracts phagocytes, activates macrophages and dendritic cells, and ultimately leads to the phagocytosis and destruction of the offending bacteria⁶. LOS and other lipopolysaccharide structures can also trigger the alternative pathway by binding C1q, and as in the MBL pathway, this pathway will ultimately lead to bacterial cell death via the membrane attack complex (MAC) (C5-C9)^5,2. Males with an x-linked deficiency in properdin – a molecule that stabilizes the association between factor B and factor C3b – are both more susceptible to infection, and, once infected, will suffer more severe infection because they are incapable of mounting an immune response via the alternative pathway⁶.

Adaptive immunity

Children initially are passively immunized by IgA from maternal breastmilk during the first few months of life. Following weaning, children begin to develop immune responses to N. lactimica, a type of Nesseria that commonly colonizes the nasopharynx during childhood. N. lactimica does not cause disease, but it is highly cross reactive with N. meningitidis, and so N. lactimica antibodies will also confer protection against N. meningitidis when encountered later in life.

In terms of an adaptive immune response, capsular polysaccharides (CPS) as the outermost organelle of meningococcal bacteria are “prime targets” for mucosal immunity¹² and are the most important antigens for mounting immune responses against serogroups A and C. For serogroup B, capsular polysaccharides resemble fetal neuronal cells, and so they are poorly immunogenic¹². Instead, for these serogroup antibody responses are mounted against other antigens including PorA, PorB, and lipopolysaccharide (LPS) class 5 outer membrane proteins¹².

On the mucosal membrane, CPS are targeted by secretory IgA. It is important to note that IgA1 proteases produced by all strains of N. meningitidis are potentially capable of debilitating IgA1 via cleavage at the hinge region. However, IgA2, a deletion mutation of IgA1, is unaffected by the protease. In addition, IgA1 proteases can be inactivated by “an abundance of antibodies” carried by the majority of humans¹². Therefore, despite the presence of bacterial proteases, IgA may still provide an effective response.

Other antibodies that are naturally acquired during childhood include antibodies to non-sialylated LOS after repeated colonization by N. meningitidis. This antibody-mediated immunity should last through adulthood, although later in life, as the efficacy of antibody responses decline, susceptibility increases. All LOS bear an epitope for IgM; however, sialiation prevents galactosaminylation, consequently preventing opsonization by IgM.

Most IgG to meningococcal polysaccharide are of the IgG2 subclass, and deficiencies in IgG2 are often associated with more severe disease. The polysaccharide capsule prevents classical pathway activation by IgG that bind subcapsular antigens. There are few antibodies against the polysaccharide capsule due to humans’ high tolerance of the sialylated capsule that mimics the protective sialiation of host cells primarily from compliment mediated destruction.

Serum bactericidal activity

Serum bactericidal activity has been the primary determinant of establishing a commensal relationship between the host and colonies of N. meningitidis. This is primarily mediated via the lysis of meningococcal bacteria, which in turn is primarily mediated by the formation of MAC^12,16.

Intravascular protection against gram-negative bacteria is believed to be mediated by antibody and compliment recognition of the bacterial surface. C3b mediates opsonophagocytosis, and MAC mediates cell lysis¹².

IgA immune lysis inhibition

IgA can inhibit immune lysis by out-competing or displacing IgM and IgG for antigen epitopes, thus blocking their stimulation of lytic activity. However, as illogical as is function may seem, IgA may have an important homeostatic function in down-regulating compliment activation and the subsequent, potentially detrimental, inflammatory response⁶.

T-cell response

It is generally thought that the immune response mounted against N. meningitidis within the serum relies mainly on SBA, but T-cells do seem to have a role in regulation and stimulation of Ab production. Most importantly, perhaps, is the T-cell’s role in the establishment of immunologic memory. A Th-2 response is stimulated by meningococcal membrane protein antigens including PorA, PorB, Opa, and Opc¹⁵. Studies have demonstrated that The Th1 response is particularly prevalent among infant immune responses become less prevalent with age as an individual switches from primarily a Th1 response to a Th2 response, signifying that immunologic memory improves as the immune system matures past infancy and early childhood. Additionally, although infants produce the same an amount of IgG1 and IgG3 as older children, their immune response is still poor, suggesting differences in Ab specificity or affinity^12,13,16.

H. influenzae

Approximately 95% of infections due to H.influenzae are of the class B serotype⁴. The virulence of H. influenzae type B is mediated by secreted endotoxins and neuraminidase (an IgA protease), fimbriae, surface lipoologosaccharide and other capsular polysaccharides⁴. The capsular polysaccharides are particularly instrumental in determining the virulence of H. influenzae because they are ineffective at inducing the alternative compliment pathway, and polyribosomal ribitol phosphate (PRP) present in the capsule is anti-phagocytic⁴. Thus, anti-capsular antibody is the primary immune response mounted against this pathogen, which in turn enable the classical compliment pathway and opsonophagocytosis⁴. Although PRP is the most well understood capsular antigen, naturally occurring antibodies to other capsular antigens have been noted, including antibodies against lipooligosaccharide, other cell wall lipopolysaccharides, and the outer membrane proteins P1 and P2⁴.

During the first two months of life, the immune systems of most infants continue to rely on passively acquired maternal antibodies from breast milk. Following weaning, however, this passive immunity wanes, and consequently the risk of meningitis from H. influenzae increases dramatically from the period beginning after weaning until about 3 years of age, the time when a child’s adaptive immune mechanisms are capable of mounting an effective immune response⁴. Until that age, an infant is highly susceptible to H. influenzae because serum anti-PRP antibody levels are low or virtually absent, and immune memory remains poor even after successive infections⁴. These deficiencies in the infant immune system are reflective of the typical, natural delay in the immune system’s ability to mount immune responses against purely polysaccharide antigens⁵.

In older children and adults, PRP antibodies are instrumental in protecting against invasive disease beyond the nasopharynx and in preventing infection in general, as has been demonstrated by the success of protective purified PRP vaccines⁵. Antibodies to PRP play a significant role in activating the classical compliment pathway, as well as have the ability to cause bacterial opsonophagocytosis. Although PRP is capable of stimulating B-cells, as a thymus independent antigen, it does not adequately stimulate T-helper cells. Consequently, inoculation with pure PRP generates only a limited immune response, does not generate immunologic memory, does not exhibit a booster response, and antibodies, primarily IgM, have a relatively low affinity for bacterial antigens⁵. Thus, vaccines must contain PRP and a protein in order to stimulate T-help that will enable both immunologic memory and antibody affinity maturation⁵.

Generally, the role of other host immune responses is less well understood. PRP IgA has been found in the mucosa, blocking and/or regulating the attachment and subsequent colonization of H. influenzae in the nasopharynx. Both capsulated and uncapsulated antigens have activated the classical pathway in vitro, suggesting that compliment deficiencies may be detrimental to the patient in terms of their susceptibility to invasive H. influenzae type B infection^4,5.
The Role of Immune Response in the CNS and CSF
The final step after bacteremia is the bacteriologic invasion of the central nervous system, primarily via adhesion to blood-brain barrier components or transport of the bacteria within phagocytic cells across the blood-brain barrier and into the CSF¹⁴. The immune response within the CNS and CSF is in fact the cause of much of the pathologic manifestations of these bacterial infections. Because the CNS is an immunologically privileged site, immune response is “virtually absent” in the brain, and mechanisms to phagocytose bacterial pathogens within the fluid medium of the CSF are inefficient¹⁴. Thus, the invasion of replicating bacteria into the CSF leads to a vigorous inflammatory response—mediated by locally produced TNF, Il-1, Il-6, and Il-8—in the subarachnoid space, beginning with the pleocytosis of neutrophils into the CSF¹⁴. The presence of neutrophils in the CSF leads to further chemotaxis of other leukocytes into the CSF and further inflammation¹⁴. The result of such pleocytosis is increased CSF and intracranial pressure, which ultimately leads to the onset of meningitis disease pathology¹⁴.

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