Mednotes

L07 I&I Immunity in meningitis

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tagsinfection-and-immunity, lecture
aliasesL07 I&I Immunity in meningitis

16 min read

Overview

This lecture traces how encapsulated bacteria (Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae type b) progress from nasopharyngeal colonisation to invasive disease and meningitis, and the layers of host defence that normally prevent this: mucosal antibody, humoral innate molecules, the three complement activation pathways and their effector functions, leukocyte recruitment, the spleen’s filtering role, and the inflammatory cascade that produces meningeal inflammation once bacteria reach the CSF. It closes with the immunology of polysaccharide versus conjugate vaccines and how these are applied against each pathogen.

Routes from colonisation to invasive disease

  • Nasopharyngeal colonisation is the first step for all three organisms. Colonisation rates: S. pneumoniae up to 90%, N. meningitidis 8-25%, H. influenzae type b 3-5%.
  • Invasive disease occurs with colonisation by a novel serotype the host has not previously encountered.
  • Two routes to invasive disease:
    • Haematogenous: translocation across the epithelium into the bloodstream (bacteraemia) → seeding to the meninges → breach of the blood-brain barrier → meningitis. Bacteraemia can also seed other sites (e.g. pneumonia, arthritis).
    • Contiguous: breach of mucociliary defences → sinusitis or otitis media → CSF leakage → meningitis. Breach of phagocytic defences in the lung can also cause pneumonia → bacteraemia → meningitis.

Mucosal immunity at the nasopharynx

  • M cells overlying nasopharyngeal lymphoid follicles take up bacterial antigen; dendritic cells in the lamina propria present this antigen to T and B lymphocytes in the germinal centre, initiating the immune response.
  • Pneumococcal colonisation leads to production of anti-capsular antibody.
  • B lymphocytes produce dimeric IgA (with J chain) and IgM, which bind the polymeric immunoglobulin receptor (pIgR) on the basolateral membrane of epithelial cells, are transcytosed through the epithelial cell, and released at the apical membrane as secretory IgA (with secretory component) into the lumen.
  • Capsule-specific (anti-capsular) antibodies protect against both colonisation and invasive infection with that serotype.

Humoral immunity: soluble defence molecules

  • Humoral immunity = soluble molecules in blood and tissue fluid, both innate and adaptive.
  • Innate: collectins (mannose-binding lectin (MBL), ficolin) and pentraxins (C-reactive protein, CRP).
  • Adaptive: antibodies.
  • Collectins, pentraxins and antibodies all feed into (a) complement activation and (b) opsonisation/phagocytosis.

Complement activation: three pathways

Three mechanisms activate complement, all converging on formation of a C3 convertase.

  1. Lectin pathway (initiated by microbial glycans): collectins (MBL, ficolin) circulate in blood and bind with high avidity to mannose and fucose residues on pathogen surfaces, which are not present on vertebrate glycans. MASP-1 and MASP-2 are associated with MBL. On binding, MASP-2 is activated and cleaves C4 then C2, forming C4b2a (the classical/lectin C3 convertase). Collectins also act directly as opsonins. Collectins protect against N. meningitidis and S. pneumoniae infection.

  2. Classical pathway (initiated by antibody), similar to the lectin pathway but using the C1 complex (C1q with C1r and C1s). C1q binds:

    • Antibody bound to antigen (IgM > IgG in binding efficiency).
    • C-reactive protein (a pentraxin), which itself binds phosphocholine on dead/dying cells and some microbes, and microbial polysaccharides (e.g. the S. pneumoniae capsule); CRP is also an opsonin in its own right.
    • Directly to bacterial cell wall components: lipopolysaccharide (LPS, Gram negatives) and outer membrane proteins.
    • On binding, C1s is activated and cleaves C4 then C2, again forming C4b2a (classical C3 convertase).

  3. Alternative pathway (initiated by spontaneous deposition of C3b): C3 spontaneously hydrolyses to C3(H2O) in plasma, initiating deposition of C3b on microbial surfaces. C3b binds factor B, which is cleaved by factor D into Ba (released) and Bb, forming C3bBb (the alternative C3 convertase). C3bBb is stabilised by properdin (factor P) and destabilised by factor H, a negative regulator that binds glycans on mammalian (host) cells to protect self tissue. Factor P deficiency is associated with N. meningitidis infection.

Convergence: all three pathways generate a C3 convertase, which cleaves C3 into C3a (released) and C3b (binds covalently to the microbial surface) — up to 1000 C3b molecules deposited per C3 convertase.

C5 convertase and MAC: a C5 convertase forms when an additional C3b binds to the C3 convertase (alternative: C3bBb + C3b → C3bBb3b; classical/lectin: C4b2a + C3b → C4b2a3b; much less is formed than C3b). This cleaves C5 into C5a (anaphylatoxin, released) and C5b (binds the pathogen surface and initiates the membrane attack complex, MAC, with C6, C7, C8, C9). MAC assembly: C5b binds C6 and C7; the C5b67 complex binds the membrane via C7; C8 binds and inserts into the membrane; 10-16 molecules of C9 bind and polymerise to form a pore (~15 nm tall, 10 nm wide, 3 nm wall) that disrupts membrane integrity, causing loss of the proton gradient and killing the pathogen. MAC formation is critical for immunity to N. meningitidis.

Downstream effector functions:

  • C3a and C5a are anaphylatoxins that recruit phagocytic cells and promote local inflammation (C5a activity > C3a).
  • Phagocytes bearing C3b receptors engulf and destroy C3b-coated pathogens (opsonisation).
  • Completion of the MAC disrupts the pathogen cell membrane, causing lysis.

Summary — what to know: lectin pathway is triggered by collectins (e.g. MBL) recognising microbial glycans; classical pathway is triggered by C1q recognising antibody bound to antigen, pentraxins (e.g. CRP), or bacterial cell wall; alternative pathway begins with spontaneous C3 → C3b, which binds factor B to form the alternative C3 convertase.

Leukocyte recruitment

  • Rolling adhesion: a weak lectin-glycan interaction between E-selectin (endothelial cell) and sialyl-Lewisx (leukocyte) lets leukocytes roll along the vessel wall.
  • Tight adhesion: an integrin-integrin interaction between ICAM-1 (endothelial cell) and LFA-1 (leukocyte).
  • Sequence: rolling adhesion → tight binding (aided by the CXCL8 chemokine/receptor) → diapedesis (via CD31) → migration through the basement membrane into tissue.
  • C3a and C5a activate the endothelium, increasing vasodilation, vascular permeability and cell-adhesion molecule expression.
  • C5a also activates neutrophils and monocytes, increasing their cell-adhesion molecules, driving chemotaxis and increasing phagocytosis.
  • Net effect: increased fluid leakage with extravasation of immunoglobulin and complement into tissue, migration of monocytes, neutrophils and lymphocytes into tissue, and increased phagocytosis by macrophages and neutrophils.

Capsules and immune evasion

  • Capsules of S. pneumoniae, N. meningitidis and H. influenzae mask complement (C3b) and antibody that are deposited on the underlying bacterial cell wall, physically preventing phagocyte C3b receptors and Fc receptors from engaging them — this inhibits opsonisation and phagocytosis.
  • Anti-capsular antibody (IgG) binds directly to epitopes on the outer surface of the capsule itself, so it is not masked, allowing phagocyte C3b and Fc receptors to engage the pathogen.
  • Anti-capsular antibody is therefore required for efficient opsonisation and phagocytosis (IgG) and for complement deposition (IgM and IgG).

Role of the spleen

  • Splenectomised patients have an increased risk of overwhelming infections, often with encapsulated bacteria; incidence of sepsis rises steadily over the 180 months (15 years) following splenectomy, compared with a lower, more slowly rising rate in non-splenectomised patients.
  • The spleen is the main organ that clears poorly opsonised and non-opsonised bacteria from the blood.
  • The liver is important for clearing opsonised bacteria.

Meningeal inflammation

  • Bacteria in the blood cross the basement membrane into the CSF and multiply there.
  • Released bacterial PAMPs (pathogen-associated molecular patterns) — pneumolysin, lipoteichoic acids, peptidoglycans — are sensed by PRRs (pattern recognition receptors: TLR4, TLR2, TLR9, NLRs) on resident phagocytic cells in the CSF.
  • This triggers release of cytokines/chemokines: IL-1, TNFα, IL-6, IL-8.
  • These cytokines act on the vascular endothelium, upregulating adhesion molecules (P-selectin, E-selectin, ICAM-1/LFA-1) and, together with C5a/C3a, drive neutrophil recruitment from blood into CSF.
  • Cytokines/chemokines also activate microglia in the brain parenchyma.

Vaccine immunology: polysaccharide vs conjugate

  • Polysaccharide vaccines: the polysaccharide is a T-independent antigen — it cross-links the B cell receptor directly, without T cell help. The B cell differentiates straight to a plasma cell producing IgM and IgG2, depleting the memory B cell pool and producing no memory B cells. Result: predominantly IgM, poor memory.
  • Conjugate vaccines: the polysaccharide is chemically conjugated to a carrier protein. The polysaccharide-specific B cell binds the conjugate via its BCR, internalises and processes the carrier protein, and presents carrier peptide via MHC class II to a carrier-peptide-specific T cell (interactions: CD40-CD40L, CD80/86-CD28, TCR-MHC). This T cell help allows the polysaccharide-specific B cell to become a plasma cell (producing IgG1 and IgG3) or a memory B cell. Result: strong IgG response with immune memory.
  • Compared with polysaccharide vaccines, conjugate vaccines are immunogenic in children under 2 years, generate a T cell response, produce immune memory, show a booster effect, give long-term protection, reduce carriage, and produce herd immunity — polysaccharide vaccines do none of these (both give a B cell response).
  • Boosting: antibody levels decline after vaccination; memory B and T cells persist, but the recall response may be too slow for some infections (~2-5 days to respond); booster vaccination raises antibody levels back above the protective threshold.

Vaccination against specific pathogens

  • Neisseria meningitidis: serogroups A, B, C, Y, W-135. Capsular polysaccharide vaccine covers A, C, Y, W-135. Conjugate polysaccharide vaccine covers A, C, Y, W-135 (MenACWY) or C alone (MenC), conjugated to diphtheria toxoid (Menactra) or tetanus toxoid (Nimenrix, MenQuadfi, NeisVac-C). No conjugate vaccine exists for serogroup B because its capsular polysaccharide cross-reacts with self antigens and is poorly immunogenic; instead Bexsero (MenB) uses 3 recombinant proteins plus outer membrane vesicles containing PorA protein (and others). NZ schedule: MenB for all infants (catch-up to 13-59 months); MenB and MenACWY for 13-25 year-olds in communal living (e.g. boarding school hostels), people with risk factors (e.g. complement deficiencies, asplenia), the immunosuppressed, and close contacts of meningococcal cases or people with prior meningococcal disease.
  • Streptococcus pneumoniae: the capsular polysaccharide vaccine covers 23 serotypes but gives short-lived antibodies, efficacy <60%, no response in children under 2 years, and poor responses in other at-risk groups (elderly, chronic disease, immunosuppressed, post-splenectomy). Protein conjugate vaccines cover 7 to 13 common serotypes, give a strong response in children under 2 years, are very effective at preventing invasive disease (~97% against vaccine serotypes), and reduce carriage of vaccine strains, producing herd immunity. NZ conjugate vaccine history: PCV7 (2008-2011), PCV10 (2011-2014), PCV13 (2014-2017), PCV10 reintroduced (2017-2022), PCV13 reintroduced (December 2022). Invasive pneumococcal disease rates fell across age groups over this period, but as PCV7-serotype disease declined, disease from non-vaccine serotypes increased (serotype replacement).
  • Haemophilus influenzae type b (Hib): the capsule is essential for virulence, and anti-capsular antibodies are required for protection. The conjugate vaccine is highly effective at preventing invasive disease in infants and children, and also prevents nasopharyngeal colonisation, producing herd immunity. US data: Hib disease incidence in children under 5 rose from ~19 to a peak of ~24 per 100,000 around 1984-85, then fell after the polysaccharide vaccine (~1985, licensed ≥18 months), conjugate vaccine (~1988, ≥18 months), and infant conjugate vaccine (~1990, ≥2 months), dropping sharply after 1990 to near 0 by the mid-1990s and remaining near 0 through 2012.

Self-test

  1. Describe the two routes by which S. pneumoniae progresses from nasopharyngeal colonisation to meningitis.
  2. What proportion of individuals carry S. pneumoniae, N. meningitidis, and H. influenzae type b in the nasopharynx, and under what circumstance does colonisation typically lead to invasive disease?
  3. Describe the steps by which antigen from colonising bacteria leads to secretory IgA production at the nasopharyngeal mucosa.
  4. List the innate and adaptive humoral molecules discussed, and state what they both feed into.
  5. Describe the steps of the lectin pathway of complement activation, from recognition to formation of the C3 convertase.
  6. Describe the steps of the classical pathway of complement activation, including the three things C1q can bind.
  7. Describe the steps of the alternative pathway of complement activation, including the roles of factor B, factor D, factor P and factor H.
  8. What clinical association is seen with factor P deficiency, and why?
  9. What do all three complement pathways converge on, and what are its two cleavage products?
  10. Describe how a C5 convertase is formed in the classical/lectin pathway versus the alternative pathway, and what it does.
  11. Describe the steps of membrane attack complex assembly and explain how it kills the pathogen.
  12. Distinguish the roles of C3a/C5a from the role of C3b in the complement system.
  13. Describe the sequence of leukocyte adhesion and migration from blood into infected tissue, naming the molecules involved at each step.
  14. Explain how bacterial capsules evade complement- and antibody-mediated opsonisation, and how anti-capsular antibody overcomes this.
  15. Distinguish the role of the spleen from the role of the liver in clearing bacteria from the blood, and state the clinical consequence of splenectomy.
  16. Describe the sequence of events that produces meningeal inflammation once bacteria reach the CSF, from PAMP recognition to neutrophil recruitment.
  17. Distinguish the B cell and T cell response to a polysaccharide vaccine from the response to a conjugate vaccine, and explain why only the conjugate vaccine produces immune memory.
  18. Why are polysaccharide vaccines poorly effective in children under 2 years, and how do conjugate vaccines overcome this?
  19. Describe the vaccines available against Neisseria meningitidis, and explain why serogroup B requires a different vaccine approach from the other serogroups.
  20. Describe how introducing conjugate pneumococcal vaccines (PCV) changed the epidemiology of invasive pneumococcal disease in NZ, including the phenomenon of serotype replacement.
  21. A patient who had a splenectomy after trauma presents years later with fulminant sepsis. Using what you know about the spleen, complement and capsules, explain why this patient is at particular risk from encapsulated bacteria, and which meningitis vaccines would be most relevant to check they had received.

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