There are 6 serotypes of Neisseria meningitidis- A, B, C, X, Y and W-135, based on the capsular polysaccharide that imparts the organism its main defense against the host immune system- resistance against phagocytosis.
W-135 and X serogroups are more common in Africa. Group C accounted for 40% of meningitis cases in children in the UK pre-1999, when the conjugate vaccine against this organism was introduced. More about the vaccine in a moment.
The organism is one of the few that is vulnerable to direct lytic attack by the complement membrane attack system, comprising factors Vb-IX. The antibodies that set off the classical pathway for complement activation are unusual in this case, in that they are not produced by B cells that have been primed by helper T cells. Rather, the B-cells are involved through a thymus independent process and are capable of directly responding to the invading meningococci without help from the T cells. Thus, menigococcal antigens are an example of thymus-independent or TI antigens.
There are 2 types of TI antigens- TI-1 and TI-2. A prototype of TI-1 antigens are the lipopolysaccharides released from gram negative organisms, which are capable of activating both mature and immature B cells. In high doses, TI-1 antigens can activate all B cells, irrespective of their antigen specificity. They are thus called B cell mitogens. This represents an useful line of defense for the body against these usually virulent organisms before T-cell mediated adaptive immunity has had time to kick in.
The capsular polysaccharide present in N.menigitidis is an example of TI-2 antigen. Such antigens typically have repetitive epitopes and inactivate immature B cells. They can however activate mature B cells by cross linking the B cell receptors through their repetitive epitopes, but if the cross linking is extensive, even mature B cells can become anergic, as happens with very high levels of antigen.
It is thought that children under the age of two years have mainly immature B cells, which would explain why they have a poor response to vaccines containing the meningococcal polysaccharide. Thus, young children do not have the capacity to respond to TI-2 antigens, unlike adults. Unfortunately, they are also the most vulnerable to this potentially deadly infection.
The problem was solved through a stroke of brilliance by observing that by conjugating TI-2 antigens to an immunogenic protein such as tetanus toxoid, you could convert TI antigens into thymus dependent (TD) antigens. Such "conjugate" antigens are dealt with by T cells, which recognise the peptide fragments presented on MHC Class II molecules by B cells, and stimulate the B cells to produce antibodies against the peptide-polysaccharide complex. Such a strategy works in children.
The United Kingdom was the first country to introduce the conjugate Meningococcus C vaccine (Men C) in November 1999. Within a few years, the proportion of the C serogroup contributing to childhood meningeal infections fell from 40% to 10%. Other countries adopted the vaccine throughout Europe with gratifying results.
Unfortunately, no such vaccine is available against Meningococcus B, which now accounts for 80% of childhood meningitis in the UK. The biggest roadblock is the fact that the polysaccharide antigen in this serogroup resembles an antigen present in neurons in the human brain, thus raising the possibility that a vaccine might cause the body to produce autoantibodies against the brain. Various strategies are being explored to overcome this diificulty.
Conjugate vaccines have also been successfully used against another erstwhile common cause of childhood meningitis- Haemophilus influenzae, group B.
Curiously, the B-cells that are most active against TI-2 antigens are not your usual B-cells. They are two evolutionally primitive cells of B cell lineage called B-1 cells (so called because they were discovered ahead of the much more common "conventional" B cells or B-2 cells) and marginal zone B cells, so named because of their location in the spleen on the periphery of T cell areas. As stated before, these B cells do not depend on the helper T cells for activation, unlike conventional B cells. It is thought however, that they do receive co-stimulatory signals from dendritic cells in the form of BAFF (B-cell activating factor- also called BLyS or B-cell stimulator), which acts on a B cell receptor called TACI. Defects in the latter can lead to a condition called Common Variable Immunodeficiency, which has been discussed elsewhere on this blog.
The importance of TI-2 response is illustrated by sufferers of another X-linked condition called Wiskott Aldrich syndrome, who are incapable or mounting a response to TI-2 antigens, and are thus susceptible to infections by bacteria with polysaccharide capsules such as Meningococcus, Pneumococcus and H.influenzae.
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