Implications/Analysis of Family History

An inquiry into Mary’s family history revealed that a distant male cousin and an aunt had both died of meningitis at an early age (<2 years). An inherited disorder is suspected when genetically linked individuals present with the same type of clinical history. Autosomal recessive defects are suspected when both males and females are affected.

Implications/Analysis of Clinical History

Both innate and adaptive immunity play a role in the elimination of bacterial pathogens, with phagocytes, complement, and B cells being the key players. Because there is no indication of prior bacterial infections, it is unlikely that there is a defect in phagocyte function or in B cells, particularly when one considers Mary’s age. That is, the protection conferred by the mother’s antibodies in utero ceases around 6 months of age. Furthermore, the only cell abnormality was an increase—not decrease—in neutrophils.

Implications/Analysis of Laboratory Investigation

The white blood cell count and differential indicated an increase in the number of circulating neutrophils, which is consistent with a bacterial infection (see Case 6). Results of the CT scan and lumbar puncture, combined with the PCR, indicated that Mary has neisserial meningitis. PCR is now used instead of culture in major laboratories because it is more accurate, even if the patient has already been taking antibiotics. Considering the family history and the severity of this infection, an investigation into possible autosomal recessive disorders was pursued.

Additional Laboratory Tests

Deficiencies in the complement terminal pathway proteins that compose the membrane attack complex (C5 to C9) or deficiencies in the components of the alternative pathway (e.g., Factor B and properdin) present most commonly as infections with Neisseria meningitidis. Therefore, laboratory investigation should now focus on analysis of the complement pathway (Fig. 11-1).

FIGURE 11-1 Overview of complement activation. Defects in the early components of the classical pathway are associated with autoimmune complex diseases, whereas defects in the terminal pathway components present as recurrent neisserial (bacterial) infections. Defects in C3 result in more infections than other defects because they affect both the alternative and the classical pathway.

(From Kumar V, Cotran R, Robbins S: Robbins Basic Pathology, 7th ed. Philadelphia, Saunders, 2002; Modified from Abbas A, Lichtman A, Pober J: Cellular and Molecular Immunology, 3rd ed. Philadelphia, Saunders, 1995.)

Rather than testing for individual complement components, an overall assessment of the alternative, classical, and terminal pathways is achieved by measuring the ability of the patient’s serum (complement) to lyse sheep red blood cells using the CH50 and AH50 tests. A CH50 test is defined as the amount of the patient’s serum that will lyse 50% of sheep red blood cells coated with antibody. The AH50 is similar to the CH50; however, the sheep red blood cells are not coated with antibody. In effect, the CH50 measures classical pathway and terminal components whereas the AH50 measures the alternative pathway and terminal components.

If the CH50 is normal, but the AH50 is abnormal, the defect lies in the alternative pathway components. In contrast, if both the CH50 and AH50 are abnormal, it is likely that there is a deficiency in one of the terminal pathway components. In Mary’s case, both the CH50 and AH50 were abnormal, indicating a defect in one of the terminal pathway components. Nephelometry can be used to identify the particular component that is deficient. However, in the absence of gene therapy, which may be a possibility in the future, information regarding the particular terminal pathway component would not alter the treatment and so is not usually performed.

Activation

The initiating stimulus for activation of the alternative pathway is the deposition of spontaneously generated C3b fragments onto a microbial cell surface. In contrast, the initiating stimulus for activation of the classical pathway of complement is the binding of the complement protein C1 to immune complexes in which either IgM or IgG is bound to antigen. Although both the alternative and classical pathways generate distinct enzymatic complexes, termed C3 and C5 convertases, that hydrolyze the complement components C3 and C5, respectively, the proteolytic products of these convertases are independent of the particular pathway that is activated.

Many cells have receptors for the proteolytically derived complement fragments and this dictates which cells respond to complement activation. Osmotic lysis of cells or microbes, however, requires that the components of the terminal pathway insert into the target cell membrane forming a protein complex referred to as the membrane attack complex (MAC).