Complement deficiency states and meningococcal disease

I m m u n o l R e s 1 9 9 3 ; 1 2 : 2 9 5 - 3 1 1

Julio Figueroa John Andreoni Peter Densen

Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa, USA

Complement Deficiency States and Meningococcal Disease

e ~ 1 7 6 1 7 6 1 7 6 1 7 4

Key Words Complement deficiency Neisserial infections Antibody response Host defense

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Abstract Analysis of complement deficiency states has supported the role of complement in host defense and elucidated diseases associated with defective complement function. Although neisserial infection plays a prominent role in these deficiency states, examination of individuals with late complement component deficiency (LCCD) reveals a particular propensity for recurrent meningococcal disease and provides important clues to the role of complement in neisserial infections. In response to meningococcal disease, LCCD individuals produce significantly greater amounts of antilipooligosaccharide (LOS) antibody which can kill group B meningococcus in a complement- sufficient in vitro system. Further studies of antibody cross- reactivity to other meningococci has led to a clearer understanding of its epitopic specificity. Nevertheless, epidemiolog- ic evidence is consistent with the relative absence of protective immunity in LCCD persons following an episode of infection and supported by quantitation of antibody to capsular polysaccharide. However, compared to anti-LOS antibodies, anti- capsular antibodies can offer immune protection to LCCD individuals via complement-dependent opsonophagocytosis - the only form of complement-mediated killing available to these persons. Thus vaccination of LCCD persons with capsular antigens is considered an important means of protecting these high-risk individuals against meningococcal disease.

Peter Densen, MD �9 1993 Department of Internal Medicine S. Ka~er AG, Basel University of Iowa 0257-277X/93/ 200 Hawkins Drive 0123-029552,75/0 Iowa City, IA 52242-1009 (USA)

Introduction

Functional activity assigned to the complement system was first described near the turn of the century [ 1 ]. The primary focus at that time was on its bactericidal and hemolytic actions. With the isolation of the complement proteins, investigators demonstrated the presence of two activation pathways, which generate a number ofeffector mechanisms in addition to the assembly of the membrane attack complex that mediates bactericidal activity. During the second half of this century, investigators explore the role of the cascade in chemotaxis, immune complex clearance, opsonophagocytosis and host tissue injury. The recent characterization of complement-regula- tory proteins has provided an understanding of host protection against the indiscriminate effects of complement activation. At present, the complement system consists of 19 plasma and at least 9 membrane proteins.

Whereas antibody-antigen interactions initiate the complement cascade through the classical pathway, the alternative pathway has no such requirement. Both pathways lead to the cleavage of the third component (C3). C3 plays a pivotal functional role through formation of the alternative pathway C3 convertase (C3bBb), microbial opsonization (C3b and iC3b) and participation in the generation of the terminal pathway (C3b). Cleavage of the fifth component (C5) by its convertase gener- ates two fragments: C5a, which acts as a chemotactic factor and serves as a mediator of inflammation, and C5b. The latter fragment functions as the anchor for the sequential addition of the terminal components (C6-C9) to complete the membrane attack complex. Insertion of this complex leads to altered cellular metabolism and cell death.

Detailed studies of individuals with complement deficiency states have supported the importance of this system to the normal host

and have elucidated diseases associated with a deficiency in complement function [2-4]. Clinically, these patients exhibit both autoimmune disease (especially systemic lupus erythematosus) and increased susceptibility to systemic infections caused by encapsulated organisms (most commonly Neisseria spe- cies). These natural experiments have en- hanced our understanding of the pathogenesis of autoimmune disease, tissue injury and host defense against microbes. This review will focus primarily on those deficiencies of plasma complement proteins which have been associated with an increased risk of infection.

Because complement deficiencies are uncommon, much of the information about them has been derived through careful analysis of accumulated case reports. This ap- proach introduces numerous opportunities for bias. For example, the ethnic background of the study population is a major determi- nant of both the prevalence of complement deficiency states as well as their associated diseases. Specifically, C2 deficiency occurs predominantly in Caucasian populations; in the US its estimated frequency is 0.01%, whereas it has not been reported in the Japa- nese population [3, 5]. In contrast, C9 deficiency is uncommon in Caucasian populations but occurs in 0.045-0.104% of normal Japanese blood donors [3, 6]. Similarly, the yearly incidence ofmeningococcal disease differs among various ethnic populations [3] (fig. 1).

Analysis is also complicated by ascertainment bias. Traditionally, investigators have associated classical component deficiencies with rheumatologic conditions. For example, a survey of 545 patients with rheumatologic disorders found one person (0.2%) with homozygous C2 deficiency and 19 individuals with definite, probable or possible heterozygous C2 deficiency [1 i]. In contrast, only 6 possible heterozygous C2 individuals were

296 Figueroa/Andreoni/Densen Complement Deficiency States and Meningococcal Disease

Fig. 1. Relationship between the prevalence of complement deficiency and the incidence of meningococcal disease. The data were obtained from the literature or by per- sonal communication as described [3] and modified by recent reports from the Faroe Islands [7, 8], Nor- way [9] and Moscow [10].

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Iowa �9 ~ M o s c o w

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6 Incidence, cases/lO population

identified among 509 individuals without rheumatologic disorders. This report prompted other studies confirming this association and leading to the notion that rheumatologic disorders, particularly systemic lupus erythematosus, were the major clinical manifestation of these deficiencies. In contrast, a recent prospective study of 675 individuals with invasive infections caused by encapsulated organisms identified two unrelated C2- deficient individuals, i.e. a frequency of 0.3 % [ 12]. Thus, the frequency of C2 deficiency in patients with these selected infections is similar to that in patients with selected rheumatologic disorders (0.3 vs. 0.2%) demonstrating that individuals with classical component deficiencies appear to have an increased but similar risk for both rheumatologic and infectious diseases. These findings underscore the potential bias inherent in disease-based population studies.

Clinical Features of Complement Deficiency States

Although the study of these patients can introduce bias associated with a retrospective literature review, such an analysis can provide important clues to the contribution of individual complement components to overall complement functions and host defense as well as to the pathogenesis of neisserial infections. Excluding C1 inhibitor deficiencies, these reviews provide support for the occurrence of four major clinical patterns: classical pathway deficiencies (C1, C4, C2), C3 deficiency (C3, factors H and I), alternative pathway deficiencies (properdin, factor D) and late complement component deficiencies (LCCD; C5-C9; table 1). These groups differ in their functional defects as well as in their spectrum and prevalence of associated diseases. To date, individuals have been de-

297

Table 1. Clinical patterns of disease in complement deficiency states

Clinical CP AP C3 LCCD variable (C1, C4, C2) (P, D) (C3, H, I) (C5-C8, C9)

Functional defect $ C' act. $ C' act. $ IC metab. ($ CTX) $IC metab. $ ops. phag. $ SBA $ imm. resp. $ imm. resp.

$ PMN $ CTX $ SBA

12 26 0 29 66 5 79 5 18 57 78 64 l 2 14 2 17

S. pneumoniae 5L meningitidis N. meningitidis ~ meningitidis N. meningitidis S. pneumoniae H. influenzae H. influenzae

Healthy, % CVD, % Systemic infection, % Median age at first infection, years Organisms 2

Infected patients with infection due to these organisms, % 40

Recurrent infection with same organism, % 6.3

91 54 99

3.5 56 50 t

CP = Classical pathway; AP =altemative pathway; IC metab. = immune complex metabolism; C'act. = complement activation; imm. resp. = immune response; ops. phag. = opsonophagocytosis; CTX = chemotaxis; SBA = serum bactericidal activity; CVD = collagen vascular disease; PMN = polymorphonuclear neutrophils. Adapted from Figueroa and Densen [3]. l Percentage differs for C9-deficient individuals, see table 2. 2 Listed in order of decreasing frequency.

scribed with a complete deficiency of each plasma complement component except factor B [3].

Classical Pathway Component Deficiencies Activation of the classical pathway pro-

motes opsonophagocytic killing, serum bactericidal activity and removal of immune com- plexes. As discussed above, the frequency of homozygous C2 deficiency in patients with rheumatologic disease is about 0.2% or 20- fold more common than that in the general US population [11 ]. These individuals most frequently exhibit a syndrome consistent with systemic lupus erythematosus. Although ho-

mozygous C1 and C4 deficiencies are quite rare, reported individuals with these deficiencies also suffer principally from rheumatologic diseases [2, 3]. A review of all reported persons with classical component deficiency reveals that about 66 % have manifestations of a collagen vascular disease (table 1).

These individuals also exhibit increased susceptibility to infection. Recurrent sinopulmonary infections and meningitis caused by encapsulated organisms, especially Strepto- coccus pneumoniae, Neisseria meningitidis and Haemophilus influenzae, predominate. In individuals with invasive infections caused by these encapsulated organisms in Iowa, the reported frequency of C2 deficiency is 0.3%,


reflecting a 30-fold increase in prevalence compared with the general population [12]. The median age of first infection is 2 years. Overall, 19% of individuals with classical component deficiencies have experienced at least one documented infection with encapsulated organisms (table 1); 4% of individuals have had both connective tissue disease and infection with encapsulated organisms [2, 3]. Since most reported patients come from sur- veys of rheumatologic disease, these frequen- cies of infection are subject to ascertainment bias and probably represent an underestimate of the true frequency of infection in this population. The disease spectrum and onset are reminiscent of those seen in immunoglobulin- deficient individuals. Indeed, several investigators have noted impaired antibody responses in guinea pigs and some humans with these deficiencies [13-15]. Thus, the clinical similarity to syndromes of defective humoral immunity may reflect the in vivo importance of the experimental phenomenon.

C3/Factor H and I Deficiencies As the focal point in the complement sys-

tem, C3 participates in numerous effector mechanisms responsible for inflammation and host defense. Consequently it is not sur- prising that C3 deficiency leads to multiple. severe derangements including immune complex disease, impaired immune responses, impaired chemotaxis, reduced opsonophagocytosis and abnormal serum bactericidal activity. As with classical component deficiencies, these individuals are at increased risk for rheumatologic disease, 79% demonstrating a lupus-like syndrome or systemic vasculitis (table 1) [2, 3]. These individuals have a striking disposition to severe and recurrent infections caused primarily by encapsulated organisms, which first manifests itself at an early age. Of the 19 patients reported with this deficiency, 15 have had at least one episode of bacterial

infection - particularly sinopulmonary infection, bacteremia or meningitis [2, 3].

As with classical component deficiencies, the clinical similarity to immunoglobulin deficiencies is striking. In experimental models C3 has been shown to modulate the humoral immune response. Specifically, C3-deficient animals have low antibody responses to primary immunization with bacteriophage q0X 174 (a T-cell-dependent antigen) as well as to T-independent antigens [13-16]. More- over, C3 participates in the cellular response to microbes. C3 fragments promote opsonophagocytosis of organisms and trigger micro- bicidal mechanisms in inflammatory cells [ 17]. Overall, individuals lacking this critical component have multiple defects which are reflected in the spectrum and severity of the associated diseases.

Factors H and I are primarily responsible for the downregulation of the fluid phase, alternative pathway C3 convertase. In the absence of either of these proteins the sponta- neous formation of the C3 convertase goes unchecked, leading to C3 consumption and depletion. Six of the 13 persons with factor H deficiency demonstrated evidence of glomer- ulonephritis; 2 had disease compatible with systemic lupus erythematosus [2, 3]. In factor I deficiency, the association with rheumatologic disease is less strong; 2 of 14 reported patients had associated arthritis or vasculitis [2, 3]. Although C3 consumption predisposes to immune complex syndromes, the small amount of residual C3 in the serum of persons lacking these factors seems to lessen their risk of these disorders. These individuals demon- strate the same propensity for and spectrum of infections seen in primary C3 deficiency [2, 3]. Eight of 13 individuals with factor H and 12 of 14 persons with factor I deficiency have experienced infection caused mostly by encapsulated organisms. Recurrent infection is also common.

299

Alternative Pathway Deficiencies Through a noncovalent association, pro-

perdin stabilizes the alternative pathway C3 convertase by a factor of 5-10 [ 18-2 I]. Al- though this effect is relatively modest in vitro, individuals with properdin deficiency exhibit a marked propensity for infections with encapsulated organisms, especially N. meningitidis. Of the 70 patients described in the literature with probable or confirmed properdin deficiency, 50-60% experienced at least one episode of meningococcal disease (table 1) [2, 3]. Compared with the frequency of meningococcal disease in the general US population, this represents a 7,000-fold increase in the risk of infection. In contrast to classical component deficiencies, patients with properdin deficiency have a later onset of infection and exhibit few recurrences (table 1). The low rate of recurrence probably reflects the high mortality associated with this infection in this deficiency as well as the development of specific antibodies which activate the classical pathway and help prevent subsequent infection. This observation supports the importance of acquired immunity to Neisseria in conjunction with the complement system for protection in the normal host.

Patients with properdin deficiency do not appear to have the same propensity for rheumatologic diseases as do individuals with either classical component or C3 deficiency states. Of the 70 persons reported, 4 individuals from the same family had discoid lupus, and 1 was found to have progressive systemic sclerosis [3]. This difference emphasizes the importance of the classical pathway in immune complex clearance.

Factor D cleaves factor B to generate the alternative pathway C3 convertase, C3bBb. The 3 patients reported with this deficiency experienced infections caused by Neisseria as well as other pathogens. In contrast to properdin deficiency, these individuals experienced

recurrent disease [3]. No data are available about the immune response of these patients, and the basis for this difference is not under- stood. However, this observation suggests that the alternative pathway convertase may be particularly important in preventing infection. In theory, individuals with properdin deficiency can generate a functionally active but less stable C3 convertase able to assist the classical pathway by amplifying C3 cleavage. In contrast, in factor D deficiency the alternative C3 convertase cannot be generated at all.

Late Complement Component Deficiency As a major effector mechanism of the com-

plement cascade, the membrane attack complex is responsible for direct complement- dependent serum bactericidal activity. Re- cent evidence suggests that it may also partici- pate in tissue injury in a wide range of diseases [22-26]. Perhaps for this reason, a small percentage (--5%) of reported individuals with LCCD have evidence of immune complex or rheumatologic disease (table I) [2, 3].

There is a marked association between LCCD and neisserial infections. This association is strongest among individuals with a deficiency of C5, C6, C7 or C8, 58% of whom have had at least one episode of neisserial infection (table 1) [2, 3]. Compared with the frequency in the general US population, LCCD increases the risk of meningococcal disease 8,000-fold. As with properdin deficiency, the median age at the first neisserial infection is in the second decade of life - a significant departure from that in the general population and in persons with classical component deficiencies.

Although cleavage of C5 leads to the generation of potent chemotactic activity, as well as the formation of the membrane attack complex, the clinical features of C5 deficiency do not differ markedly from those of other terminal component deficiencies, suggesting that


Table 2. Comparison of meningococcal disease in LCCD states

Deficiency

C5 C6 C7 C8 C9

Number of individuals 27 77 73 73 165 With meningococcal disease 19 (70) 42 (54) 45 (62) 40 (55) 15 (9.1) Recurrent disease 8 (42) 23 (55) 14 (31) 20 (50) 0 Episodes of meningococcal disease 30 75 71 69 15

CSF + blood 23 (77) 69 (92) 56 (79) 55 (80) 15 (100) Blood 1 (3.3) 5 (6.6) 5 (7.0) 3 (4.4) 0 Unspecified 6 (20) 1 (1.3) I0 (14) 11 (16) 0

Ratio of CSF:blood 23:1 14:1 11:1 18:1 15:0

Figures in parentheses indicate percentages.

the absence of C5a does not contribute significantly to the clinical picture in these individuals (table 2).

The association between C9 deficiency and neisserial infection is not as strong as in C5- C8 deficiency. Individuals with total C9 deficiency exhibit delayed but present serum bactericidal and hemolytic activities in vitro [27]. Initially, the few reported persons with this deficiency did not seem to have an increased risk of infection. However, Nagata et al. [6] demonstrated a 1,400-fold increased risk of meningococcal disease in C9-deficient patients and confirmed a 10,000-fold increased risk of this disease in C7-deficient patients (compared with complement-sufficient con- trols). These data reinforce the association between LCCD and neisserial disease and suggest that the risk of infection in C9 deficiency is 5- to 10-fold less than that seen in other terminal component deficiencies (table 2). Additionally, these observations support the utility of the in vitro bactericidal assay in understanding the in vivo risk of infection.

Meningococcal Disease in Complement Deficiency

Meningococcal disease is a prominent manifestation in a significant fraction of reported cases in all four clinical patterns of complement deficiency. In early component deficiencies, the meningococcal shares this role with the pneumococcus and H. influenzae. In contrast, it is virtually the sole clinical manifestation in properdin deficiency and LCCD. Given this singular predisposition, studies of these deficiencies provide important clues to the role of complement in the pathogenesis of meningococcal disease.

Meningococcal disease in individuals with LCCD demonstrates several important differences from that in the general population (table 3) [3]. First, the frequency of meningococcal disease in the US population is 0.0072%, whereas it is 9-58% in C9- and C5- to C8- deficient individuals, respectively, 1,000- to 10,000-fold increased risk of infection. After stratification for serogroup, meningococci isolated from LCCD individuals do not differ in their sensitivity to complement-mediated killing from those isolated from complement-suf-

301

Table 3. Comparison of meningococcal disease in normal, LCCD and properdin-deficient individuals

Parameter Normal C5-C8 C9 Properdin- deficient

Homozygotes - 250 165 54-70 With meningococcal disease - 146 15 25-37 Frequencyofinfection,% 0.0072 58 9.1 46-53 Median age at first episode, years 3 17 16 1 4-11.5 Recurrence rate, % 0.34 44 0 2-1.4 Relapse rate, % 0.6 7.9 0 0 Mortality/100 episodes, % 19 1.5 0 12-51.4 Infecting serogroup

Isolates 3,184 67 2 16 B, % 50 19.4 50 18.7 Y, % 4.4 32.8 0 37.5

Adapted from Figueroa and Densen [3]. Where a range is given, the first figure refers to documented cases, and the second figure refers to documented plus probable and possible cases.

ficient persons [28]. Therefore, the increased frequency of infection in LCCD is not due to an increase in infection caused by less pathogenic strains. Together, these data emphasize the importance of the membrane attack complex in the prevention of meningococcal disease.

Second, individuals with LCCD are infected with uncommon meningococcal serogroups more often than normal persons [2, 3]. In their review of meningococcal infections, Fijen et al. [29] confirmed the greater frequency of complement deficiency among individuals with disease caused by serogroups Y, W135 and probably X. This finding may be due in part to the propensity of these serogroups to cause disease in older individuals [30]. Moreover, although group Y organisms are more susceptible to serum bactericidal action, they exhibit greater requirements for effective opsonophagocytic killing than do group B isolates [31]. In conjunction with the bactericidal defect, these findings translate into an additional degree of difficulty for the LCCD person in the elimination of these

strains compared with those that typically cause disease in the general population.

Third, individuals with LCCD deficiency experience their initial meningococcal infection at an older median age than do normal persons (17 vs. 3 years) [2, 3]. Thus, the majority of deficient persons pass through the period of highest risk of infection for normal individuals only to develop infection in the second decade (fig. 2). This paradox is only partially explained by the fact that deficient individuals are susceptible for life while normal individuals are generally at risk only early in life. Ascertainment bias is unlikely to explain this finding because this relationship is also apparent in families where ascertainment is complete. In addition, in a prospective study of the frequency of these disorders in patients with meningococcal disease, no complement-deficient individuals identified were younger than 15 years of age [12]. These observations suggest that unidentified factors contribute to the susceptibility of deficient individuals later in life.


120

100

80

E 6O

o_ 40 Fig. 2. The age o f f irst meningo-

coccal infection in normal and 20 complement-deficient individuals. 0 Data for normal individuals ( e )

120 were provided by Dr. J. Wenger from the Centers for Disease Con- ~, 100 o~

trol, Atlanta, Ga., USA, as pub- 80 lished [32]. Data for LCCD indi- ~.

60 viduals (11) and properdin-defi- .~ cient patients (A) are from the lit- -~ 40 erature [2, 3]. Results are expressed ~ 20 as the number of infected patients o (a) or as the cumulative percentage 0 of infections (b) by age of infection. Hatches in the horizontal axis indicate discontinuity in the age scale.

_ ~ ~ . . T - : " - f - ; " , ~ . : - T T

b

0 1 2 3-4 5-9 10-19 20-29 30-59 >60 Age, years

Fourth, mortality associated with meningococcal disease (both meningitis and menin- gococcemia) ranges between 10 and 19% in the general US population but is only 1.5- 2.4% in LCCD persons (table 3) [3]. Meningo- coccal disease is a paradigm for gram-negative sepsis. Initially, meningococcal endotoxin (li- pooligosaccharide or LOS) stimulates numerous host responses including complement activation, cytokine release and infiltration of inflammatory cells [33-38]. As the disease progresses, the prominent features become those of endothelial damage and consumptive coagulopathy. Several, as yet unsubstantiated, factors may contribute to the lower mortality in deficient patients: (I) lower organism inoculum required to cause disease; (2) lower plasma endotoxin concentrations; (3) milder disease, and (4) less tissue injury.

Although quantitative data are lacking, the notion that defective bactericidal activity in

LCCD might lower the infectious dose neces- sary to initiate systemic disease provides an attractive explanation for both the increased frequency of infection and improved clinical outcome. Lower infectious inocula probably correspond to lower plasma concentrations of LOS and thus less morbidity and mortality. However, because of the bactericidal defect, an initially small inoculum could proliferate unchecked, ultimately resulting in a greater overall organism burden. In this case defective bacteriolysis consequent to the LCCD might result in less LOS release from the organism and milder disease. Unfortunately no data exist to compare the serum LOS concentration in complement-deficient and -sufficient individuals.

Due to the highly variable nature of the reported clinical information, the issue of milder disease in LCCD persons is difficult to assess from a review of reported cases. Evi-

303

dence for this hypothesis comes from the studies of Platonov and Beloborodov [39; unpubl. data], who utilized a clinical grading system to assess the severity of meningococcal disease in 30 LCCD and 100 age-matched complement-sufficient patients. Compared with normal persons, LCCD patients experienced significantly fewer cases of severe or lethal disease (70 vs. 39~ of shock (14 vs. 3%) and of brain edema (25 vs. 9%). This study also confirmed the finding of Brandt- zaeg et al. [34] that the extent of complement consumption correlated with a fatal outcome in normal patients. In contrast, LCCD individuals showed no differences in C 1, C4 and C2 activity during active meningococcal disease compared with healthy normal or LCCD individuals.

These data support the notion that the lack of complement activation decreases tissue injury and mortality in deficient individuals. Brown and Lachmann [40] demonstrated that, compared with C6-sufficient rabbits, C6-deficient rabbits had improved survival after endotoxin challenge; this advantage correlated with the preservation of the platelet count and the lack of platelet activation and release of platelet-activating factor. A possible explanation for reduced platelet activation in LCCD comes from recent experimental work showing the importance of the membrane attack complex in activation of many host cells. Although not generally lethal, insertion of the membrane attack complex activates leuko- cytes to release potentially toxic mediators and promotes a procoagulant state in endothelial cells and platelets [41-44]. In vivo, exuberant complement activation may lead to the insertion of the membrane attack complex in bystander host cells which in turn become activated to produce toxic products and a procoagulant state, that is, the beginning of tissue injury and the hallmark of septic shock. Since LCCD individuals are unable to generate the

membrane attack complex, these pathologic processes would not occur, allowing the deficient person to better tolerate a given organism and endotoxin load during sepsis.

Fifth, recurrent meningococcal disease is rare in normal and properdin-deficient individuals (table 3) [2, 3]. This finding suggests that prior infection provides specific and cross-reactive antibody to Neisseria in these persons. These antibodies can activate the classical pathway to prevent recurrence through either C3b-directed opsonophagocytosis or serum bactericidal activity. In contrast, recurrent disease is common (44%) in persons with C5-C8 deficiency suggesting that immunity does not follow initial infection in these individuals despite intact C3b- mediated phagocytosis. Support for this sug- gestion comes from scrutiny of the number of episodes of recurrent meningococcal disease in LCCD individuals [3]. This analysis indi- cates that each episode of infection is an independent event; that is prior infection does not alter the risk of infection in these persons.

Although it may not prevent disease, acquired immunity might ameliorate the severity of subsequent infection. If so, this might help explain the reduced mortality in LCCD individuals. However, in their analysis of disease severity, Platonov and Beloborodov [39; unpubl, data] observed that prior infection had no effect on the severity of subsequent infections in LCCD individuals. Moreover, the few deaths that have occurred in LCCD individuals with meningococcal diseases have not been confined to the initial infection. Thus, the occurrence and severity of meningococcal disease in LCCD seem to be com- pletely independent of prior disease.


3/68 3/87 4/87 5/87 I / / I I I

Healthy Birth

Y meningitis Tetravalent After Dx C7 def. vacc ine vaccine

Capsular antibody,

I.tg/ml

10/87 3/89 10/4/89 10/18/89 11/89 12/89 / / I / / I / / I I I I

C bacteremia d/c Rx Tetravalent After meningitis vaccine vaccine

A 5.0 122 31 70 33 64 48 67

C 0.4 11 26 0.7 0.4 53 33 41

Subcapsular 4+ 4+ 4+ 4+ antibody

Fig. 3. Longitudinal history ef a LCCD patient (C7 deficiency). Arrows indicate the occurrence of each meningococcal episode. Capsular antibody concentrations to serogroup A and C were quantitated by standardized ELISA. Subcapsular antibody concentrations were estimated quantitatively (0-4 + scale) by the degree of IgG immunoreactivity with separated meningococcal outer membrane antigens on immunoblots. Dx = Diagnosis; d/c Rx = discontinued therapy.

I m m u n i t y t o IV. meningitidis

Immunity to N. meningitidis is dependent upon antibody and complement. Studies by Goldschneider et al. [45, 46] established that antibody to subcapsular antigens is bactericidal and important in the development of natural protective immunity against meningococcal disease in normal persons. This antibody, which is acquired by the majority of the population by early adulthood, is thought to be due to the development of antibody to cross-reactive antigens on nonpathogenic Neisseria. These subcapsular antigens include surface-exposed outer membrane proteins and LOS. Antibody to these antigens is pro- duced, to a greater degree, after an episode of meningococcal disease and confers protective

immunity in a normal host. Protective immunity also follows vaccination with meningococcal capsular polysaccharides. These antibodies are bactericidal [46] and promote opsonophagocytic killing of meningococci [47]. However, meningococcal infection seems to be a relatively poor inducer of capsular antibody, and thus protective immunity in normal persons seems to be due largely to antibody to subcapsular antigens.

The typical clinical course of LCCD persons is represented in chronological fashion in figure 3. This person was diagnosed as having C7 deficiency at the time of his initial presentation in March 1987 with group Y meningococcal meningitis. Following infection, his serum contained 5- to 10-fold more antibody to subcapsular meningococcal antigens, particu-

305

Silver kD stain

4 4 . 0 - ~

29.0- ~;"2~,

18.4 -

14.3- ~

6.2- ~

3.0- ~

Convalescent J

PHS Normal LCCD

. . . . ~

m h

r Fig. 4. lmmunoreactivity of sera with meningococ-

cal outer membrane antigens. Outer membranes were prepared from meningococcal serogroup B, separated by SDS-PAGE and electrotransferred to immobilon membranes for IgG-specific immunoblotting. The first lane is the silver stain of the separated outer membrane proteins (>6 kD) and LOS (_< 6 kD). The next three lanes reflect immunoreactivity with pooled human serum (PHS) from never infected adults, convalescent normal adult serum and LCCD serum, respectively.

lady LOS, than that in convalescent sera from complement-sufficient persons as assessed by Western blotting. The tetravalent meningococcal vaccine was administered in April 1987, and serum antibody to group C capsular polysaccharide rose from <1 ~tg/ml to

- 10 p.g/ml. Despite this response, he presented in October 1989 with recurrent meningococcal meningitis, this time caused by serogroup C. Retrospective determination of anti-

body concentrations to subcapsular and capsular meningococcal antigens revealed that the former had remained unchanged, whereas the concentration to the group C polysaccharide had fallen to < 1 ~tg/ml prior to recurrent disease.

Based on the above observations, the relatively poor induction of caspular antibody in response to meningococcal infection and the dependence of LCCD persons on complement-dependent opsonophagocytosis for meningococcal elimination, we postulated that antibody to subcapsular antigens is less protective for LCCD than for normal individuals and that antibody to meningococcal capsular polysaccharide is critical for protection of these complement-deficient persons. This hypothesis provides a possible explanation for the paradox presented by the clinical case, that is why a significant amount of subcapsular antibody is not protective for LCCD persons.

To test this hypothesis we compared the bactericidal and opsonic function of antibody to capsular and subcapsular antigens. These experiments utilized LCCD sera containing only capsular, subcapsular or neither antibodies [48]. Overall, the results were consistent with this hypothesis, as subcapsular antibody promoted complement-dependent bactericidal but not opsonophagocytic activity. In contrast, capsular antibody promoted both serum bactericidal and opsonic activity. This difference in the functional effectiveness of antibodies to subcapsular and capsular antigens to promote opsonophagocytic clearance of meningococci presumably relates to the ability of the latter, but not the former, to deposit C3 on the surface of the meningococcal capsule. In this location C3 and antibody may promote ingestion of the organism through interaction with specific receptors on the surface of phagocytic cells. A similar explanation has been offered to account for the


differential opsonophagocytic potential of antibodies to pneumococcal [49] and staphylo- coccal [50] cell wall and capsular polysaccharide. Meningococci differ from these gram- positive bacteria in that the former, but not the latter, are susceptible to complement-mediated bactericidal activity and therefore antibody to meningococcal subcapsular antigens may have a more clearly defined functional role in the complement-sufficient individual.

We have also been interested in why significantly more antibody to outer membrane meningococcal antigens is present in convalescent sera from LCCD than complement- sufficient persons. The reactivity of pooled nonimmune normal serum and convalescent serum from normal or LCCD persons with SDS-PAGE separated meningococcal outer membrane proteins (>6kD) and LOS (_< 6 kD) is shown in figure 4. Clearly, convalescent LCCD serum contains considerably more antibody against both outer membrane proteins and LOS, although the increase is most significant for the latter. Higher concentrations of antibodies to class I and serotype 2 outer membrane proteins in sera from C6- deficient persons experiencing meningococcal disease have been described [5 l, 52] but further studies of the immune responses to meningococci in LCCD individuals are lacking.

This antibody response to LOS is IgG, bactericidal for serogroup B meningococci in a complement-dependent bactericidal assay and cross-reactive to LOS of other meningococcal serogroups, gonococci and H. influenzae. Due to its potential importance in protection against group B meninogococcal disease, we have examined the epitopic specificity of this cross-reactive, bactericidal antibody. Ab- sorption of convalescent LCCD sera with the Salmonella Re595 mutant, the lipopolysac- charide of which contains only ketodeoxyoctonate linked to lipid A, depleted immunoreactivity with Re595 but not meningcoccal or

gonococcal LOS. ELISA assays utilizing lipid A and Salmonella Re LOS as antigens confirmed the presence of minimal antibody to lipid A in LCCD sera and that antibody to Salmonella Re LOS was similar in sera from never infected and infected LCCD or normal individuals. These data indicate that this antibody is not directed against ketodeoxyoctonate or lipid A, which are present in all LOS structures. In contrast, absorption with group B meningococci depleted all reactivity except that for the Sal- monella Re mutant. Recent experiments place the epitopic specificity of this antibody in the oligosaccharide chain of the LOS molecule.

The immunologic basis for the quantitative difference in the specific antibody response to meningococcal LOS of LCCD compared with normal individuals is unknown. Possible factors contributing to this response include a greater organism load, intracellular survival within phagocytic cells, the absence of meningococcal bacteriolysis in LCCD plasma and altered antigen presentation consequent to the maintenance of outer membrane integrity.

Vaccination

Our data strongly suggest that antibody to meningococcal capsular polysaccharide is critical for the protection of LCCD persons from meningococcal disease. Consequently we assessed the LCCD individuals' response to the tetravalent meningococcal polysaccharide vaccine to determine if vaccination is effective in conferring immunity. The total antibody response to meningococcal serogroup A and C capsular polysaccharides was compared among individuals with LCCD, their family members and unrelated complement-sufficient persons 3-4 weeks following vaccination. The median age in all three groups was similar, and there were no individ-

307

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100

of CO {3_

lo

o

o

- - - - g

Group A Group C

o

o

8 0 o

I ~ ' - ._e_ o

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o

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-8- o o

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LCCD CS LCCD CS

Fig.& Maintenance of antibody response to the meningococcal capsular polysaccharide vaccine in LCCD and complement-sufficient (CS) individuals. Antibody concentrations to mcningococcal polysaccharide (PSS) were determined 2-2.5 years following initial vaccination and expressed as a percentage of the concentration of these antibodies in individual sera obtained 3-4 weeks following vaccination. The horizontal bar represents the mean percent change in antibody concentration. The difference between the means for the two groups was not significant for either type of polysaccharide although it approached significance for group C (p = 0.065). The number of individuals who were unable to maintain 50 % of their initial antibody response (dashed line) was not statistically different for group A. Significantly fewer LCCD than CS individuals maintained a 50% response to group C polysaccharide (p < 0.02).

uals less than 10 years of age in any of the groups. The difference in mean antibody concentrations among the various groups was not significant. For example, for meningococcal C polysaccharide the median values for unrelated completed-sufficient, complement-sufficient family members, heterozygous and homozygous complement-deficient family members were 38.9, 107, 19.2 and 37.6 ~tg/ ml, respectively. These data support the premise that the initial response of LCCD

persons to polysaccharide vaccines is normal. However, longitudinal studies suggest that LCCD persons may have a more rapid decline than complement-sufficient individuals in certain serogroup-specific polysaccharide antibodies. As the clinical case demonstrates, maintenance of adequate capsular antibody concentrations over time appears to be a cru- cial aspect of host defense against meningococcal disease of LCCD individuals. For serogroup A polysaccharide, 4 of 7 versus 7 of 10

308 Figueroa/Andreoni/Densen Complement Deficiency States and

in the LCCD and heterozygous/normal groups, respectively, maintained 50% or greater of their initial response to the vaccine (p = 0.50). In contrast, only 2 of 7 LCCD compared with 9 of 10 heterozygous deficient or normal persons maintained 50% or more of their initial serogroup C capsular antibody concentration (p < 0.02) 2-2.5 years following vaccination (fig. 5). Although the initial vaccination responses of these individuals to the Y and W135 components of the meningococcal vaccine were not available, deficient individuals demonstrated a lower mean antibody concentration to group Y capsular polysaccharide 2-2.5 years following vaccination compared with complement-sufficient individuals (18.3 vs. 122 units/ml, respectively). The mean concentration to W135 capsular polysaccharide did not differ between the two groups (64.8 vs. 79.8 units/ml, respectively).

Treatment

Our data indicate that antibody to meningococcal capsular polysaccharides is critical for protection of LCCD individuals from meningococcal disease. Thus, vaccination with the tetravalent meningococcal vaccine to promote protective immunity in these persons is strongly indicated. The longitudinal data suggest that LCCD persons may have a more rapid decline in the concentration of certain serogroup-specific polysaccharide antibodies and thus may become susceptible to meningococcal disease when this concentration falls be- low a critical threshold. Based on the opsonophagocytic assays and the aforementioned clinical case this antibody threshold appears to be about at 1-2 ~tg/ml. Thus it seems rea- sonable to quantitate capsular antibody ap- proximately 2 years after vaccination and to revaccinate if the concentration of these antibodies is less than this amount.

The hypothesis presented above and the availability of the tetravalent meningococcal capsular polysaccharide vaccine provide a ra- tionale to prevent meningococcal disease, not only in individuals with LCCD but also in persons with defects affecting the classical and alternative pathways. Antibody to capsular polysaccharide in individuals with a classical pathway defect should facilitate the use of the alternative pathway thereby enhancing both opsonophagocytosis and direct bactericidal activity. However, 4- to 8-fold greater amounts of capsular antibody are required to produce a degree of meningococcal killing in C2-deficient serum comparable to that in normal serum. High levels of antibody may also facilitate the use of the classical pathway in C2-deficient serum in an alternative-pathway-dependent manner [53].

In vitro studies similar to those described here have been performed in sera from properdin-deficient individuals. Response to the meningococcal vaccine in these individuals is associated with efficient utilization of the classical pathway and enhancement of both opsonophagocytosis and direct bactericidal activity. The high mortality from meningococcal disease in these patients makes vaccination mandatory [3, 54-56]. The efficacy of penicillin prophylaxis has been assessed by Potter et al. [56] and should be used as an adjunct to vaccination when group B meningococcal disease is epidemic or when recurrent episodes of disease occur over a brief period of time [57].

309

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Complement deficiency states and meningococcal disease

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