Classical Pathway C3 Research Articles

Inhibiting the formation of classical C3-convertase on the Alzheimer's β-amyloid peptide

Amyloid plaques are the pathological hallmark of Alzheimer Disease (AD) brains, being found primarily in the hippocampus and neocortex, where AD pathology is most evident. Complement activation is associated with amyloid plaques which are made from fibrils of aggregated amyloid peptides, 39–42 amino acids long. In vitro studies show that aggregated amyloid peptides activate complement via the classical pathway, implying that amyloid plaques themselves cause complement activation in AD brains. In order to test this hypothesis, we sought to determine if a major peptide component of amyloid plaques, Aβ1–42, supports the formation of the classical pathway C3 convertase. Using normal human serum depleted of C3, we are able to detect C3 convertase activity on aggregated Aβ1–42 in vitro. The convertase activity is associated with the binding of Clq and activation of C4 on the aggregated peptide. Inhibitors of C1 esterase and the cation chelator EGTA both block the formation of the convertase activity. Congo red, a histochemical stain for amyloid deposits and an inhibitor of amyloid aggregation, reduces C3 convertase activity on aggregated A β1–42, indicated by decreased C3a production. Our results provide further evidence that aggregated A β1–42 alone is sufficient to serve as a nidus for complement activation, and thus may be involved directly in initiating the inflammation seen in AD brains.

Neurons express proteins of the classical complement pathway in Alzheimer disease

Occurrence of the classical pathway complement proteins C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8 and C9 was studied in human hippocampus and temporal cortex by immunohistochemistry and Western blotting. In Alzheimer disease (AD) cases, positive staining for all of these proteins was observed in pyramidal neurons and senile plaques. In control cases, weaker pyramidal neuron staining was observed except for C1q and C1s which were not detected. On Western blots of AD hippocampal extracts, bands corresponding to those detected in normal serum were found for each of the complement proteins. Comparable bands were also detected in normal hippocampal extracts with the exception of C1s which was not observed. The intensity of the bands was generally stronger in AD than in normal extracts, but, in the latter, there was considerable variability between cases and between bands in a single case. These data suggest that pyramidal neurons may be a source of the complement components known to be associated with Alzheimer lesions.

Mannan-specific immunoglobulin G antibodies in normal human serum mediate classical pathway initiation of C3 binding to Candida albicans.

Candida albicans activates both the classical and alternative complement pathways. Previous studies found that immunoglobulin G (IgG) in normal human serum (NHS) mediates classical pathway initiation. The goal of this study was to determine the role of candidal mannan-specific human IgG antibodies in complement activation. Mannan was purified from the yeast cells, and naturally occurring antimannan IgG was isolated from pooled NHS or plasma samples by immunoaffinity chromatography. Early activation and binding of C3, characteristics of classical pathway activity, were abolished in yeast- or mannan-absorbed serum but could be restored to absorbed serum with added purified antimannan IgG in a dose-dependent manner. Microscopically, the immunofluorescence pattern of initial C3 binding was diffuse over the entire cell surface for yeast cells incubated in NHS or in mannan-absorbed NHS supplemented with antimannan IgG but was asynchronous and focal for yeast cells incubated in EGTA-treated or mannan-absorbed NHS. The antimannan IgG level in serum samples from 21 donors varied from 17 to 570 microg/ml of serum compared to 220 microg in pooled NHS samples. The rate of initial C3 binding to yeast cells correlated with the level of antimannan IgG in sera from different individuals (r2 = 0.94) and could be accelerated in sera containing lower amounts of antimannan IgG with exogenous antimannan IgG. These observations identify antimannan IgG as the initiator of classical pathway C3 deposition on C. albicans. Given the variability in the levels of antimannan antibodies in sera from different individuals, the presence or absence of these antibodies may be an important determinant of host resistance to disseminated candidiasis.

Contribution of the complement control protein modules of C2 in C4b binding assessed by analysis of C2/factor B chimeras.

To identify the complement control protein (CCP) module(s) of C2 that are required for C4b recognition, we constructed a panel of C2/factor B chimeras by substituting intact or partial factor B CCP modules for the corresponding ones of C2. Epitope mapping indicated that the anti-C2b mAb 3A3.3, which inhibits binding of C2 to C4b, reacts with the second CCP of C2 and similarly the anti-Ba mAb HA4-1A, which inhibits binding of factor B to C3b, reacts with the second CCP of factor B. The hemolytic activity of the chimeras CP1, CP2, and CP3a containing CCP1, CCP2, and a fragment of CCP3 of factor B, respectively, was substantially decreased compared with that of wild-type C2. The CP3 and CP1-3 chimeras, in which CCP3 and all three CCP modules of factor B, respectively, were substituted, had no hemolytic activity. Loss of activity could be attributed to the resistance of these two chimeras to C1s cleavage, which was probably due to conformational changes of the cleavage site. The combined results indicate that all three CCP modules of C2 contribute structural elements to the C4b-binding site of C2b. This site has been shown previously to be necessary for the initial binding of C2 to C4b which leads to the formation of the classical pathway C3 convertase.

Role of Complement in the Aetiology of Pickʼs Disease?

Complement in the postmortem brains of 15 cases of Pick's disease has been widely analyzed immunohistochemically and, in 2 cases, by immunoelectron microscopy. Astrocytes and the Pick bodies and cytoplasm of ballooned neurons were immunoreactive with antibodies to classical pathway components C1, C1q, C4, C2 and C3 and the terminal complex components C5, C6 and C8. In almost all cases, no immunostaining was obtained with antibodies against C9 and neoepitopes in the membrane attack complex (MAC), the complement complex responsible for cytotoxicity. However, unequivocal staining with antibodies to two soluble complement regulatory proteins, S-protein and clusterin, and to the membrane complement inhibitor CD59 was found, although three other membrane inhibitors, CR1(CD35), DAF (CD55), and MCP (CD46), were not detected. The complement immunoreactivity of astrocytes and neurons could be the result of complement biosynthesis or attack. Complement attack will be restricted by the expressed regulatory proteins. However, neurons may be the victims of attack since they show pathological change. The internalization of complement-attacked membrane, perhaps involving the genesis of Pick bodies and ballooning, may explain the intracellular immunolocalization of complement in damaged neurons. Immunoglobulins, as a possible source of complement activation, were observed in only two cases, leaving unresolved the trigger for complement activation in the other cases.

Localization of classical and alternative pathway regulatory activity within the decay-accelerating factor.

Decay-accelerating factor (DAF) is a cell-associated C regulatory protein that protects host cells from autologous C attack. It functions intrinsically in host cell surface membranes to rapidly dissociate autologous classical and alternative pathway C3 convertases whenever these amplifying enzymes assemble on host cell surfaces. It is composed of four contiguous approximately 70 amino acid long regions termed short consensus repeats (SCRs) that share homology with similar units in other C3 convertase regulatory proteins. It is attached to the cell surface membrane by a glycoinositol phospholipid (GPI) anchor that is added posttranslationally. In this study, we prepared rGPI-anchored DAF proteins devoid of individual SCRs. We then incorporated the GPI-anchored products into sheep erythrocyte (Esh) hemolytic intermediates and examined their abilities to intrinsically regulate classical or alternative pathway activation. We found that classical pathway C3 convertase regulatory function resides within SCR-2 and SCR-3, while alternative pathway C3 convertase regulatory function resides within SCR-2, -3, and -4. Functional comparisons of the variant DAF proteins in fluid phase C3 activation assays established that the differences reflect domain-specific interactions rather than changes in the spatial arrangement of SCRs above the cell surface. In accordance with these findings, we found that variant DAF molecules containing SCR-1, -2, and -3, but not SCR-4, function to selectively inhibit classical pathway activation.

Mouse complement component C4 is devoid of classical pathway C5 convertase subunit activity

It has long been known that mouse C4 has unusually low hemolytic activity relative to the C4 of other mammalian species (e.g. human and guinea pig), the measurements being done in most cases using a C4-deficient guinea pig serum reagent in a one-step assay with EA. This low activity for mouse C4 previously had been attributed to “technical” difficulties such as lability of the protein during blood collection and partial species incompatibilities with guinea pig components. Recently, we presented evidence for the involvement of human C4 β-chain residues 455–469, a putatively exposed hydrophilic segment, in contributing to a C5 binding site in the C4b subunit of the classical pathway C5 convertase, C4b3b2a. Given that there were five sequence differences between the human and mouse protein within this segment, we hypothesized that these substitutions may have compromised the C5 convertase subunit activity of mouse C4, thereby resulting in its low hemolytic activity. Using a multi-step hemolytic assay which was totally dependent upon C5 cleavage by the classical pathway, we found that mouse C4 was completely devoid of classical pathway C5 convertase subunit activity. We have been able to rule out the most obvious potential species incompatibilities (e.g. between C4 mo and C5 gp) as being responsible for this lack of activity. Moreover, we found that the low level of hemolytic activity of mouse C4 measured in the one-step assay can be ascribed totally to C5 cleavage, and subsequent terminal component assembly, by the alternative pathway C5 convertase, (C3b) 2Bb. However, the assembly of the latter enzyme complex is dependent upon the presence of C3b molecules deposited initially via the classical pathway C3 convertase in which mouse C4b is a subunit. Finally, whereas conversion of human residues 458RP to the mouse-like sequence PL was sufficient to abrogate classical pathway C5 convertase subunit activity in human C4, the five substitutions which “humanized” the 452–466 segment of mouse C4 (corresponding to human residues 455–469) were on their own insufficient to impart this activity to mouse C4. This implies that, in addition to the 455–469 β-chain segment of human C4, there are other regions of the molecule contributing to C5 binding which are also non-conserved between human and mouse C4.

Serum Amyloid P Component Binding to C4b-binding Protein

Human C4b-binding protein (C4BP), which is a regulator of the classical complement pathway C3 convertase, forms high affinity complexes with anticoagulant protein S and with the pentraxin serum amyloid P component (SAP). SAP is a plasma protein present in all amyloid deposits. Recently, SAP was shown to inhibit the complement regulatory functions of C4BP. In this investigation, we have studied the structural requirements for the C4BP-SAP interaction. C4BP was subjected to chymotrypsin digestion, which yielded two major fragments corresponding to the central core (160 kDa) and to the cleaved-off tentacles (48 kDa). SAP-Sepharose specifically bound the 160-kDa fragment, suggesting that the central core of C4BP contains the binding site for SAP. In a quantitative affinity chromatography assay, the dissociation constants for binding of intact C4BP and of the 160-kDa central core fragment to SAP were found to be 30 and 70 nM, respectively. Recombinant C4BP composed of only alpha-chains bound SAP with similar affinity (Kd = 22 nM), whereas nonglycosylated recombinant alpha-chain C4BP (synthesized in the presence of tunicamycin) bound SAP with lower affinity (Kd = 126 nM). This suggests that the carbohydrate moiety of the central core of C4BP is important for binding of C4BP to SAP in contrast to the C4BP beta-chain, which is not required. EDTA, heparin, and phosphorylethanolamine as well as a peptide comprising amino acids 27-39 of SAP were found to completely displace C4BP from the SAP matrix. Moreover, the immobilized SAP peptide bound C4BP in a reaction that, in contrast to the C4BP-SAP interaction, was not dependent on calcium.

Interaction between serum amyloid P component and C4b-binding protein associated with inhibition of factor I-mediated C4b degradation.

Serum amyloid P component (SAP) is a member of the pentraxin protein family. Although present in all types of amyloid deposits, it is also a normal constituent of blood and extravascular tissues. In blood, SAP forms a calcium-dependent, noncovalent complex with C4b-binding protein (C4BP). C4BP regulates the classical complement pathway as it binds C4b and functions as cofactor in its degradation by factor I. Although SAP and C4b bind to distinct sites on C4BP, it is not known whether the SAP-C4BP interaction affects the function of C4BP. We report that in a fluid phase system, SAP inhibited degradation of C4(H2O) (which is C4b-like) in a dose-dependent manner. Phosphorylethanolamine was found to alleviate the inhibitory effect of SAP on C4(H2O) degradation. Because this compound is known to inhibit the SAP-C4BP interaction, this indicated direct binding of SAP to C4BP to be required for inhibition of C4(H2O) degradation. Even though C4BP, C4(H2O), and SAP form a multimolecular complex in fluid phase, SAP was found to inhibit binding of C4BP to immobilized C4(H2O). The inhibitory effect was calcium dependent and alleviated by phosphorylethanolamine. Heparin, which is known to inhibit the interaction between SAP and C4BP, was also found to counteract the inhibitory effect of SAP on C4BP binding to C4(H2O). However, the effect of heparin was biphasic because high concentrations of heparin directly inhibited binding of C4(H2O) to C4BP. The inhibition of C4BP function by SAP suggests that SAP may be involved in regulation of the classical complement pathway C3 convertase.

Inhibition of complement activation by natural sulfated polysaccharides (fucans) from brown seaweed

In the present study, we demonstrate that natural sulfated polysaccharides (fucans) isolated from brown seaweed are potent inhibitors of human complement activation. A fucan fraction of chromatographic molecular weight 22,600, termed BS8, was found to inhibit classical and alternative pathway activation in whole serum in a dose-dependent fashion. Fucan BS8 inhibited formation of the classical pathway C3 convertase by interfering with C1 activation or by inhibiting C4 cleavage and the interaction between C4b and C2. The fucan also inhibited formation/function of the alternative pathway C3 convertase by suppressing the binding of B to C3b and by interfering with the stabilizing function of Properdin. The inhibitory effect of fucans on formation of the C3 convertases was dependent on the molecular weight of the polysaccharide for compounds of chromatographic molecular weight below 16,600. Fucan had no effect on the function of the terminal complex. Since fucans were more efficient than heparin in inhibiting activation of the classical pathway in whole serum and exhibited a lesser specific anticoagulant activity on a molar basis, our results suggest that these natural sulfated polysaccharides have a potential for use as anti-complementary and anti-inflammatory agents.

Biochemical analysis of the membrane and soluble forms of the complement regulatory protein of Trypanosoma cruzi

A developmentally regulated, 160-kDa trypomastigote surface glycoprotein was previously shown to bind the third component of complement and to inhibit activation of the alternative complement pathway, thus providing the parasites a means of avoiding the lytic effects of complement. We now show that this complement regulatory protein (CRP) binds human C4b, a component of the classical pathway C3 convertase, and may therefore also act to restrict classical complement activation. Characterization of the extent of carbohydrate modification of the protein revealed extensive N-linked glycosylation and no apparent O-linked sugars. The CRP purified from parasites treated with an inhibitor of N-linked glycosylation exhibited a decreased binding affinity for C3b compared with that of the fully glycosylated protein. We have previously shown that the protein was anchored to the membrane via a glycosyl phosphatidylinositol linkage and was spontaneously shed from the parasite surface. The spontaneous release of CRP from the parasite surface may augment the protection of the parasites from complement-mediated lysis by the removal of complement-CRP complexes. The majority of the shed CRP had an apparent molecular mass of 160 kDa and lacked the glycolipid anchor, whereas the membrane form was recovered with the glycolipid anchor attached and had an apparent molecular mass of 185 kDa. Both the membrane form (185 kDa) and the soluble form (160 kDa) retained binding affinity for C3b. Evidence is presented to indicate that the conversion of the 185-kDa membrane form to the 160-kDa form is the result of cleavage by an endogenous phospholipase C.

Mouse Crry/p65 is a regulator of the alternative pathway of complement activation

Like man, mouse has evolved a unique set of regulatory proteins which provide protection from complement-mediated damage to self membranes. The recently described mouse protein Crry/p65 has been shown to inhibit classical complement pathway C3 deposition on cell membranes in which it is expressed. In two distinct experimental systems, we now further delineate the regulatory activity of Crry/p65 and demonstrate its inhibitory effect on alternative complement pathway C3 activation. First, significant inhibition of mouse alternative pathway C3 deposition was demonstrated on neuraminidase-treated human K562 cells expressing recombinant Crry/p65. Second, using a baculovirus technique, recombinant Crry/p65 was synthesized as a soluble molecule and then purified. This molecule was found to inhibit mouse C3 deposition on the surface of zymosan, a potent alternative complement pathway activator. These studies, combined with our earlier findings, demonstrate that Crry/p65 can regulate both the classical and alternative complement pathways. Crry/p65 must, therefore, exert its effects prior to, or at the level of, the C3 convertases, in a fashion similar to that of human membrane cofactor protein and/or decay-accelerating factor. These studies provide further proof of the hypothesis that Crry/p65 is an evolutionarily unique, complement regulatory protein which has developed in mouse.

Potassium cyanide protects Escherichia coli from complement killing by the inhibition of C3 convertase activity.

The exact mechanism by which deposited C5b-9 complexes kill Gram-negative bacteria is unclear. It has been proposed that during complement activation the membrane attack complex triggers an energy dependent process in Gram-negative bacteria that mediates destruction of the inner membrane. This observation in part resulted from the survival of Gram-negative bacteria that were incubated with an uncoupler (DNP) or an inhibitor (KCN) of oxidative phosphorylation during complement activation. In a reexamination of this issue we employed potassium cyanide (KCN) to block energy dependent pathways and observed a dose dependent inhibition of C9 uptake on E. coli J5 during serum incubation, suggesting that cyanide was interfering with complement activation. To verify the effect on complement activation we chose specifically to study the effects of KCN on the C3 convertase of the classical pathway. Sensitized sheep erythrocytes were employed as our model system. This system allowed us to construct a series of stable intermediates that were used to test the effect of cyanide on the formation and activity of precursors of the classical pathway C3 convertase. The data illustrate that the concentrations of potassium cyanide that inhibit complement killing of J5 also inhibit C3 convertase activity on sensitized sheep erythrocytes. The results of this study refute the principal observation made by other investigators, that potassium cyanide protects bacteria from complement killing by inhibiting bacterial energy dependent pathways that spark inner membrane destruction. A better scenario is that the organisms survive because cyanide inhibits complement activation.

Determination of serum levels of complement component C4b-binding protein: influence of age and inflammation

C4b-binding protein (C4b-BP) is a high molecular weight plasma protein which inhibits the activity of the classical complement pathway C3 convertase. In addition to multiple binding sites for C4b, C4b-BP possesses a single binding site for vitamin K-dependent protein S, an inhibitor of blood coagulation. As protein S bound to C4b-BP has no anticoagulant activity, C4b-BP participates in the regulation of both the complement and the coagulation pathways. We have produced and immunochemically characterized a series of murine monoclonal antibodies to human C4b-BP. A mixture of four monoclonal antibodies precipitating C4b-BP both in agarose gel and in solution was used to develop a highly reproducible radial immunodiffusion method for the measurement of C4b-BP in human serum. C4b-BP levels were measured in sera from 284 patients referred to our central laboratory. Samples from subjects with an increased erythrocyte sedimentation rate (ESR), a1-acid glycoprotein (a1-AGP) or C-reactive protein (CRP) had significantly higher C4b-BP levels (307 mg/l, 292-322 mg/l, geometric mean and 95% confidence limits of the mean) than those from subjects without elevation of the aforementioned established acute phase reactants (231 mg/l, 226-237 mg/l, P less than 0.00001). C4b-BP was significantly (P less than 0.001) correlated with ESR (r = 0.715), a1-AGP (r = 0.692) and CRP (r = 0.567). There was no gender-related difference in C4b-BP levels. In subjects with no increased acute phase reactants there was a significant correlation between C4b-BP levels and age (r = 0.387, P less than 0.001). High C4b-BP might contribute to the increased thrombotic risk associated with inflammation and aging.

Accelerated decay of the cell bound C4b2a complex by serum of patients with membranoproliferative glomerulonephritis and acute poststreptococcal glomerulonephritis

Serum from patients with membranoproliferative glomerulonephritis (MPGN) and acute poststreptococcal glomerulonephritis (APSGN) accelerated the decay of the cell bound C4b2a (C42) and C4b hemolytic activity relative to pooled normal human serum (pNHS) after 5 min incubation at 30°C in EDTA-GVB. The accelerated decay of the C42 hemolytic activity was heat stable (56°C 30 min) and was inhibited by monoclonal antibody against human C4 binding protein (MoAb:C4BP) or C4 binding protein (C4BP) depleted serum. C4 nephritic factor (C4NeF) was employed to stabilize the labile classical pathway C3 convertase C42 complex. Serum from patients with MPGN and APSGN reduced the C4NeF stabilizing activity. Sera from 32 of 46 patients with MPGN and all of 7 patients with APSGN reduced the C42 hemolytic activity relative to 50 normal human serum (NHS) after 5 min incubation at 30°C in EDTA-GVB, and there was no relationship with the serum concentration of C4BP. In vivo, accelerated decay of C42 convertase might interfere with the clearing and processing mechanism of circulating immune complexes (IC) by reducing deposition of C3b on the IC latice.

Decreased expression of decay-accelerating factor on endothelial cells of immune complex-mediated vasculitic skin lesions

Endothelial cells may be damaged directly by the membrane attack complex of complement in immune complex vasculitis of the skin. However, for endothelial cell membrane injury to occur, normal regulatory mechanisms must fail. One of the main complement regulatory proteins of endothelial cells is decay-accelerating factor, a surface protein which interferes with either the classical or alternative pathway C3 and C5 convertases. We have investigated the expression of decay-accelerating factor in 4 patients with histologically proven cutaneous immune complex vasculitis, using an immuno-electronmicroscopic technique. We demonstrated that endothelial cells of upper dermal vessels in vasculitic lesions were almost completely devoid of decayaccelerating factor. By contrast, the expression of this protein on endothelial cells in uninvolved skin of the patients was the same as in skin of healthy volunteers. As yet, the mechanism responsible for depletion of decay-accelerating factor is not clear. Absence of decay-accelerating factor may follow enzymatic release from the phosphatidylinositol anchor, proteolytic stripping from the cell membrane or a down-regulation of decay-accelerating factor synthesis. Regardless of mechanism, endothelial cell injury or death could serve a phlogistic function to facilitate complement-mediated destruction of endothelial cells for removal and repair.

Decreased inhibition of immune precipitation by sera with the C2 B allotype

Complement-mediated precipitation inhibiting (CMPI) activity of sera of 5 individuals homozygous for C2 B was compared to that of sera of 20 individuals carrying the common C2 C allotype. Sera with the rare C2 B allotype had a depressed CMPI capacity in both the early (5 min) and the late (60 min) stages of the reaction. We have also compared the CMPI activity of seven homozygous C4A deficient ( C4A ∗Q0 ) and eight C4B deficient ( C4B ∗Q0 ) serum samples and did not find significant differences from the controls (no C4 null alleles) in any stage of the reaction. These results indicate that C2 is the critical component in the CMPI reaction of the two constituents of the classical pathway C3 convertase and that C2 B is less active than C2 C.

A new, simplified method for oxidation of human complement component C2

Oxy C2 is a valuable immunologic reagent, particularly for investigators whose research or clinical assays require a stable classical pathway C3 and/or C5 convertase or a highly active plasma complement source. To date only one method for the conversion of serum C2 or purified C2 to their respective oxy C2 forms has been published. However, this method has several disadvantages. For example, handling and dissolving the iodine crystals required in this process are difficult and time consuming. Also, the enhancement procedure results in a significant dilution of the original C2 sample. We have, therefore, developed a new, simplified method for oxidation of plasma, serum, or pure C2 which circumvents the difficulties associated with the earlier method. Moreover, this method offers additional flexibility with regard to oxidative conditions (i.e., buffer pH, temperature, and C2 concentrations) and reagent handling and final C2 product stability.

Disseminated echovirus infection in a patient with multiple myeloma and a functional defect in complement. Treatment with intravenous immunoglobulin

A man with IgG1 multiple myeloma developed fever, confusion, and progressive muscle weakness resulting in paralysis. Echovirus type 11 was isolated from cerebrospinal fluid, pleura, pleural fluid, and muscle, and muscle biopsy disclosed changes consistent with viral myositis. Immunologic evaluation revealed low serum levels of polyclonal IgG subtypes 1 and 3, reduced blood levels of T-helper/inducer and T-suppressor/cytotoxic cells, and a complement abnormality involving the function of the classical pathway C3 convertase, C4b2a. Therapy with intravenous immunoglobulin was associated with clinical recovery. This is the first reported case of disseminated central nervous system enteroviral infection in an adult with a B-cell malignancy, and in association with a documented complement abnormality. The findings suggest the efficacy of immunotherapy in this disease.

Disseminated Echovirus Infection in a Patient With Multiple Myeloma and a Functional Defect in Complement

• A man with IgG1 multiple myeloma developed fever, confusion, and progressive muscle weakness resulting in paralysis. Echovirus type 11 was isolated from cerebrospinal fluid, pleura, pleural fluid, and muscle, and muscle biopsy disclosed changes consistent with viral myositis. Immunologic evaluation revealed low serum levels of polyclonal IgG subtypes 1 and 3, reduced blood levels of T–helper/inducer and T–suppressor/cytotoxic cells, and a complement abnormality involving the function of the classical pathway C3 convertase, C4b2a. Therapy with intravenous immunoglobulin was associated with clinical recovery. This is the first reported case of disseminated central nervous system enteroviral infection in an adult with a B-cell malignancy, and in association with a documented complement abnormality. The findings suggest the efficacy of immunotherapy in this disease. (<i>Arch Intern Med.</i>1989;149:1455-1457)