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PubMed2001

Complement activation in the human brain after traumatic head injury.

The complement cascade has been suggested to be involved in the development of secondary brain injuries following brain contusions, based on animal experiments. The aim of the present study was to examine the possible involvement of the complement cascade following traumatic head injury in the human brain. Sixteen patients were included in this study, 12-77 years of age, treated at the neurointensive care unit for traumatic brain contusions. All of these patients were operated with frontal or temporal lobe resection due to intractable intracranial hypertension. The resected tissue was analyzed with regard to components related to complement activation. The time interval between accident and operation was 2-82 h. Brain tissue from three patients operated with hippocampectomy due to epilepsy, including temporal lobe resection, were used as controls. We found increased immunoreactivity for complement components C1q, C3b, and C3d and the membrane attack complex (MAC), C5b-9, in the immediate vicinity of neurons in the penumbra area of the contusion. These findings constitute histological evidence for activation of the complement cascade in the penumbra of cortical contusions in the human brain. Using in situ hybridization, we also found C3-mRNA in the penumbra, suggesting a local synthesis of complement. Furthermore, upregulation of the endogenous complement regulator clusterin was found in some neurons in the same area. We suggest that unknown compounds in the debris from injured neurons or myelin breakdown products trigger complement activation, including formation of C5b-9. Activated complement components may stimulate accumulation of inflammatory cells and formation of brain edema, as well as having membrane destructive effects by the end product MAC, thereby being mediators in the development of secondary brain damage.

Adolescent↗
PubMed1984

Establishment of a macrophage hybrid population by the fusion of mouse peritoneal macrophages with thymoma cells BW5147.

A continuous macrophage hybrid population, designated MBW-1, was produced by the fusion of peritoneal macrophages from a normal AKR mouse with thymoma cells BW5147. The hybrid cells are resistant to HA selection medium. In their nearly triploid chromosome complement they carry metacentric chromosomes typical of BW5147 cells and express the typical macrophage-like characteristics (morphology of macrophages, adherence properties, phagocytosis, expression of macrophage-specific antigen and receptor for the C3b component of complement). However, they do not express Fc receptors and the receptor for SBA lectin. An interesting property is the high resistance to the toxic action of silica particles. Thanks to the unique properties, which were not observed in other, hitherto described macrophage-like cell lines, the MBW-1 cell population provides a useful material for study of macrophage functions.

Animals↗
PubMed1996

Investigation of mechanism-based inhibitors of complement targeting the activated thioester of human C3.

An intramolecular thioester bond in complement protein C3 is vital for covalent attachment of C3b (the proteolytically activated form of C3) to biological surfaces and for activation of the complement system. Proteolytic removal of C3a from C3 activates the thioester in the C3b fragment. Activated C3b primarily forms ester bonds with hydroxyl groups of carbohydrates on complement activating surfaces, but it has also been shown to react with the hydroxyl group of tyrosine and with specific Ser and Thr residues on IgG and on complement protein C4b. To examine the reactivity of the thioester, several families of hydroxylated compounds were examined. Reactivity of a series of substituted phenols varied over two orders of magnitude and demonstrated a linear correlation between reactivity and the Hammett substituent constants. Hydroxylated drugs including members of the L-DOPA/epinephrine family and hydroxamic acids also were examined. Compounds were identified that were 20,000 times more reactive than carbohydrates. These compounds were found to inhibit both the classical and alternative pathways of complement activation. Although the specificity of the thioester for its natural biological targets appears to be determined by many structural features, the data presented here demonstrate that increasing the nucleophilic character of the target hydroxyl group can increase the potency of a synthetic inhibitor many orders of magnitude.

Complement C3↗
PubMed2002

Secretion of soluble complement inhibitors factor H and factor H-like protein (FHL-1) by ovarian tumour cells.

We observed that the soluble complement regulators factor H and factor H-like protein were abundantly present in ascites samples as well as in primary tumours of patients with ovarian cancer. RT-PCR and immunoblotting analyses showed that the two complement inhibitors were constitutively produced by the ovarian tumour cell lines SK-OV-3 and Caov-3, but not PA-1 or SW626 cells. The amounts of factor H-like protein secreted were equal to those of factor H. This is exceptional, because e.g. in normal human serum the concentration of factor H-like protein is below 1/10th of that of factor H. In ascites samples the mean level of factor H-like protein (130+/-55 microg ml(-1)) was 5.5-fold higher than in normal human serum (24+/-3 microg ml(-1)). Ovarian tumour cells thus preferentially synthesise factor H-like protein, the alternatively spliced short variant of factor H. The tumour cells were found to bind both (125)I-labelled factor H and recombinant factor H-like protein to their surfaces. Surprisingly, the culture supernatants of all of the ovarian tumour cell lines studied, including those of PA-1 and SW626 that did not produce factor H/factor H-like protein, promoted factor I-mediated cleavage of C3b to inactive iC3b. Subsequently, the PA-1 and SW626 cell lines were found to secrete a soluble form of the membrane cofactor protein (CD46). Thus, our studies reveal two novel complement resistance mechanisms of ovarian tumour cells: (i) production of factor H-like protein and factor H and (ii) secretion of soluble membrane cofactor protein. Secretion of soluble complement inhibitors could protect ovarian tumour cells against humoral immune attack and pose an obstacle for therapy with monoclonal antibodies.

Ascitic Fluid↗
PubMed1986

Differences between the binding sites of the complement regulatory proteins DAF, CR1, and factor H on C3 convertases.

Binding studies using purified decay-accelerating factor (DAF), CR1, and Factor H indicate that the primary interaction of DAF with C3 convertases is with the Bb or C2a subunits, whereas CR1 and Factor H interact primarily with the C3b or C4b subunits. The ability of soluble DAF, CR1, or Factor H to decay C3b,Bb bound to zymosan was inhibited by various concentrations of fluid-phase competitors (C3b, Bb, C3b,Bb, C3b,B, C4b, or C4b,C2a) in 0.1% NP-40 at 22 degrees C. The apparent association constants (appKa) for DAF were 0.045, 0.067, 0.91, 0.71, 0.00045, and 0.53 microM-1, respectively. The appKa for CR1 were 0.50, 0.0040, 1, 1, 1, and 1.1 microM-1, respectively. The appKa for Factor H were 4.3, 0.0005, 2.9, 6.3, 0.27, and 0.29 microM-1, respectively. Thus, C3b binds to DAF with a 10-fold lower affinity than to CR1 and a 100-fold lower affinity than to Factor H. The appKa of C3b,Bb for the three proteins were more similar: DAF (0.91 microM-1), CR1 (1 microM-1), and Factor H (2.9 microM-1). DAF binds to Bb with a 50% higher affinity than to C3b, and to C4b,C2a with a 1000-fold higher affinity than to C4b alone. In contrast, CR1 and Factor H bind almost equally well to the C3 convertases and to their noncatalytic subunits. The affinity of DAF for CVF,Bb was similar to its affinity for Bb alone, suggesting that DAF does not recognize conformational determinants unique to Bb in C3 convertases.

Binding Sites↗
PubMed1994

Inhibition of complement-mediated cytolysis by the terminal complement inhibitor of herpesvirus saimiri.

Herpesvirus saimiri (HVS) is a lymphotropic herpesvirus that induces T-cell transformation in vitro and causes lymphomas and leukemias in New World primates other than its natural host, the squirrel monkey. Nucleotide sequence analysis of the HVS genome revealed two open reading frames with significant homology to genes for human complement regulatory molecules. One of these genes encodes a predicted protein (designated HVSCD59) with 48% amino acid sequence identity to the human terminal complement regulatory protein CD59 (HuCD59). The CD59 homolog from squirrel monkey (SMCD59) was cloned, and the corresponding amino acid sequence showed 69% identity with HVSCD59. BALB/3T3 cells stably expressing HVSCD59, SMCD59, or HuCD59 were equally protected from complement-mediated lysis by human serum. However, only HVSCD59-expressing cells were effectively protected from complement-mediated lysis when challenged with rat serum, suggesting that HVSCD59 was less species restrictive. The complement regulatory activity of HVSCD59 and SMCD59 occurred after C3b deposition, indicating terminal complement inhibition. Treatment of BALB/3T3 stable transfectants with phosphatidylinositol-specific phospholipase C prior to complement attack decreased the complement regulatory function of HVSCD59, suggesting cell surface attachment via a glycosyl-phosphatidylinositol anchor. Cells expressing HVSCD59 effectively inhibited complement-mediated lysis by squirrel monkey serum in comparison with SMCD59-expressing cells. Finally HVSCD59-specific transcripts were detected in owl monkey cells permissive for lytic HVS replication but not in T cells transformed by HVS, which failed to produce virions. These data are the first to demonstrate a functional, virally encoded terminal complement inhibitor and suggest that HVSCD59 represents a humoral immune evasion mechanism supporting the lytic life cycle of HVS.

3T3 Cells↗
PubMed1981

Inhibition of complement-mediated functions of human neutrophils by impermeant stilbene disulfonic acids.

The impermeant labeling reagents 4,4'-diisothiocyanostilbene-2-2'-disulfonic acid (DIDS) and 4-acetamido-4'-isothiocyano-2,2'-disulfonic acid (SITS) inhibited in a concentration-related manner the enhanced generation of superoxide radicals (O2) by human neutrophils engaged in the phagocytosis of zymosan that had been opsonized in fresh serum, without altering the O2 generation by neutrophils exposed to zymosan opsonized in heat-decomplemented serum or to phorbol myristate acetate (PMA). That the stimulus specificity of the suppression of O2 generation by SITS and DIDS is predominantly attributable to an action on neutrophil plasma membrane receptors for complement was suggested by the similarity of the concentration dependence of the inhibition of the expression of neutrophil C3b receptors, as assessed by a rosetting assay. Washing neutrophils that had been pretreated with the covalent label DIDS failed to reverse either the suppression of C3b-dependent rosetting or the inhibition of O2 generation stimulated by opsonized zymosan. In contrast, pretreatment with DIDS and washing or erythrocytes bearing C3b and of opsonized zymosan did not inhibit their capacity to form rosettes and to stimulate O2 generation by neutrophils, respectively. In the same rosetting assay, the expression of IgG-Fc receptors was unaffected by SITS and DIDS. The rapid and apparently selective inhibition of the expression of neutrophil C3b receptors by noncytotoxic concentrations of the impermeant stilbene disulfonic acids may provide a means to analyze the complement dependence of other neutrophil effector functions.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1993

Effect of anaerobiosis and sulfide on killing of bacteria by polymorphonuclear leukocytes.

Anaerobic microorganisms in periodontal pockets produce toxic amounts of hydrogen sulfide. The capacity of polymorphonuclear leukocytes to kill a capsulated and a non-capsulated variant of a group B streptococcal strain was studied in presence and absence of sulfide. The killing was equally efficient under aerobic and anaerobic conditions. However, in presence of sulfide the killing of the capsulated variant of the strain was significantly inhibited. Since this strain required higher serum concentrations to be killed by the polymorphonuclear leukocytes, it suggested that sulfide interfered with the opsonization of the bacteria. The capacity of sulfide to split the disulfide bonds of complement factor 3 and immunoglobulin G, deposited on the bacterial surface, was evaluated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. There was no detectable effect of 2 mM sulfide on immunoglobulin G. However, sulfide released from opsonized bacteria the beta-chain of C3b C3bi, and the C-terminal part of the alpha-chain of C3bi. This region of the alpha-chain of C3bi has been suggested to bind to the complement receptor 3 of polymorphonuclear leukocytes. The beta-chain of C3b/C3bi may augment the binding of opsonized bacteria to the complement receptors of polymorphonuclear leukocytes. The formation of sulfide by the microflora of the periodontal pockets may provide conditions for the bacteria to escape important parts of the host immune system.

Anaerobiosis↗
PubMed2006

The C-terminus of complement regulator Factor H mediates target recognition: evidence for a compact conformation of the native protein.

The complement inhibitor Factor H has three distinct binding sites for C3b and for heparin, but in solution uses specifically the most C-terminal domain, i.e. short consensus repeats (SCR) 20 for ligand interaction. Two novel monoclonal antibodies (mABs C14 and C18) that bind to the most C-terminal domain SCR 20 completely blocked interaction of Factor H with the ligands C3b, C3d, heparin and binding to endothelial cells. In contrast, several mAbs that bind to the N-terminus and to the middle regions of the molecule showed no or minor inhibitory effects when assayed by enzyme-linked immunosorbent assay (ELISA) and ligand interaction assays. This paradox between a single functional binding site identified for native Factor H versus multiple interaction sites reported for deletion constructs is explained by a compact conformation of the fluid phase protein with one accessible binding site. On zymosan particles mAbs C14 and C18 blocked alternative pathway activation completely. Thus demonstrating that native Factor H makes the first and initial contact with the C terminus, which is followed by N terminally mediated complement regulation. These results are explained by a conformational hypothetical model: the native Factor H protein has a compact structure and only one binding site accessible. Upon the first contact the protein unfolds and exposes the additional binding sites. This model does explain how Factor H mediates recognition functions during complement control and the clustering of disease associated mutations in patients with haemolytic uraemic syndrome that have been reported in the C-terminal recognition domain of Factor H.

Antibodies, Monoclonal↗
PubMed1986

Evasion of alternative complement pathway by Trypanosoma cruzi results from inefficient binding of factor B.

During its differentiation in the insect vector to a stage infective for the mammalian host, Trypanosoma cruzi becomes resistant to lysis by the alternative pathway of complement. To elucidate the mechanism of complement evasion, we studied control of complement activation on the surface of the noninfective epimastigote and the infective culture-derived metacyclic trypomastigote stages (CMT) of T. cruzi. It was found that the predominant form of complement component C3 on epimastigotes is C3b, whereas the majority of C3 on CMT is in the form of the hemolytically inactive fragment iC3b, which cannot participate in C5 convertase formation or lead to deposition of the lytic C5b-9 complex. Our results also showed that C3 binds by a covalent ester linkage to surface molecules of different molecular weight in the epimastigote stage and CMT. Binding studies with purified complement components indicated that CMT do not support efficient formation of an alternative pathway C3 convertase. C3b on the parasite surface fails to bind the amplification component, factor B, rather than showing enhanced binding of the control component, factor H. These results identify the biochemical basis for evasion of complement-mediated killing in T. cruzi and reveal a mechanism for developmental regulation of complement activation.

Animals↗
PubMed1997

Ig N-glycan orientation can influence interactions with the complement system.

This study was prompted by the paradoxical observation that a pair of dinitrophenyl-specific murine monoclonal IgG2a Abs had similar monosaccharide content and yet differed in their binding to lectins. The differential lectin-binding properties were lost when the Abs were denatured, suggesting that variations in lectin binding reflected the conformational accessibility of the N-glycans rather than intrinsic differences in the lectin binding capacity of the glycans themselves. This hypothesis was supported by experiments indicating that the degree to which the N-glycans on the Abs were reactive with beta-1,4-galactosyltransferase or susceptible to peptide N-glycosidase F corresponded directly to their relative accessibility to lectins. Moreover, the relative susceptibility to these enzymes and accessibility to lectins was inversely related to the capacity of the Abs to activate the classical pathway, suggesting that the orientation of the more accessible N-glycan might inhibit C1q binding. This hypothesis was supported by evidence that enzymatic cleavage of the more accessible N-glycan resulted in enhanced Clq, C4b, and C3b deposition. Conversely, removal of the less accessible N-glycan expressed by the other Ab inhibited C1q, C4b, and C3b deposition. The respective increase or decrease in C3b deposition on the two deglycosylated Abs was magnified when complement activation was performed in factor B-depleted serum, suggesting that N-glycan conformation primarily affects the classical pathway. Collectively, these data suggest that the orientation of the N-glycan expressed on Igs can profoundly influence interaction with the complement system.

Amidohydrolases↗
PubMed2002

Streptococcus pneumoniae evades complement attack and opsonophagocytosis by expressing the pspC locus-encoded Hic protein that binds to short consensus repeats 8-11 of factor H.

Streptococcus pneumoniae is an important cause of upper and lower respiratory tract infections, meningitis, peritonitis, bacterial arthritis, and sepsis. Here we have studied a novel immune evasion mechanism of serotype 3 pneumococci, which are particularly resistant to phagocytosis. On their surfaces the bacteria express the factor H-binding inhibitor of complement (Hic), a protein of the pneumococcal surface protein C family. Using radioligand binding, microtiter plate assays, surface plasmon resonance analysis, and recombinant constructs of factor H, we located the binding site of Hic to short consensus repeats (SCRs) 8-11 in the middle part of factor H. This represents a novel microbial interaction region on factor H. The only other ligand known so far for SCRs 8-11 of factor H is C-reactive protein (CRP), an acute phase protein that binds to the pneumococcal C-polysaccharide. The binding sites of Hic and CRP within the SCR8-11 region were different, however, because CRP did not inhibit the binding of Hic and required calcium for binding. Binding of factor H to Hic-expressing pneumococci promoted factor I-mediated cleavage of C3b and restricted phagocytosis of pneumococci. Thus, virulent pneumococci avoid complement attack and opsonophagocytosis by recruiting functionally active factor H with the Hic surface protein. Hic binds to a previously unrecognized microbial interaction site in the middle part of factor H.

Bacterial Proteins↗
PubMed1998

Complement activation by diesel exhaust particles (DEP).

The effect of diesel exhaust particles (DEP) on the hemolytic activity of human serum complement was investigated. Previous treatment of human serum with DEP extracts at 37 degrees C decreased the hemolytic activity of human serum complement dose dependently, to 20% of its original value. This decrease in complement activity by DEP extracts was observed with previous incubation at 37 degrees C but not at 4 degrees C. A decrease in complement activity was observed after previous incubation at 37 degrees C in the presence of EGTA/Mg but not in the presence of EDTA, indicating that the alternative pathway of the complement system had been activated by DEP extracts. Activation of the complement system by DEP extracts was further demonstrated by observation of the cleavage of the third component of the complement (C3) in serum to C3b with immunoelectrophoresis using goat anti-human C3 antiserum. This cleavage of C3 was similarly observed in the presence of EGTA/Mg, indicating the activation of the alternative pathway of the complement system by DEP extracts. These results indicate that DEP can activate the alternative pathway of the complement system, resulting in a decrease in the hemolytic activity of complement and in the production of biologically active degradation products of complement proteins such as C3a. The biological significance of the activation of the complement by DEP in the alveolus is discussed in relation to the influx of neutrophiles.

Animals↗
PubMed1985

Mechanisms of complement activation by crystalline cholesterol.

The mechanism by which cholesterol crystals activate complement in human serum has been studied. Crystals treated with serum and washed with buffer contain a fixed C3/C5 convertase. Its generation is dependent on the presence of divalent cations (and of factor B). The cholesterol-fixed convertase is subject to decay and can be regenerated by factors B and D. C2 in combination with C1 is not essential but enhances the convertase formation. These findings indicate that it is predominantly the alternative C3/C5 convertase C3bBb(P) that assembles on cholesterol during exposure to human serum. By the use of different antisera and immunofluorescence a C3 fragment, probably C3b, was demonstrated on serum-treated crystals. Its fixation is resistant to washing with urea, and with buffers of differing pH: by hydroxylaminolysis the C3 fragment dissociates from the crystals. This indicates a covalent ester bond linking the labile binding site of activated C3 to the hydroxyl group of cholesterol. Cholesterol acetate does not fix C3 nor acquire a C3-cleaving activity upon contact with serum. In addition, cholesterol crystals bind factor I (C3b inactivator) and in this way may facilitate fixation and amplification of the alternative C3/C5 convertase.

Cholesterol↗
PubMed1982

Guinea pig erythrocytes, after their contact with influenza virus, acquire the ability to activate the human alternative complement pathway through virus-induced desialation of the cells.

Guinea pig erythrocytes that had been exposed to influenza A virus activated the alternative complement pathway in whole human serum in the absence of natural antibodies. Because all virus particles were eluted from the treated cells, activation was not dependent on antiviral antibodies or on virus particles themselves. The relative capacity of treated erythrocytes to activate the alternative pathway was dependent on the amount of virus to which the cells had been exposed and was directly related to the amount of sialic acid removed from the erythrocyte membrane during incubation with either whole virus particles or purified viral sialidase. C3b bound to cells that had been treated with virus, and P-stabilized amplification convertase sites P,C3b,Bb formed on these cells, exhibited increased resistance to the action of the regulatory proteins beta-1H and C3b Ina compared with C3b and P,C3b,Bb on untreated, nonactivating cells. The acquired resistance of the cell-bound, P-stabilized amplification convertase to decay-dissociation by beta-1H was directly related to the activating capacity of the treated cells in whole serum (r = 0.95) and to the amount of sialic acid removed from the cells by the virus (r = 0.98). Desialation represents a specific alteration of the cell surface by which a nonimmune host, through activation of the alternative pathway, may deposit C3b on a target cell that had been exposed to influenza virus and may lyse virus virus-modified cells during orthomyxovirus infections.

Animals↗
PubMed2005

Serum complement factor I decreases Staphylococcus aureus phagocytosis.

Complement-mediated opsonization of Staphylococcus aureus is a critical host defense in animal models. Specifically, C3b and CD35 play important roles in effective opsonophagocytosis of S. aureus. We have shown that complement control protein factor I mediates cleavage of the complement opsonin C3b bound to the S. aureus surface. In this study, we examined the physiologic relevance of this observation by determining whether factor I-mediated cleavage of S. aureus-bound C3b decreased phagocytosis of S. aureus by neutrophils. Compared with controls, anti-factor I antibody inhibited C3b-cleavage on the S. aureus surface by >83% (as measured by iC3b generation) and increased phagocytosis of S. aureus by >100%. Treatment of C3b-coated S. aureus with factor I increased generation of iC3b (75%), decreased the total amount of C3-fragments bound to the S. aureus surface (58%), and decreased the number of bacteria phagocytosed (40%). Testing specifically for C3-fragments shed from the S. aureus surface, we found that factor I increased shedding (43%). Notably, these factor I-mediated effects were of the same magnitude regardless of whether factor H, a known cofactor for factor I, was present. These findings indicate that S. aureus benefits from, and possibly manipulates, the normally host-protective activity of factor I cleavage of C3b, which results in bacterial escape from complement-mediated opsonophagocytosis. Because escaping opsonophagocytosis-mediated destruction is a necessary mechanism for bacterial survival resulting in human disease, preventing cleavage of C3b on the S. aureus surface, and thereby enhancing opsonophagocytosis, is a promising potential target for therapeutic intervention.

Antibodies, Blocking↗
PubMed1994

An indirect effect of an antibody on complement deposition and lysis of differently sensitized surrounding cells.

Lysis of papain-treated group A and B erythrocytes by human complement was studied by an anti-A (BRIC. 131) and an anti-B (BRIC. 30) IgM monoclonal antibody in 51Cr release assays. The indirect effect of membrane-bound antibody, i.e. its influence on complement binding to sensitized surrounding cells, was examined in a cold target competition test in which sensitized, non-labelled cells are present along with sensitized labelled cells and complement. The mode by which anti-A antibodies indirectly suppressed lysis of sensitized B cells up to 20-fold was studied by following C1q and C3b binding. C1q binding to both types of erythrocytes was not altered in mixed populations of erythrocytes in the presence of both antibodies. Binding of C3b to a mixture of both cell types was, however, suppressed, when both antibodies were present. C3b deposition in mixed cell populations did not reach a significantly higher extent than deposited to one type of erythrocyte alone. This was consistent with the results from competitive lysis and suggests that the anti-A captured most C3b at high anti-A concentrations and deprived the similarly sensitized B erythrocytes of complement. We think that this phenomenon is not due to an uneven removal of complement regulatory proteins from A and B erythrocytes by papain. Instead, the phenomenon might be due to an inherent property of anti-A mAb to better produce nucleation sites for C3 convertases which, upon binding factor B, better compete for the limiting factor D. A mathematical analysis of cold target competition experiment (containing 2430 individual measurements) also shows that the distribution of complement between the competing A and B erythrocyte population is uneven, since it predicts that in any given antibody combination the majority of complement is bound to A erythrocytes. This is consistent with the measured average percentage of lysis.

ABO Blood-Group System↗
PubMed1992

Association of subepithelial deposition of activated complement and immunoglobulin G and M response to gluten in celiac disease.

Patients with celiac disease produce not only immunoglobulin A (IgA) but also immunoglobulin G (IgG) and M (IgM) antibodies to gluten. Intake of dietary gluten may hence induce local complement activation and mucosal damage. Jejunal tissue sections from adult patients with celiac disease were examined by immunofluorescence with monoclonal antibodies to activation neoepitopes in C3b and the terminal complement complex (TCC). Subepithelial deposition of TCC was observed in 93% of 28 untreated and in 57% of 23 partly treated study subjects. The immunofluorescence staining intensity was well correlated with the serum level of gluten-specific IgG and IgM (but not IgA), the number of mucosal IgG-producing cells, and the degree of villous atrophy. Similar immune deposits were not observed in 5 successfully treated patients with celiac disease, 5 patients with dermatitis herpetiformis without jejunal villous atrophy, and 90% of 21 control patients with histologically normal jejunal mucosa. Gluten challenge increased the amount of subepithelial TCC and produced additional C3b deposition, suggesting recent complement activation. Ingested gluten might thus, via Ig-mediated subepithelial complement activation, damage the surface epithelium in celiac disease and induce compensatory crypt hyperplasia.

Adolescent↗