Biomedical subjects

A J Tenner

Publications and source records attributed to A J Tenner.

At least 37 records · Page 2Linked to original sources

PubMed1998

C1qRP, the C1q receptor that enhances phagocytosis, is detected specifically in human cells of myeloid lineage, endothelial cells, and platelets.

The complement component C1q can interact with a variety of different cells, resulting in multiple functional consequences depending on the cell type. mAbs R3 and R139, which recognize a 126,000 Mr (reduced) cell surface protein, are able to abrogate the C1q-mediated enhancement of monocyte phagocytosis. The cDNA encoding this C1q receptor that modulates phagocytosis, C1qRP, has recently been cloned. Using a DNA probe based on the coding region of the receptor, Northern blot and RT-PCR analysis of RNA isolated from different cell types showed C1qRP expression in cells of myeloid origin and in endothelial cells, but not in cells of lymphoid origin nor in the HeLa epithelial-like cell line or iliac artery smooth muscle cells. FACS analysis of cell surface expression of C1qRP, as detected by mAb R139 and R3, corresponded in all cases to the mRNA levels detected. Using the anti-C1qRP mAb, the 126,000 Mr receptor was also detected in lysates of human platelets. Interestingly, C1qRP is not expressed by the promyelocytic leukemia cell line HL-60, and differentiation of these cells with various chemical compounds did not induce C1qRP expression. It has been reported that C1q can induce specific receptor-mediated responses in fibroblasts. However, RNA and cell surface expression analysis for C1qRP indicate that this particular C1q receptor is not expressed by either human gingival or human skin fibroblasts. These data demonstrate selective expression of C1qRP in specific cell types and support the hypothesis that there is more than one C1q receptor mediating the diverse responses triggered by C1q.

Blood Platelets↗

PubMed1998

C1q receptors: regulating specific functions of phagocytic cells.

A C1q receptor that upregulates the phagocytic capacity of professional phagocytes, C1qRp, has been identified, and its primary structure determined by cDNA cloning and sequencing. Monoclonal antibodies that immunoprecipitate this 126,000 Mr polypeptide inhibit the enhancement of phagocytosis triggered not only by C1q but also by mannose binding lectin (MBL) and pulmonary surfactant protein A (SPA) providing critical evidence that this polypeptide is a functional receptor or component of the receptor that mediates this enhancement of phagocytosis. The amino acid sequence, deduced from the cloned cDNA coding for this receptor, indicates that this surface glycoprotein receptor is a novel type I membrane protein of 631 amino acid containing a region homologous to C-type lectin carbohydrate recognition domains, 5 EGF-like domains, a single transmembrane domain and a 47 amino acid intracellular domain. Expression of this receptor is limited to cells of myeloid origin, platelets and endothelial cells, consistent with a relatively selective function, and making it an attractive candidate for therapeutic modulation of function. A distinct C1q receptor that triggers superoxide in polymorphonuclear leukocytes has been functionally characterized and designated as C1qRO2-. Thus, the accumulated data that will be summarized here demonstrate that there are at least two C1q receptor/receptor complexes (C1qRp and C1qRO2-), each triggering distinct cellular responses, that multiple C1q receptors can be expressed on the same, as well as on different, cell types, and that at least one C1q receptor, C1qRp, is capable of responding to multiple ligands.

Animals↗

PubMed1998

C1q--how many functions? How many receptors?

C1, the first component of the classical pathway of complement activation is a complex of three proteins called C1q, C1r and C1s. Normally, C1q binding to aggregated IgG molecules results in activation of the classical pathway of complement. However, C1q has a number of other observed functions, not directly related to complement, that could be mediated by recently identified binding proteins acting as cell-surface receptors or soluble modulators of C1q-mediated functions. This article discusses the various activities of C1q and the evidence that these functions might be influenced by both membrane-bound and soluble C1q-binding proteins.

Animals↗

PubMed1997

Complement activation by cross-linked truncated and chimeric full-length beta-amyloid.

The activation of complement by beta-amyloid (A beta) has been implicated in the local inflammatory response in Alzheimer's disease. To assess the structural parameters required for this activation, beta-sheet-containing fibrils of A beta1-28 were induced by low pH and then chemically cross-linked to constrain the beta-sheet conformation. Chimeric A beta peptides with a substituted C-terminal sequence derived from two different transmembrane proteins were also assessed for the ability to form fibrils rich in beta-sheet structure and to activate complement. Both the cross-linked A beta1-28 and the chimeric A beta peptides were strong activators of the classical complement pathway. These results suggest that the C-terminal residues (29-42) of A beta facilitate fibril assembly required for complement activation but do not contain the interaction sites required for complement activation, further supporting the hypothesis that C1q binds to the N-terminal hydrophilic domain of A beta, and that a fibrillar beta-sheet-rich conformation is required for effective binding and activation of C1.

Amino Acid Sequence↗

PubMed1997

The progression of beta-amyloid deposition in the frontal cortex of the aged canine.

Brains from 41 aged canines (> or = 10 years of age) were examined immunohistochemically to characterize the laminar distribution and age-related progression of beta-amyloid (A beta) in frontal cortex. We classified the A beta patterns into four distinct types. Type I was characterized by small, faint deposits of A beta in deep cortical layers. Type II consisted of diffuse deposits of A beta mainly in layers V and VI. Type III had both dense plaques in superficial layers, and diffuse deposits in deep layers. Finally, Type IV had solely dense plaques throughout all layers of cortex. We compared the A beta distribution pattern between the Old canines (10-15 years, n = 22) and the Very Old canines (> 15 years, n = 19). The Old group primarily had negative staining, or Type I and Type II patterns of amyloid deposition (73%). Conversely, the Very Old group had predominantly Types II, III and IV deposits (89.5%), a difference that was significant (P < 0.05). We suggest that A beta deposition in canine frontal cortex is a progressive age-related process beginning with diffuse deposits in the deep cortical layers followed by the development of deposits in outer layers. In support of this hypothesis, the deeper layer diffuse plaques in the Very Old group of dogs also contain the largest proportion of beta-amyloid with an isomerized aspartic acid residue at position 7, indicating that these deposits had been present for some time. We also observed fiber-like A beta immunoreactivity within regions of diffuse A beta deposits. These fibers appeared to be degenerating neurites, which were negative for hyperphosphorylated tau. Therefore, these fibers may represent a very early form of neuritic change that precede tau hyperphosphorylation or develop by an alternative pathway.

Aging↗

PubMed1997

cDNA cloning and primary structure analysis of C1qR(P), the human C1q/MBL/SPA receptor that mediates enhanced phagocytosis in vitro.

The complement protein C1q, mannose-binding lectin (MBL), and pulmonary surfactant protein A (SPA) are structurally similar molecules that enhance phagocytic function in vitro. Monoclonal antibodies R3 and R139, which inhibit the enhancement triggered by these three ligands, were used to purify a 126,000 M(r) cell surface protein designated C1qR(P). Amino acid sequence was obtained and the corresponding cDNA was cloned. C1qR(P) is a novel type I membrane protein with the following putative structural elements: a C-type carbohydrate recognition domain, five EGF-like domains, a transmembrane domain, and a short cytoplasmic tail. All peptides identified by amino acid sequencing are encoded by the cDNA. Additionally, an anti-peptide antiserum was generated, which is reactive with C1qR(P). The data indicate that the cloned cDNA encodes the receptor that plays a role in C1q/MBL/SPA-mediated removal or destruction of pathogens and immune complexes by phagocytosis.

Amino Acid Sequence↗

PubMed1997

Aspartate residue 7 in amyloid beta-protein is critical for classical complement pathway activation: implications for Alzheimer's disease pathogenesis.

Fibrillar amyloid beta-protein has been implicated in the pathogenesis of Alzheimer's disease because of its neurotoxicity and its ability to activate complement. Reactive microglia, astrocytes and complement (C') components (reviewed in ref. 6) are associated with senile plaques, the fibrillar, beta-sheet assemblies of amyloid beta-peptide found predominantly in brain from individuals with AD (ref. 7). These indications of inflammatory events are not prevalent in the nonfibrillar "diffuse" plaques often seen in age-matched control cases without dementia. Clinical studies over the past several years have correlated the use of anti-inflammatory drugs with a decrease in the incidence and progression of AD dementia and/or dysfunction, supporting a role for gliosis and inflammation in AD pathogenesis (reviewed in ref. 6). C5a, a product of C' activation, is chemotactic for microglia. Thus, complement activation provides a specific mechanism for recruiting reactive glial cells to the site of the fibrillar amyloid beta-protein plaque, which could lead to inflammatory events, neuronal dysfunction and degeneration. With the use of truncated amyloid beta-peptides, the region of amyloid beta-protein limited by residues 4 and 11 has been identified as critical in the interaction between amyloid beta-protein and C1q, the recognition component of the classical complement pathway (CCP), which results in the activation of C'. Furthermore, substitution of an isoaspartic acid for aspartic acid at amyloid beta-protein residue 7 resulted in the complete elimination of CCP-activating activity. A molecular model of this interaction has been generated that should be useful in the design of candidate therapeutic inhibitors of CCP activation by amyloid beta-protein.

Alzheimer Disease↗

PubMed1996

Localization and cell association of C1q in Alzheimer's disease brain.

The complement protein, C1q, has been shown to bind to fibrillar beta-amyloid, resulting in the activation of the classical complement pathway. C1q has also been found associated with most but not all amyloid deposits in brain. To determine whether C1q is exclusively associated with plaques containing the fibrillar form of beta-amyloid, normal and Alzheimer brain were immunohistochemically double labeled using thioflavine, which specifically stains beta-amyloid in a beta-sheet conformation, and an affinity- purified antibody to human C1q. C1q immunostaining was colocalized with nearly all thioflavine-positive plaques, while C1q was not detected in beta-amyloid immunopositive plaques which were thioflavine-negative. Beta-amyloid plaques in nondemented controls (which are typically thioflavine-negative) were also negative for C1q. Microglia and astrocytes of reactive morphology were also associated with C1q-positive plaques and neurons. Interestingly, many neuronal cells in the AD brain, but not microglia or astrocytes, stained prominently with anti-C1q. Neurons in control brain were not C1q positive. Our data suggest that some of these C1q-positive structures were neurofibrillary tangles immunoreactive for hyperphosphorylated tau, which may be binding extracellular C1q. However, a large number of the C1q-positive neurons had intact cell morphology; suggesting that these cells may be synthesizing this critical complement component. Since the presence of C1q suggests the activation of complement and/or the activation of proinflammatory events, and the specific class of plaques that contain C1q are the type that corresponds to observed clinical dementia, these findings further support the hypothesis that complement plays a role in the pathogenesis of AD.

Alzheimer Disease↗

PubMed1995

Localization of the site on the complement component C1q required for the stimulation of neutrophil superoxide production.

C1q, the recognition subunit of the classical complement pathway, interacts with specific cell surface molecules via its collagen-like region (C1q-CLR). This binding of C1q to neutrophils triggers the generation of toxic oxygen species. To identify the site on C1q that interacts with the neutrophil C1q receptor, C1q was isolated, digested with pepsin to produce C1q-CLR, and further cleaved with either trypsin or endoproteinase Lys-C. The resulting fragments were separated by gel filtration chromatography and analyzed functionally (activation of the respiratory burst in neutrophils) and structurally. Cleavage of C1q-CLR with endoproteinase Lys-C did not alter its ability to trigger neutrophil superoxide production. However, when C1q-CLR was incubated with trypsin under conditions permitting optimal cleavage, the ability of C1q-CLR to stimulate superoxide production in neutrophils was completely abrogated. Fractionation of the digests obtained with the two enzymes and identification by amino acid sequencing permitted localization of the receptor interaction site to a specific region of the C1q-CLR. Circular dichroism analyses demonstrated that cleavage by trypsin does not denature the remaining uncleaved collagen-like structure, suggesting that after trypsin treatment, the loss of activity was not due to a loss of secondary structure of the molecule. However, irreversible heat denaturation of C1q-CLR also abrogated all activity. Thus, a specific conformation conferred by the collagen triple helix constitutes the functional receptor interaction site. These data should direct the design of future specific therapeutic reagents to selectively modulate this response.

Amino Acid Sequence↗

PubMed1995

C1q triggers neutrophil superoxide production by a unique CD18-dependent mechanism.

Complement protein C1q induces the production of superoxide (O2-) by neutrophils via an as yet unidentified receptor or receptor complex. Several strategies were therefore used to identify cell surface molecules involved in the response of neutrophils to C1q and its collagen-like domain (C1q-CLR). Treatment of neutrophils with phosphatidylinositol-specific phospholipase C effectively removed the phosphatidylinositol-linked surface molecules CD14 and CD16, yet did not reduce O2- production in response to C1q. Next, 17 monoclonal antibodies (mAbs) recognizing various neutrophil surface antigens were tested for their ability to inhibit C1q-CLR-mediated O2- production. Only two of the mAbs, 44a and IB4, which recognize CD11b/CD18 (complement receptor 3 or Mac-1), were inhibitory. In addition, neutrophils from a patient with leukocyte adhesion deficiency, which are CD18 deficient, did not produce O2- in response to C1q or C1q-CLR. Because CD11b/CD18 is recognized to play a role in cell adhesion, the role of adherence in C1q-mediated O2- production was explored. Adherence of neutrophils to C1q-CLR-coated surfaces occurred with kinetics, which usually paralleled those of O2- production, and was invariably abolished by the anti-CD11b mAb 44a. However, this mAb often only partially inhibited O2- production, indicating that an avid attachment of neutrophils to the C1q-CLR-coated surface is not required for O2- production.

Antibodies, Monoclonal↗

PubMed1995

Cultured rat microglia express C1q and receptor for C1q: implications for amyloid effects on microglia.

Senile plaques, the pathological hallmark of Alzheimer's disease (AD), are associated with complement components, including C1q. Reactive microglia appear to be involved in the later stages of plaque development. Since tissue macrophages are known to synthesize C1q, cultured rat microglia were examined for C1q immunoreactivity. Anti-C1q staining was detected, particularly in process-bearing microglia, indicating constitutive expression of C1q. Thus, microglia could provide a source of C1q for plaques even before becoming reactive. Since it has been previously shown that C1q binds beta 1-42, the major constituent of senile plaques, and since beta 1-42 is toxic to microglia in vitro, we asked if preincubation of beta 1-42 with C1q alters either metabolic indices of amyloid-induced degeneration in microglial cultures or the formation of amyloid deposits on these cells. While electron microscopic analysis of negatively stained amyloid fibrils confirmed that pre-incubation with C1q induced the association of C1q with the fibrils, no effect of the binding of C1q to beta 1-42 on beta 1-42 toxicity in microglia was observed. Interestingly, immunoreactivity for the C1q receptor that is known to modulate phagocytosis was found and was up-regulated in non-process-bearing microglia by interferon-gamma. While these data exclude a role for the C1q receptor in beta 1-42 toxicity in microglia, the observed expression and up-regulation of C1q receptor on microglia by interferon-gamma would be consistent with a role for C1q in complement-mediated inflammatory responses in AD and as a potential activator of microglial function in plaques.

Alzheimer Disease↗

PubMed1995

Mannose binding protein (MBP) enhances mononuclear phagocyte function via a receptor that contains the 126,000 M(r) component of the C1q receptor.

Mannose-binding protein (MBP), C1q, the recognition component of the classical complement pathway, and pulmonary surfactant protein A (SP-A) are members of a family of molecules containing a collagen-like sequence contiguous with a noncollagen-like sequence, and usually having the properties of a lectin. C1q and SP-A have been shown to enhance monocyte FcR- and CR1-mediated phagocytosis, suggesting that the common structural features of the collagen-like domains may provide a basis for this immunologically important function. Results presented here demonstrate that MBP also enhanced FcR-mediated phagocytosis by both monocytes and macrophages, and stimulated CR1-mediated phagocytosis in human culture-derived macrophages and in phorbol ester-activated monocytes. Furthermore, a monoclonal antibody that recognizes a 126,000 M(r) cell surface protein and inhibits C1q-enhanced phagocytosis, inhibited the MBP-mediated enhancement of phagocytosis. Thus, the receptors that mediate the enhancement of phagocytosis by MBP and C1q share at least one critical functional component, the 126,000 M(r) ClqRP.

Carrier Proteins↗

PubMed1994

beta-Amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain.

beta-amyloid peptides that accumulate within the brain of individuals with Alzheimer's disease bind to C1q and activate the classical C pathway via a specific interaction with a site within the collagen-like domain of C1q (C1q-CLF). Synthetic analogues of beta-amyloid peptides, beta 1-42 and beta 1-40, bound to C1q and were strong activators of C as assessed by both total C consumption and C4 consumption. beta 1-42 was significantly more effective than beta 1-40 in binding to C1q and triggering C activation, whereas beta 1-28 demonstrated little or no binding or C activation. This C-activating capacity seems to be largely correlated with the assembly of the beta 1-42 into low speed sedimentable aggregates and/or macromolecular fibrils. Radiolabeled C1q and C1q-CLF bind specifically to these aggregates or amyloid fibrils. In addition, using synthetic C1q peptides in a solid phase binding assay, the major binding site of beta 1-42 to C1q was localized to the C1q A chain collagen-like residues 14-26, a region previously described as a novel interaction site for Ab-independent activators of C1. C1q A chain peptide 14-26 blocked the ability of beta-amyloid peptides to activate the classical C pathway, providing evidence that this relatively unrecognized mechanism of C activation (via binding to the C1q-CLF) may have crucial physiologic consequences. Finally, these observations provide further support for the hypothesis that C activation and inflammation may be a component in the pathogenesis of AD and suggest possibilities for modulating the progression of AD.

Alzheimer Disease↗

PubMed1994

Cell-surface protein identified on phagocytic cells modulates the C1q-mediated enhancement of phagocytosis.

C1q, a subunit of the first component of the classical C pathway, binds to specific cells of the immune system, triggering a variety of cellular responses. To identify the functional C1qR on phagocytic cells, mAbs were generated by immunization with either C1q-binding proteins isolated from U937 cells or intact U937 cells. Immunoprecipitation followed by Western blot analysis demonstrated that three mAbs, designated R139 (IgG2b), R3 (IgM), and U40.3 (IgG1), recognize the same 100,000 M(r) protein (126,000 M(r) under reducing conditions). These mAbs also co-immunoprecipitate CD43 from detergent extracts of U937, consistent with the possibility that this C1qR is a multi-subunit structure. Two Abs, R3 and R139, but not U40.3, consistently inhibited the enhancement of phagocytosis by monocytes adhered to either C1q or the collagen-like fragment of C1q (C1q-CLF). Interestingly, binding inhibition studies demonstrated that neither R139 nor U40.3 blocked the binding of [125I]C1q-CLF to U937 cells, whereas R3 did inhibit 35 to 45% of the binding of [125I]C1q-CLF to these cells. Thus, the three mAbs recognize distinct epitopes of a 100,000 M(r) polypeptide that is a component of the monocyte C1qR that modulates phagocytosis. All three mAbs recognize the extracellular domain of the molecule on neutrophils, monocytes, and U937 cells, but were not reactive with CEM or RAJI cells, T and B lymphoblastoid cell lines, respectively. Furthermore, none of these three mAbs inhibited or mimicked the C1q-mediated stimulation of superoxide production by neutrophils, suggesting that the C1qR that mediates the enhancement of phagocytosis differs in at least some critical parameter from the C1qR that mediates superoxide generation by the neutrophil.

Antibodies, Monoclonal↗

PubMed1993

Functional aspects of the C1q receptors.

C1q, the recognition subunit of the classical complement pathway, has been shown to stimulate host defense mechanisms. It has become increasingly evident that C1q can bind to several different cell types resulting in a variety of functional consequences depending on the cell type. For example, the binding of C1q to monocytes enhances the ability of those cells to ingest pathogens, while interaction with neutrophils, eosinophils, endothelial cells and vascular smooth muscle cells triggers or enhances the generation of toxic oxygen species. While these latter oxygen products play a major role in the destruction of foreign pathogens, in some cases, such as immune-complex-induced vasculitis and myocardial infarction, these toxic oxygen molecules can cause excessive host tissue damage. The differential modulation of C1q-mediated activities by monoclonal antibodies suggest that there is more than one unique type of C1q receptor, which is not necessarily surprising given the diversity of responses reported. This review summarizes what is known about the functional consequences of the interaction of C1q with cells, and describes initial investigations of the biochemical mechanisms/signal transduction pathways involved in these C1q-induced responses. Further investigations of the C1q/C1q receptor system(s) should uncover basic mechanisms and modes of regulation of these defensive responses by the host, and potentially provide information useful for beneficial manipulation of these activities.

Animals↗

PubMed1992

Signal transduction mechanisms of C1q-mediated superoxide production. Evidence for the involvement of temporally distinct staurosporine-insensitive and sensitive pathways.

C1q, a plasma glycoprotein and the recognition component of the classical complement pathway, interacts with specific cells of the immune system resulting in the enhancement of cell function. For example, interaction of C1q with its cell-surface receptor on neutrophils induces the activation of the respiratory burst, a finding previously documented using a chemiluminescent assay to detect oxygen radical formation. In an alternative approach we have now used a modified cytochrome c reduction assay to characterize C1q-mediated production of superoxide anion (O2-) in more detail. C1q coated to microtiter wells induced O2- release, which occurred microtiter wells induced O2- release, which occurred after a lag period of 10 to 20 min, and was then sustained over approximately 1 h. O2- production could be triggered by the purified pepsin-resistant, collagen-like fragment of C1q, but not by mannose-binding protein and pulmonary surfactant protein A, proteins that also contain collagen-like domains. Concentrations of C1q which promoted a vigorous O2- generation did not induce release of neutrophil primary granules and caused little or no secondary granule release. Investigation of the biochemical events mediating C1q stimulated O2- production by neutrophils revealed that the response invoked two biochemical pathways with distinct sensitivities to previously described inhibitors. A role for Ca2+ in initiation of the response was suggested by the inhibitory effect of EGTA, the calmodulin antagonist W7, and the intracellular Ca2+ chelator BAPTA. The protein kinase inhibitor staurosporine did not inhibit the induction of the response, but did block that component of the response occurring after approximately 30 min. Neither phase of C1q-mediated O2- production was inhibited by pertussis toxin, a strong inhibitor of the G-protein-coupled FMLP-mediated response. In summary, C1q-triggered O2- production is relatively unique both in terms of the kinetics of the response and the biochemical pathways evoked. These data support the hypothesis that more than one biochemical pathway induced by ligand-receptor interaction can activate the neutrophil NADPH oxidase.

Alkaloids↗

PubMed1991

Phagocytic cell molecules that bind the collagen-like region of C1q. Involvement in the C1q-mediated enhancement of phagocytosis.

C1q binds to and elicits cellular responses by several cell types, including monocytes, macrophages, neutrophils, B cells, and fibroblasts. The cell-binding domain is located within the collagen-like pepsin-resistant region of the C1q molecule (C1q tails). An affinity matrix of C1q tails coupled to Sepharose was used to select C1q-binding proteins from detergent extracts of surface-iodinated human monocytes, polymorphonuclear leukocytes, and the U937 cells. The major radiolabeled polypeptide eluted specifically from the ligand affinity column had an apparent molecular mass (Mr) of 126,000. Minor iodinated components eluted from Sepharose-tails migrated with Mr of 216,000 and 55,000. When subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions no change in the migration of any of these polypeptide bands was detected. None of these polypeptides reacted with antibodies directed against the integrins alpha 5 beta 1 (fibronectin receptor) or alpha v beta 3 (vitronectin receptor), LFA-1, or to several other cell adhesion molecules. The Mr 126,000 band was found to contain more than one polypeptide. Lectin binding properties, susceptibility to glycosidases and proteases, and immunoreactivity with the monoclonal antibody L-10, indicated that CD43 (sialophorin/leukosialin) is a component of this band. However, further data show that a monoclonal antibody, generated by immunization with the isolated Clq-binding fractions, recognizes a cell surface sialoglycoprotein distinct from CD43 and inhibits the C1q-mediated enhancement of phagocytosis in monocytes. These latter observations provide the first definitive connection between a specific phagocytic cell surface protein and a known C1q-mediated function. While these proteins contain sialic acid, binding assays and functional assays using neuraminidase-treated cells demonstrate that the functional interaction between C1q and the cell surface is not via sialic acid. The data taken together indicate either that the functional C1q receptor on phagocytic cells is a multi-subunit complex or that multiple proteins can interact with the fragment of C1q containing the cell-binding domain, at least one of which is involved in the C1q-mediated enhancement of phagocytosis.

Amino Acid Sequence↗

PubMed1991

Complement subcomponent C1q stimulates Ig production by human B lymphocytes.

The regulation of Ig production by human B lymphocytes is a complex process involving interactions among B cells, APC, T lymphocytes and soluble factors including activation, growth, and differentiation factors. Components of the complement system, including C3a, C3b, C3d, and C5a, have been shown to influence various stages in this process. In this study, we demonstrate that the C1q subcomponent of complement binds to both small resting and large activated B cells and stimulates immunoglobulin production by Staphylococcus aureus Cowan-activated tonsillar B lymphocytes. This effect is present whether C1q is added to the B cells either at the beginning or near the end of a 7-day culture period and is not associated with enhancement of proliferation. The C1q stimulation of Ig production is, however, associated with increased steady state levels of mRNA for the mu Ig H chain. Furthermore, C1q stimulated IgM production by the human B cell line SKW 6.4, which is capable of secreting IgM in response to B cell differentiation factors (BCDF). SLE is a disorder frequently associated with polyclonal activation of B lymphocytes. We studied the effect of C1q on B cells from two patients with this disorder and one with an SLE-like illness, all selected for the predominance of either IgM or IgG in serum. Spontaneous or BCDF-stimulated Ig secretion was of the isotype predominant in vivo, whereas C1q selectively stimulated B cells to produce the other isotype (IgG vs IgM). Thus, C1q interacts with B lymphocytes in a manner distinct from that of BCDF found in mixed lymphocyte supernatants. C1q may be an important factor influencing the production of Ig by B lymphocytes in normal individuals and in patients with abnormalities of B cell activity.

B-Lymphocytes↗