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PubMed2003

Valvular endocarditis associated with Helcococcus ovis infection in a bovine.

A 12-month-old Angus bull calf with a history of fever and lethargy of several weeks' duration was necropsied. Macroscopic findings included general dehydration, congestion, and edema within the craniodorsal lobes of the lung, multifocal ecchymotic hemorrhages on the dorsal epaxial and gluteal muscles, bloody ingesta within the gastrointestinal tract, and a 4- x 4- x 5-cm irregular plaque located on the right atrioventricular heart valve. Microscopically, there were focally extensive pulmonary alveolar infiltrates of histiocytes and neutrophils, large numbers of necrotic hypereosinophilic hepatocytes located within the centrilobular and midzonal regions of the liver, and, within the plaque from the right atrioventricular valve, a large mass formed by abundant laminated fibrin that contained numerous small multifocal aggregates of gram-positive cocci. This report describes the first apparent isolation of Helcococcus ovis from cattle.

Animals↗
PubMed2001

Sperm protein 17 is expressed on normal and malignant lymphocytes and promotes heparan sulfate-mediated cell-cell adhesion.

Sperm protein 17 (Sp17) is a highly conserved mammalian protein present on acrosome-reacted sperm that is thought to promote fertilization by binding sulfated carbohydrates of the oocyte zona pellucida. Although Sp17 was originally described as a testis-specific antigen, emerging evidence indicates that it may be more ubiquitously expressed than was previously thought. With the use of a specific antiserum, Sp17 was found to be present on the surface of malignant lymphoid cells, including B- and T-lymphoid cell lines, and on the surface of primary cells isolated from 2 patients having B-lymphoid tumors. Surprisingly, circulating B lymphocytes isolated from healthy volunteers also expressed Sp17, while circulating T lymphocytes exhibited only very weak expression. The role of Sp17 in promoting lymphoid cell adhesion was addressed with the use of recombinant Sp17 (rSp17). The rSp17 binds to the surface of myeloma cells but not to cells pretreated with heparitinase, an enzyme that removes heparan sulfate from the cell surface. Moreover, rSp17 promotes extensive aggregation of cells that express the syndecan-1 heparan sulfate proteoglycan, but in contrast, cells lacking syndecan-1 expression fail to aggregate in the presence of rSp17. These findings suggest that Sp17 promotes heparan sulfate-mediated cell aggregation and thereby plays a role in regulating adhesion and migration of normal and malignant lymphocytes.

Antigens, Surface↗
PubMed1999

Alternative splicing of lactophorin mRNA from lactating mammary gland of the camel (Camelus dromedarius).

The objective of this study was to determine the corrected structure of lactophorin, a major whey protein in camel milk. The protein had 60.4% amino acid sequence identity to a proteose peptone component 3 protein from bovine whey and 30.3% identity to the glycosylation-dependent cell adhesion molecule 1 in mice. The N-terminal heterogeneity of the protein was a result of alternative mRNA splicing. About 75% of the protein was expressed as a long variant A with 137 amino acid residues and a molecular mass of 15.7 kDa; about 25% was as a short variant B with 122 amino acid residues and a molecular mass of 13.8 kDa. Both proteins are probably threefold phosphorylated. In contrast to the related proteins, no glycosylation was found in camel lactophorin. Because of this difference, specific interaction with carbohydrate binding proteins, as reported for the murine protein, can be excluded, and a function of the protein other than cell recognition or rotaviral inhibition is proposed. The concentration of lactophorin in camel milk was found to be about three times higher than the concentration of the bovine homologue in bovine milk. Pronounced similarities existed between the primary and secondary structures of bovine and camel proteins. We speculated that camel lactophorin has a similar function to that of bovine protein in milk, which is supposed to be the prevention of fat globule aggregation and the inhibition of spontaneous lipolysis by lipoprotein lipase.

Alternative Splicing↗
PubMed2003

TNF-alpha plus IFN-gamma induce connexin43 expression and formation of gap junctions between human monocytes/macrophages that enhance physiological responses.

In this work, the effects of bacterial LPS, TNF-alpha, and IFN-gamma on gap junctional communication (dye coupling) and on the expression of connexin43 (immunofluorescence, immunoblotting, and RT-PCR) in monocytes/macrophages were studied. Freshly isolated human monocytes plated at high density and treated either with LPS plus IFN-gamma or TNF-alpha plus IFN-gamma became transiently dye coupled (Lucifer yellow) within 24 h. Cells treated with LPS, TNF-alpha, or IFN-gamma alone remained dye uncoupled. In dye-coupled cells, the spread of Lucifer yellow to neighboring cells was reversibly blocked with 18 alpha-glycyrrhetinic acid, a gap junction blocker, but it was unaffected by oxidized ATP or probenecid, which block ionotropic ATP-activated channels and organic anion transporters, respectively. Abs against TNF-alpha significantly reduced the LPS plus IFN-gamma-induced increase in dye coupling. In dye-coupled monocytes/macrophages, but not in control cells, both connexin43 protein and mRNA were detected, and their levels were higher in cells with an elevated incidence of dye coupling. In dye-coupled cells, the localization of connexin43 immunoreactivity was diffuse at perinuclear regions and thin cell processes. The addition of 18-alpha-glycyrrhetinic acid induced a profound reduction of monocyte/macrophage transmigration across a blood brain barrier model. It also induced a significant reduction in the secretion of metalloproteinase-2 in cells treated with TNF-alpha plus IFN-gamma. We propose that some monocyte/macrophage responses are coordinated by connexin-formed membrane channels expressed transiently at inflammatory sites in which these cells form aggregates.

Adjuvants, Immunologic↗
PubMed1999

Cellular defects and altered gene expression in PC12 cells stably expressing mutant huntingtin.

Expanded polyglutamine tracts cause huntingtin and other proteins to accumulate and aggregate in neuronal nuclei. Whether the intranuclear aggregation or localization of a polyglutamine protein initiates cellular pathology remains controversial. We established stably transfected pheochromocytoma PC12 cells that express the N-terminal fragment of huntingtin containing 20 (20Q) or 150 (150Q) glutamine residues. The 150Q protein is predominantly present in the nuclei, whereas the 20Q protein is distributed throughout the cytoplasm. Electron microscopic examination confirmed that most of the 150Q protein is diffuse in the nucleus with very few microscopic aggregates observed. Compared with parental PC12 cells and cells expressing 20Q, cells expressing 150Q display abnormal morphology, lack normal neurite development, die more rapidly, and are more susceptible to apoptotic stimulation. The extent of these cellular defects in 150Q cells is correlated with the expression level of the 150Q protein. Differential display PCR and expression studies show that cells expressing 150Q have altered expression of multiple genes, including those that are important for neurite outgrowth. Our study suggests that mutant huntingtin in the nucleus is able to induce multiple cellular defects by interfering with gene expression even in the absence of aggregation.

Animals↗
PubMed1999

Aggregates of acetylcholine receptors are not observed under anti-agrin staining schwann cell processes at the frog neuromuscular junction.

The frog neuromuscular junction offers a unique structure in which to observe fine details in the relationship between the motor neuron, muscle, and Schwann cell, which together comprise the neuromuscular junction. Schwann cell processes that extended from the synapse stained positively with anti-agrin antibodies. Immunocytochemistry revealed strong anti-agrin staining of the extracellular matrix surrounding the entire Schwann cell and the Schwann cell processes come in close contact with the muscle fiber. Dual-labeling experiments revealed a lack of acetylcholine receptor (AChR) aggregates on the surface of the muscle fiber directly under these anti-agrin-staining Schwann cell processes. The cDNA that codes for the C-terminal portion of agrin in frog (Rana pipiens) was cloned and sequenced. Polymerase chain reaction of frog brain, nerve, and muscle cDNA revealed that like other species, agrin transcripts that contain the B8, B11, or B19 inserts were observed only in brain tissue. Unlike other species, the exact site of the B inserts in frog was slightly altered, with the B insertion site occurring within a codon sequence. Our data are consistent with the hypothesis that Schwann cells produce agrin which lacks inserts at the B region, and that agrin lacking B inserts does not direct the aggregation of AChRs in vivo under physiological conditions and concentrations.

Agrin↗
PubMed2003

Mucosal vascular addressin cell adhesion molecule-1 is expressed outside the endothelial lineage on fibroblasts and melanoma cells.

Mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1) is predominantly expressed on high endothelial venules in inflamed tissues where it assists with leucocyte extravasation. Here we report that MAdCAM-1 has the potential to be more widely expressed outside the endothelial cell lineage than previously appreciated. Thus, MAdCAM-1 RNA transcripts and cell-surface protein were expressed by NIH 3T3 fibroblasts following activation with tumour necrosis factor-alpha (TNF-alpha), and by freshly isolated and cultured primary mouse splenic and tail fibroblasts in the absence of TNF-alpha stimulation. They were constitutively expressed by B16F10 melanoma cells, and expression was enhanced by cell activation with TNF-alpha. Mucosal vascular addressin cell adhesion molecule-1 was expressed on the apical surface of isolated cells, but became predominantly localized to cell junctions in confluent cell monolayers, suggesting it may play a role in the homotypic aggregation of cells. Tumour necrosis factor-alpha enhanced the expression of a firefly luciferase reporter directed by the MAdCAM-1 promoter in NIH 3T3 and B16F10 cells. A DNA fragment extending from nt -1727 to -673 was sufficient to confer cell-type selective expression. Mucosal vascular addressin cell adhesion molecule-1 expressed by NIH 3T3 cells was biologically active, as it supported the adhesion of TK-1 T cells in an alpha4beta7-dependent fashion. The expression of MAdCAM-1 by fibroblasts, and melanomas suggests MAdCAM-1 may play a role in regulating host responses in the periphery, leucocyte transmigration across nonendothelial boundaries, or the homotypic interactions of some malignant melanomas.

Animals↗
PubMed2006

Ubiquitin ligase Hrd1 enhances the degradation and suppresses the toxicity of polyglutamine-expanded huntingtin.

E3 ubiquitin ligases catalyze the conjugation of ubiquitin onto proteins, which acts as a signal for targeting proteins for degradation by the proteasome. Hrd1 is an endoplasmic reticulum (ER) membrane-spanning E3 with its catalytic active RING finger facing the cytosol. We speculated that this topology might allow Hrd1 to ubiquitinate misfolded proteins in the cytosol. We tested this idea by using polyglutamine (polyQ)-containing huntingtin (htt) protein as a model substrate. We found that the protein levels of Hrd1 were increased in cells overexpressing the N-terminal fragment of htt containig an expanded polyQ tract (httN). Forced expression of Hrd1 enhanced the degradation of httN in a RING finger-dependent manner, whereas silencing of endogenous Hrd1 expression by RNA interference stabilized httN. Degradation of httN was found to be p97/VCP-dependent, but independent of Ufd1 and Npl4, all of which are thought to form a complex with Hrd1 during ER-associated degradation. Consistent with its role as an E3 for httN, we demonstrate that Hrd1 interacts with and ubiquitinates httN. Subcellular fractionation and confocal microscopy revealed that Hrd1recruits HttN to the ER and co-localizes with juxtanuclear aggregates of httN in cells. Interaction of Hrd1 with httN was found to be independent of the length of the polyglutamine tract. However, httN with expanded polyglutamine tracts appeared to be a preferred substrate for Hrd1. Functionally, we found that Hrd1 protects cells against the httN-induced cell death. These results suggest that Hrd1 is a novel htt-interacting protein that can target pathogenic httN for degradation and is able to protect cells against httN-induced cell death.

Adaptor Proteins, Vesicular Transport↗
PubMed1993

Inhibition of PMA-induced, LFA-1-dependent lymphocyte aggregation by ADP ribosylation of the small molecular weight GTP binding protein, rho.

Botulinum C3 exoenzyme specifically ADP-ribosylates a group of ras-related small molecular weight GTP-binding proteins, rho, and inhibits their biological activity. Using this enzyme, we examined the function of rho in PMA-induced activation of lymphocyte function-associated antigen-1 (LFA-1) in a B lymphoblastoid cell line, JY. Northern blot analysis revealed that among the three rho genes, rhoA mRNA was predominantly expressed in JY cells. Consistently, only one [32P]ADP-ribosylated band was found when the lysate of the cells was subjected to ADP ribosylation by C3 exoenzyme. When the cells were cultured with C3 exoenzyme, this substrate was ADP-ribosylated in situ in a time- and concentration-dependent manner. Concomitant with this ADP ribosylation, PMA-induced LFA-1/intercellular adhesion molecule (ICAM)-1-dependent aggregation of JY cells was inhibited. This inhibition was blocked by prior treatment of the enzyme with an anti-C3 monoclonal antibody, and overcome by stimulation with higher concentrations of PMA. The C3 exoenzyme-induced inhibition was not affected by shaking of the cell suspension, while inhibition of aggregation by cytochalasin B was abolished by this procedure, suggesting that the inhibitory effect of the C3 exoenzyme treatment was not due to decrease in cell motility. The C3 exoenzyme treatment affected neither protein phosphorylation in JY cells before and after PMA stimulation, nor affected surface expression of LFA-1 and ICAM-1. These results suggest that rhoA protein works downstream of protein kinase C activation linking PMA stimulation to LFA-1 activation and aggregation in JY cells.

ADP Ribose Transferases↗
PubMed1969

Estrogen-induced cytodifferentiation of the ovalbumin-secreting glands of the chick oviduct.

The histological, ultrastructural, and biochemical changes occurring during hormone-induced cytodifferentiation of the ovalbumin-secreting glands in the chick oviduct have been studied. Marked perivascular edema is an initial response of the immature oviduct stroma to diethylstilbestrol administration and is accompanied by an interstitial migration of mononuclear cells. Mitotic activity in the immature mucosal epithelium increases within 24 hr, and glands begin to develop on days 2-4 as budlike invaginations into the subepithelial stroma. An immediate intracellular effect of the hormone is aggregation of previously dispersed ribosomes. Ribosomal zones in the nucleolus gain prominence, and there is a progressive development of rough endoplasmic reticulum in the epithelial cells. Extensive profiles of endoplasmic reticulum are present in the gland cells by day 6. Fine apical progranules appear in the epithelial cells on day 2, and ovalbumin can be measured immunochemically by day 3 at about the same time that new species of nuclear RNA have been identified. Ovalbumin granules form within condensing vacuoles in the Golgi zone and begin to be released into the lumina of the gland acini at about day 6 of the treatment.

Animals↗
PubMed1995

Epstein-Barr virus modulates de novo protein synthesis in human neutrophils.

Neutrophils and macrophages represent the first line of defense against microbial invaders. However, the role of phagocytes in host response to viral infection is poorly understood. We have previously shown that Epstein-Barr virus (EBV) interacts with human monocytes and modulates cytokine production in this cell type, but its effects on neutrophils are still unknown. In the present study, we investigated the presence of EBV receptor (CR2 or CD21) on neutrophils by cytofluorometry using five different anti-CD21 monoclonal antibodies (MoAbs), as well as fluoroscein isothiocyanate-EBV (FITC-EBV). Whereas no significant amount of neutrophils reacted with anti-CD21 MoAbs, studies with FITC-EBV indicated that viral particles bind to 30% of cells (in some individuals, EBV binds to more than 50% of neutrophils). This interaction is specific as it was completely inhibited by nonconjugated virus or with labeled virus preincubated with neutralizing MoAbs. After EBV treatment, cellular aggregation was observed in neutrophil cultures, an indication that neutrophils were activated. Although EBV did not induce respiratory burst activity in neutrophils, pretreatment with infectious particles enhanced (priming effect) the fMLP-induced O2- release in neutrophils. Instead of restricting our analysis to specific cytokine genes, we investigated the effects of EBV on neutrophil transcriptional events in general. The effect of this virus on de novo synthesis of total cellular RNA was first investigated by measuring the incorporation of [5-3H] uridine into total RNA. The results showed that RNA synthesis in neutrophils was significantly increased (2.3- to 21.3-fold) by EBV compared with the unstimulated controls. Live and UV-inactivated virus markedly induced RNA synthesis, whereas heat-inactivated virus lost this ability. Induction of RNA transcription was EBV specific, as an EBV-neutralizing antiserum abolished this effect. Induction of protein synthesis was also studied by measuring the incorporation of [35S] methionine and [35S] cysteine into secreted and intracellular proteins in neutrophils incubated with EBV. The synthesis of both secreted and cytoplasmic proteins was induced by EBV. One- and two-dimensional gel electrophoresis analysis showed that EBV modulates protein synthesis, because activation of the synthesis of certain proteins was accompanied by the inhibition of others. Interleukin-1 beta (IL-1 beta) and IL-1 receptor antagonist (IL-1Ra) synthesis was found to be induced by EBV. Therefore, modulation of host-response proteins such as IL-1Ra could be one of the many mechanisms by which this virus avoids rejection.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1994

Functional map of the alpha subunit of Escherichia coli RNA polymerase. Deletion analysis of the amino-terminal assembly domain.

The alpha subunit of Escherichia coli RNA polymerase plays a major role in the assembly of the core enzyme. The amino-terminal two-thirds of the alpha subunit, as far as position 235, are involved in this assembly. To define the site(s) within this region required for core enzyme assembly, we constructed a set of amino-terminal and internal deletion mutants of the rpoA gene. The overexpressed alpha derivatives were purified to apparent homogeneity and examined for their abilities to assemble beta and beta' subunits into active core enzymes in vitro. Among a total of 22 alpha derivatives tested, only four mutants retained the activity form active core enzyme. These mutants had deletions of the extreme amino-terminal residues as far as amino acid residue 30. The minimum fragment with full activity of the core assembly was alpha(21 to 235), with deletions of 20 amino-terminal and 94 carboxy-terminal amino acid residues. Most of the other mutants appeared to be defective in the formation of stable alpha dimers as analyzed by high-pressure liquid chromatography gel filtration, although some formed self-aggregates. These results, taken together, suggest that the amino-terminal region of the alpha subunit with the core assembly activity is highly structured, and any deletion within this domain disrupts its ordered conformation. Deletions of the extreme amino-terminal region did not affect transcription activation by CRP at the lacP1 promoter or by OmpR at the ompC promoter.

Chromatography, Gel↗
PubMed2002

Inducible cyclooxygenase and interleukin 6 gene expressions in nasal polyp fibroblasts: possible implication in the pathogenesis of nasal polyposis.

BACKGROUND: Inflammation is believed to be related to the pathogenesis of nasal polyp (NP). Inducible cyclooxygenase (COX-2) and interleukin (IL) 6 are important mediators of inflammation. However, no information is available regarding the expression of these mediators in nasal polyp fibroblasts (NPFs). The inductive effects of proinflammatory cytokines (IL-1alpha or tumor necrosis factor alpha) alone or in combination with prostaglandin E(2) on IL-6 and COX-2 messenger RNA (mRNA) synthesis in NPFs were investigated. DESIGN: The expressions of IL-6 and COX-2 mRNAs in NPFs and in 34 surgical specimens of NP were detected by Northern blot and in situ hybridization. RESULTS: Significant amounts of constitutive IL-6 and COX-2 mRNAs were produced in NPFs. Cytokines induced IL-6 and COX-2 mRNA synthesis in NPFs. Meloxicam (a specific COX-2 inhibitor) suppressed the induction of cytokines on IL-6 mRNA levels, and these effects could be reversed by exogenous prostaglandin E(2). In situ hybridization revealed that IL-6 and COX-2 mRNAs were detected primarily in fibroblasts, macrophages, and plasma cells. Aggregation of plasma cells as well as collagen deposition in vicinity to IL-6 mRNA-producing fibroblasts was found. Rich vascularity around COX-2 mRNA(+) fibroblasts was also identified. CONCLUSIONS: The pathogenesis of nasal polyposis involves NPFs through synthesizing IL-6 to modulate the activation of immune responses (plasma cell formation) and synthesis of stroma. Inducible cyclooxygenase also contributes to NP development by promoting vasodilatation and modulating the cytokine-induced IL-6 gene expression in NPFs.

Antineoplastic Agents↗
PubMed1976

Ultrastructural changes in the developing nucleolus following axotomy.

A large, basophilic, Feulgen-negative structure has been observed within the nucleoli of golden hamster facial motor neurons. This 'intranucleolar body' was seen, at the electron microscopic level, to be composed of granules which are thought to be ribonucleoprotein particles. At 15 days postnatal age, this aggregation of granules had not yet be appeared. However, by 20--24 days, a small intranucleolar body had developed. At maturity, the intranucleolar body had a diameter of up to 2 mum. Facial nerve axotomy at 15 days did not appreciably alter the nucleolar morphology at 19 days; neither control (opposite side) nor experimental nucleoli contained intranucleolar bodies. Normal nucleoli developed intranucleolar bodies, however, between the ages of 20 and 24 days. After axotomy at 20 days and sacrifice at 24 days, a comparison of facial neuronal nucleoli demonstrated that while an intranucleolar body formed in the control, axotomy prevented this structure from forming at its normal time. Also, when the facial nerve of an adult hamster was axotomized and observed 4 days postoperatively, an intact intranucleolar body was not seen. Instead, the granular portions of the nucleolus appeared to have been dispersed into several small aggregates. We believe that the changes observed in granule distribution, both with development and after axotomy, are morphological indications of a qualitative and/or a quantitative change in rRNA synthesis.

Age Factors↗
PubMed1994

Expression of apolipoprotein serum amyloid A mRNA in human atherosclerotic lesions and cultured vascular cells: implications for serum amyloid A function.

Altered lipoprotein metabolism and vascular injury are considered to be major parts of the pathogenesis of atherosclerotic lesions. Serum amyloid A (SAA) is a family of acute-phase reactants found residing mainly on high density lipoproteins (HDL) in the circulation. Several functions for the SAAs have been proposed that could be important in atherosclerosis. These include involvement in cholesterol metabolism, participation in detoxification, depression of immune responses, and interference with platelet functions. Like other acute-phase reactants, the liver is a major site of SAA synthesis. However, studies in the mouse have revealed that several cell types including macrophages express SAA. Furthermore, we recently found that SAA mRNA expression can be induced in the human monocyte/macrophage cell line, THP-1. In the present study, human atherosclerotic lesions of coronary and carotid arteries were examined for expression of SAA mRNA by in situ hybridization. Surprisingly, SAA mRNA was found in most endothelial cells and some smooth muscle cells as well as macrophage-derived "foam cells," adventitial macrophages, and adipocytes. In addition, cultured smooth muscle cells expressed SAA1, SAA2, and SAA4 mRNAs when treated with interleukin 1 or 6 (IL-1 or IL-6) in the presence of dexamethasone. These findings give further credence to the notion that the SAAs are involved in lipid metabolism or transport at sites of injury and in atherosclerosis or may play a role in defending against viruses or other injurious agents such as oxidized lipids. Furthermore, expression of SAAs by endothelial cells is compatible with the evidence that SAA modulates platelet aggregation and function and possibly adhesion at the endothelial cell surface.

Adult↗
PubMed2006

Aggresomes and autophagy generate sites for virus replication.

The replication of many viruses is associated with specific intracellular compartments called virus factories or virioplasm. These are thought to provide a physical scaffold to concentrate viral components and thereby increase the efficiency of replication. The formation of virus replication sites often results in rearrangement of cellular membranes and reorganization of the cytoskeleton. Similar rearrangements are seen in cells in response to protein aggregation, where aggresomes and autophagosomes are produced to facilitate protein degradation. Here I review the evidence that some viruses induce aggresomes and autophagosomes to generate sites of replication.

Autophagy↗
PubMed2000

In situ analysis of sulfate-reducing bacteria related to Desulfocapsa thiozymogenes in the chemocline of meromictic Lake Cadagno (Switzerland).

Comparative sequence analysis of a 16S rRNA gene clone library from the chemocline of the meromictic Lake Cadagno (Switzerland) retrieved two clusters of sequences resembling sulfate-reducing bacteria within the family Desulfovibrionaceae. In situ hybridization showed that, similar to sulfate-reducing bacteria of the family Desulfobacteriaceae, bacteria of one cluster with similarity values to the closest cultured relatives of between 92.6 and 93.1% resembled free cells or cells loosely attached to other cells or debris. Bacteria of the second cluster closely related to Desulfocapsa thiozymogenes DSM7269 with similarity values between 97. 9 and 98.4% were generally associated with aggregates of different small-celled phototrophic sulfur bacteria, suggesting a potential interaction between the two groups of bacteria.

DNA Probes↗
PubMed2000

The rheumatoid factor response in the etiology of mixed cryoglobulins associated with hepatitis C virus infection.

Studies of mixed cryoglobulins (MC) from patients infected with hepatitis C virus (HCV) show that the principal constituents in cryoprecipitate are IgM rheumatoid factors (RF), polyclonal IgG anti-HCV antibodies, and HCV RNA. The HCV-induced RF response is biased to produce IgM RF encoded by a restricted set of Ig V genes, predominantly the VH/VL gene pair 51p1/kv325. The propensity of such IgM RF to cryoprecipitate is likely a coincidental property of their V region sequences, but the clinical effect of this bias is increased by the persistence of circulating HCV-IgG immune complexes. These complexes might induce production of cryoprecipitable IgM RF and furnish multi-molecular structures that favor binding by cryoprecipitable IgM RF. The V gene sequences of HCV-induced IgM RF have features seen in other RF responses, suggesting a common immunological mechanism that is independent of HCV. B cell proliferation is probably enhanced by HCV-specific properties, however, including the ability of HCV proteins to bind to CD81 on the B cell surface, and to influence intracellular regulatory functions following viral entry into B cells. The V gene bias in HCV-induced RF is most apparent among the B cells in monoclonal expansions responsible for type II cryoglobulins, but it might originate early the polyclonal RF response, before MC are detectable. Monoclonal B cell expansions and lymphomatoid bone marrow infiltrates in HCV+ patients predominantly involve CD5-negative IgM RF B cells. Non-RF B cells can also be expanded, including producers of IgG1 and IgG3 that are likely anti-HCV antibodies. The initial site of B cell clonal expansion may be in the liver, where lymphoid aggregates are abundant and RF are produced. Sorting out how MC formation is influenced by properties that are inherent to the RF response, or specific to HCV infection, will be a challenge to future HCV research.

Antigen-Antibody Complex↗