Polyclonal B-cell Research Articles

Specific immune response to the 40-kDa outer-membrane protein of Porphyromonas gingivalis in mice

Whether B-cell activation to Porphyromonas gingivalis in periodontal diseases is the consequence of a specific immune response or is due to non-specific polyclonal activation is still not clear. Here the immune response of mice to a purified 40-kDa recombinant protein antigen, a major outer-membrane protein specific to P. gingivalis, was investigated. Patients' sera strongly reacted to this recombinant antigen. Purified splenic T and B cells from mice immunized with 40-kDa antigen or from normal mice were reconstituted in vitro and cultured in the presence or absence of the P. gingivalis 40-kDa protein antigen and antigen-presenting cells (APCs). In vitro antibody production to this particular antigen was analysed with respect to the requirement of helper T cells and APCs by enzyme-linked immunosorbent assay. The results clearly showed that an effective secondary response required the presence of B cells, T cells and APCs. In the absence of CD4+ helper T cells, an antibody response to the 40-kDa protein was not observed. In addition, the requirement of H-2 restricted, Ia-positive APCs was evident for an adequate response to the 40-kDa protein of P. gingivalis. Thus the antibody response to the 40-kDa protein of P. gingivalis was generated in an immunologically antigen-specific manner and was not simply the result of polyclonal B-cell activation. This in vitro system could be used in the detection of antigen-specific memory B or T cells in patients with periodontal diseases.

Tumor necrosis factor alpha is an autocrine growth factor for normal human B cells.

Transcription of the human tumor necrosis factor alpha (TNF-alpha) gene is one of the earliest events that occurs after stimulation of B or T cells via their antigen receptors. Antibody directed at surface immunoglobulin (anti-Ig) on B cells has previously been shown to induce a rapid burst of TNF-alpha gene transcription, which can be blocked by the immunosuppressants cyclosporin A (CsA) and FK506. Here, TNF-alpha gene transcription is shown also to be highly and rapidly induced in human B cells after stimulation via the CD40 and interleukin 4 pathways, which similarly is inhibited by CsA and a panel of CsA or FK506 analogues that block calcineurin phosphatase activity. Endogenous TNF-alpha produced after stimulation was involved in B-cell proliferation since anti-TNF-alpha monoclonal antibody inhibited both anti-Ig- and anti-CD40-induced B-cell proliferative responses. Moreover, addition of TNF-alpha during stimulation resulted in augmentation of B-cell proliferation, which was also inhibited by anti-TNF-alpha monoclonal antibody. Although lymphotoxin alpha (LT-alpha) mRNA is induced by both pathways, it is not blocked by CsA, whereas LT-beta mRNA is constitutively expressed in B cells. Thus, TNF-alpha is a necessary autocrine growth factor for human B cells stimulated via two independent CsA-sensitive pathways and plays a role similar to that of interleukin 2 in T-cell proliferation. The autocrine nature of TNF-alpha in activated B cells implies a potential role for this cytokine in infection-related polyclonal B-cell expansion and in B-cell malignancies.

Clinical characteristics of post-transplant lymphoproliferative disorders

purpose: To study the histopathologic findings, clinical course, and therapeutic outcome of patients who developed a lymphoproliferative disorder after undergoing solid organ transplantation. patients and methods: A series of 26 patients who developed a lymphoproliferative disorder after solid organ transplant during a 27-year period were studied. results: The 26 patients ranged in age from 6 to 68 years (median 42 years). The lymphoproliferative disorder was diagnosed from 1 to 211 months (median 80 months) after transplantation. The type of transplant was kidney (n = 21), heart or heart-lung (n = 4), or liver (n = 1). Most patients received azathioprine and prednisone, in addition to antilymphocyte globulin or cyclosporine, for post-transplant immuno-suppression. Eight patients had lymphoma that could be classified according to the International Working Formulation (IWF-F, IWF-G, IWF-H). Sixteen patients had polymorphic lymphoma, and 2 patients were classified as having polymorphic lymphoid hyperplasia. Patients were staged by the Ann Arbor staging system. Nine patients had stage I disease, 4 stage II, 6 stage III, and 7 stage IV. Central nervous system, lung, or marrow involvement was present in 27%, 23%, and 14% of patients, respectively. In the 17 patients studied, immunophenotype was monoclonal B-cell (n = 12), malignant T-cell (n = 2), or polyclonal B-cell (n = 3). The initial therapeutic approach was generally a reduction in immunosuppression, but, thereafter, the approach to therapy varied. In patients with localized disease, surgical excision and/or involved field radiotherapy were utilized as applicable. For patients with more extensive disease, other approaches such as high-dose acyclovir, combination chemotherapy, or alpha interferon were utilized. Overall, 15 of 26 patients (58%) responded to systemic therapy or were rendered disease-free either by surgery or radiation, including 8 (31%) with a complete remission (CR). Only 3 of 9 patients responded to chemotherapy, whereas 4 of 13 patients responded to acyclovir (including 3 patients who experienced CR). Remission duration ranged from 8 to 122 months (median 32+ months). Twenty-one of 26 patients (81%) have died. Survival ranged from less than 1 to 122 months (median 14 months). conclusion: The outcome of patients with post-solid organ transplant lymphoproliferative disorders is poor, and the optimal approach to therapy is not clear. Newer therapeutic approaches are thus needed to improve the outcome of these patients.

Immunopathological features of rat Staphylococcus aureus arthritis.

Staphylococcus aureus is the most common bacterial species found in nongonococcal bacterial arthritis in humans. We present the first description, to our knowledge, of an outbreak of spontaneous staphylococcal arthritis in a rat colony. In a group of 10 rats, 9 displayed arthritis. Clinically, the most obvious findings were arthritis of one or both hindpaws and malaise. Bacteriophage typing showed the common phage type 85 in isolates recovered from the joints, blood, and bedding of rats and from the nose and cheeks of one person from the staff of the animal facility. The S. aureus strain proved to produce staphylococcal enterotoxin A and exhibited strong binding to collagen types I and II and bone sialoprotein, which are potentially important virulence factors. When the recovered S. aureus strain was injected intravenously into healthy rats, severe septic arthritis was induced in almost all of the animals. The arthritic lesions were characterized by infiltration of phagocytic cells and T lymphocytes into the synovium. Many of the synovial cells strongly expressed major histocompatibility complex class II molecules. Increased levels of interleukin 6 in serum as well as a prominent polyclonal B-cell activation were noted throughout the disease course. Pretreatment of S. aureus-injected rats in vivo with an antibody to the alpha beta T-cell receptor significantly decreased the severity of the arthritis. Our results indicate that alpha beta + T lymphocytes contribute to an erosive and persistent course of S. aureus arthritis.

Clonality analysis of defined B-cell populations in archival tissue sections using microdissection and the polymerase chain reaction.

A simple microdissection technique involving the use of a drawn-out glass pipette was developed for isolation of defined cell subsets from tissue sections. Using this technique and the polymerase chain reaction (PCR), clonally rearranged immunoglobulin (Ig) heavy chain genes were reliably amplified in single neoplastic follicles or few hundreds of tumour cells isolated from archival haematoxylin and eosin or immunostained sections of B-cell lymphomas. A polyclonal nature was consistently demonstrated in reactive lymphoid follicles or interfollicular reactive B-cells within the same lymphoma sections. Microdissection of lymphoma cells from within foci of chronic inflammation improved the resolution of tumour-specific PCR products by reducing amplification of background polyclonal B-cell sequences. The combination of microdissection and PCR techniques, therefore, provides an important tool for the investigation of B-cell lymphomas and also allows simple and specific access for other molecular genetic analyses of different cell subsets on tissue sections.

Epstein-Barr virus-transformed human B lymphocytes produce natural antibodies to histones

To study the mechanism(s) responsible for the appearance of Epstein-Barr virus (EBV)-induced anti-histone autoantibodies, peripheral blood B lymphocytes from healthy donors were infected with EBV and the resulting lymphoblastoid cell lines were tested for secretion of antibodies reacting with histones. It was found that EBV-transformed cells produce IgM antibody reactive with histones and that the frequency of EBV-inducible circulating B lymphocytes that produce antibodies to histones is at least 10 −5. Moreover, in cultures of tonsillar lymphoid cells, the enrichment in CD5 + B lymphocytes increases the percentage of EBV-transformed cultures making anti-histone IgM antibodies. EBV may therefore, also in vivo, induce natural anti-histone antibody by polyclonal B-cell activation without any requirement of antigen to trigger antibody response.

H- and L-Rich Ferritins Suppress Antibody Production, But Not Proliferation, of Human B Lymphocytes In Vitro

AbstractThe effect of human spleen(L-rich) and heart(H-rich) ferritins on the proliferation and differentiation of human B lymphocytes was studied in comparison with that of holo- and apo-transferrins. Ferritins rich in H and L chain, as well as the transferrins, did not inhibit the proliferative response of resting and activated B cells stimulated with polyclonal B-cell mitogen. Staphylococcus aureus Cowan strain I. In contrast, the ferritins, but not the transferrins, clearly suppressed the antibody production by B blasts in T-cell-inde-pendent as well as T-cell-dependent system. Kinetic study showed that inhibitory action of ferritins on immunoglobulin (Ig) production was caused at an early stage of B-cell differentiation. The cytoplasmic Ig-containing cells decreased in proportion to the reduction of Ig secretion. The evidence that ferritin inhibited Ig synthesis of Epstein-Barr virus-transformed human B-lymphoblastoid cell line also supported the idea that the effect of ferritin was directed toward the antibody-producing B lymphocytes. The molecular analysis showed that the inhibitory effect of ferritin was regulated at the transcriptional level of the Ig generation signal. Our results suggest that H- and L-rich ferritins exert their inhibitory action on the differentiation of B cells maturing into Ig-producing cells.

H- and L-rich ferritins suppress antibody production, but not proliferation, of human B lymphocytes in vitro

The effect of human spleen(L-rich) and heart(H-rich) ferritins on the proliferation and differentiation of human B lymphocytes was studied in comparison with that of holo- and apo-transferrins. Ferritins rich in H and L chain, as well as the transferrins, did not inhibit the proliferative response of resting and activated B cells stimulated with polyclonal B-cell mitogen, Staphylococcus aureus Cowan strain I. In contrast, the ferritins, but not the transferrins, clearly suppressed the antibody production by B blasts in T-cell-independent as well as T- cell-dependent system. Kinetic study showed that inhibitory action of ferritins on immunoglobulin (Ig) production was caused at an early stage of B-cell differentiation. The cytoplasmic Ig-containing cells decreased in proportion to the reduction of Ig secretion. The evidence that ferritin inhibited Ig synthesis of Epstein-Barr virus-transformed human B-lymphoblastoid cell line also supported the idea that the effect of ferritin was directed toward the antibody-producing B lymphocytes. The molecular analysis showed that the inhibitory effect of ferritin was regulated at the transcriptional level of the Ig generation signal. Our results suggest that H- and L-rich ferritins exert their inhibitory action on the differentiation of B cells maturing into Ig-producing cells.

Nucleotide Actions on Humoral Immune Responses

AbstractPrevious studies indicate the importance of dietary nucleotides in maintaining optimal cellular immunity. Our studies using murine spleen cells showed that polynucleotides significantly increase in vitro antibody production in response to T-cell-dependent antigen. They seem to exert actions on T-helper cells at antigen presentation, perhaps during cognitive cell-cell interactions. They do not augment the actions of cloned, antigen-specific, activated T-helper cells, nor do they increase antibody production in response to T-cell-independent antigen or polyclonal B-cell activation. Polynucleotides increase in vitro human immunoglobulin production in response to T-cell-dependent stimuli and antigen. Humoral immune responses to T-cell-dependent antigen were depressed in mice fed a nucleotide-free diet, but were restored by a mononucleotide-nucleoside mixture. Responses to T-cell-independent antigen remained intact in these mice. The mononucleotide-nucleoside mixture had no effect on in vitro antibody production and did not further increase humoral immune responses in mice fed regular lab chow. These results suggest that the in vivo actions of polynucleotides on humoral immune responses may reflect local immune responses, perhaps at the site of inflammation. Mononucleotides and nucleosides may be incorporated into the tissue nucleotide pool fairly rapidly in a state of relative nucleotide deficiency and help restore T-cell-dependent humoral immune responses. Our findings may further support the importance of dietary nucleotides.

Novel autoimmune phenomena induced in vivo by a new DNA binding protein Nuc: a study on MRL/n mice

We previously purified a 55 kDa protein that preferentially expands anti-DNA antibody production both in vitro and in vivo across the H-2 barrier from culture supernatants of KML 1-7 cells, cloned from a lupus-prone MRL/ lpr mouse. By using the purified protein, termed nucleobindin (Nuc), we cloned cDNA and produced recombinant(r) Nuc in Escherichia coli. To elucidate the function of rNuc in vivo, we initially injected intraperitoneally 5 μg of rNuc without adjuvant into female MRL/n mice at 8 weeks of age and continued injection twice a week. As early as 5 weeks after administration, all mice treated showed an increase in IgG anti-double stranded (ds) DNA antibodies accompanied by IgG hyper-gammaglobulinemia (HG). Of particular interest was that these mice also produced anti-UIRNP antibodies and rheumatoid factor (RF) of IgG class, but not anti-Sm antibodies. Histopathologically, hypercellularity with occasional crescents in the glomeruli was observed, but evidence for lupus nephritis was lacking, indicating that some factors other than Nuc are necessary for the development of a lupus syndrome observed in MRL/ lpr mice. Similar administration of lipopolysaccharide into MRL/ n mice failed to induce autoantibodies except for a slight increase in serum IgG, suggesting that these autoimmune responses are not due simply to polyclonal B-cell activation. The presence of rNuc will give us a clue for further understanding of autoimmunity.

Optimizing oral vaccines: induction of systemic and mucosal B-cell and antibody responses to tetanus toxoid by use of cholera toxin as an adjuvant

Cholera toxin (CT) is an effective mucosal antigen and acts as an adjuvant when given orally with various antigens; however, few studies have compared the levels of antibody responses to CT and coadministered protein in systemic and mucosal tissues. In this study, we used tetanus toxoid (TT) for assessment of immune responses. Time course and dose-response studies established that 250 micrograms of TT given orally with 10 micrograms of CT three times at weekly intervals induced high serum and gastrointestinal tract anti-TT and anti-CT antibody responses. Oral immunization with TT alone induced no detectable mucosal immunoglobulin A (IgA) antibodies in fecal extracts and only weak serum IgG anti-TT responses. The coadministration of CT and TT induced peak serum IgG anti-TT responses following two oral doses that remained constant after the third oral immunization, while optimal mucosal IgA responses were seen after the third oral immunization. The serum anti-TT response obtained with CT and TT proved protective against TT challenge (100 minimum lethal doses), whereas mice orally given CT or TT alone died. Antigen-specific B-cell responses were assessed with an isotype-specific Elispot assay of isolated lymphoid cells from the spleen, Peyer's patches, and the small intestinal lamina propria. Interestingly, approximately fourfold-higher numbers of IgA anti-CT than of anti-TT antibody-producing (spot-forming) cells occurred in lymphocytes from the lamina propria of mice orally immunized with both TT and CT. The adjuvant CT did not induce polyclonal B-cell responses in mice given CT by the oral route, since no significant differences in total numbers of B cells producing IgA, IgG, or IgM were found compared with the numbers in mice given TT alone. The results clearly indicate that serum and mucosal antibody responses develop with different kinetics and that protective TT-specific antibody responses are generated in the systemic compartment when TT is administered with CT via the oral route.

Central nervous system pathology in pediatric AIDS.

Children with AIDS frequently have neurological manifestations due to complications of immunodeficiency or intrinsic effects of human immunodeficiency virus type 1 (HIV-1) on the central nervous system (CNS). The most common neurological disorders not directly related to HIV-1 infection include cerebrovascular disease and lymphoma. Global anoxic-ischemic and necrotizing encephalopathies are frequent, while CNS hemorrhages and arteriopathies are less frequent. Opportunistic CNS infections are uncommon, limited predominantly to monilial and cytomegaloviral encephalitides. Only a few cases of CNS toxoplasmosis have been reported in children. CNS lymphomas often occur in the setting of systemic polymorphous, polyclonal B-cell proliferations that have been associated with Epstein-Barr virus infection. Intrinsic effects of HIV-1 on the CNS include microcephaly, diffuse gliosis, basal ganglia mineralization, HIV encephalitis, and corticospinal tract degeneration. Although viral antigens can be detected in microglia and multinucleated cells in HIV encephalitis, most of the CNS effects of HIV-1 infection cannot be attributed to detectable levels of viral antigen, suggesting that the pediatric CNS is unusually susceptible to low-level HIV-1 infection or to systemic effects of HIV-1 infection, possibly mediated by soluble factors, including the inflammatory cytokines, interleukin-1 beta, and tumor necrosis factor-alpha, which have been shown to be increased in serum and cerebrospinal fluid of children with AIDS.

Δ9-tetrahydrocannabinol selectivity inhibits T-cell dependent humoral immune responses through direct inhibition of accessory T-cell function

The major psychoactive and immunosuppressive component of marihuana, Δ9-tetrahydrocannabinol (Δ9-THC), was investigated for its effects on primary humoral immune responses in the B6C3F1 mouse strain. Oral administration of 50–200 mg/kg Δ9-THC produced a selective and dose related inhibition of primary humoral immune responses to the T-cell dependent antigen, sRBC, as measured by the antibody forming cell (AFC) response with no inhibitory effect on humoral responses to the T-cell independent antigen, DNP-Ficoll. A similar profile of immune inhibition was observed following in vitro direct addition of Δ9-THC to naive spleen cell cultures sensitized with defined antigens. Δ9-THC produced a marked and dose related inhibitio n of the in vitro sRBC AFC response while having no inhibitory effects on T-cell independent responses to either DNP-Ficoll or the polyclonal B-cell activator, lipopolysaccharide. This selective inhibition of the sRBC response was not due to a shift in the peak day of response or a direct cytotoxic effect on spleen cells. In vivo kinetic studies demonstrated that inhibition by Δ9-THC of the sRBC response was most pronounced when drug administration occured at times surrounding antigen sensitation. To further evaluate the direct effect of Δ9-THC on T-cell function, T-cell proliferative responses to stimulation by anti-CD3 monoclonal antibodies were measured. Δ9-THC was found to produce a marked and dose related inhibition of anti-CD3 mAb-induced T-cell proliferation which was cell density dependent. These results suggest that suppression of humoral responses by Δ9-THC may be mediated through early selective inhibition of T-cell accessory function.

G‐CSF enhances the immunoglobulin generation rather than the proliferation of human B lymphocytes

The effect of granulocyte-colony stimulating factor (G-CSF) on human B-cell function was studied in in vitro cultures. G-CSF alone had no effect on the proliferative response of resting B cells, but it slightly enhanced the proliferative response of these cells in the presence of polyclonal B-cell mitogen, Staphylococcus aureus Cowan strain I (SAC) at concentrations of 0.2 to 25 micrograms/ml (1.5-fold increase in the DNA synthesis). In contrast, immunoglobulin (Ig) secretion of activated B cells was increased approximately three-fold to four-fold by adding G-CSF to the cultures. The neutralization of G-CSF bioactivity with anti-G-CSF antibody abrogated this effect. Though cytoplasmic Ig-positive cells or plasma cell marker-positive cells did not change, the expression of IgM mRNA in antibody-producing B cells increased in the presence of G-CSF in the cultures. Interestingly, human B lymphocytes are shown to express the binding to biotin-conjugated G-CSF preparation, but not to biotin-conjugated GM-CSF preparation when examined by flow cytometry. These data suggest that G-CSF may influence B-cell function in special circumstances.

B-cell and T-cell function in systemic lupus erythematosus.

The process of autoantibody production in systemic lupus erythematosus is characterized by findings of both an antigen-driven response and polyclonal B-cell activation. Autoantibody production does not appear to be critically dependent on the presence of the CD5+ B cell subset. Increasing evidence supports a role for T helper cell type 2 cytokines, such as interleukin-4 and interleukin-6, in promoting and perpetuating B-cell hyperactivity and autoantibody formation.

Membrane tumour necrosis factor-alpha is involved in the polyclonal B-cell activation induced by HIV-infected human T cells.

Infection of CD4+ T cells by human immune deficiency virus-1 (HIV-1) causes severe dysfunction of cellular immunity, but paradoxically results in intense polyclonal activation of B cells, possibly accounting for both hypergammaglobulinaemia and frequent development of B-cell malignancies seen in HIV-infected patients. We have reported that human CD4+ T-cell clones infected with HIV in vitro markedly stimulate immunoglobulin synthesis by B cells through a non-cognate, contact-dependent mechanism. We show here that HIV-infected T-cell clones do not express the CD40 ligand (CD40L), a molecule critical for non-cognate B-cell activation, but a small proportion of them do express membrane tumour-necrosis factor (TNF)-alpha. The ability of HIV-infected T-cell clones to induce polyclonal B-cell activation appears to be restricted to TNF-alpha-positive T blasts and is inhibited by antibodies against both TNF-alpha and TNF-alpha receptor. Freshly isolated CD4+ T cells from HIV-infected individuals express TNF-alpha on the cell membrane and induce TNF-alpha-mediated immunoglobulin production by B cells. Thus, membrane TNF-alpha seems to be involved in the polyclonal B-cell activation induced by HIV-infected T cells.

Interaction of immunologically-active lipopeptides with membranes

Synthetic tripalmitoyl- S-glycerylcysteinyl (Pam 3Cys) peptides are derived from the N-terminal part of bacterial lipoprotein and constitute polyclonal B-lymphocyte and macrophage activators. In order to elucidate the primary events of leukocyte activation, we investigated the biophysical interaction of lipopeptides containing spin labels or fluorescent markers with phosphatidylcholine vesicles or immune cells. Utilizing fluorescence microscopy and FACS analysis we found, that surface of cells, after incubation with a fluorescein-labelled lipopeptide, was highly fluorescent. In addition, capping and patching was observed. Furthermore, fluorescence quenching experiments and electron paramagnetic resonance studies using vesicles incubated with lipopeptides suggested, that the peptide moiety and other more polar molecules linked to the lipo-amino acid are exposed to the hydrophilic compartment. These results show that in lipopeptide conjugates the Pam 3Cys moiety acts as an efficient membrane anchor for molecules covalently coupled to it. The sequestering of the fatty-acid chains of the lipopeptide within the membrane is an early step of interaction, which might induce the uptake of the lipopeptide into the cell and the stimulation of immunocompetent cells.

Autoreactive T-cell-dependent polyclonal B-cell differentiation in mantle zone lymphoma [letter

Autoreactive T-cell-dependent polyclonal B-cell differentiation in mantle zone lymphoma [letter

Peripheral Lymphoid Hyperplasia and Central Lymphoid Depletion in Mice Treated with a Bacterial B‐Cell Mitogen (F3′EP‐Si/p90)

In order to further understand the mechanism mediating the mitogenic and immunosuppressor effects of p90, a protein produced by Streptococcus intermedius, flow cytometric studies were performed on peripheral and central lymphoid organs of mice treated with this protein. p90 induced a strong blastogenic B-cell response in the spleen and lymph nodes, followed by a slight but significant polyclonal T-cell activation. B-cell repertoire analysis indicated that polyclonal B-cell responses affected similarly both CD5+ and conventional (CD5-) B cells in the spleen. Repertoire analysis of T cells failed to reveal any preferential stimulation of the V beta T-cell receptor (V beta-TcR) families studied. Peripheral lymphoid hyperplasia was observed concomitantly with central lymphoid depletion. In the bone marrow, pre-B and B cells were profoundly depleted, with a more pronounced effect on small pre-B cells. In the thymus, double-positive (CD4+CD8+) thymocytes were preferentially eliminated, with a relative enrichment of single positive (either CD4+ or CD8+) and double-negative (CD4-CD8-) thymocytes.

Enhanced expression of interleukin 6 in rat and murine arthritis models

Interleukin 6 (IL-6) is a multifunctional cytokine and plays an important role in host defense mechanisms. Enhanced production of IL-6 has been reported in polyclonal B-cell abnormalities and autoimmune diseases such as rheumatoid arthritis (RA). To investigate the role of IL-6 in inflammatory joint diseases, serum IL-6 levels of three animal models of RA, namely type II collagen (CII)-induced murine, rat arthritis and adjuvant-induced rat arthritis, were monitored. In these models, serum IL-6 increased with the development of arthritis. Serum IL-6 was not elevated by immunization with a non-arthritogenic immunogen such as bovine type I collagen (CI) and bovine serum albumin (BSA) to DBA/1J mice. The serum IL-6 level was correlated well with the severity of adjuvant-induced arthritis. The elevated IL-6 in sera may be associated with the overproduction of IL-6 at the arthritic paws, because higher IL-6 activity was detected in the homogenates of arthritic paws as compared with the control paws. Synovial fibroblasts were isolated from the arthritic knee joints of DBA/1J mice. These cells expressed type I interleukin 1 (IL-1) receptor constitutively and produced large amounts of IL-6 in response to IL-1 in vitro. Enhanced production of IL-1 was also detected at the arthritic paws. These results suggest that the elevated IL-6 in sera may be associated with the overproduced IL-6 in response to the increased IL-1 at the arthritic joints. Serum IL-6 may be a useful parameter for monitoring disease activity.