IgM Kappa Research Articles

Characterization of a Novel Human Anti-HIV-1 gp41 IgM Monoclonal Antibody Designated Clone 37

Human monoclonal antibodies (HuMAbs) demonstrate great potential for passive immunotherapy against HIV-1. The gp41 transmembrane envelope glycoprotein of HIV has an important role in the pathogenicity of AIDS and importantly displays considerably less hypervariability than the gp120 surface envelope HIV glycoprotein, which makes it particularly a better candidate for the development of passive and active immunotherapies. The general aim of this study was to develop HuMAbs to HIV surface glycoproteins and particularly gp41. Peripheral blood mononuclear cells (PBMCs) were isolated from an HIV-seropositive long-term nondisease progressing patient. B-cells from this individual were then immortalized by Epstein-Barr virus (EBV) transformation, and antibody production was stabilized by fusion of transformed cells with a heteromyeloma. Subsets of the human heterohybridomas so generated were analyzed by ELISA. The hybridoma with the highest binding by immunoassay against gp160 was further analyzed. This hybridoma, designated as clone 37 (C37), was determined to be an IgM Kappa antibody and overlapping peptides of HIV envelope proteins (derived from the MN tissue culture line adapted HIV isolate) were used to map the specific binding domain of this HuMAb. Overlapping peptides designated 2026 (SWSNKSLDDIWNN, AA614-626), and 2027 (DDIWNNMTWMQWEREIDNYT, AA621-640) within the HIV-1 gp41 transmembrane glycoprotein were demonstrated to bind to C37 indicating that the specific binding domain for the antibody was DDIWNN. High affinity binding of C37 by ELISA to recombinant gp41 was demonstrated as well. Few IgM HuMAbs against HIV have been generated and characterized. Theoretically, because of the pentameric binding nature of IgM antibodies as well as their very efficient ability to activate complement, such reagents could have potential as anti-HIV agents.

Rare Concomitance of Primary Systemic Amyloidosis with Immunoglobulin M Monoclonal Gammopathy or Waldenstrom Macroglobulinemia.

Introduction: Primary systemic amyloidosis occurs when a clonal plasma cell population secretes light chains (or light chain fragments) that deposit in tissues as amyloid and cause organ failure and ultimately patient death. Primary systemic amyloidosis generally results from non-proliferative small populations of plasma cells. While it is known that IgG, IgA and light chain producing plasma cells can secrete amyloid in association with myeloma, fewer medical professionals recognize that IgM-secreting lymphoplasmacytic cells can produce amyloid proteins. When monoclonal IgM secreting marrow lymphocytes are present, amyloidosis can result with or without overt Waldenstrom Macroglobulinemia.Patients and Methods: All patients seen at the Mayo Clinic between January 1968 and August 2000 with both a serum IgM monoclonal protein and biopsy-proven amyloidosis were analyzed. The Mayo Clinic Dysproteinemia Database recognized 128 patients (42 female, 86 male) with a median age of 65 years.Results: Seventy-two percent (n=92) of the patients have died with a median survival of 1.72 years following biopsy proven amyloidosis (figure 1). Median serum IgM monoclonal spike was 1.38 g/dL. In addition, serum IgM kappa to lambda light chain ratios (1:3) were found to be reversed in patients with IgM gammopathy when amyloid was present (compared to the reverse ratio (3:1) in patients with Waldenstrom macroglobulinemia in the absence of amyloidosis). Subcutaneous fat, rectum and bone marrow revealed amyloid in 72%, 69% and 70%, respectively, providing non-invasive techniques for amyloidosis diagnosis without the risks of bleeding associated with renal or hepatic percutaneous biopsy. Variables not shown to affect survival included the following: age, gender, serum M spike, urine protein, alkaline phosphatase, creatinine, light chain isotype, ejection fraction, and percent marrow plasma cells. The presence of amyloid cardiomyopathy (defined as a cardiac interventricular septal thickness greater than 12 mm.) was the only variable to adversely affect survival. Of the patients with echocardiographic evidence of cardiomyopathy, the median survival was 10.8 months. In contrast, the patients without echocardiographic evidence of cardiomyopathy at diagnosis had a median survival of 39 months (figure 2).Conclusion: Amyloidosis is underappreciated and should be considered in the differential diagnosis of all patients presenting with IgM gammopathy. Patients found to have amyloidosis in this setting should be tested for amyloid cardiomyopathy, as its presence predicts poor outcome. Lambda light chain in serum IgM samples should increase the index of suspicion for the presence of amyloid since IgM lambda is present in only 25% of IgM MGUS or Macroglobulinemia patients but is seen in 75% of IgM amyloidosis patients. [Display omitted]

Acute demyelinating sensorimotor polyneuropathy in B‐cell lymphoma with IGM autoantibodies against glycolipid GD1B

We report the case of an acute demyelinating sensorimotor polyneuropathy in a patient with IgM autoantibody against peripheral nerve myelin glycolipid GD1b produced by a B‐cell lymphoma. A 76‐year‐old woman presented with one month history of weight loss, paresthesias at the distal extremities of the four limbs followed by progressive and diffuse motor weakness. Neurological examination showed sensory ataxia, marked motor deficit (4 at MRC scale in proximal and distal muscle districts of limbs), superficial and proprioceptive sensory deficit with a stocking‐glove distribution, areflexia at lower limbs. Electroneurography documented absent sensory action potentials, prolonged distal latencies of motor action potentials, markedly slowed motor conduction velocities and evidence of conduction block and temporal dispersion of motor action potentials. Diagnosis of acute demyelinating sensorimotor polyneuropathy was established. CSF examination showed a slight increase of protein concentration. Haematological screening revealed a monoclonal gammopathy with high serum IgM (1151 mg/dL) and light chain kappa proteinuria. A total body CT scan evidenced a pelvic mass identified as low grade B‐cell lymphoma by rectal biopsy. Research for antiganglioside autoantibodies evidenced the presence of IgM antibodies against glycolipid GD1b. Autoantibodies anti‐Mag, anti‐Hu, anti‐Yo and anti‐Ri were negative. The pathogenetic role of serum autoantibodies against glycolipid GD1b in the development of demyelinization in the peripheral nervous system has already been documented either clinically in post‐infective polyneuropathies or experimentally in animal research. This is the first report of selective positivity of anti‐GD1b in polyneuropathy associated to B‐cell lymphoma supporting the possible paraneoplastic significance of these serum autoantibodies.

Bone Marrow Mastocytosis Associated with IgM Kappa Plasma Cell Myeloma

An association between mastocytosis and monoclonal gammopathy is a relatively rare but well recognized clinical finding. In the majority of cases, however, overt myeloma or lymphoma is not detectable morphologically. Here we describe the case of a 51 year-old male patient first presenting with paresis of the right facial nerve and the serological finding of IgM kappa paraproteinemia. The patient did not have organomegaly, lytic bone lesions, or urticaria pigmentosa-type skin lesions. Histological examination of a trephine biopsy specimen revealed the unusual coexistence of plasma cell myeloma and mastocytosis. Immunohistochemically, plasma cells were found to exhibit a monotypic staining for Ig heavy chain mu and Ig light chain kappa, thus confirming their neoplastic nature. Mast cells showed prominent spindling and formed dense multifocal infiltrates, thus enabling the diagnosis of bone marrow mastocytosis. Immunohistochemically, mast cells expressed tryptase, chymase, and KIT (CD117). In addition, aberrant expression of CD25 on mast cells was detected, confirming the coexistence of a neoplastic mast cell-proliferative disorder. According to the WHO proposal for classification of hematopoietic malignancies, this unique case, showing the association of two very rare haematologic neoplasms, can therefore best be referred to as bone marrow mastocytosis associated with IgM kappa plasma cell myeloma (SM-AHNMD).

Neuropatías paraproteinémicas: bases para un tratamiento específico con relación a la calidad de vida de los pacientes

Monoclonal gammopathy (MG) is reported in 1% of subjects above 50 years of age and in 3% of those above the age of 70. Of all patients with MG, 3% present polyneuropathy (PNP). The abbreviation MGUS (monoclonal gammopathy of undetermined significance) is used to describe a benign proliferation of M component (monoclonal) according to Kyle's criteria, with a potential to be malignant that is indicated by clinical, biochemical and haematological parameters. Aims. The aim of this study was to evaluate the effect of the clinical exacerbation of MGUS associated neuropathy, by referring to the existing literature and to our own experience in order to set out a number of proposals for treatment based on the deterioration of the patient's quality of life. Case 1: a 53 year old female with predominantly sensory sensory motor demyelinating polyradiculoneuropathy, associated to IgG lambda MGUS. Case 2: a 65 year old female with demyelinating sensory motor polyradiculoneuropathy associated to IgM kappa MGUS. In both cases there was a rapidly progressing neurological deterioration and no other data exist to suggest malign lymphoproliferation. In addition to the treatments established for MG linked PNP, which are based on the modulation of the immune response, it has also been proved that when malign proliferation of plasmacytes exists specific treatment of the gammopathy can significantly stabilise or improve the neuropathic symptoms. We propose gammopathy specific haematological treatment in patients who still meet Kyle's criteria for MGUS with a torpid neurological course and scarce response to therapy with immunomodulators, prior to an important deterioration in the quality of life. We also suggest establishing this rapidly progressing clinical course as a criterion that indicates the process of becoming malign as put forward by Eurelings et al.

Cutaneous lymphoplasmacytoid lymphoma (immunocytoma) with Waldenström's macroglobulinemia mimicking rosacea

A 50-year-old woman presented with a 2-year history of facial lesions that were resistant to rosacea therapy. Evaluation of histology, immunohistochemistry, gene rearrangement study, bone-marrow biopsy specimen, and systemic workup revealed the findings of lymphoplasmacytoid lymphoma (immunocytoma) in both the skin lesions and bone marrow, and IgM kappa paraprotein. Lesions cleared after chemotherapy.

Dealing with intractable protein cores: protein sequencing of the Mcg IgG and the Yvo IgM heavy chain variable domains.

The VH domains of two human monoclonal antibodies, designated Mcg IgG1(lambda) and Yvo IgM(kappa), were particularly intractable to standard protein sequencing protocols. Peptides liberated from the VH domains of these proteins, using standard enzymatic or chemical cleavages, invariably precipitated during the procedures. Boiling in SDS containing buffers dissolved precipitates and the peptides were separated using SDS-PAGE. Fully overlapped VH sequences were obtained with a series of 'in-gel' cleavages, followed by passive/differential transfers of peptides onto PVDF membranes. Both the in-gel cleavages and passive transfers could be applied to 'wet' or 'dry' gels so that gels could be archived and used at a later date to obtain additional sequence information from a fragment of interest. Repetitive yields of even the most insoluble peptides were such that the sequences of various peptides from relatively complex mixtures of peptides could be assigned with confidence. Despite the overall success of the sequencing, we occasionally referred to electron density maps, calculated for crystals of the Fab of Yvo IgM, to resolve particular sequences and confirm ambiguous amino acid assignments. Methods we describe in this report should be generally useful for obtaining sequences of proteins with intractable cores and may find many applications in the 'post genomic era'.

Interstitial deletion of 20q in a patient with Waldenström macroglobulinemia following chemotherapy

A 76-year-old male with a history of renal insufficiency was found to have anemia, an IgM kappa paraprotein on serum immunofixation studies, absence of lytic bone lesions, and findings in the bone marrow consistent with Waldenström macroglobulinemia (WM). Cytogenetic studies including fluorescence in situ hybridization (FISH) on the post-treatment bone marrow revealed the karyotype 46,XY,del(20)(q13.1q13.3). Less than 70 cases of karyotypic abnormalities in patients with WM have been reported, which have shown no abnormalities specific to WM. Monosomy or trisomy of chromosome 20 has been reported in approximately eight cases, but to our knowledge this is the first case report of an interstitial deletion of 20q, confirmed by FISH using chromosome 20 subtelomeric specific probes. Interstitial deletions of 20q are known to occur in polycythemia vera and other hematological malignancies, especially those of myeloid origin.

Waldenström macroglobulinemia caused by extranodal marginal zone B-cell lymphoma: a report of six cases.

Waldenström macroglobulinemia (WM) and its associated hyperviscosity syndrome (HVS) are generally caused by lymphoplasmacytoid lymphoma or other small B-cell lymphoproliferative disorders. WM associated with extranodal marginal zone B-cell-mucosa-associated lymphoid tissue lymphoma (EMZL/MALT-type) has not been emphasized. We describe 4 men and 2 women (age, 40-79 years) with clinical and laboratory manifestations of WM and EMZL/MALT-type involving one or more sites: lung, pericardium/pleura, ocular adnexa, nasopharynx, minor salivary gland, glossopharyngeal fold, skin, and stomach. The following immunophenotypic patterns were observed: CD20+, 6; CD43+, 3; kappa light chain restriction, 5; and lambda light chain restriction, 1. All were negative for CD5, CD10, and cyclin D1 expression. A clonal paraproteinemia was present in each (IgM kappa, 4; IgM lambda, 1; biclonal IgM kappa/IgA kappa, 1). All 4 patients tested had elevated plasma viscosity; clinical HVS occurred in 3, and 2 required emergency plasmapheresis. These findings suggest that EMZL/MALT-type can cause WM and that the laboratory evaluation of EMZL/MALT-type should include serum protein electrophoresis/immunofixation, and plasma viscosity measurements and urine immunofixation in select cases. EMZL/MALT-type should be considered in the differential diagnosis in patients with clinicopathologic features of WM.

Production, characterization, and cross-reactivity studies of monoclonal antibodies against the coccidiostat nicarbazin.

A cELISA was developed for the coccidiostat nicarbazin. On the basis of previous computer-assisted molecular modeling studies, p-nitrosuccinanilic acid (PNA-S) was selected as a hapten to produce antibodies to 4,4'-dinitrocarbanilide (DNC), the active component of the coccidiostat nicarbazin. Synthesis is described for the hapten [p-nitro-cis-1,2-cyclohexanedicarboxanilic acid (PNA-C)] used in a BSA conjugate as a plate coating antigen. Monoclonal antibodies (Mabs) were isolated that compete with nicarbazin, having IgM(kappa) isotype. Because of the lack of water solubility of nicarbazin, N,N-dimethylformamide (DMF) (3%, v/v) and acetonitrile (ACN) (10%, v/v) were added to the assay buffer to achieve solubility of nicarbazin and related compounds. The Nic 6 Mabs had an IC(35) value for nicarbazin of 0.92 nmol/mL, with a limit of detection of 0.33 nmol/mL. Nic 6 exhibited high cross-reactivity for PNA-S and PNA-C, and 3-nitrophenol, 4-nitrophenol, and 1-(4-chlorophenyl)-3-(4-nitrophenyl) urea. However, Nic 6 had little or no cross-reactivity with 15 other related compounds.

Tryptase-positive mast cells accompany lymphocytic as well as lymphoplasmacytic lymphoma infiltrates in bone marrow trephine biopsies.

To investigate the specificity of increased bone marrow mast cell numbers in lymphoplasmacytic lymphoma (LPL) and to evaluate the relationship between mast cell number and the immunoglobulin phenotype of neoplastic lymphoid cells. Retrospective study of bone marrow trephine biopsy specimens from patients with LPL, compared with selected cases representing chronic lymphocytic leukaemia (CLL) and multiple myeloma (MM) of known immunoglobulin light and heavy chain phenotype. Bone marrow mast cells were counted following immunohistochemical staining of sections for mast cell tryptase. We have confirmed previous observations that mast cell numbers are increased in bone marrow infiltrates of LPL. However, we found similarly high mast cell numbers in CLL. High mast cell numbers were associated with neoplastic lymphoid cells expressing an IgM kappa phenotype. Mast cell numbers were low in all cases of MM studied and in controls with no lymphoma present. We observed an apparent bias towards kappa light chain expression in our cases of LPL. Mast cell number should not be considered a reliable factor in the differential diagnosis of LPL and CLL when assessing bone marrow histology. Possible bias towards kappa light chain expression in LPL requires further study, as do the mechanism and functions of mast cell recruitment by neoplastic lymphoid cells.

Immunotactoid glomerulopathy with massive bone marrow deposits in a patient with IgM kappa monoclonal gammopathy and hypocomplementemia

A case of immunotactoid glomerulopathy with an amyloid-like material in the glomeruli and bone marrow is described. Clinically the patient was diagnosed as having severe nephrotic syndrome, hypocomplementemia, and IgM kappa monoclonal gammopathy. Immunotactoid glomerulopathy is an unusual cause of glomerulonephritis, characterized by Congo red[ndash ]negative, amyloid-like deposits in the glomeruli. This unusual case presentation shows that immunotactoid glomerulopathy may be a manifestation of systemic disease. This patient also presented with hypocomplementemia, an extremely rare associated finding that has been reported previously in only four cases of immunotactoid glomerulopathy. [copy ] 2001 by the National Kidney Foundation, Inc.

Monoclonal and polyclonal antibodies against human ferritin, a nonspecific tumor marker.

The aim of this study was to produce monoclonal and polyclonal antibodies against a nonspecific tumor marker, human ferritin. Hyperimmune ICR mice produced polyclonal antibodies after injection with 0.5 mL pristane, and were injected with NS-1 myeloma cells 2 weeks later. Hyperimmune Balb/c mice were used for the production of monoclonal antibodies (MAbs). Mice were immunized four times, given a final boost, and their spleen cells were collected and fused with NS-1 myeloma cells under the presence of PEG 1500. The fused cells were then selected in the HAT-RPMIX medium. Anti-ferritin antibody-secreting hybridoma cell lines with high titer were cloned by enzyme-linked immunoadsorbent assay (ELISA) and then subcloned by limiting dilution in 15% fetal bovine serum (FBS) HT-RPMIX medium. Five murine hybridoma-producing antiferritin MAbs were obtained and designated 1AD11F9, 1AD11E11, 2AD11D2, 2AD11A5, and 3AD11G8. Isotypes of these MAbs were identified as IgM heavy chain and kappa light chain. Hitrap Protein A and Hitrap IgM purification column were used for the purification of polyclonal and monoclonal antibodies, respectively.

Historical review of lymphomas.

Historical review of lymphomas.

Schnitzler’s syndrome: Report of a case with progression to Waldenström’s macroglobulinaemia

Schnitzler's syndrome is a rare but distinct entity in which chronic urticaria is a prominent feature. Our patient presented with an urticarial rash associated with intermittent fevers, lethargy, a migratory polyarthralgia and loss of weight. Skin biopsy revealed a neutrophilic urticaria. An IgM kappa paraprotein was detected on serum protein electrophoresis at a level of 8 g/L (0.6-2.5 g/L). Bone marrow biopsy was normal. Marked improvement of the arthralgia, fever and lethargy was obtained with oral prednisolone. The urticarial rash, however, was only partly responsive. For the next 10 years the patient remained stable but corticosteroid dependent. Over a period of 10 years the IgM paraprotein had slowly risen to 47 g/L. Repeat bone aspirate and trephine revealed a diagnosis of a low grade lymphoplasmacytic lymphoma consistent with Waldenström's macroglobulinaemia. To date, despite six cycles of chemotherapy with oral chlorambucil, his disease remains persistent but stable.

Differential Binding of Histidine-rich Glycoprotein (HRG) to Human IgG Subclasses and IgG Molecules Containing κ and λ Light Chains

In previous studies we showed that the plasma protein histidine-rich glycoprotein (HRG) binds strongly to pooled human IgG. In the present work myeloma proteins consisting of different human IgG subclasses were examined for their ability to interact with human HRG. Using an IAsys optical biosensor we found initially that IgG subclasses differ substantially in their affinity of interaction with HRG. However, the most striking finding was the observation that the kinetics of the HRG interaction was dramatically affected by whether the IgG subclasses contained the kappa or lambda light (L)-chains. Thus, the on-rate for the binding of HRG to the kappa L-chain containing IgG1 and IgG2 (IgG1kappa and IgG2kappa) was approximately 4- and approximately 10-fold faster than that for the binding of HRG to lambda L-chain containing IgG1 and IgG2 (IgG1lambda and IgG2lambda), respectively, with the dissociation constants (K(d)) in the range 3-5 nM and 112-189 nM for the kappa and lambda isoforms, respectively. In contrast, the on-rate for the binding of HRG to IgG3kappa and IgG4kappa was found to be 9- and 20-fold slower than that for the binding of HRG to IgG3lambda and IgG4lambda, respectively, with the K(d) in the range 147-268 nM and 96-109 nM for the kappa and lambda isoforms, respectively. The binding of HRG to immunoglobulins containing the kappa L-chain (particularly IgG1kappa) was generally potentiated in the presence of a physiological concentration (20 microM) of Zn(2+) (K(d) decreased to 0.60 +/- 0.01 for IgG1kappa), but Zn(2+) had no effect or slightly inhibited the binding of HRG to immobilized IgG subclasses possessing the lambda L-chain. Interestingly, HRG also bound differentially to Bence Jones (BJ) proteins containing kappa and lambda L-chains, with HRG having a 14-fold lower K(d) for BJkappa than for BJlambda when 20 microM Zn(2+) was present. HRG also bound to IgM (IgMkappa), but the affinity of this interaction (K(d) approximately 1.99 +/- 0.05 microM) was markedly lower than the interaction with IgG, and the affinity was actually decreased 4-fold in the presence of Zn(2+). The results demonstrate that both the heavy (H)- and L-chain type have a profound effect on the binding of HRG to different IgG subclasses and provide the first evidence of a functional difference between the kappa and lambda L-chains of immunoglobulins.

Molecular and functional characteristics of a protective human monoclonal antibody to serotype 8 Streptococcus pneumoniae capsular polysaccharide.

The structural characteristics and biological activity of human antibodies that are reactive with the capsular polysaccharides of most serotypes of Streptococcus pneumoniae, including serotype 8, are unknown. This paper describes the generation, molecular structure, and protective efficacy of a human monoclonal antibody (MAb) reactive with the capsular polysaccharide of serotype 8 Streptococcus pneumoniae. We generated the immunoglobulin M(kappa) [IgM(kappa)] MAb D11 by Epstein-Barr virus transformation of peripheral lymphocytes from a Pneumovax recipient. Nucleic acid sequence analysis revealed that MAb D11 uses V3-15/V(H)3 and A20/V(kappa) gene segments with evidence of somatic mutation. In vitro studies revealed MAb D11-dependent complement deposition on the capsule of serotype 8 organisms via either the classical or the alternative complement pathway. In vivo, MAb D11 prolonged the survival of both normal and C4-deficient mice with lethal serotype 8 S. pneumoniae infection. Our findings demonstrate that a serotype-specific human IgM with certain structural and functional characteristics was protective in mice lacking a functional classical complement pathway and show that alternative complement pathway activation is an important determinant of pneumococcal protection.

Bronchiolite oblitérante constrictive. À propos d'un cas

Constrictive bronchiolitis obliterans. Report of one case. Introduction. — Constrictive bronchiolitis obliterans is defined histologically as obliteration of the lumina of bronchioles by inflammatory tissue elements and progressive destruction of bronchioles, eventually replaced by fibrotic tissue. Most of the cases, which are not associated with either solid organ or bone marrow transplantation, occur in the development of rheumatoid arthritis. Exegesis. — We present the case of a 73-year-old woman who developed severe constrictive bronchiolitis obliterans without readily identifiable cause, rapidly fatal despite corticosteroid therapy. The patient had antinuclear antibodies (titer 1/1024) and antiphospholipid antibodies, but there was no anti-DNA, anti-ENA or anti-beta2GPI antibodies. Tests for rheumatoid factor were negative. Cryoglobulinemia was present (monoclonal IgM Kappa). Conclusion. — In this case, constrictive bronchiolitis obliterans was associated with serologic abnormalities and cryoglobulinemia. However, there was no clinical evidence of connective tissue disease.

Cloning and expression of a single-chain Fv fragment specific for the human interleukin 18 receptor.

We have recently reported the successful purification and characterization of the human interleukin 18 (IL-18) receptor (R) using a monoclonal antibody (MAb) of the IgM kappa class (117-10C) after immunizing mice with cells of the Hodgkin's disease-derived cell line L428. This antibody is specific for the human IL-18R and inhibits the bioactivity of IL-18. Here we report on the polymerase chain reaction (PCR)-assisted cloning and sequencing of cDNAs encoding the variable regions of the light and heavy chains of 117-10C. We expressed the antibody in the form of a single-chain Fv fragment (scFv) in Chinese Hamster Ovary (CHO) cells and purified it from culture supernatants by chromatography. The purified scFv has an affinity for IL-18R of 5.6 x 10(8) M(-1), whereas 117-10C binds to the receptor with an affinity constant of 3.6 x 10(9) M(-1). Since 117-10C is of the IgM class, it is expected to be in the pentamer form and should theoretically therefore bind IL-18R with 10 times the affinity of the single-chain fragment may explain the difference in the affinity constants for the two molecules. The inhibitory efficiency of 117-10C was found to be 6-fold that of scFv in an interferon gamma (IFN-gamma)-inducing assay on the IL-18-responsive cell line KG-1. In conclusion, we have produced a single-chain fragment of a murine anti-human IL-18R antibody that is as potent at binding IL-18 as the parent antibody, and may be useful in neutralizing the cytokine in human conditions associated with high production of IL-18.

A unique population of circulating autoantibodies promotes central nervous system remyelination.

In previous studies we demonstrated that the humoral immune response directed against unique central nervous system (CNS) antigens enhanced CNS remyelination in the Theiler's virus experimental model of multiple sclerosis (MS). To expand on this observation, a mouse IgM kappa monoclonal antibody (mAb) which enhances CNS remyelination, was raised against normal mouse spinal cord homogenate. Characterization of this mAb revealed that it is polyreactive towards variety of intracellular antigens but also reacts to an unidentified surface antigen on oligodendrocytes. The mAb is encoded by germline immunoglobulin genes without somatic mutations consistent with the observation that it is a natural autoantibody. Recently we generated another mouse IgM kappa mAb raised against normal spinal cord homogenate, which also promotes CNS remyelination. Further characterization revealed that both mAbs which promote remyelination have similar binding characteristics. Conventionally Abs which recognize normal CNS components, especially oligodendrocytes or myelin, have been considered to be a disease marker or be involved in the pathogenesis of MS. However, we have identified a unique population of circulating autoantibodies which are beneficial for myelin repair. Therefore this observation indicates the need to reevaluate autoantibody production against myelin components in CSF and blood as markers of disease activity versus repair in MS.