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Charles E Alpers - One of the best experts on this subject based on the ideXlab platform.
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Original Article All-trans-retinoic acid aggravates Cryoglobulin-associated membranoproliferative glomerulonephritis in mice
2016Co-Authors: Masayuki Iyoda, Kelly L Hudkins, Jolanta Kowalewska, Tomasz Wietecha, Miriam C Banas, Shunhua Guo, Gang Liu, Li Wang, Charles E AlpersAbstract:Background. Transgenic (tg) mice overexpressing thymic stromal lymphopoietin (TSLP) develop mixed Cryoglobulinaemia with renal disease closely resembling human Cryoglobulinaemic membranoproliferative glo-merulonephritis (MPGN), as well as systemic inflam-mation involving lung, liver and skin as a result of Cryoglobulin deposits. We assessed the effect of all-trans-retinoic acid (ATRA), a powerful anti-inflamma-tory agent, on this model of Cryoglobulinaemic MPGN. Methods. Groups of male TSLP tg mice and wild-type controls were treated with either ATRA (20mg/kg) or vehicle 3 times weekly by intraperitoneal injection for 4 or 8 weeks, when mice were then sacrificed. Routine histology and immunohistochemistry for collagen IV, a-smooth muscle actin, Mac-2 and Ki67 were per-formed. Immunoglobulin levels were measured by enzyme-linked immunosorbent assay. Results. ATRA unexpectedly exacerbated renal injury in TSLP tg mice with increased glomerular extracel-lular matrix, mesangial cell activation, glomerular cell proliferation, glomerular macrophage influx and immune complex deposition. Systemic injuries involv-ing liver and lung, and the amount of circulating Cryoglobulins were all worsened by ATRA treatment. Furthermore, ATRA resulted in increased IgG1 and IgM levels, the main components of the Cryoglobulins in TSLP tg mice, and a manifestation of an enhanced Th2 immune response. Conclusions. ATRA is not protective but instead aggravates Cryoglobulinaemic MPGN and its systemic manifestations in TSLP tg mice. We speculate these findings may be due to augmented production of pathogenic immunoglobulins and/or an enhanced systemic Th2 response. Although disappointing, our results also suggest caution in the application of retinoid therapy to human disease based on the largely positive animal data reported to date
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protease nexin 1 tpa and pai 1 are upregulated in Cryoglobulinemic membranoproliferative glomerulonephritis
Journal of The American Society of Nephrology, 2008Co-Authors: Sekiko Taneda, Kelly L Hudkins, Anja Muhlfeld, Jolanta Kowalewska, Jeffrey W Pippin, Stuart J Shankland, Charles E AlpersAbstract:Thymic stromal lymphopoietin (TSLP) transgenic mice develop Cryoglobulin-associated membranoproliferative glomerulonephritis, characterized by renal monocyte/macrophage infiltration, marked expansion of extracellular matrix, and variable intraluminal and mesangial deposits of Cryoglobulins. A microarray approach was used to study global gene expression in glomerular RNA obtained from these mice, as well as from combined TSLP transgenic and Fcγ receptor IIb null mice (TSLP/FcIIb−/−), which develop aggravated membranoproliferative glomerulonephritis. Protease nexin-1 (PN-1) and tissue plasminogen activator (tPA), two potential regulators of fibrosis that are involved in the fibrinolytic and coagulation pathways, were dramatically upregulated in TSLP mice compared with wild-type controls. In situ hybridization revealed minimal expression of PN-1 mRNA in the glomeruli of wild-type mice, increased expression in TSLP mice, and the greatest expression in the mesangial cells of TSLP/FcIIb−/− mice. Immunohistochemistry demonstrated greater expression of PN-1, tPA, and PAI-1 in the mesangial cells of TSLP mice compared with wild-type and the greatest in TSLP/FcIIb−/− mice. In cultured mesangial cells, incubation with Cryoglobulins induced an upregulation of PN-1 mRNA; increased expression of PN-1, tPA, and PAI-1 proteins; and stimulated secretion of TGF-β1. It is concluded that PN-1, tPA, PAI-1, and TGF-β1 are likely important mediators of murine Cryoglobulinemic glomerulonephritis and that the Cryoglobulins may directly upregulate their expression.
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all trans retinoic acid aggravates Cryoglobulin associated membranoproliferative glomerulonephritis in mice
Nephrology Dialysis Transplantation, 2007Co-Authors: Masayuki Iyoda, Kelly L Hudkins, Jolanta Kowalewska, Tomasz Wietecha, Miriam C Banas, Shunhua Guo, Gang Liu, Li Wang, Charles E AlpersAbstract:Background. Transgenic (tg) mice overexpressing thymic stromal lymphopoietin (TSLP) develop mixed Cryoglobulinaemia with renal disease closely resembling human Cryoglobulinaemic membranoproliferative glomerulonephritis (MPGN), as well as systemic inflammation involving lung, liver and skin as a result of Cryoglobulin deposits. We assessed the effect of alltrans-retinoic acid (ATRA), a powerful anti-inflammatory agent, on this model of Cryoglobulinaemic MPGN. Methods. Groups of male TSLP tg mice and wild-type controls were treated with either ATRA (20 mg/kg) or vehicle 3 times weekly by intraperitoneal injection for 4 or 8 weeks, when mice were then sacrificed. Routine histology and immunohistochemistry for collagen IV, a-smooth muscle actin, Mac-2 and Ki67 were performed. Immunoglobulin levels were measured by enzyme-linked immunosorbent assay. Results. ATRA unexpectedly exacerbated renal injury in TSLP tg mice with increased glomerular extracellular matrix, mesangial cell activation, glomerular cell proliferation, glomerular macrophage influx and immune complex deposition. Systemic injuries involving liver and lung, and the amount of circulating Cryoglobulins were all worsened by ATRA treatment. Furthermore, ATRA resulted in increased IgG1 and IgM levels, the main components of the Cryoglobulins in TSLP tg mice, and a manifestation of an enhanced Th2 immune response. Conclusions. ATRA is not protective but instead aggravates Cryoglobulinaemic MPGN and its systemic manifestations in TSLP tg mice. We speculate these findings may be due to augmented production of pathogenic immunoglobulins and/or an enhanced systemic Th2 response. Although disappointing, our results also suggest caution in the application of retinoid therapy to human disease based on the largely positive animal data reported to date.
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membranoproliferative glomerulonephritis associated with hepatitis c virus infection
The New England Journal of Medicine, 1993Co-Authors: Richard J Johnson, David R Gretch, Hideaki Yamabe, Jaime Hart, Carlos E Bacchi, Peter Hartwell, William G Couser, Lawrence Corey, Mark H Wener, Charles E AlpersAbstract:Background and Methods Hepatitis C virus (HCV) infection causes both acute and chronic liver disease and is also associated with mixed Cryoglobulinemia. Whether HCV is also associated with renal disease, as is the hepatitis B virus, is not known. We describe the clinical, pathologic, virologic, and immunologic features of eight patients with HCV infection who were referred to nephrologists for glomerulonephritis. Four patients were treated with interferon alfa. Results All eight patients had proteinuria, and seven had decreased renal function. Renal biopsy in all patients revealed membranoproliferative glomerulonephritis, characterized by the deposition of IgG, IgM, and C3 in glomeruli. Electron microscopy of the biopsy specimens showed Cryoglobulin-like structures in three of four patients. All eight patients had HCV RNA detected in their serum, elevated serum aminotransferase concentrations, and hypocomplementemia, and the majority had Cryoglobulins and circulating immune complexes in their serum. Cryop...
Munehiro Nakata - One of the best experts on this subject based on the ideXlab platform.
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IMMUNOBIOLOGY Level of galactosylation determines Cryoglobulin activity of murine IgG3 monoclonal rheumatoid factor
2016Co-Authors: Aki Kuroki, Thierry Fulpius, Munehiro Nakata, Luc Reininger, Shuichi Kikuchi, Yasuhiro Kuroda, Toho Toda, Yves Pastore, Liliane Fossati-jimack, Naoya KojimaAbstract:isotype have been shown to play a signifi-cant role in the development of murine lu-pus–like autoimmune syndrome.At present, the structural basis of IgG3 cryoprecipita-tion and its role in autoantibody pathogenic-ity remain to be defined. Using molecular variants of an IgG3 monoclonal rheumatoid factor, 6-19, derived from an autoimmune MRL-Faslpr mouse, we have investigated the implication of charged residues in the heavy-chain variable (VH) region, potential CH3-linked oligosaccharides, and galactosyla-tion of CH2-linked oligosaccharides in its Cryoglobulin activity. The Cryoglobulin activ-ity of the IgG3 6-19 mutant bearing more negatively charged residues at VH 6 and 23 was found to be reduced but still highly significant, whereas that of the mutant lack-ing a potential CH3 glycosylation site re-mainedunchanged. Inmarkedcontrast, IgG3 6-19 variants obtained from 6-19 heavy-chain transgenic mice displayed barely de-tectableCryoglobulinactivityassociatedwith an increased level of galactosylation in the CH2 oligosaccharide side chains. Thus, our data strongly suggest that the Cryoglobulin activity of IgG3 6-19 autoantibody is criti-cally determined by levels of galactosyla-tion in the CH2 oligosaccharide side chains, whereas VH residues play a secondary role in 6-19 IgG3 Cryoglobulin activity. (Blood
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Molecular and cellular basis for pathogenicity of autoantibodies: lessons from murine monoclonal autoantibodies.
Springer seminars in immunopathology, 2006Co-Authors: Lucie Clementine Baudino, Munehiro Nakata, Samareh Azeredo Da Silveira, Shozo IzuiAbstract:The pathogenesis of autoantibody-mediated cellular and tissue lesions in autoimmune diseases is most straightforwardly attributable to the combined action of self-antigen binding properties and effector functions associated with the Fc regions of the different immunoglobulin (Ig) isotypes. The analysis of two different sets of monoclonal autoantibodies derived from lupus-prone mice revealed remarkable differences in the pathogenic potentials of different IgG subclasses: (1) the IgG2a and IgG2b subclasses of anti-red blood cell (RBC) autoantibodies are the most pathogenic and efficiently activate two classes of activating IgG Fc receptors (FcγRIII and FcγRIV) and complement; (2) the IgG3 subclass is less pathogenic and activate only complement; and (3) the IgG1 subclass is the least pathogenic and interact only with FcγRIII. In addition, because of the unique property of IgG3 to form self-associating complexes and generate Cryoglobulins, this subclass of rheumatoid factor and anti-DNA autoantibodies became highly pathogenic and induced lupus-like nephritis and/or vasculitis. Since the switch to IgG2a and IgG3 is promoted by Th1 cytokine interferon γ, these results strongly suggest that Th1 autoimmune responses could be critically involved in the generation of more pathogenic autoantibodies in systemic lupus erythematosus. This finding is consistent with the observation that the progression of murine lupus nephritis is correlated with the relative dominance of Th1 autoimmune responses. Finally, the analysis of IgG glycosylation pattern revealed that more sialylated IgG autoantibodies remained poorly pathogenic because of limited Fc-associated effector functions and loss of Cryoglobulin activity. This suggests that the terminal sialylation of the oligosaccharide side chains of IgG could be a significant factor determining the pathogenic potential of autoantibodies. Our results thus underline the importance of subpopulations of autoantibodies, induced by the help of Th1 cells, in the pathogenesis of autoantibody-mediated cellular and tissue injuries.
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level of galactosylation determines Cryoglobulin activity of murine igg3 monoclonal rheumatoid factor
Blood, 2002Co-Authors: Aki Kuroki, Yves D Pastore, Thierry Fulpius, Liliane Fossatijimack, Luc Reininger, Shuichi Kikuchi, Yasuhiro Kuroda, Frederic Lajaunias, Toho Toda, Munehiro NakataAbstract:Autoantibodies of the cryoprecipitating IgG3 isotype have been shown to play a significant role in the development of murine lupus-like autoimmune syndrome. At present, the structural basis of IgG3 cryoprecipitation and its role in autoantibody pathogenicity remain to be defined. Using molecular variants of an IgG3 monoclonal rheumatoid factor, 6-19, derived from an autoimmune MRL-Fas(lpr) mouse, we have investigated the implication of charged residues in the heavy-chain variable (VH) region, potential CH3-linked oligosaccharides, and galactosylation of CH2-linked oligosaccharides in its Cryoglobulin activity. The Cryoglobulin activity of the IgG3 6-19 mutant bearing more negatively charged residues at VH 6 and 23 was found to be reduced but still highly significant, whereas that of the mutant lacking a potential CH3 glycosylation site remained unchanged. In marked contrast, IgG3 6-19 variants obtained from 6-19 heavy-chain transgenic mice displayed barely detectable Cryoglobulin activity associated with an increased level of galactosylation in the CH2 oligosaccharide side chains. Thus, our data strongly suggest that the Cryoglobulin activity of IgG3 6-19 autoantibody is critically determined by levels of galactosylation in the CH2 oligosaccharide side chains, whereas VH residues play a secondary role in 6-19 IgG3 Cryoglobulin activity.
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role of galactosylation in the renal pathogenicity of murine immunoglobulin g3 monoclonal Cryoglobulins
Blood, 2001Co-Authors: Tsuguo Mizuochi, Yves D Pastore, Kohdoh Shikata, Aki Kuroki, Thierry Fulpius, Munehiro Nakata, Liliane Fossatijimack, Luc Reininger, Shuichi Kikuchi, Misao MatsushitaAbstract:Cryoglobulin activity associated with murine immunoglobulin G3 (IgG3) has been shown to play a significant role in the development of murine lupuslike glomerulonephritis. A fraction, but not all, IgG3 monoclonal antibodies are capable of inducing a severe acute lupuslike glomerulonephritis as a result of direct localization of IgG3 Cryoglobulins, suggesting the importance of qualitative features of Cryoglobulins in their nephritogenic activities. Here a remarkable difference is shown in the renal pathogenicity of 2 murine IgG3 monoclonal Cryoglobulins, identical in the amino acid sequences of their heavy and light chains but different in galactosylation patterns of oligosaccharide side chains because of their synthesis in different myeloma cells. The antibody lacking the capacity to induce severe glomerulonephritis displayed an increased proportion of galactosylated heavy chains. Changes in conformation, as revealed by gel filtration analysis, reduced Cryoglobulin activity, and accelerated clearance could account for the lack of the renal pathogenicity of the more galactosylated variant. This observation provides a direct demonstration for the role of IgG galactosylation in the pathogenic potential of Cryoglobulins.
Liliane Fossatijimack - One of the best experts on this subject based on the ideXlab platform.
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the role of complement in Cryoglobulin induced immune complex glomerulonephritis
Journal of Immunology, 2005Co-Authors: Marten Trendelenburg, Liliane Fossatijimack, Shozo Izui, Josefina Corteshernandez, Daniel Turnberg, Margarita Lewis, Terence H Cook, Marina BottoAbstract:Many forms of glomerulonephritis are triggered by Ab localization in the glomerulus, but the mechanisms by which this induces glomerular inflammation are not fully understood. In this study we investigated the role of complement in a mouse model of Cryoglobulin-induced immune complex glomerulonephritis. Several complement-deficient mice on a C57BL/6 and BALB/c genetic background were used and compared with strain-matched, wild-type controls. Cryoglobulinemia was induced by i.p. injection of 6-19 hybridoma cells producing an IgG3 Cryoglobulin with rheumatoid factor activity against IgG2a of allotype a present in BALB/c, but not C57BL/6, mice. Thus, the cryoprecipitate in C57BL/6 mice consisted of the IgG3 Cryoglobulin only (type I Cryoglobulinemia) compared with IgG3-IgG2a complexes in BALB/c (type II Cryoglobulinemia). The survival of mice was not affected by complement deficiency. Glomerular influx of neutrophils was significantly less in C3-, factor B-, and C5-deficient mice compared with wild-type and C1q-deficient mice. It did not correlate with C3 deposition, but did correlate with the amount of C6 deposited. Deficiency of CD59a, the membrane inhibitor of the membrane attack complex, did not induce an increase in neutrophil infiltration, suggesting that the generation of C5a accounts for the effects observed. There was no apparent difference between Cryoglobulinemia types I and II regarding the role of complement. Our results suggest that in this model of Cryoglobulin-induced glomerulonephritis the neutrophil influx was mediated by C5 activation with the alternative pathway playing a prominent role in its cleavage. Thus, blocking C5 is a potential therapeutic strategy for preventing renal injury in Cryoglobulinemia.
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level of galactosylation determines Cryoglobulin activity of murine igg3 monoclonal rheumatoid factor
Blood, 2002Co-Authors: Aki Kuroki, Yves D Pastore, Thierry Fulpius, Liliane Fossatijimack, Luc Reininger, Shuichi Kikuchi, Yasuhiro Kuroda, Frederic Lajaunias, Toho Toda, Munehiro NakataAbstract:Autoantibodies of the cryoprecipitating IgG3 isotype have been shown to play a significant role in the development of murine lupus-like autoimmune syndrome. At present, the structural basis of IgG3 cryoprecipitation and its role in autoantibody pathogenicity remain to be defined. Using molecular variants of an IgG3 monoclonal rheumatoid factor, 6-19, derived from an autoimmune MRL-Fas(lpr) mouse, we have investigated the implication of charged residues in the heavy-chain variable (VH) region, potential CH3-linked oligosaccharides, and galactosylation of CH2-linked oligosaccharides in its Cryoglobulin activity. The Cryoglobulin activity of the IgG3 6-19 mutant bearing more negatively charged residues at VH 6 and 23 was found to be reduced but still highly significant, whereas that of the mutant lacking a potential CH3 glycosylation site remained unchanged. In marked contrast, IgG3 6-19 variants obtained from 6-19 heavy-chain transgenic mice displayed barely detectable Cryoglobulin activity associated with an increased level of galactosylation in the CH2 oligosaccharide side chains. Thus, our data strongly suggest that the Cryoglobulin activity of IgG3 6-19 autoantibody is critically determined by levels of galactosylation in the CH2 oligosaccharide side chains, whereas VH residues play a secondary role in 6-19 IgG3 Cryoglobulin activity.
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role of galactosylation in the renal pathogenicity of murine immunoglobulin g3 monoclonal Cryoglobulins
Blood, 2001Co-Authors: Tsuguo Mizuochi, Yves D Pastore, Kohdoh Shikata, Aki Kuroki, Thierry Fulpius, Munehiro Nakata, Liliane Fossatijimack, Luc Reininger, Shuichi Kikuchi, Misao MatsushitaAbstract:Cryoglobulin activity associated with murine immunoglobulin G3 (IgG3) has been shown to play a significant role in the development of murine lupuslike glomerulonephritis. A fraction, but not all, IgG3 monoclonal antibodies are capable of inducing a severe acute lupuslike glomerulonephritis as a result of direct localization of IgG3 Cryoglobulins, suggesting the importance of qualitative features of Cryoglobulins in their nephritogenic activities. Here a remarkable difference is shown in the renal pathogenicity of 2 murine IgG3 monoclonal Cryoglobulins, identical in the amino acid sequences of their heavy and light chains but different in galactosylation patterns of oligosaccharide side chains because of their synthesis in different myeloma cells. The antibody lacking the capacity to induce severe glomerulonephritis displayed an increased proportion of galactosylated heavy chains. Changes in conformation, as revealed by gel filtration analysis, reduced Cryoglobulin activity, and accelerated clearance could account for the lack of the renal pathogenicity of the more galactosylated variant. This observation provides a direct demonstration for the role of IgG galactosylation in the pathogenic potential of Cryoglobulins.
Alexandre Karras - One of the best experts on this subject based on the ideXlab platform.
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type i Cryoglobulinemia in multiple myeloma a rare entity analysis of clinical and biological characteristics of seven cases and review of the literature
Leukemia & Lymphoma, 2013Co-Authors: Judith Payet, Joel Livartowski, Niloufar Kavian, Olivia Chandesris, N Dupin, Nadege Wallet, Alexandre Karras, Carine Salliot, Felipe Suarez, Herve AvetloiseauAbstract:AbstractThe type I Cryoglobulins (CGs) account for 10–15% of all Cryoglobulins and are found in patients with hematological disorders. We here describe the largest series of seven cases of type I Cryoglobulinemia associated with multiple myeloma (MM) and provide a detailed review of the literature associated with this disorder, with the aim of improving the future diagnosis and therapeutic management of this rare disease. Six of the cases in our series were men aged 28–69 years, and most of the subject patients had an immunoglobulin G (IgG) monoclonal component and stage I indolent MM that manifested as Cryoglobulin-related symptoms. The patients were all karyotypically normal. Clinical manifestations in this group were: skin lesions (five cases, 71.4%), rheumatologic failure (four cases, 57.1%), neurological abnormalities (two cases, 28.6%), mixed cutaneous/rheumatologic/renal defects (one case, 14.3%) and one case in which the Cryoglobulinemia was asymptomatic. Two patients experienced acute renal failu...
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Cryoglobulin induced cardiomyopathy
Journal of the American College of Cardiology, 2010Co-Authors: Alexandre Karras, Louis Potier, Annehelene Reboux, Nelica Coldea, Ludivine Perdrix, Christian Jacquot, Elie MousseauxAbstract:![Figure][1] ![Figure][1] [Video 1][2] ![Figure][1] [Video 2][3] ![Figure][1] [Video 3][4] ![Figure][1] [Video 4][5] A 63-year-old woman was admitted with dyspnea and massive lower limb edema. Active hepatitis C virus (HCV) infection had been diagnosed
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renal involvement in monoclonal type i Cryoglobulinemia two cases associated with igg3κ Cryoglobulin
American Journal of Kidney Diseases, 2002Co-Authors: Alexandre Karras, Laurehelene Noel, Dominique Droz, Dominique Delansorne, Jeanpaul Saintandre, Pierre Aucouturier, Mariealexandra Alyanakian, Jeanpierre Grunfeld, Philippe LesavreAbstract:Abstract Renal involvement has been described rarely in monoclonal (type I) Cryoglobulinemia, although this complication is frequent among patients with mixed (type II or III) Cryoglobulin. We report two patients with glomerulonephritis and monoclonal IgGκ Cryoglobulin. Both patients presented with nephrotic syndrome, microscopic hematuria, and impaired renal function. Hepatitis C serology was negative, bone marrow aspiration was normal, and the renal biopsy specimen showed membranoproliferative glomerulonephritis with glomerular subendothelial deposits of monoclonal IgGκ. In both cases, circulating Cryoglobulin and monotypic tissue deposits were found to be IgG3κ, suggesting that this isotype may have a particular propensity to cause this type of membranoproliferative glomerulonephritis. Although 18 cases of type I Cryoglobulinemia with biopsy-proven glomerulonephritis have been reported to date, this is the first characterization of immunoglobulin heavy-chain isotype in this disease. Am J Kidney Dis 40:1091-1096. © 2002 by the National Kidney Foundation, Inc.
Evarist Feliu - One of the best experts on this subject based on the ideXlab platform.
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essential monoclonal gammopathy with an igm paraprotein that is a Cryoglobulin with cold agglutinin and edta dependent platelet antibody properties
British Journal of Haematology, 1998Co-Authors: Misericordia Pujol, Jose Ma Ribera, Ana Ribera, Elena Abad, C. Jiménez, Evarist FeliuAbstract:A patient with apparent anaemia and thrombocytopenia caused by a monoclonal paraprotein is described. The patient's serum contained a monoclonal IgM kappa, a Cryoglobulin and a cold agglutinin. The Cryoglobulin, similar to the serum paraprotein, was a monoclonal IgM kappa. Serum was studied to determine the relationship of the Cryoglobulin with the cold agglutinin. The Cryoglobulin and cold agglutinin were found to be the same paraprotein. Moreover, with absorption and elution techniques the reactivity of the autoantibody with both erythrocytes and platelets was demonstrated. Reports of cryoprecipitable cold agglutinins are rare and therefore this case is exceptional given that the IgM kappa paraprotein was found to be a cold agglutinin which was also reactive with platelets.