Cryoglobulinemia based on interaction between a gamma macroglobulin and 7S gamma globulin

doi:10.1016/0002-9343(62)90191-2

The American Journal of Medicine

Volume 32, Issue 1, January 1962, Pages 142-147

https://doi.org/10.1016/0002-9343(62)90191-2 Get rights and content

Abstract

A cryoglobulin is described, consisting of approximately equal quantities of 7S and 19S gamma globulins. The cold-precipitable protein was present in the serum as a soluble 22S complex.

The property of cold precipitation resided in neither of the substituents of the cryoglobulin, but stemmed from the capacity of one of the constituents (the 19S component) to combine with 7S gamma globulin to form a complex insoluble at 4 °C and soluble at room temperature. The term “incomplete cryoglobulin” is suggested for this macrogammaglobulin.

It was possible to prepare a cryoglobulin in vitro by addition of 7S gamma globulin from a normal subject to the 19S incomplete cryoglobulin obtained from the patient studied.

The “incomplete cryoglobulin” gave a number of positive reactions for the rheumatoid factor, but was distinguished from it by its inability to agglutinate sensitized sheep erythrocytes. It could be readily detected, however, by a positive reaction with heat altered fraction II, the tanned cell test, the D cell test and the latex fixation test.

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Cryoglobulins consist of serum immunoglobulins that precipitate below 37°C and resolubilize upon warming. The clinical triad of cryoglobulinemia usually includes purpura, weakness, and arthralgia. Cryoglobulinemic syndrome, clinically defined as a systemic vasculitis, is associated with chronic infection with hepatitis C virus (HCV) and autoimmune disorders and can evolve into B-cell malignancies. While the current literature about HCV-associated cryoglobulinemia is not very limited, little is known about the immunologic and serologic profiles of affected patients. Therefore, comprehension of the pathogenetic mechanisms underlying cryoprecipitation could be very helpful. Due to the persistence of viral antigenic stimulation, biomarkers to use after the worsening progression of HCV infection to lymphoproliferative and/or autoimmune diseases are widely needed. Laboratory methods used to detect and characterize low concentrations of cryoprecipitates and immunotyping patterns could improve patient management. The most critical factor affecting cryoglobulin testing is that the pre-analytical phase is not fully completed at 37°C.
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RFs are immunoglobulin M (IgM) autoantibodies binding the Fc domain of self-IgG and were among the first described autoantibodies (Franklin et al., 1957). Although RFs often appear to be benign, they are directly pathogenic in mixed cryoglobulinemic vasculitis (Lospalluto et al., 1962; Meltzer et al., 1966). In this disease, a monoclonal pentameric IgM RF binds five normal polyclonal IgG molecules, and the macromolecular complex undergoes a reversible phase transition into insoluble aggregates when cooled below 30°C.
Pathogenic autoantibodies arise in many autoimmune diseases, but it is not understood how the cells making them evade immune checkpoints. Here, single-cell multi-omics analysis demonstrates a shared mechanism with lymphoid malignancy in the formation of public rheumatoid factor autoantibodies responsible for mixed cryoglobulinemic vasculitis. By combining single-cell DNA and RNA sequencing with serum antibody peptide sequencing and antibody synthesis, rare circulating B lymphocytes making pathogenic autoantibodies were found to comprise clonal trees accumulating mutations. Lymphoma driver mutations in genes regulating B cell proliferation and V(D)J mutation (CARD11, TNFAIP3, CCND3, ID3, BTG2, and KLHL6) were present in rogue B cells producing the pathogenic autoantibody. Antibody V(D)J mutations conferred pathogenicity by causing the antigen-bound autoantibodies to undergo phase transition to insoluble aggregates at lower temperatures. These results reveal a pre-neoplastic stage in human lymphomagenesis and a cascade of somatic mutations leading to an iconic pathogenic autoantibody.
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Cryoglobulins are antibodies that precipitate at low temperatures and dissolve after rewarming. Cryoglobulinemia refers to the presence of circulating cryoglobulins and generally leads to a systemic inflammatory syndrome characterized by fatigue, arthralgia, purpura, ulcers, neuropathy and/or glomerulonephritis. The disease mainly involves small to medium-sized blood vessels and causes vasculitis due to cryoglobulin-containing immune complexes. Cryoglobulinemia is classified into three types (I, II and III) on the basis of immunoglobulin composition. Predisposing conditions include lymphoproliferative, autoimmune diseases and hepatitis C virus infection. The diagnosis of cryoglobulinemic syndrome is predominantly based on the presence of clinical features and laboratorial demonstration of serum cryoglobulins. The treatment strategy depends on the cause of cryoglobulinemia. For patients with chronic HCV infection, antiviral therapy is indicated. Immunosuppressive or immunomodulatory therapy, including steroids, plasmapheresis and cytotoxic agents, is reserved for organ-threatening manifestations. In this review, we discuss the main clinical presentations, diagnostic approach and treatment options.
The Complement System
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The complement system is a major component of the innate immune system and plays central roles in protective immune processes, including recognition of foreign antigens, pathogen clearance, amplification of humoral and cellular immunity, and bridging innate and adaptive responses. Complement activation and dysregulation has been involved in the pathogenesis and clinical manifestations of several autoimmune diseases, such as systemic lupus erythematosus and other connective tissue disease, rheumatoid arthritis, and vasculitis. Evidence linking complement activation to these diseases includes the presence of complement deposition in affected tissues, decreased levels of complement proteins, and high levels of complement activation fragments in the blood and/or synovial fluid of patients with these diseases, as well as data from experimental models. Because of its functions, complement system is an attractive therapeutic target for a wide range of diseases, and its modulation could constitute a viable therapeutic strategy for the treatment of autoimmune conditions too.
Autoimmune Kidney Diseases Associated with Chronic Viral Infections
2018, Rheumatic Disease Clinics of North America
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One common extrahepatic manifestation of chronic HCV infection is cryoglobulinemia.75–77 Cryoglobulins are proteins that circulate in the serum, precipitate below core body temperature, and dissolve on rewarming.78,79 Circulating cryoglobulins are commonly detected in HCV-infected patients; up to 50% of patients with chronic HCV will have detectable serum cryoglobulins at some point during their infection; however, only 2% to 3% develop the vasculitic symptoms that characterize hepatitis C–related mixed cryoglobulinemic syndrome (HCV-MCS).
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Life-threatening conditions such as hyperviscosity syndrome, rapidly progressive renal failure due to massive intra-tubular immunocomplex (IC) precipitation, and extended necrosis due to small vessel IC precipitation have also been described [5,6], as has a “catastrophic-like” multi-system syndrome [3,4,7–9]. The disease is caused by the proliferation of B lymphocyte clones that produce a rheumatoid-like factor [10], which is generally an IgM that binds IgG of different idiotype specificity to form ICs known as mixed cryoglobulins (MCGs), which can precipitate at temperatures of <37 °C [11]. Although MCGs can sometimes be found in healthy people, particularly the elderly [12], CV is a relatively rare disorder that can occur in association with infectious, lymphoproliferative or autoimmune diseases [3,4], particularly with chronic hepatitis C virus (HCV) infection, which is responsible for > 90% of diagnosed cases [3–5,13].
To assess the effectiveness of apheresis therapy (AT) in treating the clinical manifestations of patients with complicated cryoglobulinemic vasculitis (CV).
A retrospective cohort study of 159 CV patients attending 22 Italian Centers who underwent at least one AT session between 2005 and 2015. The response to AT was evaluated on the basis of a defined grading system.
Peripheral neuropathy was the most frequent clinical condition leading to AT. Therapeutic plasma exchange was used in 70.4% of cases. The outcome of AT was rated very good in 19 cases, good in 64, partial/transient in 40, and absent/not assessable in 36. Life-threatening CV-related emergencies and renal impairment independently correlated with failure to respond to AT. The independent variables associated with an increased risk of death were age at the time of the first AT session, multi-organ life-threatening CV, the presence of renal impairment and failure to respond to AT. The time-dependent probability of surviving until CV-related death in the second year was 84%, with an AHR in patients with absent/not assessable response to AT of 11.25.
In this study AT is confirmed to be a safe procedure in patients with CV. Early AT should be considered in patients with severe CV, especially in cases with impending renal involvement, in order to prevent irreversible kidney damage. Although its efficacy in patients with multi-organ failure is limited, AT is the only treatment that can rapidly remove circulating cryoglobulins, and should be considered an emergency treatment.

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^☆: This study was aided by Grants A-2071 and 2A-5154 from the National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, and by a Medical Care and Research Grant from the National Foundation.

¹: From the Departments of Internal Medicine and Biochemistry, University of Texas Southwestern Medical School, Dallas, Texas.

^‡: Present address: Lackland Air Force Hospital, San Antonio, Texas.

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Case reportCryoglobulinemia based on interaction between a gamma macroglobulin and 7S gamma globulin☆

Abstract

Am. J. Med.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Arch. Biochem.

J. Chronic Dis.

J. Pediat.

Am. J. Med.

Am. J. Med.

Am. J. Med.

Am. J. Med.

Am. J. Med.

Studies of cryoglobulins. II. The spontaneous precipitation of protein from serum at 5 °c. in various states

Am. J. M. Sc.

Ein Neues Krystalinisches Serumglobulin

Ztschr. f. Physiol. Chem.

Cryoglobulinemia. I. Report of two cases with discussion of clinical manifestations, incidence, and significance

Ann. Int. Med.

Case report
Cryoglobulinemia based on interaction between a gamma macroglobulin and 7S gamma globulin☆