The immunoglobulinopathies: From physiopathology to diagnosis

Abstract

The diversity of immunoglobulins (Igs) results mainly from recombinations of numerous genes within the heavy (V(Heavy), D, and J(Heavy)) and within the light (V(Light), J(Light)) chain gene loci, and from somatic hypermutations occurring during the immune response of B-cells. Igs production is controlled by complex cellular and humoral mechanisms. Plasma of healthy individuals contains polyclonal Igs. Clonal expansion of cells producing antigen-specific Igs may result from physiological as well as from pathological immune events. Exquisitely sensitive and specific molecular biology techniques have been used to evaluate the clonal diversity of cells producing antigen-specific Ig. However, the application of such techniques is hampered by the necessity to collect the totality of antigen-specific B-cells for subsequent analysis, which is impossible to perform routinely in humans. In addition, these techniques do not provide quantitative information about the concentration of the circulating Igs. It is therefore necessary to use tools allowing study of the quantity of the circulating Igs, and more particularly to detect overproduction of a single homogeneous Ig resulting from the expansion of a B-cell clone secreting Igs. Here, we review the mechanisms of B-cell differentiation and Ig synthesis, discuss the diseases associated with clonal Ig production and review the methods available in the clinical laboratory for Ig analysis.

Recent advances in blood‐related proteomics

“…Analysis of monoclonal gammopathies [45,46] and characterization of cryoproteins [47][48][49] using 2-DE has been shown to be useful in selected difficult clinical situations. Using 2-DE analyses and MS, we also recently identified a new peptide, called hSpa or CD5L [50].…”

“…Cryoproteins are defined as proteins precipitating at low temperature. Most frequently, the precipitates contain Igs and are therefore called cryoglobulins (reviewed in [46] [46]. In addition, proteins such as albumin [48] and fibrinogen [49] can also cryoprecipitate.…”

Mass Spectrometry

“…The identification of a protein component, TNFα-IgG, in a serum cryoprecipitate from a patient with cryogobulinemia by MALDI-FTICR-MS is illustrated in Figure 11.17, requiring only a minimum number of peptides [144]. Cryoglobulins are coldprecipitated serum immunoglobulins associated with a number of infectious, autoimmune, and neoplastic disorders such as hepatitis C [169,170]; therefore, their characterization using high-performance proteomics tools has become of considerable interest. The main protein components in a serum cryoprecipitate from a patient with type II cryogobulinemia were identified by MALDI-FTICR-MS as IgG and IgM μand γ-heavy chains, κand λ-light chains, and j-chains [171].…”

A better understanding of molecular mechanisms underlying human disease

“…The interest of 2-DE as well as its limitations in the analysis of monoclonal gammopathy, either in plasma/ serum or urine samples, have been described by different groups [122][123][124][125][126][127][128][129][130][131][132][133][134], and has been useful in difficult cases such as oligoclonal gammapathies, cold agglutinins or cryoglobulins [135].…”