Influence of plasma immunoglobulin level on antibody synthesis

Abstract

In previous experimental animal studies it has been demonstrated that antibody depletion is not followed by increased antibody synthesis. To assess whether these results are conferrable to antibody-depleted humans, we measured free light chains (flcs) as markers of current antibody synthesis in 8 patients treated with immunoadsorption (IA) therapy. Specific and bulk immunoglobulin levels were obtained simultaneously. The mean serum flc concentration increased to the preapheresis value within 1 day and remained unchanged thereafter. Total immunoglobulin G (IgG) and specific antibody concentrations increased to pretreatment values in 88% and 43% of the patients, respectively, and remained below the original values in the others. In conclusion, the lack of increased flc synthesis after IA confirms the absence of a feedback mechanism regulating antibody synthesis. IntroductionThe regulation of serum antibody levels has been a subject of debate for several decades. A large number of studies have provided evidence for enhanced antibody synthesis after immunoglobulin depletion and thus for the existence of an immunoregulatory feedback mechanism. [1][2][3][4][5][6][7] In contrast, Charlton and colleagues 8-10 demonstrated with a series of animal experiments that the rapid increase of antibody serum levels after plasmapheresis could be explained by immunoglobulin backflow from extravascular space and decreased catabolism alone. More than 10 years later the lack of an increased antibody synthesis in a low immunoglobulin state was confirmed in the excellent studies by Junghans and Anderson 11 and by Junghans. 12 Knock-out mice with disrupted immunoglobulin G (IgG) protection receptors, which effect increased catabolism of IgG and subsequently low IgG serum levels, had a similar biosynthesis rate as normal control subjects.The complex metabolism of IgG has so far prevented exact measurement of immunoglobulin synthesis in humans with low antibody levels. However, a prerequisite for immunoglobulin assembly is the synthesis of free light chains (flcs) that are produced in excess during antibody production and secreted as free or monomers into the vascular space. 13,14 Because flcs have a half-live of only 2 to 4 hours, 15 they reflect current immunoglobulin production and can be used for estimating the activity of diseases accompanied by autoantibody synthesis. 16,17 We hypothesized that increased antibody synthesis after immunoglobulin depletion would be accompanied by increased flc serum levels and measured free and light chain concentrations in 8 patients undergoing immunoadsorption (IA) therapy. Study designThe study protocol was approved by the local ethics committee, and the patients' informed consent was obtained. Eight patients with various autoimmune diseases and normal kidney function treated with IA therapy were recruited (Table 1). Concomitant immunosuppressive therapy was prednisolone (n ϭ 4), mycophenolate mofetil (n ϭ 3), and cyclosporine A (n ϭ 1); 3 patients received no additional therapy. We recruited additi...

A randomized and controlled study comparing immunoadsorption and plasma exchange in myasthenic crisis

“…Therapeutic effects of PE or IA in autoantibody mediated diseases can be attributed to three major mechanisms: immediate intravascular reduction of (auto-)antibody concentration, pulsed induction of antibody redistribution, and subsequent immunomodulatory changes. The restoration of serum IgG levels after IA does not result from increased antibody synthesis but is related to changes of catabolism and immunoglobulin backflow [34]. The immediate improvement of clinical symptoms in Myasthenia gravis reflects the dynamic redistribution of AChRAb between neuromuscular synapses and intravascular spaces [23,24]; however, unlike in other diseases which directly depend on the absolute concentration of pathogenic factors, in Myasthenia gravis the absolute serum level of anti AChRAb has no strict correlation with disease severity especially in acute situations.…”

Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn

“…This reduction occurred despite ongoing IgG biosynthesis, which is regenerated at a constant rate regardless of IgG concentrations (25). In addition, it was shown that, once treatment was stopped, IgG levels eventually returned to concentrations that approached predose levels.…”

Prolonged Clinical Remission of Patients with Severe Pemphigus upon Rapid Removal of Desmoglein-Reactive Autoantibodies by Immunoadsorption

“…The relatively higher reduction of total serum IgG compared to Dsg-specific autoantibodies was presumably due to the redistribution of tissue-bound autoantibodies into the circulation. The rapid increase in Dsg-reactive IgG serum levels seen overnight during consecutive IA treatments suggests that a rediffusion of tissue-bound autoantibodies into the circulation may occur, since resynthesis is unlikely to cause the renewed increase in autoantibody titers [21]. To define a treatment protocol we examined the titers of anti-Dsg3 IgG prior to and immediately after each IA treatment.…”