Peripheral neuropathy associated with monoclonal IgM anti-Pr2 cold agglutinins.

Abstract

A patient with a chronic, large fibre sensory neuropathy had an immunoglobulin MB monoclonal paraprotein reactive at titres in excess of 1/105 with NeuNAc(a2-8)NeuNAc(a2-3)Gal configured disialosyl groups present on the gangliosides GDlb, GTlb, GQlb, and GD3. The paraprotein showed weaker reactivity with GDla, GM3, and LM1 but no reactivity with GM2, GM1, or asialo-GM1. In addition, the paraprotein had cold agglutinating activity with anti-Pr2 specificity, Pr2 being an antigenic determinant on membrane glycoproteins or glycolipids in erythrocytes or both. A large fibre sensory neuropathy with monoclonal anti-disialosyl antibodies is an increasingly recognised form of paraproteinaemic neuropathy.

A somatically mutated human antiganglioside IgM antibody that induces experimental neuropathy in mice is encoded by the variable region heavy chain gene, V1-18.

“…Ha1 binding to gangliosides was shown to be highly temperature dependent, being greater at 4 Њ C than at 20 Њ C (room temperature) or 37 Њ C (body temperature), as previously noted for the serum and rbcM (19). In addition, Ha1 agglutinated human red blood cells in the cold (4 Њ C) with a hemagglutination titre (as expressed in milligrams of IgM) identical to that of the rbc-M fraction (data not shown).…”

“…Fourthly, using this approach one can assess the conduction in individual nerves by measuring spontaneous and evoked neurotransmitter release at individual neuromuscular junctions. Fifthly, even though the patient Ha's symptoms were predominantly sensory rather than motor, clinical neurophysiological assessment indicated that nerve conduction was markedly reduced in motor nerves (19). Although justifying our use of a motor preparation, we recognize the important need in future work to extend our physiological studies to include sensory nerve preparations to draw more clinically relevant pathophysiological conclusions.…”

“…The paraprotein also has cold agglutinating activity typed as anti-Pr 2 by standard techniques (22); this activity was first identified at routine cross-matching when Ha was 52 yr old in 1980 and allows one to purify the serum IgM paraprotein on red cells for experimental studies: cold agglutinating antibodies were affinity purified from the serum by temperature-dependent elution on human group O red blood cells as previously described and this fraction is referred to as rbcM. The antiganglioside activity of the serum was characterized by ELISA as previously described (19) and found to contain exclusively IgM antibodies against GD1b (titre of 1/850,000), GQ1b (1/450,000), GT1b (1/300,000), GD3 (1/260,000), GM3 (1/660) and GD1a (1/570) with no reactivity against GM1 or GM2. rbcM gave an identical pattern of reactivity.…”

“…Hybridoma specificity, stability and monoclonality were checked by ELISA, TLC overlay, and isoelectric focusing (IEF) of culture supernatants. TLC overlay was performed as previously described (19,34) using the enhanced chemiluminescence system according to manufacturer's instructions (Amersham International, Little Chalfont, UK). IEF of IgM immunoglobulins was performed in 0.5 mm agarose gels with a pH gradient composed of 1 ml Pharmalyte 5-8 and 0.25 ml Pharmalyte 3-10 using standard apparatus and reagents (Pharmacia Diagnostics, Uppsala, Sweden).…”

Monoclonal IgM Cold Agglutinins with Anti-Pr(1d) Specificity in a Patient with Peripheral Neuropathy

“…The reactivity of anti-Pr CA with gangliosides has been investigated by Uemura et al [4] by thin-layer chromatog gliosides containing disialosyl groups (GDlb, GTlb, GQlb and GD3) and which have no activity for GM1 have been identified in 5 patients with predominantly sensory neuro pathies [10][11][12][13][14]. The clinical and serological findings for this group of patients have recently been reviewed [14].…”