Anti-peripherin B lymphocytes are positively selected during diabetogenesis.
Rearrangement analysis of immunoglobulin genes is an exceptional opportunity to look back at the B lymphocyte differentiation during ontogeny and the subsequent immune response, and thus to study the selective pressures involved in autoimmune disorders. In a recent study to characterize the antigenic specificity of B lymphocytes during T1D progression, we generated hybridomas of islet-infiltrating B lymphocytes from NOD mice and other related strains developing insulitis, but with different degrees of susceptibility to T1D. We found that a sizable proportion of hybridomas produced monoclonal antibodies reactive to peripherin, an intermediate filament protein mainly found in the peripheral nervous system. Moreover, we found that anti-peripherin antibody-producing hybridomas originated from B lymphocytes that had undergone immunoglobulin class switch recombination, a characteristic of secondary immune response. Therefore, in the present study we performed immunoglobulin VL and VH analysis of these hybridomas to ascertain whether they were derived from B lymphocytes that had undergone antigen-driven selection. The results indicated that whereas some anti-peripherin hybridomas showed signs of oligoclonality, somatic hypermutation and/or secondary rearrangements (receptor edition and receptor revision), others seemed to directly derive from the preimmune repertoire. In view of these results, we conclude that anti-peripherin B lymphocytes are positively selected and primed in the course of T1D development in NOD mice, and reinforce the idea that peripherin is a relevant autoantigen targeted during T1D development in this animal model.
Carrillo
Jorge
J
Laboratory of Immunobiology for Research and Application to Diagnosis & Center for Transfusion and Tissue Bank (BST), Institut d'Investigacio Germans Trias i Pujol, Badalona, Barcelona, Spain.
Puertas
Maria Carmen
MC
Planas
Raquel
R
Pastor
Xavier
X
Alba
Aurora
A
Stratmann
Thomas
T
Pujol-Borrell
Ricardo
R
Ampudia
Rosa Maria
RM
Vives-Pi
Marta
M
Verdaguer
Joan
J
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D002999:Clone Cells; D022801:Complementarity Determining Regions / Q000737:chemistry; D003920:Diabetes Mellitus / Q000276:immunology* / Q000473:pathology; D015322:Gene Rearrangement, B-Lymphocyte / Q000276:immunology; D006825:Hybridomas / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D007381:Intermediate Filament Proteins / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000276:immunology*; D064531:Peripherins; D012641:Selection, Genetic; D027041:Somatic Hypermutation, Immunoglobulin / Q000276:immunology
D000906:Antibodies; D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D064531:Peripherins