A single helper T cell clone is sufficient to commit polyclonal naive B cells to produce pathogenic IgG in experimental pemphigus vulgaris.
The development of naive B cells into IgG-producing memory B cells requires cognate T cell-B cell interaction in Ag-specific immune responses. It is unknown whether a single T cell clone is sufficient or whether multiple clones are necessary to induce polyclonal IgG production in vivo. We addressed this issue using a mouse model of pemphigus vulgaris, a fatal autoimmune blistering skin disease caused by IgG autoantibodies against desmoglein (Dsg) 3. We previously isolated several Dsg3-reactive T cell clones from Dsg3(-/-) mice. Among these, two pathogenic T cell clones induced anti-Dsg3 IgG production and the development of a pemphigus phenotype when adoptively transferred with unprimed B cells from Dsg3(-/-) mice. IgG Abs harvested from recipient mice reacted with at least three parts of the extracellular domain of Dsg3, as determined using domain-swapped Dsg3/Dsg1 molecules. The anti-Dsg3 IgGs included at least two subclasses among IgG1, IgG2a, IgG2b, and IgG3 in each mouse. The anti-Dsg3 IgG induced by Dsg3-reactive T cell clones with primed B cells from Dsg3(-/-) mice also showed reactivity against different parts of the molecule, with a similar epitope distribution. Together, these results indicate that a single potent Dsg3-reactive T cell is sufficient to commit polyclonal naive B cells to produce pathogenic anti-Dsg3 IgG Abs and induce the PV phenotype. These findings provide an important framework for examining immunological mechanisms in Ab-mediated autoimmune diseases.
Takahashi
Hayato
H
Department of Dermatology, Division of Rheumatology, Keio University School of Medicine, Tokyo, Japan.
Kuwana
Masataka
M
Amagai
Masayuki
M
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002999:Clone Cells; D051184:Desmoglein 3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D018985:Epitopes, B-Lymphocyte / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010392:Pemphigus / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000637:transplantation*
D051184:Desmoglein 3; C495300:Dsg3 protein, mouse; D018985:Epitopes, B-Lymphocyte; D007074:Immunoglobulin G