B Lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse.
Systemic sclerosis (SSc) is characterized by fibrosis and autoimmmunity. Peripheral blood B cells from SSc patients specifically overexpress CD19, a critical cell-surface signal transduction molecule in B cells. CD19 deficiency in B cells also attenuates skin fibrosis in the tight-skin (TSK/+) mouse, a genetic model for SSc. Herein we analyzed two transgenic mouse lines that overexpress CD19. Remarkably, 20% increase of CD19 expression in mice spontaneously induced SSc-specific anti-DNA topoisomerase I (topo I) antibody (Ab) production, which was further augmented by 200% overexpression. In TSK/+ mice overexpressing CD19, skin thickness did not increase, although anti-topo I Ab levels were significantly augmented, indicating that abnormal CD19 signaling influences autoimmunity in TSK/+ mice and also that anti-topo I Ab does not have a pathogenic role. The molecular mechanisms for abnormal CD19 signaling were further assessed. B-cell antigen receptor crosslinking induced exaggerated calcium responses and augmented activation of extracellular signal-regulated kinase in TSK/+ B cells. CD22 function was specifically impaired in TSK/+ B cells. Consistently, CD19, a major target of CD22-negative regulation, was hyperphosphorylated in TSK/+ B cells. These findings indicate that reduced inhibitory signal provided by CD22 results in abnormal activation of signaling pathways including CD19 in TSK/+ mice and also suggest that this disrupted B cell signaling contribute to specific autoantibody production.
Department of Regenerative Medicine, Research Institute, International Medical Center of Japan, Tokyo, Japan.
Noriko
N
Asano
Manabu
M
Fujimoto
Norihito
N
Yazawa
Senji
S
Shirasawa
Minoru
M
Hasegawa
Hitoshi
H
Okochi
Kunihiko
K
Tamaki
Thomas F
TF
Tedder
Shinichi
S
Sato
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D018941:Antigens, CD19 / Q000235:genetics / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D001323:Autoantibodies / Q000378:metabolism*; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D015815:Cell Adhesion Molecules; D003432:Cross-Linking Reagents; D004264:DNA Topoisomerases, Type I / Q000276:immunology; D005260:Female; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D037102:Lectins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051918:Sialic Acid Binding Ig-like Lectin 2; D015398:Signal Transduction; D012867:Skin / Q000473:pathology*
D015703:Antigens, CD; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte; D001323:Autoantibodies; C497867:CD22 protein, human; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; D003432:Cross-Linking Reagents; D037102:Lectins; D011947:Receptors, Antigen, B-Cell; D051918:Sialic Acid Binding Ig-like Lectin 2; D020928:Mitogen-Activated Protein Kinases; D004264:DNA Topoisomerases, Type I; D002118:Calcium