A critical role for complement C3d and the B cell coreceptor (CD19/CD21) complex in the initiation of inflammatory arthritis.
Complement C3 cleavage products mediate the recognition and clearance of toxic or infectious agents. In addition, binding of the C3d fragment to Ag promotes B lymphocyte activation through coengagment of the BCR and complement receptor 2 (CD21). Signal augmentation is thought to be achieved through enhanced recruitment and activation of CD21-associated CD19. In this study we show, using the DBA/1 collagen-induced arthritis (CIA) model, that conjugation of C3d to heterologous type II collagen is sufficient to cause disease in the absence of the mycobacterial components of CFA. Transient depletion of C3 during the inductive phase of CIA delays and lessens the severity of disease, and DBA/1 mice deficient for coreceptor components CD19 or CD21 are not susceptible to CIA. Adoptive transfer experiments revealed that CD21 expression on either B cells or follicular dendritic cells is sufficient to acquire disease susceptibility. Although CD19(-/-) and CD21(-/-) mice produce primary Ab responses to heterologous and autologous type II collagen, they are impaired in the ability to activate T cells, form germinal centers, and produce secondary autoantibody responses. These findings indicate that binding of C3d to self-Ags can promote autoimmunity through enhanced Ag retention and presentation by follicular dendritic cells and B cells, respectively.
Del Nagro
Christopher J
CJ
Program of Inflammatory Disease Research, Infectious and Inflammatory Disease Center, The Burnham Institute, La Jolla, CA 92037, USA.
Kolla
Ravi V
RV
Rickert
Robert C
RC
D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D024043:Collagen Type II / Q000276:immunology; D015933:Complement C3d / Q000378:metabolism / Q000502:physiology*; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D017464:Receptors, Complement 3d / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology
D018941:Antigens, CD19; D024043:Collagen Type II; D017464:Receptors, Complement 3d; D015933:Complement C3d