Innate immunity and human B cell clonal expansion: effects on the recirculating B2 subpopulation.
Foci of autoantigen-specific B lymphocytes in nonlymphoid tissues have been associated with development of autoimmune disease. To better understand the genesis of such ectopic lymphoid tissue, this study investigated whether several B cell-tropic innate immune system molecules, known to be elevated in response to inflammatory stimuli, can cooperate in fostering the T cell-independent clonal expansion of mature human B2 cells under conditions of limiting BCR engagement. Notable synergy was observed between BCR coligation with the C3dg-binding CD21/CD19 costimulatory complex, B cell-activating factor belonging to the TNF family (BAFF), and IL-4 in generating B cell progeny with sustained CD86 and DR expression. The synergy was observed over a wide range of BCR:ligand affinities and involved: 1) cooperative effects at promoting early cell cycle progression and viability; 2) BCR:CD21 coligation-promoted increases in BAFF receptors that were highly regulated by IL-4; 3) reciprocal effects of IL-4 and BAFF at dampening daughter cell apoptosis typical of stimulation by BCR:CD21 and either cytokine alone; and 4) BAFF-sustained expression of antiapoptotic Mcl-1 within replicating lymphoblasts. The results suggest that significant clonal proliferation of recirculating B2 cells occurs upon limited binding to C3dg-coated Ag in an inflammatory in vivo milieu containing both BAFF and IL-4. When rare autoantigen-presenting B cells undergo such expansions, both B cell and T cell autoimmunity may be promoted.
Mongini
Patricia K A
PK
Department of Rheumatology, Hospital for Joint Diseases, New York University Medical Center, NY 10003, USA. patricia.mongini@med.nyu.edu
Inman
John K
JK
Han
Hanna
H
Kalled
Susan L
SL
Fattah
Rasem J
RJ
McCormick
Steven
S
D000293:Adolescent; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D018941:Antigens, CD19 / Q000502:physiology; D053264:B-Cell Activating Factor; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000502:physiology*; D002470:Cell Survival; D002648:Child; D002675:Child, Preschool; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D006801:Humans; D007113:Immunity, Innate; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000494:pharmacology / Q000502:physiology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D017464:Receptors, Complement 3d / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D016196:S Phase; D053303:Transmembrane Activator and CAML Interactor Protein; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000888:Antibodies, Anti-Idiotypic; D018941:Antigens, CD19; D053264:B-Cell Activating Factor; D000949:Histocompatibility Antigens Class II; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D017464:Receptors, Complement 3d; D018124:Receptors, Tumor Necrosis Factor; C108467:TNFRSF13B protein, human; C505719:TNFSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D014409:Tumor Necrosis Factor-alpha; C044203:anti-IgM; D015847:Interleukin-4