Regulation Of B-Lymphocyte Responses To Foreign And Self-Antigens By The CD19+/CD21+ Complex
Fearon DT, Carroll MC
Annu Rev Immunol 2000;18:393-422
University of Cambridge, School of Clinical Medicine, Department of Medicine, Wellcome Trust Immunology Unit, United Kingdom
The Membrane Protein Complex CD19+/CD21+ couples the Innate Immune recognition of Microbial Antigens by the Complement System to the activation of B-Cells.
CD21+ binds the C3d fragment of activated C3 that becomes covalently attached to targets of Complement activation, and CD19+ co-stimulates signaling through the Antigen receptor, membrane ImmunoGlobulin.
CD21+ is also expressed by Follicular Dendritic Cells and mediates the long-term retention of Antigen that is required for the maintenance of Memory B-Cells.
Understanding of the biology of this receptor complex has been enriched by analyzes of genetically modified mice; these analyzes have uncovered roles not only in positive responses to foreign Antigens.
But, also in the development of Tolerance to Self-Antigens. Studies of signal transduction have begun to determine the basis for the CoReceptor activities of CD19+.
The integration of Innate and Adaptive Immune recognition at this molecular site on the B-Cell guides the appropriate selection of Antigen by Adaptive Immunity and emphasizes the importance of this CoReceptor Complex.
Regulation Of Humoral Immune Responses By CD21+/CD35+
Chen Z, Koralov SB, Kelsoe G
Immunol Rev 2000 Aug;176:194-204
Duke University Medical Center, Department of Immunology, Durham, North Carolina 27710, USA
Before Antigen-specific Immunity arises, the Complement System responds by activation through the Classical and/or Alternative Pathways leading to the covalent deposition of Complement fragments.
Three models, not mutually exclusive, have been proposed to explain how these Complement fragments interact with their Receptors, CD21+/CD35+, to enhance Humoral Immune Responses:
- CD21+/CD35+ retain and focus Antigens for optimal presentation
- CD21+/CD35+ on B-Cells serve as enhancing CoReceptors for B-Cell Antigen Receptor (BCR) signaling
- CD21+/CD35+ regulate B-Cell responses, by CD19+ aggregation
The CoReceptor model led us to predict that CD21+/CD35+ may lower the threshold of BCR affinity to diversify the repertoire of Humoral Immune Responses.
But surprisingly, CD21+/CD35+-deficient mice expressing a transgenic BCR with very low affinity (Kalpha approximately =1.2 x 10(5) M(-1)) for the (4-Hydroxy-3-Nitrophenyl) Acetyl Hapten generated significant AntiBody and germinal center responses to even low doses of Antigens in alum.
The magnitudes of these responses were much below those of normal controls but higher doses of Antigens substantially rectified these deficits.
Thus, while CD21+/CD35+ play important roles in Humoral Immunity, our observations provide little support to the hypothesis that CD21+/CD35+ promote Clonal diversity in Immune Responses by helping recruit low-affinity B-Cells.
The Role Of Complement In The Acquired Immune Response
Nielsen CH, Fischer EM, Leslie RG
Immunology 2000 May;100(1):4-12
University of Southern Denmark, Department of Immunology and Microbiology, Odense, Denmark
Studies over the past three decades have clearly established a central role for Complement in the promotion of a Humoral Immune Response.
The primary function of Complement, in this regard, is to Opsonize Antigen or Immune Complexes for uptake by Complement Receptor Type 2 (CR2, CD21+) expressed on B-Cells, Follicular Dendritic Cells (FDC) and some T-Cells.
A variety of mechanisms appear to be involved in Complement-mediated promotion of the Humoral Response. These include:
- Enhancement of Antigen (Ag) uptake and processing by both Ag-specific and non-specific B-Cells for presentation to specific T-Cells
- The activation of a CD21+/CD19+ complex-mediated signalling pathway in B-Cells
- which provides a stimulus synergistic to that induced by Antigen interaction with the B-Cell Receptor (BCR)
- Promotion of the interaction between B-Cells and Dendritic Cells (FDC)
- where C3d-bearing Immune Complexes participate in InterCellular bridging
- Current studies suggest that CR2 may also play a role in the determination of B-Cell Tolerance towards Self-Antigens.
And, thereby hold the key to the previously observed correlation between deficiencies of the early Complement components and AutoImmune Disease.
Role Of The Complement C3 Protein In The Control Of The Specific Immune Response
Villiers CL, Villiers MB, Marche PN
Ann Biol Clin (Paris) 1999 Mar-Apr;57(2):127-35
Inserm U. 238 et Universite Joseph-Fourier, Laboratoire D'ImmunoChimie, CEA-G, DBMS/ICH, 17, rue des Martyrs, F38054 Grenoble cedex 9
Whereas Complement System was usually considered as a member of Innate defence, one of its components (C3) is now thought to facilitate Acquired Immunity.
This role is due first to its capacity to covalently bind to Antigens and secondly to the interactions of its ProteoLytic fragments with different receptors expressed on most cells involved in the Acquired Immune Response.
After activation in the Plasma, C3 is ProteoLysed in fragments which possess various biological activities, as a modification in cell activities occurred after binding to Cell Surface Receptors.
Injection of low amount of Antigen results in a modified Immune Response in C3 deficient animals with a decrease in the level of specific AntiBodies and an absence of IgM/IgG switch.
One of the fragments of C3 (C3d) and its Receptor (CR2) seem particularly important : knock out animals in C3 or CR2 have similar phenotypes.
Mice with a deficit in CR2 restricted to the B-Lymphocytes present a strong reduction in the number and the size of germinal centers. Moreover, expression of CR2 on Follicular Dendritic Cells is necessary for the generation of a strong Memory Response.
C3 is also involved in the control of the IntraCellular processing of the Antigen as the use of covalent complex (C3b-Antigen) instead of free Antigen increases the amount of stable MHC Class II molecules at the Antigen-Presenting Cells surface.
In summary, C3 fragments increase cell to cell interactions, induce IntraCellular signalling after binding to their Receptors and increases IntraCellular processing of Antigens.
A better knowledge of the different roles of C3 may be useful to modify the Immune Response and to promote the Immune Memory, a domain where C3 seems particularly important.
Complement Opsonization Is Required For Presentation Of Immune Complexes By Resting Peripheral Blood B-Cells
Boackle SA, Morris MA, Holers VM, Karp DR
J Immunol 1998 Dec 15;161(12):6537-43
University of Colorado Health Sciences Center, Department of Medicine, Denver 80262, USA
Complement Receptor 2 (CD21+, CR2) is a B-Cell Receptor for Complement degradation products bound to Ag or Immune Complexes. The role of CD21+ in mediating Ag presentation of soluble Immune Complexes by resting B-Cells was studied.
Complement-coated Immune Complexes were formed by the incubation of Influenza Virus with Serum from Immune donors.
These complexes bound to peripheral blood B-Cells in a Complement-dependent manner. The binding required CD21+ or, to a lesser extent, Complement Receptor 1 (CR1, CD35+).
B-Cells pulsed with Immune Complexes containing Complement elicited a response from a panel of influenza-specific T-Cell clones, while those pulsed with Immune Complexes formed in the absence of Complement did not.
The expression of the early activation marker CD69+ and the CoStimulatory Molecule CD86+ were not induced by CD21+ Ligation alone, suggesting that CD21+-mediated Ag presentation occurs independently of B-Cell activation.
Up-regulation of these markers required exposure to T-Cell factors elicited by the recognition of Ag derived from Complement-containing Immune Complexes.
These findings suggest that binding of Ag to CD21+ enables Ag-nonspecific B-Cells to participate in the activation of Ag-specific T-Cells in a process that occurs independently of well-characterized B-Cell activation events.