Antibodies can completely suppress or enhance the antibody response to their specific antigen by several hundredfold. Immunoglobulin M (IgM) enhances antibody responses via the complement system, and complement activation by IgM probably starts the chain of events leading to antibody responses to suboptimal antigen doses. IgG can enhance primary antibody responses in the absence of the complement system and seems to be dependent on Fc receptors for IgG (FcgammaRs). IgE enhances antibody responses via the low-affinity receptor for IgE (FcepsilonRII/CD23). The precise effector mechanisms that cause enhancement are not known, but direct B-cell signaling, antigen presentation, and increased follicular localization are all possibilities. IgG, IgE, and IgM may also suppress antibody responses when used in certain immunization regimes, and it seems reasonable that an important mechanism behind suppression is the masking of antigenic epitopes by antibodies. In addition, FcgammaRIIB, which contains a cytoplasmic inhibitory motif, acts as a negative regulator of antibody responses. This receptor, however, may prevent the antibody responses from exceeding a certain level rather than causing complete suppression.

IgG antibodies can suppress more than 99% of the antibody response against the antigen to which they bind. This is used clinically to prevent rhesus-negative (Rh ؊ ) women from becoming immunized against Rh ؉ erythrocytes from their fetuses. The suppressive mechanism is poorly understood, but it has been proposed that IgG͞erythrocyte complexes bind to the inhibitory

Receptors for immunoglobulin (Ig)G (FcγRs) are important for the antibody-mediated effector functions of the immune system. FcγRI and FcγRIII trigger cell activation through a common γ chain, whereas FcγRII acts as a negative regulator of antibody production and immune complex–triggered activation. Here we describe the in vivo consequences of FcγR deficiency in a mouse model of human rheumatoid arthritis. FcRγ chain–deficient mice on arthritis-susceptible DBA/1 background were immunized with collagen for induction of collagen-induced arthritis. The DBA/1 mice lacking FcRγ chain were protected from collagen-induced arthritis in contrast to wild-type mice, although both groups produced similar levels of IgG anticollagen antibodies. In comparison, DBA/1 mice lacking FcγRII developed an augmented IgG anticollagen response and arthritis. These observations suggest a crucial role of FcγRI and FcγRIII in triggering autoimmune arthritis.

Activation of serum complement triggers Th17 cell–dependent spontaneous autoimmune disease in an animal model. In genetically autoimmune-prone SKG mice, administration of mannan or β-glucan, both of which activate serum complement, evoked Th17 cell–mediated chronic autoimmune arthritis. C5a, a chief component of complement activation produced via all three complement pathways (i.e., lectin, classical, and alternative), stimulated tissue-resident macrophages, but not dendritic cells, to produce inflammatory cytokines including IL-6, in synergy with Toll-like receptor signaling or, notably, granulocyte/macrophage colony-stimulating factor (GM-CSF). GM-CSF secreted by activated T cells indeed enhanced in vitro IL-6 production by C5a-stimulated macrophages. In vivo, C5a receptor (C5aR) deficiency in SKG mice inhibited the differentiation/expansion of Th17 cells after mannan or β-glucan treatment, and consequently suppressed the development of arthritis. Transfer of SKG T cells induced Th17 cell differentiation/expansion and produced arthritis in C5aR-sufficient recombination activating gene (RAG)−/− mice but not in C5aR-deficient RAG−/− recipients. In vivo macrophage depletion also inhibited disease development in SKG mice. Collectively, the data suggest that complement activation by exogenous or endogenous stimulation can initiate Th17 cell differentiation and expansion in certain autoimmune diseases and presumably in microbial infections. Blockade of C5aR may thus be beneficial for controlling Th17-mediated inflammation and autoimmune disease.

SummaryBALB/c mice were injected intravenously with three different monoclonal antibodies (mAbs) specific for complement receptor 1 (CR1). Two of the mAbs crossreacted with CR2 . 24 h later, the mice were immunized with horse erythrocytes or keyhole limpet hemocyanin (KLH), and the primary antibody response was measured . One of the anti-CR antibodies, 7G6, suppressed >99% of the direct plaque-forming cell response against horse red blood cells (HRBC). The same antibody markedly suppressed the serum antibody responses to both HRBC and KLH.To be optimally suppressive, the mAb had to be injected before suboptimal concentrations of antigen . The other two complement receptor-specific antibodies had very moderate, ifany, effects on the antibody response. 7G6 was able to downregulate CRl and CR2 on the surface of B cells and, in addition, to inhibit rosette formation with C3d-coated sheep erythrocytes (EC3d) . One of the antibodies with a weak effect downregulated only CRl . The other downregulated both CRl and CR2, although not as efficiently as 7G6, and was unable to inhibit EC3d rosette formation . We conclude that the reason 7G6 is outstanding in its suppressive capacity is that it is the only mAb tested that functionally blocks CR2 . The data suggest that CR2 is of crucial importance in the initiation ofa normal antibody response to physiological concentrations ofantigen.

IgE Abs, passively administered together with their specific Ag, can enhance the production of Abs recognizing this Ag by >100-fold. IgE-mediated feedback enhancement requires the low affinity receptor for IgE, CD23. One possible mechanism is that B cells take up IgE-Ag via CD23 and efficiently present Ag to Th cells, resulting in better Ab responses. To test whether IgE Abs have an effect on Th cells in vivo, mice were adoptively transferred with CD4+ T cells expressing a transgenic OVA-specific TCR, before immunization with IgE anti-TNP (2,4,6-trinitrophenyl) plus OVA-TNP or with OVA-TNP alone. IgE induced a 6- to 21-fold increase in the number of OVA-specific T cells. These cells acquired an activated phenotype and were visible in splenic T cell zones. The T cell response peaked 3 days after immunization and preceded the OVA-specific Ab response by a few days. Transfer of CD23+ B cells to CD23-deficient mice rescued their ability to respond to IgE-Ag. Interestingly, in this situation also CD23-negative B cells produce enhanced levels of OVA-specific Abs. The data are compatible with the Ag presentation model and suggest that B cells can take up Ag via “unspecific” receptors and activate naive T cells in vivo.

Objective. To investigate the production of type I1 collagen (CII) antibodies in the synovial fluid (SF) of rheumatoid arthritis (RA) patients, and to examine the HLA dependence of this local production.Methods. The ELISPOT method was used for enumerating anti-CII-reactive cells. Serologic tissue typing was performed.Results. Anti-CII-reactive cells were found in the SF of 16 of 31 patients, but not in any of the peripheral blood samples obtained in parallel. SF anti-CII antibody production showed no correlation with clinical parameters, but its frequency increased significantly with age. The IgG anti-CII response occurred exclusively in patients who were positive for HLA-DR4 and was significantly associated with DR4.Conclusion. Anti-CII production may be important in local immune complex formation. The indirect demonstration of a DR4-restricted T cell response to CII is an indication of a pathogenetic role of collagen autoimmunity in RA.The extent to which autoimmune reactions to type I1 collagen (CII) occur in rheumatoid arthritis (RA), and whether these reactions contribute to the

Antibodies administered in vivo together with the antigen they are specific for can regulate the immune response to that antigen. This phenomenon is called antibody‐mediated feedback regulation and has been known for over 100 years. Both passively administered and actively produced antibodies exert immunoregulatory functions. Feedback regulation can be either positive or negative, resulting in >1000‐fold enhancement or >99% suppression of the specific antibody response. Usually, the response to the entire antigen is up‐ or downregulated, regardless of which epitope the regulating antibody recognizes. IgG of all isotypes can suppress responses to large particulate antigens like erythrocytes, a phenomenon used clinically in Rhesus prophylaxis. IgG suppression works in mice lacking the known Fc‐γ receptors (FcγR) and a likely mechanism of action is epitope masking. IgG1, IgG2a and IgG2b administered together with soluble protein antigens will enhance antibody and CD4+ T‐cell responses via activating FcγR, probably via increased antigen presentation by dendritic cells. IgG3 as well as IgM also enhance antibody responses but their effects are dependent on their ability to activate complement. A possible mechanism is increased B‐cell activation caused by immune complexes co‐crosslinking the B‐cell receptor with the complement‐receptor 2/CD19 receptor complex, known to lower the threshold for B‐cell activation. IgE‐antibodies enhance antibody and CD4+ T‐cell responses to small soluble proteins. This effect is entirely dependent on the low‐affinity receptor for IgE, CD23, the mechanism probably being increased antigen presentation by CD23+ B cells.