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PubMed2006

Cytogenetic anomalies in hyaline vascular Castleman disease: report of two cases with reappraisal of histogenesis.

The pathogenesis of hyaline vascular Castleman disease (HVCD) is poorly understood. Although generally considered reactive in nature, a subset of cases has been shown to harbor focal proliferations of stromal cells, such as follicular dendritic cell (FDC) and angiomyoid proliferations. We report two typical cases of HVCD with cytogenetic anomalies: one was t(1;22)(qter;q13) and the other was t(7;8)(q37.3;q12) in cultured stromal cells, as demonstrated by conventional cytogenetic analysis. The cultured cells were immunoreactive for smooth muscle actin but negative for CD21, CD31, and CD34, and ultrastructurally possessed thin filaments (5-7.5 nm) with dense bodies, and pinocytotic vesicles, characteristic of smooth muscle cells. The lack of monoclonality of lymphoid cells in lesional tissues by immunohistochemical and molecular analyses also supports the origin of these anomalies from the stromal cells, most likely myoid cells. Moreover, the absence of overt stromal proliferations suggests that cytogenetic changes in stromal cells of HVCD precede histologic evidence of stromal overgrowth, which may account for the occurrence of angiomyoid proliferations arising in some cases of HVCD. Further studies with more cases are needed to decipher whether part or even most of HVCD cases bear genetic changes in the beginning of the disease without morphologically stromal overgrowth.

Adult↗
PubMed2004

Role of complement receptors 1 and 2 (CD35 and CD21), C3, C4, and C5 in survival by mice of Staphylococcus aureus bacteremia.

Complement-mediated opsonization and phagocytosis of encapsulated serotype 5 Staphylococcus aureus are essential to host defense. We describe the effects of complement depletion and deficiencies of C4, C5, and complement receptors 1 and 2 on mouse survival after intravenous exposure to S aureus. Depletion of complement proteins in C57BL/6 mice with the use of cobra-venom factor decreased survival compared with that of controls after the induction of bacteremia with mucoid (90% mortality), encapsulated (73%), and unencapsulated (59%) S aureus strains. In this model complement is even more important in the control of infection with encapsulated S aureus (80% of clinical isolates) than in the control of infection by unencapsulated strains. C4-deficient mice demonstrated similar mortality from bacteremia caused by encapsulated S aureus compared with controls, suggesting that in the unimmunized animal the alternative complement pathway contributes more to control of bacteremia caused by encapsulated S aureus than the classical complement pathway or mannan-binding lectin pathway. C5-deficient mice (B10.D2-H2(d) H2-T18(c) Hc(0)/oSnJ) showed similar mortality when subjected to bacteremia caused by encapsulated S aureus compared with C5-sufficient (B10.D2-Hc(1) H2(d) H2-T18(c)/nSnJ) mice, suggesting that in this model the anaphylatoxin C5a and the late complement cascade are not critical to survival of bacteremia induced with the use of these strains. However, C5-deficient mice depleted of C3 with the use of cobra-venom factor had 60% decreased survival compared with untreated C5-deficient mice with bacteremia induced by encapsulated S aureus, suggesting that in this model C3 is more critical than C5 in controlling S aureus bacteremia. Complement receptor 1 (CD35) is the primary receptor for the opsonin C3b. Mice deficient in CD35/CD21 showed a 67% decrease in survival compared with normal mice, suggesting that CD35/CD21 is of major importance in the control of S aureus-induced bacteremia.

Animals↗
PubMed2004

The complement system in B cell regulation.

Early studies of animals bearing natural deficiencies in complement C3 and C4 and mice transiently deficient in C3 suggested that the complement system played a role in humoral immunity. Identification and characterization of the complement receptors CD21 and CD35 and their expression on B lymphocytes provided evidence for a direct role for complement in "linkage of innate and adaptive immunity". More recent studies of mice bearing targeted deficiencies in complement proteins C3, C4 or the receptors CD21/CD35 has confirmed the importance of complement in B cell responses in vivo and extended our understanding to distinct stages in B cell differentiation in which complement participates in humoral immunity. In this review, a role for complement is described in five distinct stages of B cell differentiation.

Animals↗
PubMedDate not supplied

Expression of CR1/2 receptor on alloantigen-stimulated mouse T cells.

Antibodies can mediate injury of organ transplants by several mechanisms, including complement activation and interaction with Fc receptors on cells. We tested the hypothesis that antibodies could also cause up-regulation of complement receptors on cells to increase the responses to complement activation by interaction with split products of C3. In our experimental model, B10.A (H-2(a)) cardiac transplants survive significantly longer in C57BL/6 (H-2(b)) immunoglobulin knockout recipients (IgKO) than in their wild-type counterparts. Passive transfer of specific antibodies to donor MHC class I to IgKO recipients of cardiac allografts at the time coinciding with a vigorous cellular infiltration reconstituted acute rejection. We tested the effects of alloantibodies on CR1/2 expression by alloantigen-stimulated T cells. Both CD4(+)/CR1/2(+) and CD8(+)/CR1/2(+) populations of T cells were expanded in C57BL/6 splenocytes stimulated by B10.A alloantigen in 7-day MLR after coculture with endothelial cells sensitized with IgG1 and IgG2b mAb specific to MHC. Endothelial cells sensitized with antibodies also caused an expansion of CD8(+) T cells expressing CR1/2 in lymph node lymphocytes harvested from a C57BL/6 recipient of a B10.A cardiac allograft. These data suggest that antibodies can augment the cellular rejection process through expanding the population of T cells interacting with complement split products.

Animals↗
PubMed1994

Hormonal regulation of complement components and receptors throughout the menstrual cycle.

OBJECTIVES: Complement components have been recently demonstrated to be present in the reproductive tract. Among these components, C3 synthesis by glandular epithelium of the rat uterus has been shown to be regulated by estrogen; progesterone inhibits this synthesis. However, the hormonal regulation of C3 and the presence of other complement factors in the human has not been investigated to date. In this study we examined the presence and the hormonal regulation of different complement components and receptors in the human endometrium at various phases of the menstrual cycle of normally cycling women with no pelvic pathologic abnormalities. STUDY DESIGN: Endometrial tissue was obtained from normally cycling women, and immunohistochemistry was performed by means of monoclonal antibodies against C3, factors B, decay-accelerating factor, membrane cofactor protein, and complement receptor types 1, 2, and 3. The tissue was incubated with minimal essential media without methionine containing methionine labeled with sulfur 35. Immunoprecipitations were performed on the media with goat antihuman C3 antibody, and the proteins were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis. RESULTS: C3 was found to be present in the glandular epithelial cells of luteal endometrium. Biosynthesis as analyzed by immunoprecipitation with anti-C3 antibody was found to increase during the luteal phase of the cycle and to be minimal in the proliferative phase. Like C3, factor B and decay-accelerating factor were localized to the luteal glandular epithelial cells. In contrast, membrane cofactor protein was found to be present in the glandular epithelium throughout the menstrual cycle, and complement receptor type 1 was present only in the stromal compartment of luteal endometrium. Complement receptor type 3 was present only in the infiltrating leukocytes in the luteal endometrium, whereas complement receptor type 2 was undetectable. CONCLUSIONS: These findings suggest that several components of the complement system exist in the human endometrium in a hormone-dependent manner and may play a role in normal reproductive function.

Adult↗
PubMed2000

The role of complement in B cell activation and tolerance.

It is becoming well accepted that innate immunity serves as a natural adjuvant in enhancing and directing the adaptive immune response. In this review, I have discussed how the complement system, a major mediator of innate immunity, links the two systems. The recent availability of knockout mice bearing selective deficiencies in the critical complement proteins and receptors has allowed formal demonstration of the importance of complement in enhancement of humoral immunity. Characterization of the mice has also uncovered mechanisms for maintaining survival of activated B cells within the lymphoid compartment. For example, co-ligation of the CD21/CD19/Tapa-1 receptor with the BCR not only reduces the threshold for B cell follicular survival but provides a unique signal for survival in the germinal centers. In addition complement receptors are critical for localization of antigen and C3d ligand to FDCs for maintenance of long-term B cell memory. A surprise that has come from analysis of the deficient mice is that complement is also important in negative selection of B lymphocytes. This observation provides new insight to a long-standing enigma that the major predisposing factor in lupus is deficiency in complement C1q or C4. The seeming contradiction of dual role for complement in both B cell activation and tolerance is reconciled by the hypothesis that natural IgM provides a mechanism to selectively identify self-antigens that are highly conserved and cross-react with microbial ones such as DNA and nuclear proteins. Thus, the importance of complement in tolerance to self-antigens is restricted to those self-antigens that are evolutionary conserved, and they are identified by natural antibody. The future should hold further surprises as to the intricate interactions between the complement system and acquired immunity.

Adjuvants, Immunologic↗
PubMed1999

Functional characterization of soluble and membrane-bound forms of vaccinia virus complement control protein (VCP).

Vaccinia virus secretes a 35 kD protein, vaccinia virus complement control protein (VCP), that inhibits the classical and alternative pathways of complement at several points, indicating that it may be a viral analogue of human complement receptor type 1 (CR1; CD35). Structurally, however, CR1 is composed of 30 short consensus repeats (SCRs), whereas VCP consists entirely of four SCRs. We have begun a structure-function analysis of VCP to define the minimum number of SCRs necessary for function, the functional differences between VCP and CR1, and the potential therapeutic roles for VCP. We addressed these questions by creating and characterizing recombinant soluble and membrane-bound forms of VCP. We have determined that (1) VCP requires all four SCRs to bind C3b, (2) whereas CR1 binds C3b and iC3b, VCP binds C3b but not iC3b, and (3) although normally secreted, if expressed on the membrane of mammalian cells, VCP effectively protects the cells from complement-mediated lysis. Thus, VCP appears to be a compact and unique complement regulatory protein with the ability to inhibit both arms of the complement cascade, but lacking affinity for iC3b. By releasing rather than capturing iC3b-bearing complexes following inactivation of C3b, VCP may 'recycle' its active site locally among infected cells, and thereby enable the virus to evade more efficiently host immune and inflammatory responses. The unique function, compact structure, and capacity of VCP to protect mammalian cells from complement-mediated attack, suggests that it could be used both to better understand the structure-function relationship of complement regulatory proteins, in general, and also to rationally design and develop novel therapeutic agents.

Animals↗
PubMed2000

Immunomodulatory functions of murine CR1/2.

C3-fragments generated upon complement activation play an important role in the formation and regulation of immune responses. Receptors interacting with various activation fragments of this versatile complement component are expressed on a wide variety of cell types, such as lymphocytes, macrophages, dendritic cells, follicular dendritic cells, granulocytes, erythrocytes, consequently C3-products may influence several biological functions at different sites of the body, where complement activation takes place. In the last decade, genes, protein structure and functions played by murine complement receptors CR1 and CR2 (mCR1/2) have been deciphered. In this review, we wish to relate these properties, and fit it into the context of events following in vivo complement activation. We separately address the roles played by murine mCR1/2 as BCR coreceptor and as BCR independent structure, and propose a mchanism for the utilization of antigen-C3d conjugates bound on B cells. Finally, we raise some of the questions that remain to be elucidated in order to get a more precise picture of the functions of mCR1/2.

Animals↗
PubMed1999

Targeting of influenza epitopes to murine CR1/CR2 using single-chain antibodies.

Single-chain variable fragment (scFv) antibodies are genetically engineered molecules comprising the variable regions responsible for specific binding. scFv that recognize certain surface molecules on professional antigen presenting cells could therefore be suitable for targeting Ag to these cells. We have produced an scFv that recognizes murine complement receptors 1 and 2 (CR1/CR2) and genetically fused it with different numbers of influenza hemagglutinin peptides which contain both B and T cell epitopes. The CR1/CR2 specific hybridoma 7G6 was used for RT-PCR to obtain the variable regions, which were then combined to create an scFv fragment. The influenza hemagglutinin intersubunit peptide HA317-41 (IP) was engineered to the N terminus of the scFv in one, two or three copies. The so obtained IP(1-3)7G6scFv still bound the complement receptors; the peptides in the construct were recognized by the peptide specific monoclonal IP2-11-1 on Western blots and ELISAs. The CR1/CR2 positive B lymphomas A20 and 2PK3 presented the peptide to an I-Ed restricted IP specific T cell hybridoma more efficiently when incubated with the IP(1)7G6 constructs as compared to the free peptide. The results suggest that scFv could work as targeting devices in subunit vaccines.

Amino Acid Sequence↗
PubMed2002

Role for complement receptors (CD21/CD35) in the regulation of recombination activating gene expression in murine peripheral B cells.

A population of peripheral B cells have been shown to express recombination activating gene products, RAG-1 and RAG-2, which are considered to be involved in revising the B cell antigen receptor (BCR) in the periphery. BCR engagement has been reported to turn off RAG expression in peripheral B cells, whereas the same treatment has an opposite effect on immature B cells in the bone marrow. In contrast to receptor editing that is involved in the removal of autoreactivity in immature B cells, it has been shown that secondary V(D)J rearrangement in peripheral B cells, termed receptor revision, contributes to affinity maturation of antibodies. Here, we show that RAG-2 expression in murine splenic B cells was abrogated by the coligation of BCR with complement receptors (CD21/CD35) much more efficiently than by the engagement of BCR alone. On the other hand, the same coligation augmented proliferation of anti-CD40-stimulated B cells. These findings suggest a crucial role for CD21/CD35 in directing the conservation or the revision of BCRs in peripheral B cells.

Animals↗
PubMed2000

Human complement regulators: a major target for pathogenic microorganisms.

The C3 convertases of the human complement system are controlled by fluid-phase and membrane proteins in the RCA (regulators of complement activation) family. Accumulated data show that many pathogenic microorganisms interact with these complement regulators. Recent advances in this field include determination of the crystal structure of the binding domains in the measles virus receptor CD46 and identification of a CD46 transgenic mouse line that is sensitive to measles virus. Moreover, recent findings support the hypothesis that pathogenic bacteria binding fluid-phase RCA proteins exploit these proteins to escape complement attack. These studies provide novel insight into the interplay between pathogens and the innate immune system and may have implications for the plans to use animals expressing an RCA protein for xenotransplantation.

Antigens, CD↗
PubMed1998

A critical role for complement in maintenance of self-tolerance.

The role of complement in the maintenance of self-tolerance has been examined in two models: an immunoglobulin transgenic model of peripheral tolerance and a lupus-like murine model of CD95 (Fas) deficiency. We find that self-reactive B lymphocytes deficient in complement receptors CD21/CD35 or transferred into mice deficient in the complement protein C4 are not anergized by soluble self-antigen. In the second model, deficiency in CD21/CD35 or C4 combined with CD95 deficiency results in high titers of anti-nuclear antibodies leading to severe lupus-like disease. These findings suggest a novel role for the complement system in B cell tolerance and provide insight into the genetic association of complement deficiency with susceptibility to systemic lupus erythematosus.

Animals↗
PubMed2002

Complement receptors CD21/35 link innate and protective immunity during Streptococcus pneumoniae infection by regulating IgG3 antibody responses.

The CD21/35 receptor provides an important link between innate and adaptive immunity. Its importance during protective immune responses to encapsulated extracellular bacteria was assessed using a new line of mice completely deficient in CD21/35 expression (CD21/35(-/-)). CD21/35 expression was essential for the rapid trapping of C3dg-antigen complexes by B cells in vivo, especially in splenic marginal zones. Despite normal B cell development in CD21/35(-/-) mice, T cell-independent and -dependent antibody responses to low-dose antigens were significantly decreased, with a striking impairment in IgG3 responses. Accordingly, CD21/35(-/-) mice were more susceptible to acute lethal Streptococcus pneumoniae infection. Thus, CD21/35 expression is critical for early protective antibody responses to lethal pathogens that rapidly multiply and quickly overwhelm the immune system.

Animals↗
PubMed2003

Follicular dendritic cell tumor in the oro-pharyngeal region: report of a case and a review of the literature.

A case of follicular dendritic cell tumor (FDC tumor) arised in the aro-pharyngeal region is reported in a 16-year-old Japanese boy. He had a swelling in the right retromolar trigone and soft palate. Clinical examination disclosed a 25 mm x 30 mm, elastic hard, ulcerated mass. CT scans showed a low density lesion in the right medial parapharyngeal area. The biopsy specimen revealed a low-grade malignant tumor. The patient underwent a tumorectomy which was extended to include the adjacent palatine tonsil. The tumor cells, with a clear cytoplasm and oval nucleus, were immunoreactive for S-100 (N/A), CD 21 (1F8), fascin (55K-2) and FDC (CNA42). The fascicular sheet pattern arrangement of the tumor cells was partly characteristic. The final diagnosis was an follicular dendritic cell tumor. Three courses of adjuvant chemoradiotherapy were administered postoperatively. Clinical features, pathological diagnosis and immunohistochemical markers for distinguishing FDC tumor are reviewed.

Adolescent↗
PubMed2000

Regulation of humoral immune responses by CD21/CD35.

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: i) CD21/CD35 retain and focus antigens for optimal presentation; ii) CD21/CD35 on B cells serve as enhancing co-receptors for B-cell antigen receptor (BCR) signaling; iii) CD21/CD35 regulate B-cell responses, by CD19 aggregation. The coreceptor model led us to predict that CD21/CD3 5 may lower the threshold of BCR affinity to diversify the repertoire of humoral immune responses, but surprisingly, CD21/CD3 5-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.

Animals↗
PubMed2001

Structure and flexibility of the multiple domain proteins that regulate complement activation.

In this review we summarise more than 10 years of biophysical exploration into the structural biology of the regulators of complement activation (RCA). The five human proteins responsible for regulation of the early events of complement are homologous and are composed largely from building blocks called "complement control protein (CCP) modules". Unlike most multiple domain proteins they do not contain any of the other widely occurring module types. This apparent simplicity of RCA structure, however, is belied by their sophistication of function. In fact, the structures of the individual CCP modules exhibit wide variations on a common theme while the extent and nature of intermodular connections is diverse. Some neighbouring modules within a protein stabilise each other and some co-operate to form specific binding surfaces. The degree of true "modularity" of CCPs is open to debate. The study of RCA proteins clearly illustrates the value of combining complementary structural biology techniques. The results could have implications for folding, evolution, flexibility and structure-function relationships of other molecules in the large, diverse and little understood category of multiple domain proteins.

Amino Acid Motifs↗
PubMed2002

Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors.

Autoreactive B cells are present in the lymphoid tissues of healthy individuals, but typically remain quiescent. When this homeostasis is perturbed, the formation of self-reactive antibodies can have serious pathological consequences. B cells expressing an antigen receptor specific for self-immunoglobulin-gamma (IgG) make a class of autoantibodies known as rheumatoid factor (RF). Here we show that effective activation of RF+ B cells is mediated by IgG2a-chromatin immune complexes and requires the synergistic engagement of the antigen receptor and a member of the MyD88-dependent Toll-like receptor (TLR) family. Inhibitor studies implicate TLR9. These data establish a critical link between the innate and adaptive immune systems in the development of systemic autoimmune disease and explain the preponderance of autoantibodies reactive with nucleic acid-protein particles. The unique features of this dual-engagement pathway should facilitate the development of therapies that specifically target autoreactive B cells.

Adaptor Proteins, Signal Transducing↗