Molecular analyses of phage-displayed antibody Fab fragments bound by IVIG cloned from patients with autoimmune thrombocytopenia in our laboratory often originated from the V3-23 and V3-30/3-30.5 VH germline genes (Fischer et. al., 1999; Jendreyko et. al., 1998). One of the autoimmune thrombocytopenic patients' illness progressed to systemic lupus erythematosus (SLE). Furthermore, the same germline genes were also observed to be the most frequently used VH genes for Fabs bound by IVIG from a library constructed from a patient with Kawasaki disease (Leucht et. al., 2001), and also from a healthy individual in a control study (Hoffmann et. al., 2000). The aim of this study was to learn more about the interaction of IVIG with Fabs by analyzing at the molecular level, Fabs bound by IVIG from a phage display library constructed from a patient with SLE and rheumatic fever, and at the same time compare these Fabs to those from the autoimmune thrombocytopenic patients.
The library for this study was constructed from peripheral blood lymphocytes isolated from an 8-1/2 year-old girl. The blood was drawn 24 days after the patient had undergone IVIG therapy. The combinatorial antibody library system, instead of engineering single antibodies, creates millions of different clones by random processes and use the powerful selection panning process to isolate antibodies with the desired characteristics (Persson, 1993). However, the technique is not without problems. Plastic-binding clones which often are enriched over desired clones during the panning process makes it difficult to isolate antigen-specific clones. One of the factors that contributed to the success of this study was the 'elimination' of (as much as possible) bald clones that had no light and heavy chain DNA fragments. This optimization step during the library construction contributed heavily to the isolation of unselected clones with both functional heavy and light chain genes and paved the way for completion of the study. A total of 23 Fab phages bound by IVIG were isolated and characterized. The VH sequences from all 23 antibodies bound by IVIG were derived from two putative germline genes namely V3-23 and the V3-30/3-30.5 polymorphic variant. In contrast, the VH sequences from five unselected clones were derived from at least five different VH region loci. There were no specific enrichment of a particular light chain loci as observed for the heavy chain. This purported to show that the heavy chain may be the major target of IVIG during the selection process, since IVIG-selected Fabs devoid of light chains, or those without functional light chains have been isolated before in our laboratory (Leucht et. al., 2001; Hoffmann et. al., 2000).
None of the IVIG-binding Fabs from the library of the patient with systemic lupus erythematosus and rheumatic fever bound platelets, in contrast to IVIG-binding Fabs isolated from patients with idiopathic thrombocytopenic purpura (Fischer et. al., 1999; Jendryeko et. al., 1998). 8 of 16 Fab fragments from the three libraries constructed from the patients with thrombocytopenia bound platelets, though the majority of them were derived from the VH4 family (Fischer et. al., 1999). This perhaps suggest that the platelet-specific antibodies from the patients with thrombocytopenia were those that were relevant for the disease at the time the material was obtained. Mutation rates varied between the extremes of zero to high replacement rates, and CDR3 composition was between short to long residues. The mechanisms of replacement mutations which are thought to be initiated by unknown antigen selection may influence binding through the positioning of side chains that contact antigen, or by providing new contact residues in the antigen combining sites, or by replacing repulsive or low affinity residues with more favorable contact residues (Hoogenboom, 1997).
The V3-23 and V3-30/3-30.5 genes have been observed to be the most frequently rearranged and expressed VH gene in the immune repertoire (Matsuda et. al., 1998; Cook and Tomlinson, 1995).It has been observed that there is not an equal representation of the various VH families in the fetal and adult repertoire. The immune system is biased with some VH families being over-represented and others under-represented. The known maximum number of functional segments of the human immunoglobulin heavy chain repertoire is 51 (Cook and Tomlinson, 1995), though another study by Matsuda et. al. (1998) reported 44 functional genes. The difference between these two studies is attributed to insertion/deletion polymorphism which when present results in the gain of some functional genes. 22 VH3 family segments account for 43.1 % of the 51 functional VH segments (Tomlinson, 1997). Some genes, such as V3-23 and V3-30 have been demonstrated to be over-represented at all stages of B cell development. The V3-23 gene which is well represented in the fetal repertoire and comprising about 25 % of all VH3 clones in the normal adult peripheral B cells, is present in all individuals tested (Kraj et. al., 1997). De Wildt et. al., (1999) investigating the pairings of VH and VL chains from 365 human IgG+ B cells observed that the most frequently utilized VH germline genes were from the V3-23 and V3-30/3-30.5 locus. In a large study involving more than 4,500 independent VH3 family gene segments from 12 unrelated individuals, Huang et. al. (1996) observed that V3-23 and V3-30 were most frequently expressed in the normal repertoire with mean representations of 24.3 % and 16.1 % respectively. The significance of the study affirmed that the representation of the adult repertoire is not by random VH rearrangement by which the frequency of utilization of variable region segments of a family may be proportional to family size/complexity. In a more recent study, the V3-23 and V3-30 gene segments were found to be the most frequently rearranged VH3 family genes at the pro-B cell stage (Rao et. al., 1999). In B cell differentiation and development, the pro B cell is a precursor B cell that has productively rearranged VHDJH genes but has not as yet expressed the μ (mu) protein. For this reason, pro-B cells are unaffected by selection mechanisms arising out of contact with antigen. In the B cell lineage, pro-B cells that have successfully rearranged a productive VHDJH gene may differentiate into pre-B cells which expresses the pre-B cell receptor consisting of μ-surrogate light chain complex (Melchers et. al., 1993). Further differentiation takes place through immature and mature B cells (with the disappearance of the pre-B cell receptor), and the expression of surface immunoglobulin (sIgM) and IgD respectively. Rao and colleagues reasoned that earlier observations indicating the preferential rearrangement and over-representation of certain VH segments and families in the repertoire were made from B cells that have already rearranged productive chains and have already been committed to selection (De Wildt et. al., 1999; Kraj et. al., 1997; Huang et. al., 1996). In their study, they demonstrated that even in pro-B cells that do not express antigen receptors, the V3-23 and V3-30 gene segments were the most frequently rearranged VHDJH segments representing about 20 % and 24 % respectively among 760 VH3 family genes. The study showed that the repertoire is already biased long before the expression of antigen receptors on the surface of the B cell (Rao et. al., 1999).
The detection of solely VH3 Fabs (seven independent clones comprising six V3-23 and one V3-30) in the library from the patient with systemic lupus erythematosus and rheumatic fever does not seem to reflect an artifact. To make the library as diverse as possible, the V genes from the patient were isolated using degenerate PCR primers that can amplify all human VH germline genes (Kang et. al., 1991b). To access the clonal diversity of the library and to access that the library was not dominated by clones arising from an artifact of preferential amplification of a few clones, 12 unselected clones were analyzed by BstN1 restriction. BstN1 frequently cuts in the VH region but only at 2 sites in the pComb3H vector. The restriction pattern which was confirmed by sequencing of 5 unselected clones revealed that the library was heterogenous. Whereas the IVIG library utilized only two VH3 family loci namely V3-23 and V3-30, the immunoglobulins isolated from the unselected library used different VH3 family genes namely 3-13, 3-23, 3-15, and one that has not as yet been assigned to a VH locus, as well as a VH1 family segment 1-69, emphasizing that the unselected library from the patient did not comprise VH genes solely from the V3-23 and V3-30 loci. Similarly, sequencing of unselected clones from libraries studies in our laboratory showed no bias for a certain germline gene loci; rather a variety of different germline genes not observed among the IVIG-bound Fabs have been observed (Leucht et. al., 2001; Hoffmann et. al., 2000).
The normal/healthy immune system frequently produces autoantibodies, however autoimmunity is a rare event. This implies autoimmunity results from a perturbation of the control mechanisms (Potter and Capra, 1995). It has been observed that the germline gene loci dominating the IVIG-selected Fabs (V3-23 and V3-30) were also frequently utilized for coding other autoantibodies though it has not been established that only limited VH segments could be used for autoantibodies (Matsuda et. al., 1993). For example, the V3-30 sequence is homologous to RF-TS2, RF-SJ1 and RF-SJ2 cDNA for rheumatoid factors (Pascual et. al., 1990). This same germline VH segment was 99.7 % identical to cDNA for Kim4.6 autoantibody (Cairns et. al., 1989) which has DNA binding activity. The V3-23 segment is identical to the anti-DNA autoantibody (18/2) (Dersimonian et. al., 1987) and 30P1 cDNA found in fetal liver (Schroeder and Wang, 1990, Schroeder et. al., 1987). In addition, the V3-15 segment, which is the germline gene of 20P1 cDNA expressed in fetal liver is 99.7 % identical to cDNA for 4B4, an anti-Sm antibody encountered in systemic lupus erythematosus (Sanz et. al., 1989). Matsuda et. al. (1993) hypothesized that the correlation between autoantibody VH genes and the early repertoire VH, indicated that the preferred usage of autoantibody VH segments in early stages of ontogeny may be due to positive selection by self-antigens. Though autoantibodies displaying given specificities are most often associated with different human autoimmune diseases, several studies in mice and humans have demonstrated that healthy individuals regularly produce several autoantibodies encoded by germline immunoglobulin variable regions with no somatic mutations. These autoantibodies do not provoke autoimmune pathology, in contrast to patient-derived autoantibodies that are highly specific for their respective autoantigens (Potter and Capra, 1995; Hoffmann et. al., 2000). The presence of autoantibodies in the normal immune system suggests that they may play some important physiological roles by augmenting the opsonization of infectious agents and the clearance of immune complexes and senescent cells. The importance of an autoreactive variable region gene in the development of the humoral immune system was demonstrated in a study where it was shown that a VH gene frequently expressed in fetal liver was homozygously deleted in 20 % of patients with systemic lupus erythematosus and rheumatoid arthritis, but in only 2 % of healthy controls. This germline gene, designated Humhv3005, belongs to the V3-30 germline polymorphic gene variants, and encodes an amino acid sequence identical to the 56P1 VH germline gene which is frequently expressed in fetal liver. The hv3005 gene is also 99 % homologous to the 1.9III germline VH gene which in turn is identical to the heavy chain of the kim4.6 anti-DNA antibody. Olee et. al. (1991) contended that homeostasis of the early B cell repertoire is maintained through interactions between autoreactive V genes and autoantigens, and subsequently through an interconnecting network of idiotypes-antiidiotypes. Thus a complete deletion of a cluster of developmentally important autoreactive V genes such as hv3005-like genes may alter the humoral immune response to bacterial and/or viral infections resulting in the overproduction of aberrant antibodies that may contribute to the initiation and/or perpetuation of autoimmune diseases.
The VH3 sequences expressed by the Fab phages isolated in this study utilized different D and JH CDR3 region genes. The CDR3s were encoded by different D (D6-19, D4; D2-8; D4-11; D6-25; D3-3; and D3-22) and JH (JH4b; JH3b; JH1; and JH6b) gene segments, and the lengths of the CDR3 regions were also variable. These features of the D and JH genes indicated that the CDR3 region was not crucial in binding by IVIG. The interaction of IVIG with V3-23 and V3-30 from the VH3 gene family was also demonstrated in a control study where the subjects were healthy individuals (Hoffmann et. al., 2000). In this study, 21/27 (78 %) of Fabs bound by IVIG were derived from VH3 gene family. Of note, 14/21 (66.6 %) of these VH3 Fabs were from the V3-23 and V3-30 loci which accounted for about 52 % (14/27) of the entire Fabs isolated. Hence the selection of these Fabs is linked to the preferential interaction of IVIG with V3-23 and V3-30. Thus, the results from Fischer, et. al. (1999); Jendreyko et. al. (1998); Hoffmann et. al. (2000), and this current study reveal that the preferential interaction of IVIG with Fabs from the V3-23 and V3-30/3-30.5 germline origins was not restricted to the healthy status of the donor, neither to treatment with IVIG. In conclusion, the observed interaction of IVIG with the Fabs was characteristic of binding of a B cell superantigen. In this regard, we compared the specific IVIG binding of our Fabs with the 2 best characterized B cell superantigens namely, staphylococcal protein A (SpA) and HIV-1 gp120.
B cell superantigens are proteins that interact with B cell and T cell receptors as well as immunoglobulins molecules outside the classical antigen binding sites (Silverman, 1997). They are potent activators of lymphocytes and have the capability of activating more than 5 % of the naive lymphocyte pool (an enormous population) in contrast to conventional peptide antigens that stimulate less than 0.01 %, representing a 500-fold enhanced lymphocyte activation potential (White et. al., 1989). Staphylococcal protein A (SpA) is a 42-kDa membrane protein of Staphylococcus aureus (Silverman, 1997). SpA, secreted by nearly all known clinical isolates of S. aureus, enhances virulence of the pathogen although the mechanisms have not been identified. SpA is a tandem of five extra-membrane domain proteins E, D, A, B, C and an additional transmembrane domain named X. Each of the extramembrane domain has 58 - 61 amino acids and share a primary amino acid homology of about 80 % with each other. SpA has two distinct types of immunoglobulin binding specificities; one in the Fab portion of immunoglobulins of the IgM, IgA, IgG, and IgE isotypes and the other in the Fc portion of IgG1, IgG2, IgG3, and IgG4 immmunoglobulins (Potter et. al., 1997). Each extramembrane domain is thought to be capable of mediating Fcγ binding. The Fcγ binding property of Protein A is extensively utilized in purification and labeling of proteins (Graille et. al., 2000). All five extramembrane domais have also been demonstrated to show human Fab binding (Janssson et. al., 1998).
SpA specifically binds to antibodies from the human VH3 gene family but not immunoglobulins from other VH families(Silverman, 1997).Immunoglobulins bound specifically by SpA share conserved sequences in FR1, FR3 and the C-terminal portion of CDR2 outside the H2 loop unique only to the VH3 gene family. Kirkham and Schroeder (1994), suggested that the C-terminal portion of CDR2 (from the VH3 family that correlates with SpA binding activity) is an invariant VH3 family-specific stretch sequence which could be more appropriately designated as part of the FR3 subdomain. Studies with three different phage display antibody libraries demonstrated that multiple rounds of panning on SpA resulted in selection of VH3 Fabs that were encoded by the V3-23 gene (Silverman, 1998). Within the human genome, the V3-23 gene is closest to the consensus sequence of all inherited human VH3 genes, and it encodes for VH regions that contain one of the most highly conserved VH FR1/FR3 surfaces (Schroeder et. al., 1990). Of all VH3 antibodies with binding to SpA that have so far been evaluated, the V3-23 derived antibodies have the strongest binding interactions with the native SpA (Silverman et. al., 1997). The crystal structure of domain D of SpA complexed to a V3-30 derived Fab has confirmed earlier studies that the critical amino acids necessary for binding are located in the FR1, FR3 and CDR2 of the VH3 immunoglobulin molecule (Graille et. al., 2000; Potter et. al., 1998). Silverman and colleagues investigating the unconventional nature of SpA binding demonstrated that 13 VH3 amino acid residues in FR2/FR3 and CDR2 are essential for SpA binding (Graille et. al., 2000; Cary et. al., 2000). Among the 13 VH residues implicated as SpA contacts, VH3 genes include frequent germline sequence variations only at position 57. This position is not a core position and substitution of isoleucine (I) and threonine (T) for lysine (K) are permissive for SpA binding. The other 12 remaining VH residues which are highly conserved in the VH3 family have been found to be in direct contact with domain D of SpA. By comparison, other nonbinding germline VH family genes have been found to contain two or more residue differences at the 13 VH positions identified as SpA contacts (Cary et. al., 2000). A detailed structural study by Graille et. al. (2000) identified 7 core residues among the 13 VH contact residues: arginine/lysine (R/K)-19, glycine (G)-65, arginine (R)-66, threonine (T)-68, serine (S)-70, glutamine (Q)-81, and asparagine (N)-82a. These core of 7 VH residues constitutes the structural motif of SpA binding, and conveys the restricted specificity for VH3-encoded immunoglobulin and their homologoues. All Fabs isolated here expressed these 13 VH amino acid residues and importantly, the 7 core residues as well. However, their binding to SpA varied in intensity. The observed binding differences could be due to subtle conformational variations which could be permissive for some immunoglobulins and not others.
Karray et. al. (1998), observed that gp120 immunoglobulin binders are highly sensitive to mutation. They demonstrated that V3-30 gene-encoded immunoglobulins with less than 96 % homology to germline genes lose the capacity to bind gp120, thus suggesting that hypermutation may have an adverse effect on gp120 binding. This inverse correlation between the degree of somatic mutation and gp120 binding is similar to the reported binding pattern described for SpA. V gene hypermutation associated with somatic selection of the B cell repertoire by exogenous antigens apparently often results in a loss of that B cell superantigen's binding capacity. The B cell receptor has a distinctive feature of undergoing somatic hypermutation, which influences the representation of superantigen binding B cell receptors in the somatic immune repertoire. Germline encoded V region structures demonstrate higher affinities (and avidities) in immature animals and in naive lymphocyte subsets than in IgG bearing B cells (Silverman et. al., 1997). While only about 80 - 85 % of VH3 IgMs from adult sources bind SpA, SpA binding activity has been demonstrated for every non-mutated VH3 immunoglobulin that has so far been tested (Hillson et. al., 1993 as reviewed in Silverman, 1997). Also, the frequency of superantigen binding in IgG populations which generally show greater levels of hypermutation is much lower than for IgM populations (Sasano et. al., 1993). Though many immunoglobulins (VH3 family) that have undergone class switch and somatic mutation lose the ability to bind SpA, a substantial number of these antibodies still bind SpA. Silverman (1997) reported that at least 16 of the 22 (72 %) known functional VH3 germline encoded genes have SpA binding activity while Sasano et. al. (1993) demonstrated that 60 % of VH3 Fab fragments had SpA-binding activity. Since some somatically-mutated VH3 encoded antibodies can bind SpA, both the position and nature of the mutations affect SpA binding (Potter et. al., 1997).
Thus, hypermutation somewhat adversely affects the frequency and avidity of VH3 mediated SpA binding. However, from our results, the presence of mutations alone may not account for the observed SpA binding pattern exhibited by the Fab phages. Fab phage SH51, maintaining all the residues known for SpA binding and with an R/S ratio greater than 2.9 showed strong interaction with SpA, whilst Fab phages SH21 and SH58 with 99.6 % and 99.3 % homologies to the V3-23 germline gene, respectively, did not show any appreciable binding to SpA. SH21 has an extremely long VH CDR3 (17 amino acids), which could result in structural interference with binding to SpA. Could the association of different light chains influence these VH3 non-SpA binding interactions? Potter and Capra (1995), reported the loss of a mouse monoclonal antibody LC1 reactivity against human monoclonal antibody with rheumatoid factor reactivity when some light chains were paired with an LC1 reactive heavy chain. LC1 detects a cross-reactive idiotope on the heavy chain of many non-pathogenic IgM antibodies and monoclonal IgM autoantibodies, many of which exhibit rheumatoid factor reactivity. The loss of LC1 reactivity indicates that the light chain influenced the availability of the LC1 determinant and provides another mechanism, other than mutation to explain the loss of an heavy chain isotype. The light chain could also provide conformational variations which could be non-permissive for some immunoglobulins and thus influence its binding abilities. In certain cases however, light chain pairing may influence the capacity of SpA to bind VH3 containing heavy chains (Domiati-Saad and Lipsky, 1997).
The critical residues for binding gp120 to VH3 gene families, though not so well defined, (Neshat et. al., 2000) may be in overlapping regions to that of SpA. On the whole, our IVIG Fabs showed weak binding to gp120 whilst stronger reactivities on SpA were recorded for some clones. The observed binding differences between SpA and gp120 for the Fab phages could be that SpA and gp120 target different sites on VH3 immunoglobulins, some of these contact sites partially overlap though (Karray et. al., 1998). In addition, none of the two superantigens tested in this study (SpA and gp120) was able to compete with IVIG in binding to the Fabs, indicating that at least some of the contact residues on IVIG must be different from those for SpA and gp120. Delineating the exact mechanism(s) of binding of IVIG to V3-23 and V3-30 Fabs is an enormous task, granted the huge variety of immunoglobulins present in the IVIG pool. As a solution, our IVIG-selected Fabs may now be used to clone antibodies representative of this IVIG subfraction from a healthy donor library. This will enable the study of the structural basis for recognition and possible regulatory influence on the B cell repertoire during normal development and disease (Osei et. al., 2000).
The beneficial therapeutic effects of IVIG are well documented, but the underlying molecular mechanisms are not fully understood. Recent investigations from our laboratory into the molecular analysis of Fabs bound by IVIG from patients suffering from autoimmune thrombocytopenia revealed that the most frequently selected Fabs originated from the V3-23 and V3-30 VH germline genes. A subsequent study with IgG and IgM phage display libraries from a healthy donor also demonstrated a preferential reactivity of IVIG to Fabs of V3-23 and V3-30 origin. That study revealed that the unique reactivity of IVIG to Fabs of these two VH gene loci was not restricted to the autoimmune nature of the donors, neither to previous treatment with IVIG. One of the thrombocytopenia patients developed lupus. This study was undertaken to study the molecular interaction of IVIG with antibodies selected from a patient suffering from systemic lupus erythematosus and rheumatic fever using phage display technology, and to compare the results with the previous studies.
Twenty-three Fabs representing seven independent clones were isolated. In contrast to ITP-derived clones, none of the Fabs selected in this study reacted with platelets. The Fab phages bound by IVIG were sequenced in order to determine their VH gene usage and clonal relatedness. V3-23 and V3-30 VH genes were found to be exclusively utilized by the Fab phages bound by IVIG. Moreover, different CDR3 regions including different D and JH gene segments were observed to be used by these Fabs. The results further showed that the binding of IVIG to the Fabs was independent of the light chain since different light chains were observed to be associated with the VH3 immunoglobulins. Detailed sequence analysis of the Fabs revealed the presence of amino acid residues at positions within FR1, FR3, and the 3' end of CDR2 that are known to be contacted by the B cell superantigen Staphylococcus protein A (SpA). Some of the Fabs were shown to bind strongly to SpA, but there was no correlation with the binding-intensity to IVIG. Some bound very weakly to HIV gp120, another B cell superantigen. This study, together with previous results, suggests that a subset of IVIG may function as a B cell superantigen that may significantly shape the B cell repertoire. The binding mechanism appears to be similar but not identical to the other tested B cell superantigens.
Therapeutische Erfolge von IVIG sind gut dokumentiert, aber die zu Grunde liegenden molekularen Mechanismen sind noch nicht vollständig erforscht. Molekulare Analysen unseres Labors über die Interaktion von IVIG mit Fabs von Patienten, die an einer autoimmunen Thrombozytopenie (ITP) leiden zeigten, dass die am häufigsten selektierten Fab von den V3-23 und V3-30 VH-Keimbahngenen abstammten. Eine weitere Studie mit IgG und IgM Phagen-Display Bibliotheken von einem gesunden Spender zeigten ebenfalls eine bevorzugte Reaktivierung von IVIG mit Fabs vom Ursprung der V3-23 und V3-30 Gene. Es konnte gefolgert werden, dass diese Interaktion von IVIG mit Fabs von diesen zwei VH-Genen weder alleine auf den Gesundheitsstatus des Spenders zurückzuführen war, noch auf eine zuvor erfolgte Behandlung mit IVIG. Diese Dissertation wurde unter Verwendung der Phagen-Display Technologie unternommen, um die molekulare Interaktion von IVIG mit Antikörpern zu erforschen, die von einem Patienten kloniert wurden, der an einem systemischen Lupus erythematodes und rheumatischem Fieber leidet. Die Resultate waren mit den früheren Studien zu vergleichen, insbesondere mit den Daten eines Patienten, der zu der ITP einen Lupus entwickelte.
23 Fabs, welche 7 unabhängige Klone repräsentierten, wurden isoliert. Im Gegensatz zu von Patienten mit ITP abstammenden Klonen reagierte keines von den in dieser Studie selektierten Fabs mit Thrombozyten. Die über IVIG gebundene Fab-Phagen stammten hierbei ausschließlich von den V3-23 und V3-30 VH-Genen ab. Darüber hinaus wurde beobachtet, dass von diesen Fabs verschiedene CDR3 Regionen einschließlich verschiedenen D- und JH-Gensegmenten benutzt wurden. Die Ergebnisse zeigten weiterhing, dass die Bindung von IVIG an die Fabs unabhängig von der Leichten Kette war. Ihrem Keimbahngen-Ursprung entsprechend hatten die Fabs Aminosäuren an Positionen in den FR1, FR3 und im 3’-Ende von CDR2, die dafür bekannt sind, dass sie für die Bindung des B-Zell-Superantigens Staphylococcus Protein A (SpA) essentiell sind. Es wurde gezeigt, dass sich zwar einige von den Fabs stark an SpA banden, aber keine Korrelation in der Intensität zur Bindung mit IVIG vorlag. Einige Fabs zeigten eine schwache Bindung an HIV gp120, einem anderen B-Zell-Superantigen. Zusammenfassend lässt sich aus der vorliegenden Studie und den vorherigen Ergebnissen schließen, dass ein Anteil von IVIG wie ein B-Zellen Superantigen funktionieren könnte, das für die Bildung und Regulation des normalen B-Zellen Repertoires wichtig ist. Der Bindungsmechanismus scheint ähnlich, aber nicht identisch mit dem der anderen getesteten B-Zellen-Superantigene zu sein.
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