Immunoglobulin J-Chains
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Immunoglobulins
Immunoglobulin G
Immunoglobulin A
Analysis of V(H)-D-J(H) gene transcripts in B cells infiltrating the salivary glands and lymph node tissues of patients with Sjogren's syndrome. (1/244)
OBJECTIVE: In patients with Sjogren's syndrome (SS), B lymphocytes have been found to infiltrate salivary glands, resulting in sialadenitis and keratoconjunctivitis. The disease is frequently associated with benign and neoplastic lymphoproliferation. The present study was undertaken to investigate whether clonal B cell expansion takes place in lymphocytic infiltrations of salivary glands under (auto- [?]) antigen stimulation, by analyzing in more detail the variable part (V(H)-D-J(H)) of the immunoglobulin heavy chain genes expressed in these B cells. METHODS: Biopsies of the labial salivary glands and lymph nodes were performed on 2 female patients with SS. The Ig gene rearrangements in these tissues were amplified by reverse transcriptase-polymerase chain reaction using specific primers. RESULTS: A total of 94 V(H)-D-J(H) transcripts were cloned and sequenced. Our data suggest a polyclonal origin of the B cell infiltrates. In 92 of the transcripts, V(H) genes were modified by somatic mutation. Further analysis showed counterselection for replacement mutations within the framework regions, suggesting that those B cells were stimulated and selected for functional expression of a surface Ig. In labial salivary glands from both patients, clonally related B cells became evident. Members of 1 particular clone were found in both the lip and lymph node material. CONCLUSION: These data provide evidence, on the nucleotide sequence level, that an antigen-triggered clonal B cell expansion takes place in the salivary glands of patients with SS who do not have histologic evidence of developing lymphoma. It may be speculated that those B cell clones expand during disease progression, resulting in lymphomagenesis. (+info)Induction of Ig somatic hypermutation and class switching in a human monoclonal IgM+ IgD+ B cell line in vitro: definition of the requirements and modalities of hypermutation. (2/244)
Partly because of the lack of a suitable in vitro model, the trigger(s) and the mechanism(s) of somatic hypermutation in Ig genes are largely unknown. We have analyzed the hypermutation potential of human CL-01 lymphocytes, our monoclonal model of germinal center B cell differentiation. These cells are surface IgM+ IgD+ and, in the absence of T cells, switch to IgG, IgA, and IgE in response to CD40:CD40 ligand engagement and exposure to appropriate cytokines. We show here that CL-01 cells can be induced to effectively mutate the expressed VHDJH-C mu, VHDJH-C delta, VHDJH-C gamma, VHDJH-C alpha, VHDJH-C epsilon, and V lambda J lambda-C lambda transcripts before and after Ig class switching in a stepwise fashion. In these cells, induction of somatic mutations required cross-linking of the surface receptor for Ag and T cell contact through CD40:CD40 ligand and CD80: CD28 coengagement. The induced mutations showed intrinsic features of Ig V(D)J hypermutation in that they comprised 110 base substitutions (97 in the heavy chain and 13 in the lambda-chain) and only 2 deletions and targeted V(D)J, virtually sparing CH and C lambda. These mutations were more abundant in secondary VHDJH-C gamma than primary VHDJH-C mu transcripts and in V(D)J-C than V lambda J lambda-C lambda transcripts. These mutations were also associated with coding DNA strand polarity and showed an overall rate of 2.42 x 10(-4) base changes/cell division in VHDJH-CH transcripts. Transitions were favored over transversions, and G nucleotides were preferentially targeted, mainly in the context of AG dinucleotides. Thus, in CL-01 cells, Ig somatic hypermutation is readily inducible by stimuli different from those required for class switching and displays discrete base substitution modalities. (+info)Humoral immune responses in periodontal disease may have mucosal and systemic immune features. (3/244)
The humoral immune response, especially IgG and IgA, is considered to be protective in the pathogenesis of periodontal disease, but the precise mechanisms are still unknown. Immunoglobulins arriving at the periodontal lesion are from both systemic and local tissue sources. In order to understand better the local immunoglobulin production, we examined biopsy tissue from periodontitis lesions for the expression of IgM, IgG, IgA, IgE and in addition the IgG and IgA subclasses and J-chain by in situ hybridization. Tissues examined were superficial inflamed gingiva and the deeper granulation tissue from periodontal sites. These data confirm that IgM, and IgG and IgA subclass proteins and J-chain can be locally produced in the periodontitis tissues. IgG1 mRNA-expressing cells were predominant in the granulation tissues and in the gingiva, constituting approx. 65% of the total IgG-expressing plasma cells. There was a significantly increased proportion of IgA-expressing plasma cells in the gingiva compared with the granulation tissue (P < 0.01). Most of the IgA-expressing plasma cells were IgA1, but a greater proportion expressed IgA2 mRNA and J-chain mRNA in the gingival tissues (30.5% and 7.5%, respectively) than in the periodontal granulation tissues (19% and 0-4%, respectively). The J-chain or dimeric IgA2-expressing plasma cells were located adjacent to the epithelial cells, suggesting that this tissue demonstrates features consistent with a mucosal immune response. Furthermore, we were able to detect the secretory component in gingival and junctional epithelial cells, demonstrating that the periodontal epithelium shares features with mucosal epithelium. In contrast, deeper tissues had more plasma cells that expressed IgM, and less expressing IgA, a response which appears more akin to the systemic immune response. In conclusion, this study suggests that immune mechanisms involved in the pathogenesis of periodontitis may involve features of both the mucosal and systemic immune systems, dependent on tissue location. (+info)Two stages of increased IgA transfer during lactation in the marsupial, trichosurus vulpecula (Brushtail possum). (4/244)
The polymeric Ig receptor (pIgR) and J chain molecules are involved in the transfer of IgA across the mammary gland epithelia into milk. The J chain binds two IgA molecules to form dimeric IgA, and the pIgR transports this complex through epithelial cells. We report here the cloning of the first marsupial homologues for the pIgR and J chain from the brushtail possum. Marsupial young are born after a short gestation and are less developed than eutherian newborn. The pouch young is completely dependent on milk as its sole source of nutrition during early lactation and this phase can be considered to be equivalent to an external gestation. Two periods of increased expression of pIgR, J chain, and IgA heavy chain mRNAs were observed in the mammary gland during lactation. The first occurs for a brief period after birth of the pouch young and is likely to reflect IgA transfer via the colostrum. The second period of increased expression, which is unique to marsupials, occurs after the early lactation period and just before young exit the pouch. We propose that this represents a second colostral-like phase at the end of the external gestation. (+info)B cell-specific activator protein prevents two activator factors from binding to the immunoglobulin J chain promoter until the antigen-driven stages of B cell development. (5/244)
The immunoglobulin J chain gene is inducibly transcribed in mature B cells upon antigen recognition and a signal from interleukin-2 (IL-2). B cell-specific activator protein (BSAP), a transcription factor that silences J chain transcription, has been identified as a nuclear target of the IL-2 signal. The levels of BSAP progressively decrease in response to IL-2 and this change correlates with the differentiation of B cells into antibody secreting plasma cells. Here we report the binding of the upstream stimulatory factor (USF) to an E-box motif immediately upstream from the BSAP site on the J chain promoter. Mutations in the USF binding motif significantly decrease J chain promoter activity in J chain expressing B cell lines. We also show that a functional relationship exists between USF and a second J chain positive-regulating factor, B-MEF2, using co-immunoprecipitation assays and transfections. Finally, we provide evidence that the binding of BSAP prevents USF and B-MEF2 from interacting with the J chain promoter during the antigen-independent stages of B cell development. It is not until the levels of BSAP decrease during the antigen-driven stages of B cell development that both USF and B-MEF2 are able to bind to their respective promoter elements and activate J chain transcription. (+info)Molecular and cellular basis of the altered immune response against arsonate in irradiated A/J mice autologously reconstituted. (6/244)
The humoral immune response to arsonate (Ars) in normal A/J mice is dominated in the late primary and particularly in the secondary response by a recurrent and dominant idiotype (CRIA) which is encoded by a single canonical combination of the variable gene segments: VHidcr11-DFL16.1-JH2 and Vkappa10-Jkappa1. Accumulation of somatic mutations within cells expressing this canonical combination or some less frequent Ig rearrangements results in the generation of high-affinity antibodies. By contrast, in partially shielded and irradiated A/J mice (autologous reconstitution) immunized with Ars-keyhole limpet hemocyanin (KLH), both the dominance of the CRIA idiotype and the affinity maturation are lost, whereas the anti-Ars antibody titer is not affected. To understand these alterations, we have analyzed a collection of 27 different anti-Ars hybridomas from nine partially shielded and irradiated A/J mice that had been immunized twice with Ars-KLH. Sequence analysis of the productively rearranged heavy chain variable region genes from those hybridomas revealed that (i) the canonical V(D)J combination was rare, (ii) the pattern of V(D)J gene usage rather corresponded to a primary repertoire with multiple gene combinations and (iii) the frequency of somatic mutations was low when compared to a normal secondary response to Ars. In addition, immunohistological analysis has shown a delay of 2 weeks in the appearance of full blown splenic germinal centers in autoreconstituting mice, as compared to controls. Such a model could be useful to understand the immunological defects found in patients transplanted with bone marrow. (+info)Lack of J chain inhibits the transport of gut IgA and abrogates the development of intestinal antitoxic protection. (7/244)
Recent publications have provided confusing information on the importance of the J chain for secretion of dimeric IgA at mucosal surfaces. Using J chain-deficient (J chain-/-) mice, we addressed whether a lack of J chain had any functional consequence for the ability to resist challenge with cholera toxin (CT) in intestinal loops. J chain-/- mice had normal levels of IgA plasma cells in the gut mucosa, and the Peyer's patches exhibited normal IgA B cell differentiation and germinal center reactions. The total IgA levels in gut lavage were reduced by roughly 90% as compared with that in wild-type controls, while concomitantly serum IgA levels were significantly increased. Total serum IgM levels were depressed, whereas IgG concentrations were normal. Following oral immunizations with CT, J chain-/- mice developed 10-fold increased serum antitoxin IgA titers, but gut lavage anti-CT IgA levels were substantially reduced. However, anti-CT IgA spot-forming cell frequencies in the gut lamina propria were normal. Anti-CT IgM concentrations were low in serum and gut lavage, whereas anti-CT IgG titers were unaltered. Challenge of small intestinal ligated loops with CT caused dramatic fluid accumulation in immunized J chain-/- mice, and only 20% protection was detected compared with unimmunized controls. In contrast, wild-type mice demonstrated 80% protection against CT challenge. Mice heterozygous for the J chain deletion exhibited intermediate gut lavage anti-CT IgA and intestinal protection levels, arguing for a J chain gene-dosage effect on the transport of secretory IgA. This study unequivocally demonstrates a direct relationship between mucosal transport of secretory SIgA and intestinal immune protection. (+info)Ig lambda and heavy chain gene usage in early untreated systemic lupus erythematosus suggests intensive B cell stimulation. (8/244)
To determine the distribution of Vlambda and Jlambda as well as VH and JH gene usage in a patient with systemic lupus erythematosus (SLE), productive and nonproductive VJ and V(D)J rearrangements were amplified from individual peripheral CD19+ B cells and were analyzed. No differences in the Vlambda and Jlambda or the VH and JH gene usage in the nonproductive gene repertoire of this SLE patient were found compared with the distribution of genes found in normal adults, whereas marked skewing of both Vlambda and VH was noted among the productive rearrangements. The distribution of productive Vlambda rearrangements was skewed, with significantly greater representation of the Jlambda distal cluster C Vlambda genes and the Vlambda distal Jlambda7 element, consistent with the possibility that there was receptor editing of the Vlambda locus in this patient. Significant bias in VH gene usage was also noted with VH3 family members dominating the peripheral B cell repertoire of the SLE patient (83%) compared with that found in normal subjects (55%; p < 0.001). Notably, a clone of B cells employing the VH3-11 gene for the heavy chain and the Vlambda1G segment for the light chain was detected. These data are most consistent with the conclusion that extreme B cell overactivity drives the initial stages of SLE leading to remarkable changes in the peripheral V gene usage that may underlie on fail to prevent the emergence of autoimmunity. (+info)Immunoglobulin J-chains are small protein structures that play a role in the assembly and structure of certain types of antibodies, specifically IgM and IgA. The J-chain is a polypeptide chain that contains multiple cysteine residues, which allow it to form disulfide bonds with the heavy chains of IgM and IgA molecules.
In IgM antibodies, the J-chain helps to link the five identical heavy chain units together to form a pentameric structure. In IgA antibodies, the J-chain links two dimeric structures together to form a tetrameric structure. This polymerization of IgM and IgA molecules is important for their function in the immune system, as it allows them to form large complexes that can effectively agglutinate and neutralize pathogens.
The J-chain is synthesized by a specialized group of B cells called plasma cells, which are responsible for producing and secreting antibodies. Once synthesized, the J-chain is covalently linked to the heavy chains of IgM or IgA molecules during their assembly in the endoplasmic reticulum of the plasma cell.
Overall, the Immunoglobulin J-chain plays a crucial role in the structure and function of certain classes of antibodies, contributing to their ability to effectively combat pathogens and protect the body from infection.
Immunoglobulin J (JOINING) recombination signal sequence-binding protein, also known as RAG1 or RAG-1, is a protein that plays a critical role in the adaptive immune system. It is a component of the RAG complex, which also includes RAG2 and several other proteins.
The RAG complex is responsible for initiating the V(D)J recombination process, during which the variable regions of immunoglobulin (antibody) genes and T-cell receptor genes are assembled from gene segments called variable (V), diversity (D), and joining (J) segments. This process generates a diverse repertoire of antigen receptors that enable the immune system to recognize and respond to a wide range of pathogens.
RAG1 is an endonuclease that recognizes and cleaves specific sequences in the DNA called recombination signal sequences (RSSs) that flank the V, D, and J segments. Cleavage of these RSSs by RAG1 and RAG2 creates double-stranded breaks in the DNA, which are then processed by other proteins to form functional antigen receptor genes through a process called non-homologous end joining (NHEJ).
Therefore, Immunoglobulin J recombination signal sequence-binding protein is a crucial player in the adaptive immune system's ability to generate a diverse repertoire of antigen receptors and respond effectively to pathogens.
Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by the immune system's B cells in response to the presence of foreign substances, such as bacteria, viruses, and toxins. These Y-shaped proteins play a crucial role in identifying and neutralizing pathogens and other antigens, thereby protecting the body against infection and disease.
Immunoglobulins are composed of four polypeptide chains: two identical heavy chains and two identical light chains, held together by disulfide bonds. The variable regions of these chains form the antigen-binding sites, which recognize and bind to specific epitopes on antigens. Based on their heavy chain type, immunoglobulins are classified into five main isotypes or classes: IgA, IgD, IgE, IgG, and IgM. Each class has distinct functions in the immune response, such as providing protection in different body fluids and tissues, mediating hypersensitivity reactions, and aiding in the development of immunological memory.
In medical settings, immunoglobulins can be administered therapeutically to provide passive immunity against certain diseases or to treat immune deficiencies, autoimmune disorders, and other conditions that may benefit from immunomodulation.
Immunoglobulin G (IgG) is a type of antibody, which is a protective protein produced by the immune system in response to foreign substances like bacteria or viruses. IgG is the most abundant type of antibody in human blood, making up about 75-80% of all antibodies. It is found in all body fluids and plays a crucial role in fighting infections caused by bacteria, viruses, and toxins.
IgG has several important functions:
1. Neutralization: IgG can bind to the surface of bacteria or viruses, preventing them from attaching to and infecting human cells.
2. Opsonization: IgG coats the surface of pathogens, making them more recognizable and easier for immune cells like neutrophils and macrophages to phagocytose (engulf and destroy) them.
3. Complement activation: IgG can activate the complement system, a group of proteins that work together to help eliminate pathogens from the body. Activation of the complement system leads to the formation of the membrane attack complex, which creates holes in the cell membranes of bacteria, leading to their lysis (destruction).
4. Antibody-dependent cellular cytotoxicity (ADCC): IgG can bind to immune cells like natural killer (NK) cells and trigger them to release substances that cause target cells (such as virus-infected or cancerous cells) to undergo apoptosis (programmed cell death).
5. Immune complex formation: IgG can form immune complexes with antigens, which can then be removed from the body through various mechanisms, such as phagocytosis by immune cells or excretion in urine.
IgG is a critical component of adaptive immunity and provides long-lasting protection against reinfection with many pathogens. It has four subclasses (IgG1, IgG2, IgG3, and IgG4) that differ in their structure, function, and distribution in the body.
Immunoglobulin A (IgA) is a type of antibody that plays a crucial role in the immune function of the human body. It is primarily found in external secretions, such as saliva, tears, breast milk, and sweat, as well as in mucous membranes lining the respiratory and gastrointestinal tracts. IgA exists in two forms: a monomeric form found in serum and a polymeric form found in secretions.
The primary function of IgA is to provide immune protection at mucosal surfaces, which are exposed to various environmental antigens, such as bacteria, viruses, parasites, and allergens. By doing so, it helps prevent the entry and colonization of pathogens into the body, reducing the risk of infections and inflammation.
IgA functions by binding to antigens present on the surface of pathogens or allergens, forming immune complexes that can neutralize their activity. These complexes are then transported across the epithelial cells lining mucosal surfaces and released into the lumen, where they prevent the adherence and invasion of pathogens.
In summary, Immunoglobulin A (IgA) is a vital antibody that provides immune defense at mucosal surfaces by neutralizing and preventing the entry of harmful antigens into the body.
Immunoglobulin M (IgM) is a type of antibody that is primarily found in the blood and lymph fluid. It is the first antibody to be produced in response to an initial exposure to an antigen, making it an important part of the body's primary immune response. IgM antibodies are large molecules that are composed of five basic units, giving them a pentameric structure. They are primarily found on the surface of B cells as membrane-bound immunoglobulins (mlgM), where they function as receptors for antigens. Once an mlgM receptor binds to an antigen, it triggers the activation and differentiation of the B cell into a plasma cell that produces and secretes large amounts of soluble IgM antibodies.
IgM antibodies are particularly effective at agglutination (clumping) and complement activation, which makes them important in the early stages of an immune response to help clear pathogens from the bloodstream. However, they are not as stable or long-lived as other types of antibodies, such as IgG, and their levels tend to decline after the initial immune response has occurred.
In summary, Immunoglobulin M (IgM) is a type of antibody that plays a crucial role in the primary immune response to antigens by agglutination and complement activation. It is primarily found in the blood and lymph fluid, and it is produced by B cells after they are activated by an antigen.