Search

Two major antibody classes operate in saliva: secretory IgA (SIgA) and IgG. The former is synthesized as dimeric IgA by plasma cells (PCs) in salivary glands and is exported by the polymeric Ig receptor (pIgR). Most IgG in saliva is derived from serum (mainly via gingival crevices), although some is locally produced. Gut-associated lymphoid tissue (GALT) and nasopharynx-associated lymphoid tissue (NALT) do not contribute equally to mucosal PCs throughout the body. Thus, enteric immunostimulation is an inadequate mode of stimulating salivary IgA antibodies, which are poorly associated with the intestinal SIgA response, for instance after enteric cholera vaccination. Nevertheless, the IgA response in submandibular/sublingual glands is better related to B cell induction in GALT than the parotid response. Such disparity is suggested by the elevated levels of IgA in submandibular secretions of AIDS patients, paralleling their highly upregulated intestinal IgA system. Moreover, in patients with active celiac disease, IgA antibodies to disease-precipitating gliadin are reliably represented in whole saliva but not in parotid secretion. Parotid SIgA may be more consistently linked to immune induction in palatine tonsils and adenoids (human NALT), as supported by the homing molecule profile of NALT-derived B cell blasts. Also several other variables influence the levels of antibodies in oral secretions. These include difficulties with reproducibility and standardization of immunoassays, the impact of flow rate, acute or chronic stress, protein loss during sample handling, and uncontrolled admixture of serum-derived IgG and monomeric IgA. Despite such problems, saliva remains an interesting biological fluid with great scientific and clinical potentials. [ABSTRACT FROM AUTHOR]

Mucosal antibody defense depends on a complex cooperation between local B cells and secretory epithelia. Mucosa-associated lymphoid tissue gives rise to B cells with striking J-chain expression that are seeded to secretory effector sites. Such preferential homing constitutes the biological basis for local production of polymeric immunoglobulin A (pIgA) and pentameric IgM with high affinity to the epithelial pIg receptor that readily can export these antibodies to the mucosal surface. This ultimate functional goal of mucosal B-cell differentiation appears to explain why the J chain is also expressed by IgG- and IgD-producing plasma cells (PCs) occurring at secretory tissue sites; these immunocytes may be considered as ‘spin-offs’ from early effector clones that through class switch are on their way to pIgA production. Abundant evidence supports the notion that intestinal PCs are largely derived from B cells initially activated in gut-associated lymphoid tissue (GALT). Nevertheless, insufficient knowledge exists concerning the relative importance of M cells, major histocompatibility complex class II-expressing epithelial cells, and professional antigen-presenting cells for the uptake, processing, and presentation of luminal antigens in GALT to accomplish the extensive and sustained priming and expansion of mucosal B cells. Likewise, it is unclear how the germinal center reaction in GALT so strikingly can promote class switch to IgA and expression of J chain. Although B-cell migration from GALT to the intestinal lamina propria is guided by rather well-defined adhesion molecules and chemokines/chemokine receptors, the cues directing preferential homing to different segments of the gut require better definition. This is even more so for the molecules involved in homing of mucosal B cells to secretory effector sites beyond the gut, and in this respect, the role of Waldever's ring (including the palatine tonsils and adenoids) as a regional inductive tissue needs further characterization. Data suggest a remarkable compartmentalization of the mucosal immune system that must be taken into account in the development of effective local vaccines to protect specifically the airways, eyes, oral cavity, small and large intestines, and urogenital tract. [ABSTRACT FROM AUTHOR]

Immunoglobulin A (IgA) is the major antibody class present in external secretions of mammals. At the vulnerable mucosal surfaces, IgA provides a crucial first-line defence by neutralizing pathogens. Primates also have a substantial level of IgA in serum and although not well understood, the biological role of this IgA depends, at least partly, on its ability to interact with specific receptors (FcαRs) on the surface of leucocytes. The human FcαR, CD89, was the first IgA Fc receptor to be identified and binding of IgA-coated particles to CD89 triggers numerous cellular effector functions, including phagocytosis, antibody-dependent cellular cytotoxicity, and release of inflammatory mediators, all of which may play an important role in both systemic and mucosal immunity. For many years humans were the only species known to express CD89, however, it has recently been cloned from cows and rats. Here, we describe the identification of the CD89 gene in three additional species: horses, chimpanzees, and Rhesus macaques. Equine CD89 was identified at the cDNA level, whereas the chimpanzee and Rhesus macaque genes were identified from the available draft genomic sequence. Interestingly, when compared with humans and other primates, horses, cows and rats have a relatively low concentration of serum IgA, so the role of CD89 in these species is of particular interest. The identification and characterization of CD89 in different species will contribute to a greater understanding of the biological role of IgA and CD89 in mucosal and systemic immunity throughout evolution. [ABSTRACT FROM AUTHOR]

Haddeland U, Karstensen AB, Farkas L, Bø KO, Pirhonen J, Karlsson M, Kvåvik W, Brandtzaeg P, Nakstad B. Putative regulatory T cells are impaired in cord blood from neonates with hereditary allergy risk.Pediatr Allergy Immunol 2005.© 2005 Blackwell MunksgaardThe hygiene hypothesis implies that the increasing prevalence of allergy in‘westernized’ countries is explained by reduced bacterial exposure in early life, but the underlying mechanism remains elusive. We therefore wanted to study the effect of bacterial lipopolysaccharide (LPS) on the generation of regulatory T (TR) cells in neonates, and to analyze differences between neonates with allergy risk because of a family history of atopy (FH+) and controls without such hereditary risk (FH−). Cord blood mononuclear cells from the FH+ and FH− groups were stimulated withβ-lactoglobulin in the presence of LPS. T-cell phenotypes suggestive of TR cells [CD25+, CD25high and integrin(CD103+)], and the intracellular proliferation antigen Ki-67 were quantified by flow cytometry. Release of the immunosuppressive cytokine transforming growth factorβ1 (TGF-β1) from its inactive complex was determined by enzyme-linked immunosorbent assay. The analyses revealed the generation of T-cell phenotypes suggestive of TR cells including a CD25high T-cell subset which was inversely related to T-cell proliferation (r = −0.54, p < 0.05) and to activation-induced release of TGF-β1 (r = −0.80, p < 0.001). The CD25high T-cell subset tended to be impaired in the FH+ group (% of CD3+ T cells: FH+, 5.1% vs. FH−, 12.6%), and notably, the FH+ group showed a significantly reduced capacity for generation of both CD25+ (FH+, 16.2% vs. FH−, 34.9%; p < 0.01) andT cells (FH+, 2.1% vs. FH−, 3.9%; p < 0.05). Our findings suggested that early-life exposure to a dietary antigen in the presence of LPS might modulate the immune system by generating TR cells. This capacity was impaired in neonates with hereditary allergy risk, but clinical follow-up will be required to determine a possible effect on allergy emergence. [ABSTRACT FROM AUTHOR]

Secretory IgA (SIgA) is widely held to be responsible for the defense of the mucosae against pathogenics and other potentially harmful agents. In this study, polymeric Ig receptor (pIgR) knockout mice, which lack secretory antibodies (SAb), were used to investigate the role of vaccine-elicited SAb in protection against gastrointestinal bacterial infections. An essential role for specific SAb in protection against Vibrio cholerae was evident from experiments showing that vaccinated pIgR mice, but not vaccinated C57BL/6 mice, were susceptible to cholera toxin challenge. Vaccination of C57BL/6 mice with Salmonella typhimurium elicited strong antigen-specific, mucosal responses, which blocked in vitro invasion of epithelia. However, vaccinated C57BL/6 and pIgR mice were equally resistant to challenge infection with virulent S. typhimurium. Finally, we investigated the importance of SIgA in protection against recurrent infections with Citrobacter rodentium. Although higher numbers of bacteria were detected early after challenge infection in feces of vaccinated pIgR mice compared with vaccinated C57BL/6 mice, both mouse strains showed complete clearance after 9 days. These results suggested that, in immune animals, SIgA is crucial for the protection of gastrointestinal surfaces against secreted bacterial toxins, may inhibit early colonization by C. rodentium, but is not essential for protection against re-infection with S. typhimurium or C. rodentium. [ABSTRACT FROM AUTHOR]

Two populations of CD8 IEL generally express restricted, but apparently random and non-overlapping TCR repertoires. Previous studies in mice suggested that this could be explained by a dual origin of CD8 IEL, i.e. that CD8αβ IEL derive from a few peripheral CD8 T cell lymphoblasts stimulated by microbial antigens in gut-associated lymphoid tissue, whereas CD8αα IEL descend from an inefficient intestinal maturation pathway. We show here that the gut mucosa, instead, becomes seeded with surprisingly broad and generally non-overlapping CD8 IEL repertoires and that oligoclonality is induced locally after microbial colonization. In germ-free (GF) rats, both CD8αβ and CD8αα IEL displayed surprisingly diverse TCR Vβ repertoires, although β-chain diversity tended to be somewhat restricted in the CD8αα subset. CDR3 length displays in individual Vβ-Cβ and Vβ-Jβ combinations generally revealed polyclonal distributions over 6-11 different lengths, similar to CD8 lymph node T cells, and CDR3β sequencing provided further documentation of repertoire diversity. By contrast, in ex-GF rats colonized with normal commensal microflora, both CD8αβ and CD8αα IEL displayed oligoclonal CDR3 length distributions for most of the Vβ genes analyzed. Our data suggest that microbial colonization induces apparently random clonal expansions of CD8αβ and CD8αα IEL locally in the gut. [ABSTRACT FROM AUTHOR]

Here, we describe the cloning, sequencing and characterization of an immunoglobulin A (IgA) Fc receptor from cattle (bFcαR) . By screening a translated EST database with the protein sequence of the human IgA Fc receptor (CD89) we identified a putative bovine homologue. Subsequent polymerase chain reaction (PCR) amplification confirmed that the identified full-length cDNA was expressed in bovine cells. COS-1 cells transfected with a plasmid containing the cloned cDNA bound to beads coated with either bovine or human IgA, but not to beads coated with bovine IgG2 or human IgG. The bFcαR cDNA is 873 nucleotides long and is predicted to encode a 269 amino-acid transmembrane glycoprotein composed of two immunoglobulin-like extracellular domains, a transmembrane region and a short cytoplasmic tail devoid of known signalling motifs. Genetically, bFcαR is more closely related to CD89, bFcγ2R, NKp46, and the KIR and LILR gene families than to other FcRs. Moreover, the bFcαR gene maps to the bovine leucocyte receptor complex on chromosome 18. Identification of the bFcαR will aid in the understanding of IgA–FcαR interactions, and may facilitate the isolation of FcαR from other species. [ABSTRACT FROM AUTHOR]

Antigen-presenting cells (APCs) of the human gut are heterogeneous, including both macrophages, a variety of dendritic cells and B cells. They are found both in gut-associated lymphoid tissue and in the mucosal lamina propria, especially beneath the surface epithelium. APCs have diverse phenotypes and therefore probably different functions in various locations; their expression levels of a variety of costimulatory molecules are most likely important for immunological decision making of stimulated T cells, either locally in the gut or in regional lymph nodes to which migrating APCs (dendritic cells) carry antigen. Thus, APCs are involved in active immunity as well as in induction of oral tolerance. However, their precise role in food allergy remains to be defined. [ABSTRACT FROM AUTHOR]

The mucosae and exocrine glands harbour the largest activated B-cell system of the body, amounting to some 80-90% of all immunoglobulin (Ig)-producing cells. The major product of these immunocytes is polymeric (p)IgA (mainly dimers) with associated J chain. Both pIgA and pentameric IgM contain a binding site for the polymeric Ig receptor (pIgR), or secretory component (SC), which is a requirement for their active external transport through secretory epithelia. The pIgR/SC binding site depends on covalent incorporation of the J chain into the quaternary structure of the polymers when they are produced by the local immunocytes. This important differentiation characteristics appears to be sufficient functional justification for the J chain to be expressed also by most B cells terminating at secretory effector sites with IgD or IgD production; they probably represent a "spin-off" from sequential downstream C[sub H] switching on its way to pIgA expression, thus apparently reflecting a maturational stage of effector B-cell clones compatible with homing to these sites. Observations in IgA-deficient individuals suggest that the magnitude of this homing is fairly well maintained even when the differentiation pathway to IgA is blocked. Certain microenvironmental elements such as specific cytokines and dendritic cells appear to be required for induction of IgA synthesis, but it remains virtually unknown why this isotype normally is such a dominating product of local immunocytes and why they have such a high level of J chain expression. Also, despite the recent identification of some important requirements in terms of adhesion molecules (e.g. integrin α4β7 and MAdCAM-1) that explain the "gut-seeking" properties... [ABSTRACT FROM AUTHOR]

Correlations were sought between indices of gingival inflammation and dental caries experience and serum antibody titers to five species of oral bacteria. The material comprised 53 young adult males. A statistically significant, negative correlation was observed between the antibody titer to a pool of Veillonella strains and dental caries experience. Multiple regression analyses failed to reveal significant associations between periodontal disease and serum antibody titers, However, the data suggested a combined association of the titers to the strains of Veillonella and a strain of Fusobacterium with the periodontal index. [ABSTRACT FROM AUTHOR]

A 23-year-old man suffering from sero-negative rheumatoid arthritis developed severe penicillamine-induced mouth ulcerations and erythematous macules. Immunohistochemical staining in a biopsy specimen from the affected lingual mucosa showed substantial deposition of IgM and C3 in vessel walls below the necrotic epithelium. In the affected skin, irregular granular staining for IgG and IgM along the epidermal basement membrane zone was noted, and granular deposits of IgM were present in small vessels of dermal papillae. The mouth ulcerations healed promptly after withdrawal of the drug, whereas the macules persisted for some months. The immunohistochemical findings indicated that the drug eruptions were related to a vasculitis induced by deposition of immune complexes. [ABSTRACT FROM AUTHOR]

The complications of endodontic treatment in an AIDS patient are described and related to the immunopathological findings in a periapical granuloma. The lesion contained abundant polyclonal immunoglobulin-producing plasma cells but was virtually devoid of CD4-positive T cells (putative "helper" phenotype), indicating compromised local immune function. Delayed healing of apical periodontitis after endodontic treatment of teeth with periapical lesions was found in several teeth in this case. Root canal treatment of teeth with vital pulps was performed successfully. Extraction of teeth and endodontic treatment in combination with root resection were uneventful. [ABSTRACT FROM AUTHOR]

Discusses the role of J chain and secretory component in receptor-mediated glandular and hepatic transport of immunoglobulins in man. Preferential external translocation of both immunoglobulin A (IgA) and immunoglobulin M (IgM); Schematic representation of IgG, IgA and IgM concentrations in human serum and exocrine secretions; Models for glandular Ig transport; Evidence of an epithelial receptor function of secretory component (SC); Characteristics of the SC-binding sites of Ig polymers; Differentiation of B cells; Immunohistochemistry of dysplastic and neoplastic secretory epithelium.

The interaction of pathogenic bacteria with host serum and matrix proteins is a common strategy to enhance their virulence. Streptococcus pneumoniae colonizes the human upper respiratory tract in healthy individuals and is also able to cause invasive diseases. Here, we describe a novel pneumococcal surface protein, SpsA, capable of binding specifically to human secretory immunoglobulin A (SlgA). The dissociation constant of SlgA binding to SpsA was 9.3-10-9M. Free secretory component (SC) also binds to S. pneumoniae, whereas serum lgA does not, suggesting that pneumococcal binding to SlgA is mediated by the SC. To our knowledge, this is the first defined interaction of SC with a prokaryotic protein. The spsA gene encodes a polypeptide of 523 amino acids with a predicted molecular mass of 59151 Da. The SlgA- or SC-binding domain is located in the N-terminal part of SpsA and exhibits no significant homology to any other proteins. The purified SlgA-binding domain of SpsA could completely inhibit the binding of SlgA to pneumococci. SpsA was expressed by 73% of the tested S. pneumoniae isolates and was substantially conserved between different serotypes. The interaction between S. pneumoniae and SC via SpsA represents a novel biological interaction that might increase virulence by the impairment of bacterial clearance. [ABSTRACT FROM AUTHOR]

The local resistance factors of the gingival area are divided into two groups: (1) Physical and biochemical factors; (2) Immunologic and phagocytic activities. The status of the gingival epithelium and connective tissue may be important for the penetrability of the gingival area to bacteria and their products. The gingival pocket fluid and the saliva may be of significance in local resistance both through mechanical rinsing effects and the presence of antibacterial substances such as lysozyme. The oral microbiota by itself contributes to local resistance by bacterial antagonism. A local immune response apparently occurs in the gingiva during the development of periodontitis. The products of this response most likely include antibodies active against components and metabolites of the gingival bacteria. These antibodies may exert protective functions within the tissue as well as in the gingival pocket fluid and the saliva. Moreover, the milieu within the tissue and in the two fluids may promote phagocytosis The inflammatory response and the possibility of hypersensitivity reactions in the gingiva are discussed in relation to local resistance. [ABSTRACT FROM AUTHOR]

The article focuses on the address to the members of Scandinavian Society for Immunology (SSI) by the president of SSI. The economic situation of the Society is quite satisfactory. This is partly due to an excellent cooperation with the "Scandinavian Journal of Immunology," which last year contributed 84,000 NOK to the activities of the Society. The 23rd Annual Meeting of SSI will be held in Oslo, Norway, and the tentative dates are May 28-31, immediately preceding the 24th Scandinavian Congress of Hematology to be held in Malmo, Sweden, from May31-June3. The travel grants are made available to every year to members of SSI who attend the annual meeting.