Cancer-retina antigens — A new group of tumor antigens

Some photoreceptor proteins normally specific for the eye retina are aberrantly expressed in malignant tumors. These proteins include recoverin, visual rhodopsin, transducin, cGMP-phosphodiesterase 6 (PDE 6), cGMP-dependent cationic channels, guanylyl cyclase 1, rhodopsin kinase, and arrestin. By analogy with cancer-testis antigens, these photoreceptor proteins form the group of cancer-retina antigens. It is shown that an aberrant demethylation of the promoter region of recoverin is involved in the aberrant expression of this protein. The cascade Wnt5a → Frizzled-2 → transducin → PDE 6 is shown to function in skin melanoma cells, and this suggests that these cancer-retina antigens can play a functional role. The events accompanying the signal transduction in this cascade, including those involving calcium ions and cGMP-dependent protein kinase (protein kinase G), are discussed.     

Do histocompatibility antigens recognize themselves?

In the Simonsen spleen weight assay, theH-2K ^ba mutant does not respond against theH-2K ^bd mutant orH-2K ^bd /H-2K ^b hybrid, while the parentalH-2K ^b haplotype does respond. TheH-2K ^ba /H-2K ^b hybrid reacts strongly to bothH-2K ^bd andH-2K ^bd /H-2K ^b , indicating that the donor genotype could influence the reactivity against the same antigenic difference. The response of theH-2 ^ba mutant against a number of unrelated H-2 antigens does not differ from that of the parental haplotype. TheH-2K ^bd mutant reacts againstH-2K ^b andH-2K ^ba , and theH-2K ^b parent reacts against both theH-2K ^ba andH-2K ^bd mutants. The specific defect of reactivity in theH-2K ^ba mutant is effectively complemented by crossing with a number of unrelatedH-2 haplotypes. TheH-2 ^ka andH-2 ^fa mutants complement poorly compared to corresponding parental strains CBA and A.CA, while the B10.M (H-2 ^f ) strain does not complement at all (which is probably attributable to an undetectedH-2 mutation in the last strain). The data strongly suggest that the product of theH-2K locus-which is known to function as a transplantation antigen, lymphocyte activating determinant, and serologically defined antigen-also influences the immune response capacity against a mutant histocompatibility determinant.     

Are Actinomyces viscosus antigens B cell mitogens?

An extracellular heteroglycan (ECHG) and a sonicated cell supernatant (SCS) of Actinomyces viscosus Ny 1 induced strong lymphocyte proliferation. This was shown with spleen and thoracic duct cells form germfree rats and confirmed with cells from conventional "nude" mouse spleens. Spleen cells developed direct plaque-forming cells against densely coupled TNP-SRBC. The mitogenic property of ECHG was diminished considerably after mild alkaline hydrolysis for lymphocytes form rat spleens and was totally abolished for cells from "nude" mouse spleens. These results suggest that ECHG and SCS have B cell mitogenicity.     

Interrelationships of the “Ly-6 complex” antigens

Competitive binding studies and immunoprecipitation experiments define at least five distinct epitopes encoded by Ly-6-linked genes—Ly-6A.2, Ly-6B.2, Ly-6C.2, Ly-6D.2, and ThB. Ly-6A.2, a 33 kd protein, and Ly-6D.2 are closely overlapping epitopes that can be distinguished by their unique thymus reactions of 10–20% or >90%, respectively. Similarly, the Ly-6C.2 antigen present on a 14 kd moiety loosely overlaps the Ly-6B.2 antigen. Ly-6C.2 and Ly-6B,2 antigens are distinct from Ly-6A.2 and Ly-6B.2, however. ThB is a 16–18 kd antigen which is not associated on the cell surface with any other Ly-6 antigens. In addition, independently derived antibodies made to the Ly-6C.2 antigen detect an identical epitope, as do antibodies to Ly-6A.2 and Ly-6B.2. These results imply the existence of a single antigenic site on each of these molecules.     

Ia antigens contain two distinct forms of β chain

Two new forms of chain, ₁ and ₂, in I-A immunoprecipitates are described, which differ in their migration values in SDS-PAGE under nonreducing conditions, but which migrate identically in a reduced form. This behavior is very likely due to a different arrangement of intramolecular disulfide bonds which may influence mobility in SDS-PAGE. Peptide map analysis confirmed that ₁ and ₂, possess identical primary polypeptide structures. These two forms of chain are also expressed on the cell surface and it is suggested that both associate with chains. The structural differences in these complexes may lead to an increase in heterogeneity of la antigens which could be of importance for T-cell recognition.     

An expeditious synthesis of blood-group antigens,ABO histo-blood group type II antigens and xenoantigen oligosaccharides with amino type spacer−arms

Blood group oligosaccharides are one of the most clinically important antigen families and they may also act as secondary ligands for bacterial toxins from Escherichia coli and Vibrio cholerae. Herein we report the synthesis of spacered (sp = CH₂CH₂CH₂NH₂) glycosides of A antigen {α-D-GalNAc-(l→3)-[α-L-Fuc-(l→2)]-β-D-Gal-}, B antigen{α-D-Gal-(l→3)-[α-L-Fuc-(l→2)]-β-D-Gal-}, LewisX{α-D-Gal-(l→4)-[α-L-Fuc-(l→3)]-β-D-GlcNAc-}, A type-II {α-D-GalNAc-(l→3)-[α-L-Fuc-(l→2)]-β-D-Gal-(1→4)-β-D-GlcNAc-}, B type-II {α-D-Gal-(l→3)-[α-L-Fuc-(l→2)]-β-D-Gal-(1→4)-β-D-GlcNAc-}, H type-II{α-L-Fuc-(l→2)-β-D-Gal-(1→4)-β-D-GlcNAc-}, xenoantigen {α-D-Gal-(l→3)-β-D-Gal-(1→4)-[α-L-Fuc-(l→2)]-β-D-GlcNAc-} and Linear B Type II {α-D-Gal-(l→3)-β-D-Gal-(1→4)-β-D-GlcNAc-} useful for a range of biochemical investigations. This linker was chosen so as to facilitate the future conjugation of the antigens to proteins or other molecules. We also measured the affinities of some synthesized oligosaccharides against El Tor CTB strain from V. cholera.     

Embryonic surface antigens: A “quasi-endodermal” teratoma antigen

Hyperimmune antisera against a teratoma-derived endodermal carcinoma of the mouse were used in cytotoxicity tests and by absorption analysis to define a surface antigen. This antigen was found to be present on all tumor cells tested that were of endodermal origin as well as on embryonic liver, and was therefore designated “Endo.” Further testing, however, revealed that Endo was represented on several inappropriate cell types such as young embryos before the appearance of endoderm, sperm, and a small proportion of non-endodermal tumors. Endo must therefore be considered a “quasi-endodermal” antigen.     

ESAT-6 proteins: protective antigens and virulence factors?

The 6kDa early secreted antigenic target from Mycobacterium tuberculosis, ESAT-6, is the prototype of a novel family of small proteins of unknown function produced by Actinobacteria. Export of ESAT-6, a potent T-cell antigen, and related proteins requires a dedicated secretory apparatus that is encoded by a cluster of genes, several of which also code for proteins that are recognized strongly by T cells. ESAT-6 systems can thus be considered as immunogenicity islands and there is growing evidence that the corresponding genes are subject to selective pressure imposed by the immune system of the host. Recently, there has been major progress in understanding the biogenesis, secretion and antigenicity of ESAT-6 proteins and, at least in the case of ESAT-6 system 1, in unravelling their role in pathogenicity. Here, we discuss these findings and their implications for the development of new therapeutic and prophylactic interventions against tuberculosis.     

Immunodominance in the immune response to “multiple” histocompatibility antigens

Cytotoxic effector T cells putatively specific for multiple non-H-2 histocompatibility (H) antigens were generated by immunizing and boosting C57BL/6 and B6.C-H-2 ^dmice with BALB.B and BALB/c stimulator cells, respectively. The generated effectors were tested for cell-mediated lympholysis on a panel of targets whose BALB/c-derived non-H-2 H antigens were donated by CXB recombinant inbred mice. The spectrum of reactivity of cytotoxic effector T cells with CXB targets demonstrated that the effectors did not recognize multiple H antigens but rather preferentially recognized a single immunodominant non-H-2 H antigen. The identity of the immunodominant H antigen was determined by the H-2 genotype of the stimulator cells when (B6 × B6.C-H-2 ^d)F ₁ cytotoxic effectors were tested. These observations indicate that despite the fact that responders were challenged with more than 40 individual non-H-2 H antigens, they preferentially responded to a single immunodominant antigen.     

Pre-erythrocytic antigens of Plasmodium falciparum: from rags to riches?

A growing number of Plasmodium genomes have joined the sequencing treadmill, and the genome of Plasmodium falciparum has recently been published. Most malaria vaccinologists will soon be confronted by a bewildering array of new potential antigens from the recently completed genome of this parasite. However, for those aiming to target the pre-erythrocytic stages of the hepatic parasite, the wait might be long. In the absence of readily available materials and specific reagents, the selection of pre-erythrocytic antigens from raw sequence data is likely to prove difficult. Here, current knowledge of pre-erythrocytic antigens is updated in the light of recent results, and the post-genomic prospects of completing the antigenic repertoire of these immunologically important and intriguing stages is discussed.     

IFN-γ-mediated efficacy of allergen-free immunotherapy using mycobacterial antigens and CpG-ODN

Epidemiological and experimental evidence supports the notion that microbial infections that are known to induce Th1-type immune responses can suppress Th2 immune responses, which are characteristics of allergic disorders. However, live microbial immunization might not be feasible for human immunotherapy. Here, we evaluated whether induction of Th1 immunity by the immunostimulatory sequences of CpG-oligodeoxynucleotides (CpG-ODN), with or without culture filtrate proteins (CFP), from Mycobacterium tuberculosis would suppress ongoing allergic lung disease. Presensitized and ovalbumin (OVA)-challenged mice were treated subcutaneously with CpG, or CpG in combination with CFP (CpG/CFP). After 15 days of treatment, airway inflammation and specific T- and B-cell responses were determined. Cell transfer experiments were also performed. CpG treatment attenuated airway allergic disease; however, the combination CpG/CFP treatment was significantly more effective in decreasing airway hyperresponsiveness, eosinophilia and Th2 response. When an additional intranasal dose of CFP was given, allergy was even more attenuated. The CpG/CFP therapy also reduced allergen-specific IgG1 and IgE antibodies and increased IgG2a. Transfer of spleen cells from mice immunized with CpG/CFP also reduced allergic lung inflammation. CpG/CFP treatment induced CFP-specific production of IFN-γ and IL-10 by spleen cells and increased production of IFN-γ in response to OVA. The essential role of IFN-γ for the therapeutic effect of CpG/CFP was evidenced in IFN-γ knockout mice. These results show that CpG/CFP treatment reverses established Th2 allergic responses by an IFN-γ-dependent mechanism that seems to act both locally in the lung and systemically to decrease allergen-specific Th2 responses.     

The presence and possible significance of cross-reactive antigens inRhizobium — legume associations

Soluble antigens of threeRhizobium species were compared by the agar-gel double-diffusion technique with those of eight legumes representing compatible and non-compatible hosts. Cross-reactive antigens were found between all the legume hosts and the three rhizobia. These common antigens among hosts and bacteria were not related to the specificity of compatibleRhizobium-legume associations. The cross-reactive antigens were absent between rhizobia and eight non-legume plants tested, but present between five out of eleven gramnegative phytopathogenic bacteria and legumes. The potential significance of cross-reactive antigens betweenRhizobium and legume hosts in nodule development is discussed.     

How do antigenically varying pathogens avoid cross-reactive responses to invariant antigens?

Pathogens such as trypanosomes and malaria use antigenic variation to evade immune responses and prolong the duration of infections. As pathogens typically express more than one antigen, even relatively rare conserved antigens might be expected to trigger cross-reactive immune responses capable of clearing the infection. We use simple mathematical models that explicitly consider the dynamic interplay between the replicating pathogen, immune responses to different antigens and immune exhaustion to explore how pathogens can escape the responses to both variable and invariant (conserved) antigens. Our results suggest two hypotheses. In the first, limited quantities of invariant antigens on each pathogen may lead to saturation in killing by cross-reactive responses. In the second, antigenic variation of the dominant antigens prolongs the duration of infection sufficiently to allow for exhaustion of the cross-reactive responses to subdominant, invariant epitopes prior to their being able to control the infection. These hypotheses make distinct predictions: the former predicts that cross-reactive responses will always be ineffective while the latter predicts that appropriately timed treatment could, by preventing exhaustion, lead to the generation of long-lasting protective cross-reactive immunity and thus act similarly to a vaccine.     

Interspecies exchange of β 2-microglobulin and associated MHC and differentiation antigens

Radiolabeled human ₂-microglobulin (₂m) can bind to mouse histocompatibility (H-2) antigens on the cell surface or to partially purified H-2 antigens in solution. The complexes containing human ₂m and H-2 antigens from C3H (H-2^k) mice could be immunoprecipitated specifically with alloantisera, rabbit anti-H-2 xenoantisera, and with monoclonal H-2-specific antibodies. Specific association with H-2 antigens was also observed with other haplotypes. The only exception was B10.D2 (H-2 ^d ) from which complexes containing human ₂M could only be precipitated with anti-H-2 xenosera. Thus radiolabeled human ₂M can be used as a specific label for mouse H-2 antigens in precipitation and radioimmunoassays. The application of this finding extends to major histocompatibility complex antigens of other species, and to differentiation antigens with primary association with ₂m.Abbreviations used in this paper MHC major histocompatibility complex - ₂m ₂-microglobulin - LcH Lens culinaris hemagglutinin     

“Weak” histocompatibility antigens generate functionally “strong” humoral immunity

The kinetics and complexity of the immune responses generated by weak histocompatibility antigens on transplants of normal tissues were investigated by analyzing (1) the survival times of test skin grafts on mice that had been initially immunized with skin, liver, or kidney implants, (2) the survival times of test skin grafts on mice that had received putatively immune sera or lymphocytes harvested from an allografted host, and (3) the cytotoxic potential of these cells and sera in vitro. The data indicate that despite chronic rejection, weak antigens rapidly immunize hosts, and that the immune response includes a major humoral component that can either accelerate graft rejection or prolong graft survival.     

The worm and the protozoa: stereotyped responses or distinct antigens?

Studies of parasitic diseases have provided the best in vivo correlates of the division of CD4+ helper T cells into distinct functional phenotypes, designated T(H)I and T(H)2, that mediate the balanced regulation of cellular and humoral immunity. In this article, Steven Reiner and Richard Locksley focus on why parasitic infections tend to generate such clearly polarized responses and emphasize that early events that mediate maturation signals towards T(H)1- or T(H)2-effector and memory cells remain incompletely defined. Effective vaccination that seeks to mold the developing immune response will need to consider the role of interleukins and various cell-surface molecules that have been identified, thus far, to influence CD4 subset differentiation.     

Synthesis and absolute structures of Mycoplasma pneumoniae β-glyceroglycolipid antigens

Just recently, a pair of β-glycolipids was isolated from the cell membrane of Mycoplasma pneumoniae as a mixture of the two compounds. They are the major immunodeterminants of this pathogenic Mycoplasma and indicate high medicinal potential. They have a β-(1→6)-linked disaccharide structure close to each other; one has β-d-galactopyranoside (β-Gal-type 1) at the non-reducing terminal, and another has β-d-glucopyranoside (β-Glc-type 2). In the present study, the first stereoselective synthesis was conducted for each of the two β-glycolipids 1 and 2. ¹H NMR and TLC-immunostaining studies of the synthetic compounds enable us to establish the absolute structures having the β-(1→6)-linked disaccharides at the glycerol sn-3 position.