Target antigens in malaria transmission blocking immunity

Malaria transmission blocking immunity has been found to operate against two distinct phases of development of malaria parasites in the mosquito midgut: (i) against the extracellular gametes and newly fertilized zygotes shortly after ingestion by a mosquito of parasitized blood and (ii) against the zygotes during their subsequent development into ookinetes. Immunity is antibody-mediated and stage-specific. A set of three proteins, synthesized in the gametocytes, expressed on the surface of the gametes and newly fertilized zygotes and subsequently shed during later transformation of the zygotes, has been identified as the target antigens of anti-gamete fertilization blocking antibodies. A single protein, synthesized and expressed on the zygote surface during its development to ookinetes, has been identified as the target of antibodies which block the development of the fertilized parasites in the mosquito. Immunization of human populations against gamete or zygote antigens, while not directly protecting an immunized individual from inflection, would reduce the transfer of malaria within the population. Such immunity, in addition to reducing the overall rate of malaria transmission, would, if combined with a vaccine against the asexual (disease-causing) stages, reduce the chance of selection of parasites that are resistant to the asexual vaccine by preventing their entry into the mosquito population.     

Studies on antigen-induced arthritis in mice. II. Immunologic correlates of arthritis susceptibility in mice.

Antigen-induced arthritis was developed in mice as a model of human rheumatoid arthritis by using methylated bovine serum albumin (mBSA) as antigen. It was found that most strains were susceptible, whereas CBA mice were resistant. We therefore investigated the humoral and cell-mediated immune responses to mBSA in resistant mice (CBA) and susceptible mice (exemplified by C57BL) to determine whether these were associated with susceptibility to arthritis. The resistant strain (CBA) differed from the suceptible strains in the following respects. First, there was a lower humoral immune response to mBSA as measured by passive hemagglutination, but this could be overcome by a larger immunogenic dose. Secondly, there were differences in response to low doses of DNP-mBSA after mBSA carrier preimmunization. Thirdly, there were striking differences in delayed-type hypersensitivity (DTH) to mBSA as determined by a radioisotopic assay in vivo; the response of CBA mice occurred early, at 5 days, declined quickly, and was weaker, whereas that of C57BL mice developed later and was long sustained. Genetic studies of the DTH response with hybrids and backcrosses showed an oligogenic control of immune responsiveness, with one gene being linked to the H-2b allele of the susceptible C57BL mice, and another being independent of the H-2 complex. Our findings indicate that in mice, susceptibility to antigen-induced arthritis with mBSA correlates with a higher responder state to this antigen, and that T cells are the major if not the only determinant of the high responder state.     

Reversible inhibition by diamide of cyclic AMP-dependent protein kinases from bovine thyroid.

The effects of diamide on protein kinases isolated from bovine thyroid were studied. Cyclic AMP-dependent protein kinase activity was directly, rapidly, and reversibly inhibited by diamide. This inhibition was non-competitive with respect to ATP or histone and could be prevented by thiol-reducing agents. However, a cyclic nucleotide-independent thyroid protein kinase was not affected. Our data indicate that diamide specifically inhibits protein kinases which are cyclic AMP-dependent.     

Repertoires of T cells directed against a large protein antigen, beta-galactosidase. I. Helper cells have a more restricted specificity repertoire than proliferative cells

The proliferative and helper T cell repertoires were compared in the CBA/J mouse for the response to the large protein antigen, tetrameric beta-galactosidase (GZ = 1021 a.a/monomer). The systems assessed the ability of cyanogen bromide (CB) peptides of GZ to: 1) prime for a T cell proliferative response to GZ; or 2) generate T cell help, measured by the production of anti-FITC PFC in the in vitro response to GZ-FITC. Priming for in vitro proliferation was attempted with 11 CB peptides comprising 70% of the GZ molecule. Strong priming was found with five peptides and intermediate priming was found with four other peptides; two peptides were without effect (CB-20 = a.a 767-862, and CB-4 = a.a. 188-202). Despite this indication of generally dispersed recognition of GZ epitopes, only two CB peptides, CB-2 (a.a. 3-92) and CB-10 (a.a. 378-418) were able to induce a T helper cell response. The surprising dearth of helper T cell-inducing epitopes may be peculiar to the limited fluorescein (FITC) substitution on GZ-FITC (17-25 FITC residues per tetramer) or it may reflect the constraints involved in T cell recognition required for T-B collaboration. Also considered was the possibility that the helper T cell repertoire might be distinct from the proliferative repertoire, the latter reflecting DNA synthesis and recruitment by other functional T cell subpopulations.     

Effects of pH and ionic strength on the structure of collagen fibrils

The roles of pH and ionic strength on the structure and stability of collagen fibrils have been investigated by means of x-ray and neutron diffraction techniques. High-angle x-ray diffraction shows that a salt concentration of 0.5M KCl is sufficient to reduce the osmotic swelling and related disordering in the pH range 1–3. The relative intensities of the low-angle meridional x-ray and neutron diffraction Bragg reflections vary with pH. Difference Fourier syntheses between pH 7 and 1.6 data indicate, for both x-ray and neutron diffraction, a reduced scattering contribution from the telopeptides at low pH. Lyotropic relaxation is a crucial step in the appearance at low pH of a doubling of the 668-Å axial periodicity (D) of collagen fibrils. These results suggest that electrostatic interactions are essential for the structural stability of the telopeptide regions and of the 1D and 3D intermolecular staggers between collagen molecules.