Case report: Myocardial perfusion gated-SPECT in pulmonary artery hypertension-the Movahed's sign.

Primary pulmonary artery hypertension (PAH) is a clinical diagnosis that requires the exclusion of other underlying causes of pulmonary hypertension (PH). Increased pulmonary artery (PA) pressure and subsequent right ventricular (RV) pressure overload often result in a flattening of the curved interventricular septum, leading to a D-shaped left ventricle (LV), as observed in echocardiographic short-axis views. A similar finding may be also observed on myocardial perfusion SPECT images, the so-called Movahed's sign. We present a clinical case of a female patient with PAH and progression of exertional dyspnea that underwent myocardial perfusion SPECT to investigate LV myocardial ischemia. The SPECT images revealed enhanced tracer uptake in the dilated right ventricle. Additionally, we observed a D-shaped LV or Movahed's sign, which may serve as a potential marker of RV pressure overload, along with a small stress-induced perfusion defect on the LV septal wall. Our findings highlight the importance of considering the presence of a D-shaped LV and signs of RV pressure overload, as they can alter the interpretation of LV perfusion deficits on SPECT images. This case report aims to emphasize the complex nature of right heart abnormalities in pathologies such as PAH and the consideration of the RV implications in myocardial SPECT images-which typically focus solely on the LV.

S. mansoni Trapping in Lungs Contributes to Resistance to Reinfection.

Worm transplantation studies show that physiological and reproductive status of the worm is influenced by the microenvironment of the host and critical for vaccine design. Worm migration studies in rats with (75)Se-methionine labeled cercariae demonstrated that resistance to reinfection (R/R) requires a host immune response resulting in worm death. In permissive hosts, inflammation due to anti eggs immunity leads to host death, whereas in non-permissive hosts this is not the case due to reduced egg burdens. Eggs-induced pathology and inflammatory debris resulting from immune attack on worms are important for vaccine design. Protective immune responses are perhaps induced when naïve hosts are vaccinated with either schistosome-derived molecules or attenuated cercariae as suggested by the induction of protective anti-parasite antibodies and monoclonals. However, these immunological strategies rarely produce 85-90% R/R as is achievable by portal-caval shunting. Alternatively, induction of anti-schistosoma immunity may induce portacaval shunting, seems highly unlikely although not yet tested. Differential screening with sera from twice-infected rats, protective (F2x) from Fisher vs. non-protective (W2x) from Wistar-Furth rats, was used to identify candidate vaccine antigens.

C3d adjuvant effects are mediated through the activation of C3d-specific autoreactive T cells.

Complement fragment C3d covalently attached to antigens enhances immune responses, particularly for antigens lacking T-cell epitopes. Enhancement has been attributed to receptor cross-linking between complement receptor CR2 (CD21) and polysaccharide antigen to surface IgM on naïve B cells. Paradoxically, C3d has still been shown to increase immune responses in CD21 knockout mice, suggesting that an auxiliary activation pathway exists. In prior studies, we demonstrated the CD21-independent C3d adjuvant effect might be due to T-cell recognition of C3d T-helper epitopes processed and presented by major histocompatibility complex class II on the B-cell surface. C3d peptide sequences containing concentrated clusters of putative human C3 T-cell epitopes were identified using the epitope-mapping algorithm, EpiMatrix. These peptide sequences were synthesized and shown in vitro to bind multiple human leukocyte antigen (HLA)-DR alleles with high affinity, and induce interferon-γ responses in healthy donor peripheral blood mononuclear cells. In the present studies, we establish further correlations between HLA binding and HLA-specific lymphocyte reactions with select epitope clusters. In addition, we show that the T-cell phenotype of C3d-specific reactive T cells is CD4(+)CD45RO(+) memory T cells. Finally, mutation of a single T-cell epitope residing within the P28 peptide segment of C3d resulted in significantly diminished adjuvant activity in BALB/c mice. Collectively, these studies support the hypothesis that the paradoxical enhancement of immune responses by C3d in the absence of CD21 is due to internalization and processing of C3d into peptides that activate autoreactive CD4(+) T-helper cells in the context of HLA class II.

Novel function of complement C3d as an autologous helper T-cell target.

The C3d fragment of complement component C3 has been shown to enhance immune responses to antigens that lack T-cell epitopes such as bacterial polysaccharides. C3d binds to the B-cell complement receptor 2 (CR2 or CD21); this binding serves as a co-activation signal to the B cell when the polysaccharide antigen portion binds simultaneously to the B-cell receptor (surface Ig). Bringing together receptor-associated signal transduction molecules CD19 and Igalpha/beta, respectively, results in a lower threshold of activation. Paradoxically, C3d has also been shown to enhance antibody titers in the CD21 knockout (KO) mouse model as well as increase Th1 and Th2 cytokine secretion, suggesting that that an auxiliary CR2-independent pathway of immune activation may exist. We hypothesized that in addition to its molecular adjuvant property that enhances signal 1 during B-cell activation (co-signal 1), C3d also contains T-cell epitopes that are able to stimulate autoreactive C3d peptide-specific helper T cells which we term 'co-signal 2'. Using the EpiMatrix T-cell epitope-mapping algorithm, we identified 11 putative T-cell epitopes in C3d, a very high epitope density for a 302 amino-acid sequence. Eight of these epitope candidates were synthesized and shown to bind a variety of class II HLA-DR molecules of different haplotypes, and to stimulate C3d peptide-specific T cells to secrete pro-inflammatory cytokines in vitro. Further, we demonstrate a C3d-peptide specific increase in CD4(+) intracellular IFN-gamma(+) T cells in peripheral blood mononuclear cells (PBMCs) exposed to C3d peptides in vitro. We believe that the discovery of these autologous T cells autoreactive for C3d provides evidence supporting the 'co-signal 2' hypothesis and may offer a novel explanation of the CD21 KO paradox.

Microinfusion into the rat brain of antibodies against Semliki Forest Virus produces changes in behavioral response to apomorphine.

Anti-SFV antibodies generated during SFV infection may affect CNS function due to cross-reactivity with a peptide of oligodendrocyte myelin glycoprotein. To explore this possibility, total IgG from SFV immunized or normal control rabbits was unilaterally microinfused into the subthalamic region of normal rat brain. Behavior of the IgG-infused rats was determined using a bioassay, measuring rotational locomotion following systemic injection of apomorphine. Anti-SFV IgG-infused rats demonstrated a significantly increased (p<0.005) ipsilateral turning response compared to control rats, persisting for at least a month. Results suggest that brain cross-reactive antibodies in anti-SFV IgG may affect brain function.

Protective human immunity as a vaccine discovery tool for falciparum malaria.

BACKGROUND: Plasmodium falciparum malaria remains a leading cause of morbidity and mortality in developing countries, and malaria-associated severe anemia is the major factor driving the high transfusion requirements in pediatric populations living in endemic areas. STUDY DESIGN AND METHODS: In this report, we identify and evaluate the targets of naturally acquired protective antibody responses in a cohort of n = 143 male volunteers residing in a P. falciparum holoendemic area of western Kenya. Volunteers were drug-cured of current malaria infection, blood was collected 2 weeks after treatment, and blood smears were collected weekly for 18 weeks. We identified and pooled plasma from the 10 most resistant (RP) and the 7 most susceptible individuals (SP) and utilized these pools in a differential screen of a P. falciparum cDNA expression library. We screened 550,000 clones and identified 7 clones that were uniquely recognized by RP but not by SP. Two clones encoded a C-terminal region polypeptide from rhoptry-associated membrane antigen (RAMA-pr), a recently described rhoptry-associated membrane antigen. RESULTS: We measured RAMA-pr antibody levels in plasma obtained 2 weeks after treatment. Individuals with detectable immunoglobulin G(1) anti-RAMA-pr (n = 24) had fewer positive blood films (p < 0.003) and 43 percent lower density of parasitemia (p < 0.02) than individuals with undetectable (n = 115) antibody levels. CONCLUSION: RAMA-pr is a rationally identified vaccine candidate preferentially recognized by antibodies produced by humans with a high level of naturally acquired resistance to P. falciparum infection. Our results demonstrate that naturally acquired protective antibody responses are useful tools to identify vaccine candidates for falciparum malaria.

Antibodies to rhoptry-associated membrane antigen predict resistance to Plasmodium falciparum.

Previously, we collected plasma from 143 male volunteers residing in an area of western Kenya where Plasmodium falciparum is holoendemic. Volunteers were cured of current malaria infection by use of drugs, blood was collected 2 weeks after treatment, and blood films were collected weekly for 18 weeks. We identified and pooled plasma from the 10 most resistant individuals (RP) and the 7 most susceptible individuals (SP) and used these pools in a differential screen of a P. falciparum cDNA expression library. We screened 550,000 clones and identified 7 clones that were uniquely recognized by RP but not by SP. Two clones encoded a C-terminal region polypeptide from rhoptry-associated membrane antigen (RAMA-pr), a recently described RAMA. We measured anti-RAMA-pr antibody levels in plasma obtained 2 weeks after treatment. Individuals with detectable immunoglobulin G1 anti-RAMA-pr (n = 24) had fewer positive blood films (odds ratio, 1.7 [95% confidence interval, 1.21-2.44]; P < .003), 43% lower density of parasitemia (P < .02), and prolonged time to reinfection (P < .0027), compared with individuals without detectable antibody levels (n = 115), after known determinants of resistance were accounted for. In summary, RAMA-pr is a rationally identified vaccine candidate that is preferentially recognized by antibodies produced by humans with a high level of naturally acquired resistance to P. falciparum infection.