anti-PS IgG Research Articles

Prothrombotic autoantibodies targeting platelet factor 4/polyanion are associated with pediatric cerebral malaria.

BACKGROUNDFeatures of consumptive coagulopathy and thromboinflammation are prominent in cerebral malaria (CM). We hypothesized that thrombogenic autoantibodies contribute to a procoagulant state in CM.METHODSPlasma from children with uncomplicated malaria (UM) (n = 124) and CM (n = 136) was analyzed by ELISA for a panel of 8 autoantibodies including anti-platelet factor 4/polyanion (anti-PF4/P), anti-phospholipid, anti-phosphatidylserine, anti-myeloperoxidase, anti-proteinase 3, anti-dsDNA, anti-β-2-glycoprotein I, and anti-cardiolipin. Plasma samples from individuals with nonmalarial coma (NMC) (n = 49) and healthy controls (HCs) (n = 56) were assayed for comparison. Associations with clinical and immune biomarkers were determined using univariate and logistic regression analyses.RESULTSMedian anti-PF4/P and anti-PS IgG levels were elevated in individuals with malaria infection relative to levels in HCs (P < 0.001) and patients with NMC (PF4/P: P < 0.001). Anti-PF4/P IgG levels were elevated in children with CM (median = 0.27, IQR: 0.19-0.41) compared with those with UM (median = 0.19, IQR: 0.14-0.22, P < 0.0001). Anti-PS IgG levels did not differ between patients with UM and those with CM (P = 0.39). When patients with CM were stratified by malaria retinopathy (Ret) status, the levels of anti-PF4/P IgG correlated negatively with the peripheral platelet count in patients with Ret+ CM (Spearman's rho [Rs] = 0.201, P = 0.04) and associated positively with mortality (OR = 15.2, 95% CI: 1.02-275, P = 0.048). Plasma from patients with CM induced greater platelet activation in an ex vivo assay relative to plasma from patients with UM (P = 0.02), and the observed platelet activation was associated with anti-PF4/P IgG levels (Rs= 0.293, P = 0.035).CONCLUSIONSThrombosis mediated by elevated anti-PF4/P autoantibodies may be one mechanism contributing to the clinical complications of CM.

Acquisition of anti-phosphatidylserine IgM and IgG antibodies by infants and their mothers over time in Uganda.

Production of anti-phosphatidylserine (anti-PS) antibodies has been associated with malaria and can aggravate pathology. How these autoantibodies develop during early childhood in a malaria context is not known. We examined levels of anti-PS IgG and IgM antibodies in a longitudinal cohort of mother-baby pairs during birth, in the infants at 2.5, 6 months, and in mothers and their babies at 9 months postpartum. There was no difference between levels of anti-PS IgG in cord blood and the mothers' peripheral blood at birth. However, anti-PS IgM levels were significantly higher in the mothers compared to the infants' cord blood, and IgM levels were steadily increasing during the first 9 months of the infants' life. In infants that had the highest anti-PS IgM levels at birth, there was a decline until 6 months with a rise at 9 months. Infants that possessed high anti-PS IgG at birth also exhibited a progressive decline in levels. When anti-PS were correlated to different fractions of B-cells, there were several correlations with P. falciparum specific atypical B cells both at birth and at 2.5 months for the infants, especially for anti-PS IgM. Anti-PS also correlated strongly to C1q-fixing antibodies at birth. These results show that anti-PS IgG acquired by mothers could be transferred transplacentally and that IgM antibodies targeting PS are acquired during the first year of life. These results have increased the knowledge about autoimmune responses associated with infections in early life and is critical for a comprehensive understanding of malaria vaccine functionality in endemic areas.

Steroid-Refractory Paroxysmal Cold Hemoglobinuria in a 6-Year-Old Male

Background Paroxysmal Cold Hemoglobinuria (PCH) is a rare autoimmune hemolytic anemia (AIHA) that is often seen as a sequela of viral upper respiratory tract infections and immunizations in children. It is characterized by a positive Coombs test with a biphasic auto anti-P IgG known as the “Donath-Landsteiner antibody,” which sensitizes red cells and fixes complement at 0-4°C, and hemolyzes red cells near body temperature. The mainstay treatment of PCH includes cold avoidance, intravenous hydration, and supportive blood transfusions. Glucocorticoids may be used in the setting of significant hemolysis, with debated efficacy. We present a case of steroid-refractory PCH in a 6-year-old boy secondary to human rhinovirus/enterovirus. Methods Patient clinical data was abstracted from the electronic medical record. Blood bank testing was performed through the in-house blood bank. Donath-Landsteiner testing was performed at a reference laboratory. Findings A 6-year-old male with a history of mild upper respiratory tract infection 1 week prior presented to the emergency department with abdominal pain, dark urine, and jaundice. Initial laboratory evaluation uncovered anemia with hemoglobinuria, hyperbilirubinemia, elevated LDH, and decreased haptoglobin, raising concerns for acute hemolytic anemia (Table 1). Follow-up blood bank testing revealed a cold autoantibody. Viral PCR was positive for human rhinoenterovirus. Despite supportive therapy through intravenous fluids and warming, the patient's anemia worsened significantly (Hgb 5.1g/dL) and packed red blood cell (pRBC) transfusion was required. Methylprednisolone 0.8 mg/kg IV twice daily was initiated as empiric therapy for autoimmune hemolysis without significant improvement. Blood was sent for Donath-Landsteiner antibody testing at a reference laboratory and revealed a bi-phasic hemolysin consistent with paroxysmal cold hemoglobinuria. The patient required an additional pRBC transfusion and was discharged after 4 days inpatient. Conclusion Our case supports a growing body of evidence that finds steroid therapy inefficacious in the treatment of hemolysis in the setting of PCH.

Antibodies against Neisseria meningitidis serogroups A, C, W and Y in serum and saliva of Norwegian adolescents

IntroductionThe incidence of invasive meningococcal disease (IMD) among Norwegian 16–19-year-olds was 1–7/100,000 in the decade before the COVID-19 pandemic, with serogroup Y (MenY) dominance. In contrast to many other European countries, meningococcal vaccines are not part of the national immunisation program (NIP) in Norway. This cross-sectional study aimed to measure the degree of natural immunity against Neisseria meningitidis among adolescents in Norway to evaluate the need for introducing tetravalent meningococcal conjugate vaccine (MCV4) in the NIP. Materials and methodsSerum and saliva samples were collected from students in upper and lower secondary schools in Norway in 2018. Samples were analysed for meningococcal capsular polysaccharide (PS)-specific antibodies using a bead-based multiplex immunoassay. PS-specific antibody levels were linked to data on meningococcal carriage, vaccination status and risk factors for carriage (assessed with questionnaire) and analysed by linear regression of log transformed concentrations. A subset of samples from unvaccinated individuals was analysed for serum bactericidal antibodies (SBA). ResultsA total of 1344 participants, median age 16 years (range 12–24), were included in the study. Overall, 60.9% of the participants were female and 1137 (84.6%) were not vaccinated with MCV4. PS-specific antibody concentrations in serum and saliva were low among unvaccinated individuals for all serogroups and only 6.7–20.0% of the subpopulation with high PS-specific antibodies assessed with SBA had protective levels. Unvaccinated MenY carriers had higher levels of MenY anti-PS IgG in serum and IgA in saliva than those not carrying MenY. Use of Swedish snus was associated with lower anti-PS IgG levels in serum and waterpipe use with lower anti-PS IgG levels in saliva. ConclusionUnvaccinated adolescents in Norway have a low degree of natural immunity against the serogroups of N. meningitidis predominating among cases of IMD in this age group. Therefore, introduction of MCV4 for adolescents in the NIP is recommended.

Anti-phosphatidylserine antibody levels are low in multigravid pregnant women in a malaria-endemic area in Nigeria, and do not correlate with anti-VAR2CSA antibodies.

Anemia is a common malaria-associated complication in pregnant women in endemic regions. Phosphatidylserine (PS) is exposed to the immune system during the massive destruction of red blood cells (RBCs) that accompany malaria, and antibodies against PS have been linked to anemia through destruction of uninfected RBCs. We determined levels of anti-PS IgG antibodies in pregnant women in Ibadan, Nigeria and correlated them to parameters of importance in development of anemia and immunity. Anti-PS correlated inversely with Packed Cell Volume (PCV), indicating that the antibodies could contribute to anemia. There was no correlation with anti-VAR2CSA IgG, haptoglobin or parasitemia, indicating that the modulation of anti-PS response is multifactorial in nature. Anti-PS levels were lowest in multigravidae compared to both primigravidae and secundigravidae and correlated inversely with age. In conclusion, lower levels of anti-PS in multigravidae could be beneficial in avoiding anemia.

Neuroprotective effect of microglia against impairments of auditory steady-state response induced by anti-P IgG from SLE patients in na\xefve mice

ObjectiveAutoantibodies against ribosomal P proteins (anti-P antibodies) are strongly associated with the neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE). The present study was designed to assess whether anti-P antibodies can induce abnormal brain electrical activities in mice and investigate the potential cytopathological mechanism.MethodsAffinity-purified human anti-ribosomal P antibodies were injected intravenously into mice after blood–brain barrier (BBB) disruption. The auditory steady-state response (ASSR) was evaluated based on electroencephalography (EEG) signals in response to 40-Hz click-train stimuli, which were recorded from electrodes implanted in the skull of mice. Immunofluorescence staining was used to examine the morphology and density of neurons and glia in the hippocampus and cortex. The presence of apoptosis in the brain tissues was studied using the TUNEL assay. A PLX3397 diet was used to selectively eliminate microglia from the brains of mice.ResultsCirculating anti-P antibodies caused an enhancement of the ASSR and the activation of microglia through the disrupted BBB, while no obvious neural apoptosis was observed. In contrast, when microglia were depleted, anti-P antibodies induced a serious reduction in the ASSR and neural apoptosis.ConclusionOur study indicates that anti-P antibodies can directly induce the dysfunction of auditory-evoked potentials in the brain and that microglia are involved in the protection of neural activity after the invasion of anti-P antibodies, which could have important implications for NPSLE.

Quality, immunogenicity and stability of meningococcal serogroup ACWY-CRM197, DT and TT glycoconjugate vaccines

A physicochemical and immunological study of the stability of three different meningococcal (Men) ACWY conjugate vaccines was performed to evaluate any patterns of serogroup oligo- or polysaccharide-specific or carrier protein-specific stability that would affect immunogenicity. Critical quality and stability-indicating characteristics were measured, with the study supporting the suitability of both HPLC-SEC and HPAEC-PAD methods to detect changes following inappropriate vaccine storage. All three final products, ACWY-CRM197, -DT and -TT conjugate vaccines had expected quality indicator values and similar immunogenicity in a mouse model (anti-PS IgG and rSBA) when stored at +2–8°C. When stored at ≥+37°C, all conjugated carrier proteins and serogroup saccharides were affected. Direct correlations were observed between the depolymerization of the MenA saccharide as evidenced by a size-reduction in the MenA conjugates (CRM197, DT and TT) and their immunogenicity. MenA was the most labile serogroup, followed by MenC; then MenW and Y, which were similar. At high temperatures, the conjugated carrier proteins were prone to unfolding and/or aggregation. The anti-MenC IgG responses of the multivalent conjugate vaccines in mice were equivalent to those observed in monovalent MenC conjugate vaccines, and were independent of the carrier protein. For any newly developing MenACWY saccharide-protein conjugate vaccines, a key recommendation would be to consider the lyophilization of final product to prevent deleterious degradation that would affect immunogenicity.

The Effect of a BSA Conjugate of a Synthetic Hexasaccharide Related to the Fragment of Capsular Polysaccharide of Streptococcus pneumoniae Type 14 on the Activation of Innate and Adaptive Immune Responses.

We report the effect of a bovine serum albumin (BSA) conjugate of a synthetic hexasaccharide (HS) related to the fragment of the capsular polysaccharide (PS) of Streptococcus pneumoniae type 14 on the stimulation of innate immune system and the subsequent development of a PS-specific antibody response. Glycoconjugate (GC) in the presence (GC + AL) or absence of aluminum hydroxide was administered to mice twice. GC increased the number of TLR2-expressing cells and induced the maturation of dendritic cells (CD11c+, CD80+ and, MHCII+), which secreted IL-1β, IL-6, and TNFα into the culture medium. The level of IL-1β, IL-10, IFNγ, and TNFα in the blood increased within 24 h after the single GC administration to mice. On day 7, the numbers of splenic CD4+ and CD8+ T lymphocytes and B lymphocytes increased. After the second immunization, the levels of CD4+ and CD8+ T lymphocytes were lower than in the control, whereas the B cell, NK cell, and MHC class II-expressing cell numbers remained enhanced. However, of the presence of anti-PS, IgG antibodies were not detected. The addition of aluminum hydroxide to GC stimulated the production of GM-CSF, IL-1β, IL-5, IL-6, IL-10, IL-17, IFNγ, and TNFα. Anti-PS IgG1 antibody titers 7 days after the second immunization were high. During that period, normal levels of splenic CD4+ T lymphocytes were maintained, whereas reduced CD8+ T lymphocyte numbers and increased levels of B lymphocytes, NK cells, and MHC class II-expressing cell numbers were observed. Anti-PS IgG levels diminished until day 92. A booster immunization with GC + AL stimulated the production of anti-PS IgG memory antibodies, which were determined within 97 days. The elucidation of specific features of the effect of the synthetic HS conjugate on the stimulation of innate, cell-mediated immunity, and antibody response can favor the optimization of GC vaccine design.

Antibody-specific behavioral effects: Intracerebroventricular injection of antiphospholipid antibodies induces hyperactive behavior while anti-ribosomal-P antibodies induces depression and smell deficits in mice

This study compares the effects of human antiphospholipid (aPL) and anti-P-ribosomal (anti-P) IgG and control IgG on the brain. Intracerebroventricular (ICV) injected aPL mice (exAPS) displayed specific hyperactivity compared to anti-P-injected (exSLE) and control mice. In contrast ICV injected anti-P-injected mice specifically displayed depression-like behavior and olfactory impairment compared to the other 2 groups. Both anti-P and aPL injected mice were impaired in the passive avoidance test compared to controls. The distinct cognitive effects of the 2 pathogenic antibodies argue for a specific and differential direct action of these autoantibodies on the brain in clinical disease.

AB0652 Profiling of antiphospholipid antibodies – association with clinical symptoms in follow-up samples of APS patients

BackgroundPatients with antiphospholipid syndrome (APS) may develop during the course of disease several antiphospholipid antibodies (aPL). Such aPL antibody profiles are suggested to be associated with particular clinical symptoms.ObjectivesAssessment of...

ANTI-PHOSPHATIDYLSERINE ANTIBODIES IN ACUTE MYOCARDIAL INFARCTION

Acute Myocardial Infarction (AMI) is the combined result of environmental factors and personal predispositions. Many factors play a role in AMI in cluding anti-Phospholipid (aPL) antibodies, that may act in the induction of immunological response leading to the development of AMI. AntiPhosphatidylserine (PS) antibody is detected in var ious diseases like rheumatoid arthritis, systemic lupus erythematosus and anti-phospholipid antibody syndrome. The study of anti-PS antibody in AMI might shed light on etiologic mechanisms in the pat hogenesis of acute coronary syndromes. This study was conducted to evaluate whether prevalence of ant i-PS antibodies, in patients who had AMI and to analyze their relationship with traditional cardiov ascular risk factors. The prevalence of anti-PS IgG and IgM in a well characterized group of patients w ith AMI as a case group and in age and sex matched healthy subjects as control group. Sera fro m two groups were tested to evaluate the presence of IgG and IgM isotypes to anti-PS by ELISA method. The frequencies of positive test for anti-PS IgG were 26.70 and 8.90% among patients and controls re spectively with significant difference (p = 0.003). The anti-PS IgM frequencies were 12.20 and 1.10% in patients and the controls, with significant difference (p = 0.005). The findings of this study suggest that anti-PS antibodies seemed to play a ro le in AMI, independent risk factors for AMI, which may represent a link between autoimmunity and atherosclerosis in patients with AMI. Further studi es with bigger sample size including patients with AMI and healthy people are recommended to explore the exact role of anti-PS antibodies in AMI.

Anti-phosphatidylserine, anti-cardiolipin, anti-β2 glycoprotein I and anti-prothrombin antibodies in recurrent miscarriage at 8–12 gestational weeks

To investigate the association of antibodies to β2-glycoprotein I (anti-β2GPI), cardiolipin (ACA), phosphatidylserine (anti-PS) and prothrombin (anti-PT) with recurrent spontaneous miscarriage (RSM). Case-control study involving 277 RSM cases and 288 controls: autoantibody levels were measured by ELISA. Differences between cases and controls were analyzed by nonparametric Mann-Whitney test, and logistic regression was used in analyzing the association of autoantibodies with RSM. Anti-PS IgG, ACA IgM and IgG, and anti-PT IgM were significantly associated with RSM risk, and differential antibody association was noted according to BMI and primary and secondary RSM. Higher prevalence of elevated anti-PS IgG was seen in cases, with the strongest risk above the 99th percentile. For ACA IgM, 28 cases (10.1%) and 5 controls (1.7%) were positive, with increasing OR for increasing cut-off points, which was significant at antibody titers >99th percentile. For ACA IgG, 101 cases (36.5%) and 13 controls (4.5%) were positive, with graded increase in OR for increasing cut-off points, which was significant at titers >90th percentile (maximal at titers >99th percentile). For anti-PT, 23 cases (12.0%) and 9 controls (6.1%) were positive, with increased OR at titers >90th percentile. Regression analyses confirmed the independent association of anti-PS IgG, ACA IgM and IgG with RSM, and significant RSM risk was associated with high anti-PS IgG (P<0.001) and ACA IgM (P<0.001) titers, and a dose-dependent increase in RSM risk was seen with progressively increased ACA IgG titers. No significant association existed between anti-PT IgM and RSM. Elevated ACA IgM and IgG, and anti-PS IgG antibodies are positively associated with RSM.

Autoantibodies targeting phosphatidylserine, cardiolipin, β2-glycoprotein I, annexin V and prothrombin in patients with recurrent spontaneous miscarriage (148.18)

Abstract An association between human reproductive failure and the presence of anti-phospholipid autoantibodies (APA) was suggested; both traditional and nontraditional APAs were associated with increased risk of recurrent spontaneous miscarriage (RSM). We measured levels of antibodies to phosphatidylserine (anti-PS), cardiolipin (ACA), β2-glycoprotein-I (anti-β2GPI), annexin V (anti-Anx V) and prothrombin (anti-PT) in 277 women with idiopathic RSM, and 288 control women by ELISA. Anti-PS IgG, ACA IgM/IgG, anti-Anx V IgM/IgG, and anti-PT IgM positivity were significantly associated with higher RSM risk, after controlling for age, BMI, menarche, and gravida. RSM was independently associated with high levels of ACA IgM (OR, 6.5; 95% CI, 2.5-17.1) and IgG (OR, 12.1; 95% CI, 6.6-22.2), anti-PS IgG (OR, 13.3; 95% CI, 6.4-27.4), anti-AnxV IgM (OR, 31.1; 95% CI, 15.7-56.6) and IgG (OR, 23.3; 95% CI, 8.8-51.7), and anti-PT IgM (OR, 2.8; 95% CI, 1.3-5.9). Levels of autoantibodies were categorized into 5 strata (percentiles 1-75, 76-99, 91-95, 96-99, &amp;gt;99 among control patients) and analyzed in logistic regression models. The adjusted OR increased as the percentile value of ACA IgM/IgG ,anti-PS IgG and anti-Anx V IgM/IgG, and anti-PT IgM, increased. In conclusion, the presence of ACA IgM/IgG, anti-Anx IgM/IgG, anti-PS IgG, and anti-PT IgM antibodies are risk factors for RSM. The strongest association was seen for anti-Anx V IgM and IgG, followed by ACA IgG, and anti-PS IgG antibodies.

Outer Membrane Protein Complex of Meningococcus Enhances the Antipolysaccharide Antibody Response to Pneumococcal Polysaccharide–CRM197Conjugate Vaccine

Bacterial polysaccharides (PS) are T cell-independent antigens that do not induce immunologic memory and are poor immunogens in infants. Conjugate vaccines in which the PS is covalently linked to a carrier protein have enhanced immunogenicity that resembles that of T cell-dependent antigens. The Haemophilus influenzae type b (Hib) conjugate vaccine, which uses the outer membrane protein complex (OMPC) from meningococcus as a carrier protein, elicits protective levels of anti-capsular PS antibody (Ab) after a single dose, in contrast to other conjugate vaccines, which require multiple doses. We have previously shown that OMPC robustly engages Toll-like receptor 2 (TLR2) and enhances the early anti-Hib PS Ab titer associated with an increase in TLR2-mediated induction of cytokines. We now show that the addition of OMPC to the 7-valent pneumococcal PS-CRM₁₉₇ conjugate vaccine during immunization significantly increases the anti-PS IgG and IgM responses to most serotypes of pneumococcus contained in the vaccine. The addition of OMPC also increased the likelihood of anti-PS IgG3 production against serotypes 4, 6B, 9V, 18C, 19F, and 23F. Splenocytes from mice who had received OMPC with the pneumococcal conjugate vaccine produced significantly more interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ) than splenocytes from mice who received phosphate-buffered saline (PBS) plus the conjugate vaccine. We conclude that OMPC enhances the anti-PS Ab response to pneumococcal PS-CRM₁₉₇ conjugate vaccine, an effect associated with a distinct change in cytokine profile. It may be possible to reduce the number of conjugate vaccine doses required to achieve protective Ab levels by priming with adjuvants that are TLR2 ligands.

Anti-ribosomal P protein antibody induces Th1 responses by enhancing the production of IL-12 in activated monocytes

Autoantibodies to ribosomal P proteins (anti-P) are detected in 12–16% of patients with systemic lupus erythematosus (SLE), and have been found to be associated with some manifestations, including lupus psychosis, nephritis and hepatitis. We have recently disclosed that anti-P react with activated human peripheral blood monocytes, and enhance their production of tumor necrosis factor-α and interleukin (IL)-6. It is also possible that anti-P might regulate other monocyte functions, including the regulation of T helper (Th) responses. The current study was therefore undertaken to explore the effects of anti-P on the induction of Th1 responses. Peripheral blood mononuclear cells (PBMC) from healthy donors were cultured with affinity-purified anti-P or control IgG. Highly purified monocytes were cultured with interferon (IFN)-γ in the presence of anti-P or normal IgG. Anti-P significantly enhanced the production of IFN-γ by PBMC. Of note, anti-IL-12 monoclonal antibodies almost completely abrogated the anti-P-mediated upregulation of the IFN-γ production of PBMC. Accordingly, anti-P significantly enhanced the production of IL-12 by activated monocytes. These results indicate that anti-P induce Th1 responses by upregulating the production of IL-12 by activated monocytes. The data therefore suggest that anti-P play an important role in the pathogenesis of SLE through the promotion of Th1 responses.

Anti-ribosomal P protein antibody induces Th1 responses by enhancing the production of IL-12 in activated monocytes

Autoantibodies to ribosomal P proteins (anti-P) are detected in 12-16% of patients with systemic lupus erythematosus (SLE), and have been found to be associated with some manifestations, including lupus psychosis, nephritis and hepatitis. We have recently disclosed that anti-P react with activated human peripheral blood monocytes, and enhance their production of tumor necrosis factor-α and interleukin (IL)-6. It is also possible that anti-P might regulate other monocyte functions, including the regulation of T helper (Th) responses. The current study was therefore undertaken to explore the effects of anti-P on the induction of Th1 responses. Peripheral blood mononuclear cells (PBMC) from healthy donors were cultured with affinity-purified anti-P or control IgG. Highly purified monocytes were cultured with interferon (IFN)-γ in the presence of anti-P or normal IgG. Anti-P significantly enhanced the production of IFN-γ by PBMC. Of note, anti-IL-12 monoclonal antibodies almost completely abrogated the anti-P-mediated upregulation of the IFN-γ production of PBMC. Accordingly, anti-P significantly enhanced the production of IL-12 by activated monocytes. These results indicate that anti-P induce Th1 responses by upregulating the production of IL-12 by activated monocytes. The data therefore suggest that anti-P play an important role in the pathogenesis of SLE through the promotion of Th1 responses.

Mice lacking IgA exhibit defective IgG antibody responses to polysaccharide conjugate vaccine (84.14)

Abstract Streptococcus pneumoniae is a leading cause of global disease. While capsular polysaccharide conjugate vaccines have decreased disease burden; a portion of the population remains unresponsive to vaccination. In order to understand the mechanisms responsible vaccine non-responsiveness, studies have been performed using mice with a targeted gene deletion that causes lack of IgA but few alterations in expression of other Ig isotypes. Surprisingly, IgA-/- mice were found nonetheless to exhibit specific defects in both IgA and IgG antibody responses to the polysaccharide (PS) component of pneumococcal conjugate vaccine. Neither IgM anti-PS responses nor IgG antibody responses to the protein component of the conjugate vaccine were affected. Furthermore, IgA-/- mice expressed fewer peritoneal B1a cells. As B1a and marginal zone B cells are considered to be the primary cell types that respond to polysaccharide antigens, this might to some extent explain the decreased anti-PS serum antibody titers seen in IgA-/- mice. Studies using bone marrow chimeras showed that reconstitution of IgA-/- mice with IgA+/+ B cells failed to restore antibody responsiveness to the PS component of the conjugate vaccine. Taken together, these results indicate that a defect in IgA expression affects B cell homeostasis, which is partially influenced by the environment that is present during B cell activation. (Supported by NIH grants RO1 41715 and R21 83878).

The role of antiphospholipid antibodies toward the protein C/protein S system in venous thromboembolic disease

The association between venous thromboembolism (VTE) and antibodies anti-Protein C (PC)/Protein S (PS) is still uncertain. We performed a case-control study to determine the risk of VTE related to the presence of these auto-antibodies considered independently of the presence of lupus anticoagulant (LAC) or anti-cardiolipin antibodies (ACA). One hundred thirty-five patients with idiopathic VTE and 164 healthy subjects were enrolled. Anti-PC and anti-PS antibodies (both IgG and IgM) were assessed using commercially available ELISA kits. Among cases there was a higher prevalence of elevated anti-PC IgM antibodies than in controls (OR 2.44, 95%CI 1.00-5.94). The presence of anti-PC IgG and anti-PS IgG and IgM antibodies was also higher in cases than in controls, but the difference was not statistically significant. Only five patients had both anti-PC or anti-PS antibodies and LAC or ACA. We performed a stepwise multivariate logistic regression analysis showing that anti-PC IgM>958 percentile was a significant predictor of VTE after adjustment for LAC or ACA (OR 2.52, 95%CI 1.01-6.24)). Larger prospective studies are needed to confirm this finding.

Antiribosomal-P protein antibodies in a patient with systemic lupus erythematosus and non-Hodgkin’s lymphoma: more than coincidental finding?

Patients with systemic lupus erythematosus (SLE) are at an increased risk of lymphomas, but mechanisms underlying this association are obscure. Recently, it has been shown that antiribosomal-P protein (anti-P) antibodies cross-react with phospholipids and enhance the production of cytokines which may influence lymphomagenesis. We report a 46-year-old woman who suffered high grade diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) 28 months after the diagnosis of SLE. Development of lymphoma was associated with occurrence of serum monoclonal IgM, and pronounced prolongation of phospholipid-dependent clotting tests. Anti-P IgG antibodies were highly positive both on HEp-2 cells and in ELISA test. Anticardiolipin, anti-beta2 glycoprotein I, and antiprothrombin IgM antibodies have also been found in high concentrations. Complete remission of DLBCL and SLE, with normalisation of clotting tests, and disappearance of M component was achieved with administration of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. The progression of SLE to DLBCL associated with presence of anti-P antibodies has not been previously reported. This association may not be coincidental, but further investigations are required to confirm this hypothesis.

A Clinical Electrophysiological Study of Emotional Lability in Patients With Systemic Lupus Erythematosus

A Clinical Electrophysiological Study of Emotional Lability in Patients With Systemic Lupus Erythematosus