lipid-a and Autoimmune-Diseases

The process of natural selection favours germ-line gene segments that encode CDRs that have the ability to recognize a range of structurally related antigens. This presents an immunological advantage to the host, as it can confer protection against a common pathogen and still cope with new or changing antigens. Cross-reactive and polyspecific antibodies also play a central role in autoimmune responses, and a link has been shown to exist between auto-reactive B cells and certain bacterial infections. Bacterial DNA, lipids, and carbohydrates have been implicated in the progression of autoimmune diseases such as systemic lupus erythematosus. As well, reports of anti-lipid A antibody polyspecificity towards single-stranded DNA together with the observed sequence homology amongst isolated auto- and anti-lipid A antibodies has prompted further study of this phenomenon. Though the lipid A epitope appears cryptic during Gram-negative bacterial infection, there have been several reported instances of lipid A-specific antibodies isolated from human sera, some of which have exhibited polyspecificity for single stranded DNA. In such cases, the breakdown of negative selection through polyspecificity can have the unfortunate consequence of autoimmune disease. This review summarizes current knowledge regarding such antibodies and emphasizes the features of S1-15, A6, and S55-5, anti-lipid A antibodies whose structures were recently determined by X-ray crystallography.

Topics: Animals; Antibody Specificity; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Bacterial Infections; DNA, Single-Stranded; Humans; Lipid A; Models, Molecular; Protein Conformation; Structure-Activity Relationship

Novel adjuvants that contain immunoenhancer molecules are now present in human vaccines either registered or in clinical trials. These adjuvants have the potential to provide clear benefits in improving the magnitude and duration of various aspects of the adaptive immune response. However, the use of immunoenhancers in vaccine formulations may be perceived as introducing theoretical safety risks that need to be addressed during the course of vaccine development. In addition to classical clinical safety evaluation, the licensing authorities recommend that novel adjuvants should be evaluated in non-clinical toxicology studies, both as separate entities and as part of the final vaccine formulation. We present here our approach for the safety evaluation of adjuvanted vaccines using AS04-adjuvanted vaccines as example. This evaluation consists of three tiers: non-clinical toxicology, adjuvant mode-of-action investigations and clinical safety assessment in controlled clinical trials and post-marketing surveillance. We also discuss how the knowledge of adjuvant mode of action can support the current practice of safety evaluation.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aged; Aged, 80 and over; Aluminum Hydroxide; Animals; Autoimmune Diseases; Child; Clinical Trials as Topic; Female; Humans; Lipid A; Male; Mice; Middle Aged; Rabbits; Viral Vaccines; Young Adult

Newly licensed vaccines against human papillomavirus (HPV) and hepatitis B (HBV), and several vaccines in development, including a vaccine against genital herpes simplex virus (HSV), contain a novel Adjuvant System, AS04, composed of 3-O-desacyl-4' monophosphoryl lipid A and aluminium salts. Given the background incidence of autoimmune disorders in some of the groups targeted for immunisation with these vaccines, it is likely that autoimmune events will be reported in temporal association with vaccination, even in the absence of a causal relationship. The objective of this integrated analysis was to assess safety of AS04 adjuvanted vaccines with regard to adverse events (AEs) of potential autoimmune aetiology, particularly in adolescents and young adults. All randomised, controlled trials of HPV-16/18, HSV and HBV vaccines were analysed in an integrated analysis of individual data (N = 68,512). A separate analysis of the HPV-16/18 vaccine trials alone was also undertaken (N = 39,160). All data were collected prospectively during the vaccine development programmes (mean follow-up of 21.4 months), and included in the analysis up to a pre-defined data lock point. Reporting rates of overall autoimmune events were around 0.5% and did not differ between the AS04 and control groups. The relative risk (AS04/control) of experiencing any autoimmune event was 0.98 (95% confidence intervals 0.80, 1.21) in the integrated analysis and 0.92 (0.70, 1.22) in the HPV-16/18 vaccine analysis. Relative risks calculated overall, for disease category or for individual events were close to 1, and all confidence intervals around the relative risk included 1, indicating no statistically significant difference in event rates between the AS04 and control groups. This integrated analysis of over 68,000 participants who received AS04 adjuvanted vaccines or controls demonstrated a low rate of autoimmune disorders, without evidence of an increase in relative risk associated with AS04 adjuvanted vaccines.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aged; Aged, 80 and over; Autoimmune Diseases; Databases, Factual; Female; Humans; Lipid A; Male; Middle Aged; Risk Factors; Viral Vaccines; Young Adult

This community-randomized controlled trial was initiated to assess the overall and herd effects of 2 different human papillomavirus (HPV) immunization strategies in over 80,000 girls and boys aged 12-15 y in 33 communities in Finland (ClinicalTrials.gov NCT00534638). Overall, 14,838 adolescents received HPV-16/18 vaccine (2,440 boys and 12,398 girls) and 17,338 received hepatitis-B virus (HBV) vaccine (9,221 boys and 8,117 girls). In an interim analysis, vaccine safety was assessed by active monitoring and surveillance via health registry linkage. Active monitoring showed that the HPV-16/18 vaccine has acceptable safety and reactogenicity in boys. In all study participants, the observed incidences (per 100,000 person-years) of serious adverse events (SAEs) possibly related to vaccination were 54.3 (95% Confidence Interval [CI]: 34.0-82.1) in the HPV-16/18 group and 64.0 (95% CI: 43.2-91.3) in the HBV group. During the follow-up period for this interim analysis, the most common new-onset autoimmune diseases (NOADs; with incidence rate ≥15 per 100,000) in any group based on hospital discharge registry (HILMO) download were ulcerative colitis, juvenile arthritis, celiac disease, insulin-dependent diabetes mellitus (IDDM) and Crohn's disease. No increased NOAD incidences were observed in HPV-16/18 vaccine recipients compared to HBV vaccine recipients. In both the SAE possibly related- and HILMO-analyses, a lower incidence of IDDM was observed in HPV-16/18 vaccinees compared to HBV vaccinees (relative risks, 0.26 [95% CI: 0.03-1.24] and 0.16 [95% CI: 0.03-0.55], respectively).

Topics: Adolescent; Aluminum Hydroxide; Autoimmune Diseases; Child; Drug-Related Side Effects and Adverse Reactions; Female; Finland; Hepatitis B Vaccines; Humans; Lipid A; Male; Papillomavirus Infections; Papillomavirus Vaccines

To assess the risk of autoimmune disease (AD) in 9-25 year-old women within 1 year after the first AS04-HPV-16/18vaccine dose, a retrospective, observational database cohort study was conducted using CPRD GOLD. From CPRD GOLD 4 cohorts (65,000 subjects each) were retrieved: 1 exposed female cohort (received ≥1 AS04-HPV-16/18 vaccine dose between Sep2008-Aug2010) and 3 unexposed cohorts: historical female (Sep2005-Aug2007), concurrent male, and historical male. Co-primary endpoints were confirmed neuroinflammatory/ophthalmic AD and other AD, secondary endpoints were confirmed individual AD. Risk of new onset of AD was compared between cohorts (reference: historical cohort) using Poisson regression. The main analysis using confirmed cases showed no neuroinflammatory/ophthalmic AD cases in the female exposed cohort. Incidence rate ratio (IRR) (95% CI) of other AD was 1.41 (0.86 to 2.31) in female and 1.77 (0.94 to 3.35) in male cohorts when compared to the female and male historical cohort, respectively. Secondary endpoints were evaluated for diseases with >10 cases, which were Crohn's disease (IRR: 1.21 [0.37 to 3.95] for female and 4.22 [0.47 to 38.02] for male cohorts), autoimmune thyroiditis (IRR: 3.75 [1.25 to 11.31] for female and no confirmed cases for male cohorts) and type 1 diabetes (IRR: 0.30 [0.11 to 0.83] for female and 2.46 [1.08 to 5.60] for male cohorts). Analysis using confirmed and non-confirmed cases showed similar results, except for autoimmune thyroiditis in females, IRR: 1.45 (0.79 to 2.64). There was no evidence of an increased risk of AD in women aged 9 to 25 years after AS04-HPV-16/18 vaccination.

Topics: Adolescent; Adult; Aluminum Hydroxide; Autoimmune Diseases; Child; Female; Humans; Lipid A; Papillomavirus Vaccines; Retrospective Studies; Risk Assessment; United Kingdom; Young Adult

Septic shock is a leading cause of death, and it results from an inflammatory cascade triggered by the presence of microbial products in the blood. Certain LPS from Gram-negative bacteria are very potent inducers and are responsible for a high percentage of septic shock cases. Despite decades of research, mAbs specific for lipid A (the endotoxic principle of LPS) have not been successfully developed into a clinical treatment for sepsis. To understand the molecular basis for the observed inability to translate in vitro specificity for lipid A into clinical potential, the structures of antigen-binding fragments of mAbs S1-15 and A6 have been determined both in complex with lipid A carbohydrate backbone and in the unliganded form. The two antibodies have separate germ line origins that generate two markedly different combining-site pockets that are complementary both in shape and charge to the antigen. mAb A6 binds lipid A through both variable light and heavy chain residues, whereas S1-15 utilizes exclusively the variable heavy chain. Both antibodies bind lipid A such that the GlcN-O6 attachment point for the core oligosaccharide is buried in the combining site, which explains the lack of LPS recognition. Longstanding reports of polyspecificity of anti-lipid A antibodies toward single-stranded DNA combined with observed homology of S1-15 and A6 and the reports of several single-stranded DNA-specific mAbs prompted the determination of the structure of S1-15 in complex with single-stranded DNA fragments, which may provide clues about the genesis of autoimmune diseases such as systemic lupus erythematosus, thyroiditis, and rheumatic autoimmune diseases.

Topics: Amino Acid Sequence; Animals; Antibodies, Monoclonal; Antibody Specificity; Ascites; Autoimmune Diseases; Binding Sites, Antibody; DNA, Single-Stranded; Glycoconjugates; Immunoglobulin Fab Fragments; Lipid A; Mice; Models, Molecular; Molecular Sequence Data; Protein Binding; Sequence Alignment; Sequence Homology, Amino Acid; Static Electricity

In last centuries, vaccines reduced the incidence of several infectious diseases. In last decades, some vaccines aimed at preventing also some cancers, where viruses play a causative role. However, several adverse events have been described after vaccines, but a causal relationship has been established only in a minority of cases. Here, we describe a pseudo-neurological syndrome occurred shortly after the administration of the bivalent HPV vaccine. Some autoimmune disorders, including neurological demyelinating diseases, have been reported after HPV vaccines, but the patient showed no organic lesions. The patient was diagnosed as having a functional somatoform syndrome, which was supposed to be autoimmune/inflammatory syndrome induced by adjuvants (ASIA), seen the temporal link with vaccination and the presence of anti-phospholipid autoantibodies. Immunological mechanisms of vaccines-and of adjuvants-have not been completely elucidated yet, and although there is no evidence of statistical association with many post-vaccination events, a causal link with vaccine cannot be excluded in some individuals.

Topics: Aluminum Hydroxide; Autoimmune Diseases; Female; Humans; Inflammation; Lipid A; Papillomavirus Vaccines; Somatoform Disorders; Syndrome

Both Helicobacter pylori and Campylobacter jejuni are highly prevalent Gram-negative microaerophilic bacteria which are gastrointestinal pathogens of humans; H. pylori colonizes the gastroduodenal compartment and C. jejuni the intestinal mucosa. Although H. pylori causes chronic gastric infection leading to gastritis, peptic ulcers and eventually gastric cancer while C. jejuni causes acute infection inducing diarrhoeal disease, the endotoxin molecules of both bacterial species contrastingly contribute to their pathogenesis and the autoimmune sequelae each induces. Compared with enterobacterial endotoxin, that of H. pylori has significantly lower endotoxic and immuno-activities, the molecular basis for which is the underphosphorylation and underacylation of the lipid A component that interacts with immune receptors. This induction of low immunological responsiveness by endotoxin may aid the prolongation of H. pylori infection and therefore infection chronicity. On the other hand, this contrasts with acute infection-causing C. jejuni where overt inflammation contributes to pathology and diarrhoea production, and whose endotoxin is immunologically and endotoxically active. Futhermore, both H. pylori and C. jejuni exhibit molecular mimicry in the saccharide components of their endotoxins which can induce autoreactive antibodies; H. pylori expresses mimicry of Lewis and some ABO blood group antigens, C. jejuni mimicry of gangliosides. The former has been implicated in influencing the development of inflammation and gastric atrophy (a precursor of gastic cancer), the latter is central to the development of the neurological disorder Guillain-Barré syndrome. Both diseases raise important questions concerning infection-induced autoimmunity awaiting to be addressed.

Topics: Animals; Autoimmune Diseases; Campylobacter Infections; Campylobacter jejuni; Carbohydrate Conformation; Carbohydrate Sequence; Endotoxins; Gangliosides; Guillain-Barre Syndrome; Helicobacter Infections; Helicobacter pylori; Humans; Lewis Blood Group Antigens; Lipid A; Molecular Mimicry; Molecular Sequence Data; Molecular Structure

Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Autoimmune Diseases; Humans; Lipid A; Vaccines

Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Autoimmune Diseases; Humans; Lipid A; Vaccines

Topics: Amino Acid Sequence; Anemia, Hemolytic, Autoimmune; Antibodies, Anti-Idiotypic; Antibodies, Antinuclear; Antibodies, Monoclonal; Antibody Specificity; Antigens, Bacterial; Autoantigens; Autoimmune Diseases; Bacterial Infections; Cross Reactions; DNA; Erythrocytes; Genes, Immunoglobulin; Hemagglutinins; Humans; I Blood-Group System; Immunoglobulin Heavy Chains; Immunoglobulin M; Immunoglobulin Variable Region; Lipid A; Lupus Erythematosus, Systemic; Molecular Mimicry; Molecular Sequence Data; Sequence Alignment; Sequence Homology, Amino Acid