Vacunas y autoinmunidad: Dedicado al Dr. Agustín Páez M.
Este Nota está dedicada a la Grata memoria del Dr. Carlos Agustín Páez M. (Tin) incansable luchador contra la corrupción de algunas áreas de nuestra sociedad, por la seguridad social y la medicina basada en la evidencia.
Fotografía tomada personalmente el día en que los personeros del Ministerio de Salud, no quisieron asistir al foro sobre vacunación, realizado en la Ciudad Científica de nuestra Universidad de Costa Rica.
¿Debo Vacunarme?
La Creación de este Blogs fue motivada por el inicio o reactivación de enfermedades inmunológicas en pacientes, luego de aplicarse alguna vacuna y la aparición de una nueva modalidad de polineuropatía axonal en personas con antecedentes personales o familiares de enfermedades autoinmunes. Se planteó la teoría de que la población con antecedentes de trastornos inmunológicos del tipo “hiperfunción” son más susceptibles a desarrollar enfermedades autoinmunes, la idea no es original, ya que este tema lo discutimos en mi época de estudiante con médicos de formación científica sólida.
Desgraciadamente este tipo de investigación no encuentra usualmente patrocinio económico y más bien es combatida por las multinacionales farmacéuticas. Sin embargo las personas que han leído el Blog se han enterado de que algunos pocos valientes han hecho publicaciones sobre el asunto y en este momento hay varios grupos de investigadores que publican en muy pocas revistas médicas, estudios realizados en animales e investigaciones en pacientes que han empeorado o iniciado una enfermedad autoinmune a raíz de una vacunación.
A continuación los resúmenes y citas bibliográficas que apoyan nuestras teorías.
Vaccine model of antiphospholipid syndrome induced by tetanus vaccine
L Dimitrijevic´1, I Zˇ ivkovic´1, M Stojanovic´1, V Petrusˇic´1 and S Zˇ ivancˇevic´-Simonovic´2 1Institute of Virology, Vaccines and Sera – Torlak, Department of Research and Development, Belgrade, Serbia; and 2Medical Faculty, University of Kragujevac, Institute of Pathophysiology, Kragujevac, Serbia
Successful induction of antiphospholipid syndrome (APS) in two different non-autoimmune prone mouse strains, BALB/c and C57BL/6, was achieved by tetanus toxoid (TTd) hyperimmunization using different adjuvants (glycerol or aluminium hydroxide), and different adjuvant pretreatments (glycerol or Complete Freund’s Adjuvant (CFA)). APS had different manifestations of reproductive pathology in BALB/c and C57BL/6 mice: fetal resorption (as a consequence of extreme T-cell activation obtained in the course of pretreatment), and lowering of fecundity (as a consequence of polyclonal B-cell stimulation), respectively. In BALB/c mice fetal resorption coincided with glycerol and CFA pretreatments, while in C57BL/6 mice lowering of fecundity was most obvious in CFA-pretreated mice immunized with TTd in aluminium hydroxide. Both molecular mimicry and polyclonal B-cell activation occur in APS induction, with molecular mimicry effects being dominant in BALB/c mice, and polyclonal cell activation being dominant in C57BL/6 mice. Confirmation of molecular mimicry effects, which in the condition of T-cell stimulation generated fetal resorptions in the BALB/c strain, was achieved by passive infusion of monoclonal antibody (MoAb) T-26 specific for TTd and anti-b2-glycoprotein I obtained after TTd hyperimunization. High polyclonal B-cell activation in C57BL/6 mice prevented fetal resorption but induced fecundity lowering, as was the case in passive administration of MoAb T-26 in this mouse strain. Passive infusion of anti-idiotypic MoAb Y7 into C57BL/6 mice induced fetal resorptions and confirmed the above suggestion on the protective role of polyclonal B-cell stimulation in fetal resorptions. Lupus (2012) 21, 195–202.
Key words: anticardiolipin antibodies; antiphospholipid syndrome; pregnancy
Induction of the ‘ASIA’ syndrome in NZB/NZWF1 mice after injection of complete Freund’s adjuvant (CFA)
N Bassi1, R Luisetto2, D Del Prete3, A Ghirardello1, M Ceol3, S Rizzo4, L Iaccarino1, M Gatto1, ML Valente4, L Punzi1 and A Doria1 1Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Italy; 2Department of Experimental Surgery, University of Padova, Italy; 3Division of Nephrology, Department of Medical and Surgical Sciences, University of Padova, Italy; and 4Division of Pathology, University of Padova, Italy
Adjuvants, commonly used in vaccines, may be responsible for inducing autoimmunity and autoimmune diseases, both in humans and mice. The so-called ‘ASIA’ (Autoimmune/inflammatory Syndrome Induced by Adjuvants) syndrome has been recently described, which is caused by the exposure to a component reproducing the effect of adjuvants.
The aim of our study was to evaluate the effect of injection of complete Freund’s adjuvant (CFA) in NZB/ NZWF1 mice, a lupus-prone murine model. We injected 10 NZB/NZWF1 mice with CFA/ PBS and 10 with PBS, three times, 3 weeks apart, and followed-up until natural death. CFAinjected mice developed both anti-double-stranded DNA and proteinuria earlier and at higher levels than the control group. Proteinuria-free survival rate and survival rate were significantly lower in CFA-treated mice than in the control mice (p¼0.002 and p¼0.001, respectively). Histological analyses showed a more severe glomerulonephritis in CFA-injected mice compared with the control mice. In addition, lymphoid hyperplasia in spleen and lungs, myocarditis, and vasculitis were observed in the former, but not in the latter group. In conclusion, the injection of CFA in NZB/NZWF1 mice accelerated autoimmune manifestations resembling ‘ASIA’ syndrome in humans. Lupus (2012) 21, 203–209.
Autoimmune response following influenza vaccination in patients with autoimmune inflammatory rheumatic disease
K Perdan-Pirkmajer1, GG Thallinger2, N Snoj3, S Cˇ ucˇnik1, P Zˇ igon1, T Kveder1, D Logar1, S Praprotnik1, M Tomsˇicˇ1, S Sodin-Semrl1 and A Ambrozˇ icˇ1 1University Medical Centre Ljubljana, Department of Rheumatology, Ljubljana, Slovenia; 2Graz University of Technology, Institute for Genomics and Bioinformatics, Graz, Austria; and 3University Medical Centre Ljubljana, Institute of Clinical Chemistry and Biochemistry, Ljubljana, Slovenia
Vaccines have undoubtedly brought overwhelming benefits to mankind and are considered safe and effective. Nevertheless, they can occasionally stimulate autoantibody production or even a recently defined syndrome known as autoimmune/inflammatory syndrome induced by adjuvants (ASIA). There is scarce data regarding autoimmune response after seasonal/influenza A (H1N1) vaccine in patients with autoimmune inflammatory rheumatic disease (AIRD). The objective of our study was therefore to determine autoimmune response in a large group of AIRD patients vaccinated against seasonal and/or H1N1 influenza. We conducted a prospective cohort study with a 6-month follow-up. Two-hundred and eighteen patients with AIRD (50 vaccinated against seasonal influenza, six against H1N1, 104 against both, 58 non-vaccinated controls) and 41 apparently healthy controls (nine vaccinated against seasonal influenza, three against H1N1, 18 against both, 11 non-vaccinated controls) were included. Blood samples were taken and screened for autoantibodies [antinuclear antibody (ANA), antiextractable nuclear antigen (anti-ENA), anticardiolipin (aCL) IgG/IgM antibodies, anti-beta 2-glycoprotein I (anti-b2GPI)] at inclusion in the study, before each vaccination, 1 month after the last vaccination and 6 months after inclusion. For non-vaccinated participants (patients and healthy controls) blood samples were taken at the time of inclusion in the study and 6 months later. We report that after the administration of seasonal/H1N1 vaccine there were mostly transient changes in autoantibody production in AIRD patients and in healthy participants. However, a small subset of patients, especially ANA-positive patients, had a tendency towards anti-ENA development. Although no convincing differences between the seasonal and H1N1 vaccines were observed, our results imply that there might be a slight tendency of the H1N1 vaccine towards aCL induction. Although seasonal and H1N1 vaccines are safe and effective, they also have the potential to induce autoantibodies in selected AIRD patients and healthy adults. Follow-up of such individuals is proposed and further research is needed. Lupus (2012) 21, 175–183.
Oily adjuvants and autoimmunity: now time for reconsideration?
M Whitehouse School of Medicine, Griffith University, Gold Coast, Queensland, Australia and Therapeutics Research Centre, Princess Alexandra Hospital, Brisbane, Queensland, Australia
Immunologists have relied heavily on oil-based adjuvants to generate antibodies or induce auto-allergic responses in experimental animals. These are rarely used today for human vaccination because of their persistent irritancies and propensity to cause ulcers at sites of injection. However oily materials with adjuvant properties abound in our modern environment, both personal and extraneous.
Their inadvertent impact as cryptotoxins may contribute to the rising incidence of auto-allergic diseases in recent times. Experimentally, the potential adjuvanticity of various oils, fats and other lipids can be evaluated by their ability (or otherwise) to induce auto-allergic disease(s) in rats and mice with, or even without, the addition of a mycobacterial immunostimulant.
Genetic factors have been recognized that determine an animal’s susceptibility or resistance to these oil-induced immunopathies. So it may be profitable to further characterize these factors, first in animals and then perhaps in human populations, to help find ways to enhance natural resistance to those adjuvant-active oils that may be widely distributed in the personal environment, notably mineral oil(s). (The six tables in this article summarize some relevant facts and a few conjectures.) A caveat: This review is restricted to the adjuvant properties of some oils in the personal environment. It does not cover the mechanisms of adjuvanticity2. Lupus (2012) 21, 217–222.
Aluminum as an adjuvant in Crohn’s disease induction
A Lerner1,2 1Pediatric Gastroenterology and Nutrition Unit, Carmel Medical Center, Haifa, Israel; and 2B. Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
Alum (AlK(SO4)2) is an adjuvant commonly utilized in vaccines, and is a ubiquitous element used extensively in contemporary life. Food, air, water, waste, the earth’s surface, and pharmaceuticals all represent pathways of aluminum (Al) exposure. Crohn’s disease (CD) is a chronic relapsing intestinal inflammation in genetically susceptible individuals and is caused by yet unidentified environmental factors. Al is a potential factor for the induction of inflammation in CD, and its immune activities share many characteristics with the immune pathology of CD: many luminal bacterial or dietary compounds can be adsorbed to the metal surface and induce Th1 profile cytokines, shared cytokines/chemokines, co-stimulatory molecules, and intracellular pathways and stress-related molecular expression enhancement, affecting intestinal macrobiota, transmural granuloma formation, and colitis induction in an animal CD model. The inflammasome plays a central role in Al mode of action and in CD pathophysiology. It is suggested that Al adjuvant activity can fit between the aberrations of innate and adaptive immune responses occurring in CD. The CD mucosa is confronted with numerous inappropriate bacterial components adsorbed on the Al compound surface, constituting a pro-inflammatory supra-adjuvant. Al fits the diagnostic criteria of the newly described autoimmune/inflammatory syndrome induced by adjuvants. If a cause and effect relationship can be established, the consequences will greatly impact public health and CD prevention and management. Lupus (2012) 21, 231–238.
Gulf War Syndrome as a part of the autoimmune (autoinflammatory) syndrome induced by adjuvant (ASIA)
E Israeli The Zabludowicz Center for Autoimmune Diseases, Tel-Hashomer, Israel
Gulf War syndrome (GWS) is a multi-symptom condition comprising a variety of signs and symptoms described in the literature, which not been fully resolved.
The various symptoms of the condition include muscle fatigue and tiredness, malaise, myalgia, impaired cognition, ataxia, diarrhoea, bladder dysfunction, sweating disturbances, headaches, fever, arthralgia, skin rashes, and gastrointestinal and sleep disturbances. In addition, excessive chemical sensitivity and odour intolerance is reported. The aetiology of the condition is unclear, but many reviews and epidemiological analyses suggest association with pyridostigmine bromide (PB), certain vaccination regimes, a variety of possible chemical exposures, including smoke from oil-well fires or depleted uranium from shells, as well as physical and psychological stress. Recently, Shoenfeld et al. suggested that four conditions – siliconosis, macrophagic myofaciitis (MMF), GWS and post-vaccination phenomena – that share clinical and pathogenic resemblances, may be incorporated into common syndrome called ‘Autoimmune (Autoinflammatory) Syndrome induced by Adjuvants’ (ASIA). Symptoms and signs of the four conditions described by Shoenfeld et al. show that at least eight out of ten main symptoms are in correlation in all four conditions. Namely, myalgia, arthralgias, chronic fatigue, neurological cognitive impairment, gastrointestinal symptoms, respiratory symptoms, skin manifestations and appearance of autoantibodies. Regardless of the aetiology of GWS, be it exposure to environmental factors or chemical drugs, vaccinations or the adjuvants in them, GWS fits well with the definition of ASIA and is included as part of ‘Shoenfeld’s
syndrome’. Lupus (2012) 21, 190–194.
Macrophagic myofasciitis: characterization and pathophysiology
RK Gherardi1,2,3 and FJ Authier1,2,3 1AP-HP, Hoˆ pital H. Mondor, France; 2Universite´ Paris Est, Faculte´ de Me´decine, France; and 3Inserm, U955, France
Aluminium oxyhydroxide (alum), a nanocrystalline compound forming agglomerates, has been used in vaccines for its immunological adjuvant effect since 1927. Alum is the most commonly used adjuvant in human and veterinary vaccines, but the mechanisms by which it stimulates immune responses remain incompletely understood. Although generally well tolerated, alum may occasionally cause disabling health problems in presumably susceptible individuals. A small proportion of vaccinated people present with delayed onset of diffuse myalgia, chronic fatigue and cognitive dysfunction, and exhibit very long-term persistence of alum-loaded macrophages at the site of previous intramuscular (i.m.) immunization, forming a granulomatous lesion called macrophagic myofasciitis (MMF). Clinical symptoms associated with MMF are paradigmatic of the recently delineated ‘autoimmune/inflammatory syndrome induced by adjuvants’ (ASIA). The stereotyped cognitive dysfunction is reminiscent of cognitive deficits described in foundry workers exposed to inhaled Al particles. Alum safety concerns will largely depend on whether the compound remains localized at the site of injection or diffuses and accumulates in distant organs. Animal experiments indicate that biopersistent nanomaterials taken up by monocyte-lineage cells in tissues, such as fluorescent alum surrogates, can first translocate to draining lymph nodes, and thereafter circulate in blood within phagocytes and reach the spleen, and, eventually, slowly accumulate in the brain. Lupus (2012) 21, 184–189.
Influenza vaccination can induce new-onset anticardiolipins but not b2-glycoprotein-I antibodies among patients with systemic lupus erythematosus
ES Vista1,2, SR Crowe1, LF Thompson1, GM Air3, JM Robertson1, JM Guthridge1 and JA James1,3 1Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; 2University of Santo Tomas Hospital, Manilla, Philippines; and 3University of Oklahoma Health Science Center, Oklahoma City, OK USA
Background: Antiphospholipid syndrome is characterized by autoantibodies against cardiolipins (aCL), lupus anticoagulant, and independent b2-glycoprotein (b2GPI). Controversy exists as to whether vaccination triggers the development of antiphospholipid antibodies (aPL) in patients with systemic lupus erythematosus (SLE). Methods: Patients with SLE (101) and matched controls (101) were enrolled from 2005–2009 and received seasonal influenza vaccinations. Sera were tested by ELISA for aCL at baseline, 2, 6, and 12 weeks after vaccination. Vaccine responses were ranked according to an overall anti-influenza antibody response index. Individuals with positive aCL were further tested for b2GPI antibodies.
Results: Patients with SLE and healthy controls can develop new-onset aCL post vaccination, although at rates which do not differ between patients and controls (12/101 cases and 7/101 controls, OR 1.81, p¼0.34). New-onset moderate aCL are slightly enriched in African American SLE patients (5/36 cases; p¼0.094). The optical density measurements for aCL reactivity in patients were significantly higher than baseline at 2 weeks (p<0.05), 6 weeks (p<0.05), and 12 weeks (p<0.05) post vaccination. No new b2GPI antibodies were detected among patients with new aCL reactivity. Vaccine response was not different between patients with and without new-onset aCL reactivity (p¼0.43). Conclusions: This study shows transient increases in aCL, but not anti-b2GPI responses, after influenza vaccination. Lupus (2012) 21, 168–174.
Systemic lupus erythematosus following HPV immunization or infection?
HF Soldevilla, SFR Briones and SV Navarra
University of Santo Tomas, Manila, Philippines
Background and purpose: The link between autoimmunity and infectious agents has been strongly suggested by reports of lupus or lupus-like syndromes following immunization. This report describes three patients with either newly diagnosed systemic lupus erythematosus (SLE) or SLE flare, following vaccination for human papilloma virus (HPV). Case 1: A 17- year-old female completed two doses of HPV vaccine uneventfully. Two months later, she developed arthralgias with pruritic rashes on both lower extremities, later accompanied by
livedo reticularis, bipedal edema with proteinuria, anemia, leucopenia, hypocomplementemia and high titers of anti-nuclear antibody (ANA) and anti-double-stranded DNA (antidsDNA). Kidney biopsy showed International Society of Nephrology/Renal Pathology Society Class III lupus nephritis. She was started on high dose steroids followed by pulse cyclophosphamide therapy protocol for lupus nephritis, and subsequently went into remission. Case 2: A 45-year-old housewife, previously managed for 11 years as having rheumatoid arthritis, had been in clinical remission for a year when she received two doses of HPV immunization. Four months later, she developed fever accompanied by arthritis, malar rash, oral ulcers, recurrent ascites with intestinal pseudo-obstruction, and behavioral changes. Cranial MRI showed vasculitic lesions on the frontal and parietal lobes. Laboratory tests showed anemia with leucopenia, hypocomplementemia, proteinuria, ANA positive at 1:320, and antibodies against dsDNA, Ro/SSA, La/SSB and histone. She improved following pulse
methylprednisolone with subsequent oral prednisone combined with hydroxychloroquine. Case 3: A 58-year-old housewife diagnosed with SLE had been in clinical remission for 8 years when she received two doses of HPV immunization. Three months later, she was admitted to emergency because of a 1-week history of fever, malar rash, easy fatigability, cervical lymph nodes, gross hematuria and pallor. Laboratory exams showed severe anemia, thrombocytopenia, active urine sediments, and hypocomplementemia. Despite pulse steroid therapy, blood transfusions, intravenous immunoglobulin and aggressive resuscitative measures, she expired a day after hospital admission. Summary: These cases narrate instances of the onset or exacerbation of lupus following HPV immunization suggesting adjuvantinduced autoimmunity. On the other hand, there are reports of higher incidence of HPV infection in SLE, with the infection per se possibly contributing to disease activity. Thus, the benefit of HPV immunization may still outweigh the risk among these individuals. Lupus (2012) 21, 158–161.
Autoimmunity following Hepatitis B vaccine as part of the spectrum of ‘Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants’ (ASIA): analysis of 93 cases
Y Zafrir1*, N Agmon-Levin1*, Z Paz1, T Shilton1 and Y Shoenfeld1,2 1The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel; and 2Sackler Faculty of Medicine,Tel Aviv University, Tel Aviv, Israel
Objectives: In this study we analyzed the clinical and demographic manifestations among patients diagnosed with immune/autoimmune-mediated diseases post-hepatitis B vaccination. We aimed to find common denominators for all patients, regardless of different diagnosed diseases, as well as the correlation to the criteria of Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants (ASIA).
Patients and methods: We have retrospectively analyzed the medical records of 114 patients, from different centers in the USA, diagnosed with immune-mediated diseases following immunization with hepatitis-B vaccine (HBVv). All patients in this cohort sought legal consultation. Of these, 93/114 patients diagnosed with disease before applying for legal consultation were included in the study. All medical records were evaluated for demographics, medical history, number of vaccine doses, peri-immunization adverse events and clinical manifestations of diseases. In addition, available blood tests, imaging results, treatments and outcomes were recorded. Signs and symptoms of the different immune-mediated diseases were grouped according to the organ or system involved. ASIA criteria were applied to all patients.
Results: The mean age of 93 patients was 26.5!15 years; 69.2% were female and 21% were considered autoimmune susceptible. The mean latency period from the last dose of HBVv and onset of symptoms was 43.2 days. Of note, 47% of patients continued with the immunization program despite experiencing adverse events. Manifestations that were commonly reported included neuro-psychiatric (70%), fatigue (42%) mucocutaneous (30%), musculoskeletal (59%) and gastrointestinal (50%) complaints. Elevated titers of autoantibodies were documented in 80% of sera tested. In this cohort 80/93 patients (86%), comprising 57/59 (96%) adults and 23/34 (68%) children, fulfilled the required criteria for ASIA.
Conclusions: Common clinical characteristics were observed among 93 patients diagnosed with immune-mediated conditions post-HBVv, suggesting a common denominator in these diseases. In addition, risk factors such as history of autoimmune diseases and the appearance of adverse event(s) during immunization may serve to predict the risk of post-immunization diseases. The ASIA criteria were found to be very useful among adults with post-vaccination events. The application of the ASIA criteria to pediatric populations requires further study. Lupus (2012) 21, 146–152.
