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VACCINES AND AUTOIMMUNE DISORDERS & Immune Amplification Dangers of Vaccinations and Juvenile IDDM Insulin Dependent Diabetes Mellitus Dr Bill Deagle MD June 2007 ABSTRACT QUOTES There are uncertainties as to whether a susceptible subpopulation may be at a higher risk of developing an autoimmune disease without causing an overall increase in the disease incidence. Based on selected examples, this review highlights the difficulties in assessing this issue. We suggest that a potential link between vaccines and autoimmune diseases cannot be definitely ruled out and should be carefully explored during the development of new candidate vaccines.(1) We suggest that a potential link between vaccines and autoimmune diseases cannot be definitely ruled out and should be carefully explored during the development of new candidate vaccines.(19) In healthy puppies immunized with a variety of commonly given vaccines, a variety of autoantibodies have been documented but no frank autoimmune illness was recorded. The findings could also represent a polyclonal activation (adjuvant reaction). The mechanism (or mechanisms) of autoimmune reactions following immunization has not yet been elucidated. One of the possibilities is molecular mimicry; when a structural similarity exists between some viral antigen (or other component of the vaccine) and a self-antigen. This similarity may be the trigger to the autoimmune reaction. Other possible mechanisms are discussed. Even though the data regarding the relation between vaccination and autoimmune disease is conflicting, it seems that some autoimmune phenomena are clearly related to immunization (e.g. Guillain-Barre syndrome).The issue of the risk of vaccination remains a philosophical one, since to date the advantages of this policy have not been refuted, while the risk for autoimmune disease has not been irrevocably proved. We discuss the pros and cons of this issue (although the temporal relationship (i.e. always 2-3 months following immunization) is impressive).(2) In order for vaccinations to 'work', the immune system must be stimulated. The concern that immunizations may lead to the development of autoimmune disease (AID) has been questioned. Since AID occur in the absence of immunizations, it is unlikely that immunizations are a major cause of AID. Epidemiological studies are needed, however, to assess whether immunizations may increase the risk in some susceptible individuals. This paper discusses the evidence for and against vaccination as a risk factor for AID. Evidence for immunizations leading to AID come from several sources including animal studies, single and multiple case reports, and ecologic association. However more rigorous investigation has failed to confirm most of the allegations. Unfortunately the question remains difficult to address because for most AIDs, there is limited knowledge of the etiology, background incidence and other risk factors for their development. This information is necessary, in the absence of experimental evidence derived from controlled studies, for any sort of adequate causality assessment using the limited data that are available. Several illustrative examples are discussed to highlight what is known and what remains to be explored, and the type of epidemiological evidence that would be required to better address the issues. Examples include the possible association of immunization and multiple sclerosis (and other demyelinating diseases), type 1 diabetes mellitus, Guillain-Barre Syndrome, idiopathic thrombocytopenic purpura, and rheumatoid arthritis.(4) The possibility cannot be ruled out that, in genetically susceptible individuals, vaccination can result in the unmasking of an autoimmune disease triggered by the immunization. We also critically examine the existing data suggesting a link between immunization against MMR and autism, and briefly discuss the controversial evidence pointing to a possible relationship between mercury exposure from vaccines and autistic disorders.(5) Passive surveillance systems (e.g., VAERS) are subject to multiple limitations, including underreporting, reporting of temporal associations or unconfirmed diagnoses, and lack of denominator data and unbiased comparison groups. Because of these limitations, determining causal associations between vaccines and adverse events from VAERS reports is usually not possible. Vaccine safety concerns identified through adverse event monitoring nearly always require confirmation using an epidemiologic or other (e.g., laboratory) study.(6) VAERS data have recognized limitations such as underreporting (that may differ by vaccine) and are nearly always insufficient to prove causality between a vaccine and an adverse event.(7) The association between infection and autoimmune disease has, however, stimulated a debate as to whether such diseases might also be triggered by vaccines. Indeed there are numerous claims and counter claims relating to such a risk. Here we review the mechanisms involved in the induction of autoimmunity and assess the implications for vaccination in human beings.(8) Vaccines, in several reports were found to be temporally followed by a new onset of autoimmune diseases. The same mechanisms that act in infectious invasion of the host, apply equally to the host response to vaccination. It has been accepted for diphtheria and tetanus toxoid, polio and measles vaccines and GBS. Also this theory has been accepted for MMR vaccination and development of autoimmune thrombocytopenia, MS has been associated with HBV vaccination.(9) The question of a connection between vaccination and autoimmune illness (or phenomena) is surrounded by controversy. A heated debate is going on regarding the causality between vaccines, such as measles and anti-hepatitis B virus (HBV), and multiple sclerosis (MS). Brain antibodies as well as clinical symptoms have been found in patients vaccinated against those diseases. Other autoimmune illnesses have been associated with vaccinations. Tetanus toxoid, influenza vaccines, polio vaccine, and others, have been related to phenomena ranging from autoantibodies production to full-blown illness (such as rheumatoid arthritis (RA)). Conflicting data exists regarding also the connection between autism and vaccination with measles vaccine. So far only one controlled study of an experimental animal model has been published, in which the possible causal relation between vaccines and autoimmune findings has been examined: in healthy puppies immunized with a variety of commonly given vaccines, a variety of autoantibodies have been documented but no frank autoimmune illness was recorded. The findings could also represent a polyclonal activation (adjuvant reaction). The mechanism (or mechanisms) of autoimmune reactions following immunization has not yet been elucidated. One of the possibilities is molecular mimicry; when a structural similarity exists between some viral antigen (or other component of the vaccine) and a self-antigen. This similarity may be the trigger to the autoimmune reaction. Other possible mechanisms are discussed. Even though the data regarding the relation between vaccination and autoimmune disease is conflicting, it seems that some autoimmune phenomena are clearly related to immunization (e.g. Guillain-Barre syndrome).The issue of the risk of vaccination remains a philosophical one, since to date the advantages of this policy have not been refuted, while the risk for autoimmune disease has not been irrevocably proved. We discuss the pros and cons of this issue (although the temporal relationship (i.e. always 2-3 months following immunization) is impressive).(10) Macrophages and/or dendritic cells are the first cell types to infiltrate the pancreatic islets. Macrophages play an essential role in the development and activation of beta cell-cytotoxic T cells. B lymphocytes play a role as antigen-presenting cells, and T cells have been shown to play a critical role as final effectors that kill beta cells. Cytokines secreted by immunocytes, including macrophages and T cells, may regulate the direction of the immune response toward Th1 or Th2 as well as cytotoxic effector cell or suppressor cell dominance. Beta cells are destroyed by apoptosis through Fas-Fas ligand and TNF-TNF receptor interactions and by granzymes and perforin released from cytotoxic effector T cells. Therefore, the activated macrophages and T cells, and cytokines secreted from these immunocytes, act synergistically to destroy beta cells, resulting in the development of autoimmune IDDM.(12) Macrophages, CD4+ T cells, and CD8+ T cells synergistically destroy beta cells, resulting in the onset of autoimmune IDDM.(13) Macrophages are primary contributors to the creation of the immune environment conducive to the development and activation of beta cell-specific Th1-type CD4+ T cells and CD8+ cytotoxic T cells that cause autoimmune diabetes in NOD mice. CD4+ and CD8+ T cells are both believed to be important for the destruction of beta cells. These cells, as final effectors, can kill the insulin-producing beta cells by the induction of apoptosis. In addition, CD8+ cytotoxic T cells release granzyme and cytolysin (perforin), which are also toxic to beta cells. In this way, macrophages, CD4+ T cells and CD8+ T cells act synergistically to kill the beta cells in conjunction with beta cell autoantigens and MHC class I and class II antigens, resulting in the onset of autoimmune type I diabetes.(14) Results demonstrate the primary importance of MHC class I molecules in the pathogenesis of diabetes recurrence postislet transplantation.(17) Cytokine deletion studies have provided the best evidence for pathologic roles for proinflammatory cytokines (IL-1, TNF alpha, and IL-6) and type 1 cytokines (IFN gamma, IL-2 and IL-12) in IDDM development.(18) The possible association of immunization and multiple sclerosis (and other demyelinating diseases), type 1 diabetes mellitus, Guillain-Barre Syndrome, idiopathic thrombocytopenic purpura, and rheumatoid arthritis.(19) 1: Eur J Dermatol. 2004 Mar-Apr;14(2):86-90. Links Autoimmune diseases and vaccinations. Vial T, Descotes J. Centre Antipoison et Centre Régional de Pharmacovigilance, 162, avenue Lacassagne, 69424 Lyon, France. [email protected] The potential association between vaccination and autoimmune diseases has been largely questioned in the past few years, but this assumption has mostly been based on case reports. The available evidence derived from several negative epidemiological studies is reassuring and at least indicates that vaccines are not a major cause of autoimmune diseases. However, there are still uncertainties as to whether a susceptible subpopulation may be at a higher risk of developing an autoimmune disease without causing an overall increase in the disease incidence. Based on selected examples, this review highlights the difficulties in assessing this issue. We suggest that a potential link between vaccines and autoimmune diseases cannot be definitely ruled out and should be carefully explored during the development of new candidate vaccines. Copyright John Libbey Eurotext 2003. PMID: 15196997 [PubMed - indexed for MEDLINE] 2: J Autoimmun. 2000 Feb;14(1):1-10. Links Vaccination and autoimmunity-'vaccinosis': a dangerous liaison? Shoenfeld Y, Aron-Maor A. Department of Internal Medicine B, Sheba Medical Center, Tel Hashomer, Israel. [email protected] The question of a connection between vaccination and autoimmune illness (or phenomena) is surrounded by controversy. A heated debate is going on regarding the causality between vaccines, such as measles and anti-hepatitis B virus (HBV), and multiple sclerosis (MS). Brain antibodies as well as clinical symptoms have been found in patients vaccinated against those diseases. Other autoimmune illnesses have been associated with vaccinations. Tetanus toxoid, influenza vaccines, polio vaccine, and others, have been related to phenomena ranging from autoantibodies production to fullblown illness (such as rheumatoid arthritis (RA)). Conflicting data exists regarding also the connection between autism and vaccination with measles vaccine. So far only one controlled study of an experimental animal model has been published, in which the possible causal relation between vaccines and autoimmune findings has been examined: in healthy puppies immunized with a variety of commonly given vaccines, a variety of autoantibodies have been documented but no frank autoimmune illness was recorded. The findings could also represent a polyclonal activation (adjuvant reaction). The mechanism (or mechanisms) of autoimmune reactions following immunization has not yet been elucidated. One of the possibilities is molecular mimicry; when a structural similarity exists between some viral antigen (or other component of the vaccine) and a self-antigen. This similarity may be the trigger to the autoimmune reaction. Other possible mechanisms are discussed. Even though the data regarding the relation between vaccination and autoimmune disease is conflicting, it seems that some autoimmune phenomena are clearly related to immunization (e.g. Guillain-Barre syndrome).The issue of the risk of vaccination remains a philosophical one, since to date the advantages of this policy have not been refuted, while the risk for autoimmune disease has not been irrevocably proved. We discuss the pros and cons of this issue (although the temporal relationship (i.e. always 2-3 months following immunization) is impressive). Copyright 2000 Academic Press. PMID: 10648110 [PubMed - indexed for MEDLINE] 3: Eur J Dermatol. 2004 Mar-Apr;14(2):86-90. Links Autoimmune diseases and vaccinations. Vial T, Descotes J. Centre Antipoison et Centre Régional de Pharmacovigilance, 162, avenue Lacassagne, 69424 Lyon, France. [email protected] The potential association between vaccination and autoimmune diseases has been largely questioned in the past few years, but this assumption has mostly been based on case reports. The available evidence derived from several negative epidemiological studies is reassuring and at least indicates that vaccines are not a major cause of autoimmune diseases. However, there are still uncertainties as to whether a susceptible subpopulation may be at a higher risk of developing an autoimmune disease without causing an overall increase in the disease incidence. Based on selected examples, this review highlights the difficulties in assessing this issue. We suggest that a potential link between vaccines and autoimmune diseases cannot be definitely ruled out and should be carefully explored during the development of new candidate vaccines. Copyright John Libbey Eurotext 2003. PMID: 15196997 [PubMed - indexed for MEDLINE] 4: J Autoimmun. 2001 May;16(3):309-18. Links Epidemiology of autoimmune reactions induced by vaccination. Chen RT, Pless R, Destefano F. Vaccine Safety and Development Activity, National Immunization Program, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA. [email protected] In order for vaccinations to 'work', the immune system must be stimulated. The concern that immunizations may lead to the development of autoimmune disease (AID) has been questioned. Since AID occur in the absence of immunizations, it is unlikely that immunizations are a major cause of AID. Epidemiological studies are needed, however, to assess whether immunizations may increase the risk in some susceptible individuals. This paper discusses the evidence for and against vaccination as a risk factor for AID. Evidence for immunizations leading to AID come from several sources including animal studies, single and multiple case reports, and ecologic association. However more rigorous investigation has failed to confirm most of the allegations. Unfortunately the question remains difficult to address because for most AIDs, there is limited knowledge of the etiology, background incidence and other risk factors for their development. This information is necessary, in the absence of experimental evidence derived from controlled studies, for any sort of adequate causality assessment using the limited data that are available. Several illustrative examples are discussed to highlight what is known and what remains to be explored, and the type of epidemiological evidence that would be required to better address the issues. Examples include the possible association of immunization and multiple sclerosis (and other demyelinating diseases), type 1 diabetes mellitus, Guillain-Barre Syndrome, idiopathic thrombocytopenic purpura, and rheumatoid arthritis. Copyright 2001 Academic Press. PMID: 11334497 [PubMed - indexed for MEDLINE] 5: J Investig Allergol Clin Immunol. 2002;12(3):155-68. Links Vaccines, viruses, and voodoo. Borchers AT, Keen CL, Shoenfeld Y, Silva J, Gershwin ME. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA. Vaccinations are invaluable in protection from a wide variety of diseases that can cause substantial morbidity and mortality. Although a rare complication of vaccination, autoimmune disorders represent one of these morbidities. Recently, widespread public concern has arisen from case reports suggesting that--similar to what has been observed after natural viral infections--there might be an association between specific immunizations and autoimmune diseases. Herein we address the biological plausibility of such a connection, focusing particularly on the examples of hepatitis B, rubella, and measles-mumps-rubella (MMR) vaccinations, and the autoimmune diseases they are potentially associated with. Our review of the available data suggests that, for the general population, the risk: benefit ratio is overwhelmingly in favor of vaccinations. However, the possibility cannot be ruled out that, in genetically susceptible individuals, vaccination can result in the unmasking of an autoimmune disease triggered by the immunization. We also critically examine the existing data suggesting a link between immunization against MMR and autism, and briefly discuss the controversial evidence pointing to a possible relationship between mercury exposure from vaccines and autistic disorders. There is a continued urgent need for rigorously designed and executed studies addressing these potential associations, although the use of vaccinations remains a critical public health tool for protection against infectious disease. PMID: 12530114 [PubMed - indexed for MEDLINE] 6: MMWR Surveill Summ. 2003 Jan 24;52(1):1-24. Links Erratum in: MMWR Morb Mortal Wkly Rep. 2003 Feb 14;52(06):113. Surveillance for safety after immunization: Vaccine Adverse Event Reporting System (VAERS)--United States, 1991-2001. Zhou W, Pool V, Iskander JK, English-Bullard R, Ball R, Wise RP, Haber P, Pless RP, Mootrey G, Ellenberg SS, Braun MM, Chen RT. Epidemic Intelligence Service Program, Epidemiology Program Office, CDC, USA. PROBLEM/CONDITION: Vaccines are usually administered to healthy persons who have substantial expectations for the safety of the vaccines. Adverse events after vaccinations occur but are generally rare. Some adverse events are unlikely to be detected in prelicensure clinical trials because of their low frequency, the limited numbers of enrolled subjects, and other study limitations. Therefore, postmarketing monitoring of adverse events after vaccinations is essential. The cornerstone of monitoring safety is review and analysis of spontaneously reported adverse events. REPORTING PERIOD COVERED: This report summarizes the adverse events reported to the Vaccine Adverse Event Reporting System (VAERS) from January 1, 1991, through December 31, 2001. DESCRIPTION OF SYSTEMS: VAERS was established in 1990 under the joint administration of CDC and the Food and Drug Administration (FDA) to accept reports of suspected adverse events after administration of any vaccine licensed in the United States. VAERS is a passive surveillance system: reports of events are voluntarily submitted by those who experience them, their caregivers, or others. Passive surveillance systems (e.g., VAERS) are subject to multiple limitations, including underreporting, reporting of temporal associations or unconfirmed diagnoses, and lack of denominator data and unbiased comparison groups. Because of these limitations, determining causal associations between vaccines and adverse events from VAERS reports is usually not possible. Vaccine safety concerns identified through adverse event monitoring nearly always require confirmation using an epidemiologic or other (e.g., laboratory) study. Reports may be submitted by anyone suspecting that an adverse event might have been caused by vaccination and are usually submitted by mail or fax. A web-based electronic reporting system has recently become available. Information from the reports is entered into the VAERS database, and new reports are analyzed weekly. VAERS data stripped of personal identifiers can be reviewed by the public by accessing http://www.vaers.org. The objectives of VAERS are to 1) detect new, unusual, or rare vaccine adverse events; 2) monitor increases in known adverse events; 3) determine patient risk factors for particular types of adverse events; 4) identify vaccine lots with increased numbers or types of reported adverse events; and 5) assess the safety of newly licensed vaccines. RESULTS: During 1991-2001, VAERS received 128,717 reports, whereas >1.9 billion net doses of human vaccines were distributed. The overall dose-based reporting rate for the 27 frequently reported vaccine types was 11.4 reports per 100,000 net doses distributed. The proportions of reports in the age groups <1 year, 1-6 years, 7-17 years, 18-64 years, and >/= years were 18.1%, 26.7%, 8.0%, 32.6%, and 4.9%, respectively. In all of the adult age groups, a predominance among the number of women reporting was observed, but the difference in sex was minimal among children. Overall, the most commonly reported adverse event was fever, which appeared in 25.8% of all reports, followed by injection-site hypersensitivity (15.8%), rash (unspecified) (11.0%), injectionsite edema (10.8%), and vasodilatation (10.8%). A total of 14.2% of all reports described serious adverse events, which by regulatory definition include death, life-threatening illness, hospitalization or prolongation of hospitalization, or permanent disability. Examples of the uses of VAERS data for vaccine safety surveillance are included in this report. INTERPRETATION: As a national public health surveillance system, VAERS is a key component in ensuring the safety of vaccines. VAERS data are used by CDC, FDA, and other organizations to monitor and study vaccine safety. CDC and FDA use VAERS data to respond to public inquiries regarding vaccine safety, and both organizations have published and presented vaccine safety studies based on VAERS data. VAERS data are also used by the Advisory Committee on Immunization Practices and the Vaccine and Related Biological Products Advisory Committee to evaluate possible adverse events after vaccinations and to develop recommendations for precautions and contraindications to vaccinations. Reviews of VAERS reports and the studies based on VAERS reports during 1991-2001 have demonstrated that vaccines are usually safe and that serious adverse events occur but are rare. PUBLIC HEALTH ACTIONS: Through continued reporting of adverse events after vaccination to VAERS by health-care providers, public health professionals, and the public and monitoring of reported events by the VAERS working group, the public health system will continue to be able to detect rare but potentially serious consequences of vaccination. This knowledge facilitates improvement in the safety of vaccines and the vaccination process. PMID: 12825543 [PubMed - indexed for MEDLINE] 7: Pediatrics. 2004 Apr;113(4):e353-9. Links An analysis of rotavirus vaccine reports to the vaccine adverse event reporting system: more than intussusception alone? Haber P, Chen RT, Zanardi LR, Mootrey GT, English R, Braun MM; VAERS Working Group. National Immunization Program, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA. [email protected] BACKGROUND: The rhesus-human rotavirus reassortant-tetravalent vaccine (RRV-TV) was licensed on August, 31, 1998, and subsequently recommended for routine infant immunizations in the United States. After approximately 1 million doses had been administered, an increase in acute risk of intussusception in vaccinees led to the suspension of the use of RRV-TV and its withdrawal from the market. These postmarketing safety studies focused on a single adverse event (intussusception) and, to minimize the risk of a false-positive finding, accepted only cases that met a strict case definition. Safer rotavirus vaccines are needed to prevent the substantial global morbidity and mortality caused by rotavirus infections; their development and future use may benefit from a better understanding of the postmarketing safety profile of RRV-TV beyond intussusception. OBJECTIVE: To characterize more completely the postmarketing surveillance safety profile of RRV-TV more completely by review and analysis of Vaccine Adverse Event Reporting System (VAERS) case reports to better understand 1) whether severe adverse events other than intussusception may have occurred after RRV-TV and 2) the likely scope of gastrointestinal illnesses, of which the previously identified, highly specific intussusception cases may account for just a fraction. SETTING AND PARTICIPANTS: Infants vaccinated with RRV-TV and other vaccines in the United States and for whom a report was submitted to VAERS during September 1, 1998, to December 31, 1999. METHODOLOGY: To detect adverse events of interest other than intussusception, we used proportional morbidity analysis to compare the adverse event profile of VAERS reports among infants who received routine vaccines including RRV-TV (after excluding confirmed and suspected intussusception reports) with infants who received identical vaccine combinations but without RRV-TV. Next, to better capture all described diagnoses, signs, and symptoms associated with the suspected adverse events, a set of new codes was developed and assigned to each VAERS report. All 448 nonfatal RRV-TV-associated reports (including intussusception) were recoded manually from the clinical description on the VAERS report and categorized into clinical groups to better describe a spectrum of reported illnesses after the vaccine. Each report was assigned to one of the following hierarchical and mutually exclusive clinical groups: 1) diagnosed intussusception; 2) suspected intussusception; 3) illness consistent with either gastroenteritis or intussusception; 4) gastroenteritis; 5) other gastrointestinal diagnoses (ie, not consistent with intussusception or rotavirus-like gastroenteritis); and 6) nongastrointestinal diagnoses. RESULTS: Even after excluding intussusception cases, a higher proportion of RRV-TV reports than non-RRV-TV reports included fever and various gastrointestinal symptoms, most notably bloody stool but also vomiting, diarrhea, abdominal pain, gastroenteritis, abnormal stool, and dehydration. Distribution of RRV-TV reports by clinical groups was as follows: diagnosed intussusception (109 [24%], suspected intussusception (36 [8%]), and illness consistent with gastroenteritis or intussusception (33 [7%]), gastroenteritis (101 [22%]), other gastrointestinal diagnoses (10 [2%]), and nongastrointestinal outcomes (159 [35%]). The median time interval between vaccination and illness onset decreased incrementally among the first 4 clinical groups: from 7 days for diagnosed intussusceptions to 3 days for gastroenteritis. CONCLUSIONS: Intussusception and gastroenteritis were the most commonly reported outcomes; however, a substantial number of reports indicate signs and symptoms consistent with either illness, possibly suggestive of a spectrum of gastrointestinal illness(es) related to RRV-TV. Although VAERS data have recognized limitations such as underreporting (that may differ by vaccine) and are nearly always insufficient to prove causality between a vaccine and an adverse event, this safety profile of RRV-TV may aid better understanding of the pathophysiology of intussusception as well as development of future safer rotavirus vaccines. PMID: 15060267 [PubMed - indexed for MEDLINE] 8: Lancet. 2003 Nov 15;362(9396):1659-66. Links Vaccination and autoimmune disease: what is the evidence? Wraith DC, Goldman M, Lambert PH. Department of Pathology and Microbiology, University of Bristol, Bristol, UK. [email protected] As many as one in 20 people in Europe and North America have some form of autoimmune disease. These diseases arise in genetically predisposed individuals but require an environmental trigger. Of the many potential environmental factors, infections are the most likely cause. Microbial antigens can induce cross-reactive immune responses against self-antigens, whereas infections can non-specifically enhance their presentation to the immune system. The immune system uses fail-safe mechanisms to suppress infection-associated tissue damage and thus limits autoimmune responses. The association between infection and autoimmune disease has, however, stimulated a debate as to whether such diseases might also be triggered by vaccines. Indeed there are numerous claims and counter claims relating to such a risk. Here we review the mechanisms involved in the induction of autoimmunity and assess the implications for vaccination in human beings. PMID: 14630450 [PubMed - indexed for MEDLINE] 9: Autoimmunity. 2005 May;38(3):235-45. Links Infection, vaccines and other environmental triggers of autoimmunity. Molina V, Shoenfeld Y. Department of Medicine B and The Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel. The etiology of autoimmune diseases is still not clear but genetic, immunological, hormonal and environmental factors are considered to be important triggers. Most often autoimmunity is not followed by clinical symptoms unless an additional event such as an environmental factor favors an overt expression. Many environmental factors are known to affect the immune system and may play a role as triggers of the autoimmune mosaic. Infections: bacterial, viral and parasitic infections are known to induce and exacerbate autoimmune diseases, mainly by the mechanism of molecular mimicry. This was studied for some syndromes as for the association between SLE and EBV infection, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and more. Vaccines, in several reports were found to be temporally followed by a new onset of autoimmune diseases. The same mechanisms that act in infectious invasion of the host, apply equally to the host response to vaccination. It has been accepted for diphtheria and tetanus toxoid, polio and measles vaccines and GBS. Also this theory has been accepted for MMR vaccination and development of autoimmune thrombocytopenia, MS has been associated with HBV vaccination. Occupational and other chemical exposures are considered as triggers for autoimmunity. A debate still exists about the role of silicone implants in induction of scleroderma like disease. Not only foreign chemicals and agents have been associated with induction of autoimmunity, but also an intrinsic hormonal exposure, such as estrogens. This might explain the sexual dimorphism in autoimmunity. Better understanding of these environmental risk factors will likely lead to explanation of the mechanisms of onset and progression of autoimmune diseases and may lead to effective preventive involvement in specific high-risk groups.So by diagnosing a new patient with autoimmune disease a wide anamnesis work should be done. PMID: 16126512 [PubMed - indexed for MEDLINE] 10: J Autoimmun. 2000 Feb;14(1):1-10. Links Vaccination and autoimmunity-'vaccinosis': a dangerous liaison? Shoenfeld Y, Aron-Maor A. Department of Internal Medicine B, Sheba Medical Center, Tel Hashomer, Israel. [email protected] The question of a connection between vaccination and autoimmune illness (or phenomena) is surrounded by controversy. A heated debate is going on regarding the causality between vaccines, such as measles and anti-hepatitis B virus (HBV), and multiple sclerosis (MS). Brain antibodies as well as clinical symptoms have been found in patients vaccinated against those diseases. Other autoimmune illnesses have been associated with vaccinations. Tetanus toxoid, influenza vaccines, polio vaccine, and others, have been related to phenomena ranging from autoantibodies production to fullblown illness (such as rheumatoid arthritis (RA)). Conflicting data exists regarding also the connection between autism and vaccination with measles vaccine. So far only one controlled study of an experimental animal model has been published, in which the possible causal relation between vaccines and autoimmune findings has been examined: in healthy puppies immunized with a variety of commonly given vaccines, a variety of autoantibodies have been documented but no frank autoimmune illness was recorded. The findings could also represent a polyclonal activation (adjuvant reaction). The mechanism (or mechanisms) of autoimmune reactions following immunization has not yet been elucidated. One of the possibilities is molecular mimicry; when a structural similarity exists between some viral antigen (or other component of the vaccine) and a self-antigen. This similarity may be the trigger to the autoimmune reaction. Other possible mechanisms are discussed. Even though the data regarding the relation between vaccination and autoimmune disease is conflicting, it seems that some autoimmune phenomena are clearly related to immunization (e.g. Guillain-Barre syndrome).The issue of the risk of vaccination remains a philosophical one, since to date the advantages of this policy have not been refuted, while the risk for autoimmune disease has not been irrevocably proved. We discuss the pros and cons of this issue (although the temporal relationship (i.e. always 2-3 months following immunization) is impressive). Copyright 2000 Academic Press. PMID: 10648110 [PubMed - indexed for MEDLINE] 11: Endocr Rev. 1994 Aug;15(4):516-42. Links Insulin-dependent diabetes mellitus as an autoimmune disease. Bach JF. INSERM U 25, Hôpital Necker, Paris, France. IDDM is unquestionably an autoimmune disease, as reflected by the presence of betacell-reactive autoantibodies and T cells, T cell-mediated transfer of the disease in nondiabetic mice, rats, and humans, and disease sensitivity to immunosuppressive therapy. T cells are predominantly, if not exclusively, involved in creating the islet lesions that lead to beta-cell atrophy after a stage of reversible inflammation. A full understanding of the disease pathogenesis will require a better definition of the nature of the triggering and target autoantigen(s) and of the effector mechanisms (cytokines, cytotoxic cells?). Much less information is available on the etiology than on the pathogenesis. Genetic factors are mandatory and the involvement of predisposition genes (HLA and non-HLA) is now being unravelled. The modulatory role of environmental factors is demonstrated by the high disease discordance rate in identical twins and by experimental data showing positive and negative modulation of the disease by a number of agents, notably infectious agents and food constituents. It is not clear, however, whether a given environmental factor, e.g. a precise virus or a cow's milk component, plays a real etiological role in a selected genetic background. IDDM thus appears as a multifactorial disease. It is not known, however, whether all factors intervene concomitantly in a given individual or separately in subsets of patients, explaining the clinical heterogeneity of the disease. The mechanisms underlying the loss of tolerance to self beta-cell autoantigen(s) are still unknown. Defective intrathymic negative selection of autoantigen-specific autoreactive T cell clones is unlikely. Breakdown of T cell anergy could occur according to various mechanisms, including aberrant expression of MHC molecules and molecular mimicry. Defective suppressor T cell function, perhaps related to TH1/TH2 imbalance, probably intervenes by amplifying the anti-beta-cell autoimmune response whatever its triggering mechanism. Before putative etiological agents are identified, one must base immunotherapy on nonantigen-specific agents. Results recently obtained in NOD mice indicate that the goal of nontoxic long-lasting immune protection from the disease is feasible if treatment is started early enough. In some cases (anti-T cell monoclonal antibodies), it appears that specific unresponsiveness can be induced. This double strategy (early intervention, tolerance induction) is the main challenge for immunodiabetologists.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 7988484 [PubMed - indexed for MEDLINE] 12: Ann N Y Acad Sci. 2001 Apr;928:200-11. Links Cellular and molecular pathogenic mechanisms of insulindependent diabetes mellitus. Yoon JW, Jun HS. Department of Microbiology and Infectious Disease, Julia McFarlane Diabetes Research Centre, Faculty of Medicine, The University of Calgary, Alberta, Canada. [email protected] Insulin-dependent diabetes mellitus (IDDM), also known as type 1 diabetes, is an organspecific autoimmune disease resulting from the destruction of insulin-producing pancreatic beta cells. The hypothesis that IDDM is an autoimmune disease has been considerably strengthened by the study of animal models such as the BioBreeding (BB) rat and the nonobese diabetic (NOD) mouse, both of which spontaneously develop a diabetic syndrome similar to human IDDM. Beta cell autoantigens, macrophages, dendritic cells, B lymphocytes, and T cells have been shown to be involved in the pathogenesis of autoimmune diabetes. Among the beta cell autoantigens identified, glutamic acid decarboxylase (GAD) has been extensively studied and is the best characterized. Beta cell-specific suppression of GAD expression in NOD mice results in the prevention of IDDM. Macrophages and/or dendritic cells are the first cell types to infiltrate the pancreatic islets. Macrophages play an essential role in the development and activation of beta cell-cytotoxic T cells. B lymphocytes play a role as antigen-presenting cells, and T cells have been shown to play a critical role as final effectors that kill beta cells. Cytokines secreted by immunocytes, including macrophages and T cells, may regulate the direction of the immune response toward Th1 or Th2 as well as cytotoxic effector cell or suppressor cell dominance. Beta cells are destroyed by apoptosis through Fas-Fas ligand and TNF-TNF receptor interactions and by granzymes and perforin released from cytotoxic effector T cells. Therefore, the activated macrophages and T cells, and cytokines secreted from these immunocytes, act synergistically to destroy beta cells, resulting in the development of autoimmune IDDM. PMID: 11795511 [PubMed - indexed for MEDLINE] 13: Autoimmunity. 1998;27(2):109-22. Links Cellular and molecular mechanisms for the initiation and progression of beta cell destruction resulting from the collaboration between macrophages and T cells. Yoon JW, Jun HS, Santamaria P. Department of Microbiology and Infectious Disease, Julia McFarlane Diabetes Research Centre, Faculty of Medicine, University of Calgary, Alberta, Canada. Insulin-dependent diabetes mellitus (IDDM) is caused by the progressive autoimmune destruction of insulin-producing pancreatic beta cells. Although the pathogenesis of autoimmune IDDM has been extensively studied, the precise mechanisms involved in the initiation and progression of beta cell destruction remain unclear. Animal models used in the study of IDDM, such as the BioBreeding (BB) rat and the nonobese diabetic (NOD) mouse, have greatly enhanced our understanding of the pathogenic mechanisms involved in this disease. In these animals, macrophages and/or dendritic cells are the first cell types to infiltrate the pancreatic islets. Macrophages must be involved in the pathogenesis of IDDM early on, since inactivation of macrophages results in the near-complete prevention of insulitis and diabetes in both NOD mice and BB rats. The presentation of beta cell-specific autoantigens by macrophages and/or dendritic cells to CD4+ T helper cells, in association with MHC class II molecules, is considered the initial step in the development of autoimmune IDDM. The activated macrophages secrete IL-12, which stimulates Th1 type CD4+ T cells. The CD4+ T cells secrete IFN-gamma and IL-2. IFNgamma activates other resting macrophages, which, in turn, release cytokines, such as IL1beta, TNF-alpha, and free radicals, which are toxic to beta cells. During this process, IL2 and other cytokines induce the migration of CD8+ peripheral T cells to the inflamed islets, perhaps by inducing the expression of a specific homing receptor. The precytotoxic CD8+ T cells that bear beta cell-specific autoantigen receptors differentiate into cytotoxic effector T cells upon recognition of the beta cell-specific peptide bound to MHC class I molecules in the presence of beta cell-specific CD4+ T helper cells. The cytotoxic CD8+ T cells then effect beta cell damage by releasing perforin and granzyme, and by Fasmediated apoptosis. In this way, macrophages, CD4+ T cells, and CD8+ T cells synergistically destroy beta cells, resulting in the onset of autoimmune IDDM. PMID: 9583742 [PubMed - indexed for MEDLINE] 14: Arch Pharm Res. 1999 Oct;22(5):437-47. Links Cellular and molecular roles of beta cell autoantigens, macrophages and T cells in the pathogenesis of autoimmune diabetes. Yoon JW, Jun HS. Dept. of Microbiology and Infectious Disease, Faculty of Medicine, The University of Calgary, Alberta, Canada. [email protected] Type I diabetes, also known as insulin-dependent diabetes mellitus (IDDM) results from the destruction of insulin-producing pancreatic beta cells by a progressive beta cellspecific autoimmune process. The pathogenesis of autoimmune IDDM has been extensively studied for the past two decades using animal models such as the non-obese diabetic (NOD) mouse and the BioBreeding (BB) rat. However, the initial events that trigger the immune responses leading to the selective destruction of the beta cells are poorly understood. It is thought that beta cell autoantigens are involved in the triggering of beta cell-specific autoimmunity. Among a dozen putative beta cell autoantigens, glutamic acid decarboxylase (GAD) has been proposed as perhaps the strongest candidate in both humans and the NOD mouse. In the NOD mouse, GAD, as compared with other beta cell autoantigens, provokes the earliest T cell proliferative response. The suppression of GAD expression in the beta cells results in the prevention of autoimmune diabetes in NOD mice. In addition, the major populations of cells infiltrating the islets during the early stage of insulitis in BB rats and NOD mice are macrophages and dendritic cells. The inactivation of macrophages in NOD mice results in the prevention of T cell mediated autoimmune diabetes. Macrophages are primary contributors to the creation of the immune environment conducive to the development and activation of beta cellspecific Th1-type CD4+ T cells and CD8+ cytotoxic T cells that cause autoimmune diabetes in NOD mice. CD4+ and CD8+ T cells are both believed to be important for the destruction of beta cells. These cells, as final effectors, can kill the insulin-producing beta cells by the induction of apoptosis. In addition, CD8+ cytotoxic T cells release granzyme and cytolysin (perforin), which are also toxic to beta cells. In this way, macrophages, CD4+ T cells and CD8+ T cells act synergistically to kill the beta cells in conjunction with beta cell autoantigens and MHC class I and class II antigens, resulting in the onset of autoimmune type I diabetes. PMID: 10549569 [PubMed - indexed for MEDLINE] 15: Am J Ther. 2005 Nov-Dec;12(6):580-91. Links Autoimmune destruction of pancreatic beta cells. Yoon JW, Jun HS. Rosalind Franklin Comprehensive Diabetes Center, Department of Pathology, Chicago Medical School, North Chicago, IL 60064, USA. [email protected] Type 1 diabetes results from the destruction of insulin-producing pancreatic beta cells by a beta cell-specific autoimmune process. Beta cell autoantigens, macrophages, dendritic cells, B lymphocytes, and T lymphocytes have been shown to be involved in the pathogenesis of autoimmune diabetes. Beta cell autoantigens are thought to be released from beta cells by cellular turnover or damage and are processed and presented to T helper cells by antigen-presenting cells. Macrophages and dendritic cells are the first cell types to infiltrate the pancreatic islets. Naive CD4+ T cells that circulate in the blood and lymphoid organs, including the pancreatic lymph nodes, may recognize major histocompatibility complex and beta cell peptides presented by dendritic cells and macrophages in the islets. These CD4+ T cells can be activated by interleukin (IL)-12 released from macrophages and dendritic cells. While this process takes place, beta cell antigen-specific CD8+ T cells are activated by IL-2 produced by the activated TH1 CD4+ T cells, differentiate into cytotoxic T cells and are recruited into the pancreatic islets. These activated TH1 CD4+ T cells and CD8+ cytotoxic T cells are involved in the destruction of beta cells. In addition, beta cells can also be damaged by granzymes and perforin released from CD8+ cytotoxic T cells and by soluble mediators such as cytokines and reactive oxygen molecules released from activated macrophages in the islets. Thus, activated macrophages, TH1 CD4+ T cells, and beta cell-cytotoxic CD8+ T cells act synergistically to destroy beta cells, resulting in autoimmune type 1 diabetes. PMID: 16280652 [PubMed - indexed for MEDLINE] 16: Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18425-30. Epub 2005 Dec 9. Links Autoreactive CD8 T cells associated with beta cell destruction in type 1 diabetes. Pinkse GG, Tysma OH, Bergen CA, Kester MG, Ossendorp F, van Veelen PA, Keymeulen B, Pipeleers D, Drijfhout JW, Roep BO. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands. Type 1 diabetes is a T cell-mediated autoimmune disease, and insulin is an important target of the autoimmune response associated with beta cell destruction. The mechanism of destruction is still unknown. Here, we provide evidence for CD8 T cell autoreactivity associated with recurrent autoimmunity and loss of beta cell function in type 1 diabetic islet transplant recipients. We first identified an insulin B chain peptide (insB10-18) with extraordinary binding affinity to HLA-A2(*0201) that is expressed by the majority of type 1 diabetes patients. We next demonstrated that this peptide is naturally processed by both constitutive and immuno proteasomes and translocated to the endoplasmic reticulum by the peptide transporter TAP1 to allow binding to HLA-A2 in the endoplasmic reticulum and cell surface presentation. Peripheral blood mononuclear cells from a healthy donor were primed in vitro with this peptide, and CD8 T cells were isolated that specifically recognize target cells expressing the insulin B chain peptide. HLAA2(insB10-18) tetramer staining revealed a strong association between detection of autoreactive CD8 T cells and recurrent autoimmunity after islet transplantation and graft failure in type 1 diabetic patients. We demonstrate that CD8 T cell autoreactivity is associated with beta cell destruction in type 1 diabetes in humans. PMID: 16339897 [PubMed - indexed for MEDLINE] #17: Characterization of the role of major histocompatibility complex in type 1 diabetes recurrence after islet transplantation. Young HY, Zucker P, Flavell RA, Jevnikar AM, Singh B. Department of Microbiology and Immunology, University of Western Ontario, London, ON, Canada. BACKGROUND: Major histocompatibility complex (MHC) molecules are essential determinants of beta-cell destruction in type 1 diabetes (T1D). MHC class I- or class IInull nonobese diabetic (NOD) mice do not spontaneously develop autoimmune diabetes and are resistant to adoptive transfer of disease. Both CD4+ and CD8+ T cells are associated with graft destruction after syngeneic islet transplantation. MHC molecules within the graft (i.e., on beta-cells or donor lymphocytes) may influence the interactions between antigen presenting cells and effector T cells and, therefore, the survival outcome of the graft. METHODS: Donor islets from NOD mice deficient in one or both of beta2microglobulin and class II transactivator genes were transplanted into diabetic NOD mice. Immunohistochemistry was performed to identify the phenotype of infiltrating cells and to assess graft insulin production. The presence of cytokines in the grafts was assayed by reverse transcription polymerase chain reaction. RESULTS: MHC class IInull islets demonstrated rates of rejection comparable with control wild-type (wt) islets. In contrast, MHC class I- and II-null islets demonstrated indefinite survival (over 100 days). Infiltrates of both failed and surviving grafts were comprised of cytotoxic lymphocytes (CTL), helper T cells, and macrophages. Grafts also showed the presence of both Th1- and Th2-type cytokines (interleukin [IL]-2, IL-4, IL-10, and interferongamma), independent of graft status. CONCLUSIONS: These results demonstrate the primary importance of MHC class I molecules in the pathogenesis of diabetes recurrence postislet transplantation. Conversely, MHC class II expression is not a necessary mechanistic component of transplant destruction. In addition, these results implicate MHC class I-restricted CTLs but not MHC class II-restricted T cells in disease recurrence. PMID: 15446308 [PubMed - indexed for MEDLINE] 18: Diabetes Metab Rev. 1998 Jun;14(2):129-51. Links An update on cytokines in the pathogenesis of insulindependent diabetes mellitus. Rabinovitch A. Department of Medicine, University of Alberta, Edmonton, Canada. Correlation studies between cytokines expressed in islets and autoimmune diabetes development in NOD mice and BB rats have demonstrated that beta-cell destructive insulitis is associated with increased expression of proinflammatory cytokines (IL-1, TNF alpha, and IFN alpha) and type 1 cytokines (IFN gamma, TNF beta, IL-2 and IL-12), whereas non-destructive (benign) insulitis is associated with increased expression of type 2 cytokines (IL-4 and IL-10) and the type 3 cytokine (TGF beta). Cytokines (IL-1, TNF alpha, TNF beta and IFN gamma) may be directly cytotoxic to beta-cells by inducing nitric oxide and oxygen free radicals in the beta-cells. In addition, cytokines may sensitize beta-cells to T-cell-mediated cytotoxicity in vivo by upregulating MHC class I expression on the beta-cells (an action of IFN gamma), and inducing Fas (CD95) expression on beta-cells (actions of IL-1, and possibly TNF alpha and IFN gamma). Transgenic expression of cytokines in beta-cells of non-diabetes-prone mice and NOD mice has suggested pathogenic roles for IFN alpha, IFN gamma, IL-2 and IL-10 in insulin-dependent diabetes mellitus (IDDM) development, and protective roles for IL-4, IL-6 and TNF alpha. Systemic administrations of a wide variety of cytokines can prevent IDDM development in NOD mice and/or BB rats; however, a given cytokine may retard or accelerate IDDM development, depending on the dose and frequency of administration, and the age and the diabetes-prone animal model studied (NOD mouse or BB rat). Islet-reactive CD4+ T-cell lines and clones that adoptively transfer IDDM into young NOD mice have a Th1 phenotype (IFN gamma-producing), but other islet-specific Th1 clones that produce TGF beta can adoptively transfer protection against IDDM in NOD mice. NOD mice with targeted deletions of IL-12 and IFN gamma genes still develop IDDM, albeit delayed and slightly less often. In contrast, post-natal deletions of IL-12 and IFN gamma, also IL-1, TNF alpha, IL-2, and IL-6--by systemic administrations of neutralizing antibodies, soluble receptors and receptor antagonists, and receptor-targeted cytotoxic drugs--significantly decrease IDDM incidence in NOD mice and/or BB rats. These cytokine deletion studies have provided the best evidence for pathologic roles for proinflammatory cytokines (IL-1, TNF alpha, and IL-6) and type 1 cytokines (IFN gamma, IL-2 and IL-12) in IDDM development. PMID: 9679667 [PubMed - indexed for MEDLINE] 19: J Autoimmun. 2001 May;16(3):309-18. Links Epidemiology of autoimmune reactions induced by vaccination. Chen RT, Pless R, Destefano F. Vaccine Safety and Development Activity, National Immunization Program, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA. [email protected] In order for vaccinations to 'work', the immune system must be stimulated. The concern that immunizations may lead to the development of autoimmune disease (AID) has been questioned. Since AID occur in the absence of immunizations, it is unlikely that immunizations are a major cause of AID. Epidemiological studies are needed, however, to assess whether immunizations may increase the risk in some susceptible individuals. This paper discusses the evidence for and against vaccination as a risk factor for AID. Evidence for immunizations leading to AID come from several sources including animal studies, single and multiple case reports, and ecologic association. However more rigorous investigation has failed to confirm most of the allegations. Unfortunately the question remains difficult to address because for most AIDs, there is limited knowledge of the etiology, background incidence and other risk factors for their development. This information is necessary, in the absence of experimental evidence derived from controlled studies, for any sort of adequate causality assessment using the limited data that are available. Several illustrative examples are discussed to highlight what is known and what remains to be explored, and the type of epidemiological evidence that would be required to better address the issues. Examples include the possible association of immunization and multiple sclerosis (and other demyelinating diseases), type 1 diabetes mellitus, Guillain-Barre Syndrome, idiopathic thrombocytopenic purpura, and rheumatoid arthritis. Copyright 2001 Academic Press. PMID: 11334497 [PubMed - indexed for MEDLINE]