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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]