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3
Evaluating Biological Mechanisms
of Adverse Events
Charged with reporting on biological mechanisms, the committee re-
viewed evidence presented in case reports/clinical write-ups, laboratory
tests, and animal models. Based on the array of adverse events and types
of vaccines being reviewed, the committee compiled a list of mechanisms it
deemed most likely to contribute to the development of adverse events after
vaccination. The pathophysiologies and, at times, the evidence needed to
identify a mechanism as operative were discussed. The mechanisms include
immune-mediated reactions, viral activity, and injection-related reactions.
The committee also discussed the coagulation cascade and its contribution
to disease. In addition, the committee discussed the mechanisms that could
lead to the development of adverse events in susceptible individuals, as well
as the role vaccination could have in revealing an underlying immunodefi-
ciency. The committee also discussed alterations in brain development that
included a discussion of autism. Lastly, the advantages and disadvantages
of applying evidence of a mechanism derived from an animal model to a
human condition are discussed.
LATENCY BETWEEN ANTIGEN EXPOSURE AND
PEAK ADAPTIVE IMMUNE RESPONSE
Antigen exposure initiates an array of reactions involving the immune
system, including the activation of white blood cells called lymphocytes that
fight infection. After antigen exposure, two types of lymphocytes, B cells
and T cells, differentiate into effector (e.g., antibody-producing B cells and
cytotoxic and helper T cells) and memory cells. For both B and T cells in a
57
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58 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
typical immune response to an antigen exposure, the latency between the
first (primary) exposure and development of the primary response is charac-
terized by a lag phase, logarithmic phase, and plateau phase. The lag phase
is characterized by the initial activation of B and T cells upon encounter
with the antigen for which they are specific, and this triggers the cells’ dif-
ferentiation into effector and memory cells. The lag phase between primary
exposure to an antigen and the logarithmic phase is classically thought to
be 4 to 7 days, but it varies depending on route of exposure and the antigen
itself. For B cells, the logarithmic phase is characterized by an increase in
serum antibody levels that classically is logarithmic. The plateau phase is
characterized by the maintenance of peak antibody levels for a length of
time that is followed by a decline in the serum antibody levels. For many
antigens the latency (lag phase) between primary exposure and development
of the primary antibody response is 7 to 10 days. Due to the development
of memory B and T cells during the primary immune response, the latency
between subsequent exposure to the antigen and development of the immune
response will usually be shorter. The lag phase is generally 1 to 3 days; the
logarithmic phase of the secondary antibody response occurs over the next
3 to 5 days. As mentioned for the primary immune response, these time
periods will vary depending on the route of exposure, the timing of the
subsequent exposure, the antigen itself, and the antigen dose. While this
discussion is not specific to a particular antigen, it can be used as a reference
point for the latency between antigen exposure and the initiation of some of
the immune-mediated mechanisms described below.
Contributing to the activation of B and T cells and the initiation of the
adaptive immune response are cells classically associated with the innate im-
mune system (e.g., macrophages and dendritic cells). These cells play roles at
each of the stages mentioned above and are usually the first cells of the im-
mune system to be exposed to antigen. Upon antigen encounter, macrophages
and dendritic cells engulf the antigen, a process that also activates these
innate immune cells to become antigen-presenting cells. Antigen-presenting
cells, as their name suggests, present the antigen to T cells (see “Effector
Functions of T Cells” below) and release inflammatory mediators (e.g.,
cytokines and chemokines) that contribute to the recruitment, activation, and
proliferation of B and T cells. Activated B and T cells in turn release inflam-
matory mediators leading to the recruitment and activation of additional
immune cells that further amplify the immune response through the release
of inflammatory mediators. Regulatory cells and soluble immunoregulatory
mediators (not discussed in this report) play roles in suppressing the immune
response. Chaplin (2010) provides a review of the immune response including
discussion of the interplay between the innate and adaptive arms of the im-
mune system, cells associated with the innate and adaptive immune systems,
and inflammatory/immunoregulatory mediators.
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EVALUATING BIOLOGICAL MECHANISMS OF ADVERSE EVENTS
Many vaccines, particularly subunit vaccines (e.g., recombinant hepa-
titis B and tetanus toxoid), contain adjuvants that help to increase the
response rates to vaccines and facilitate the use of fewer and smaller doses
(Coffman et al., 2010). Currently, two adjuvants (alum as aluminum phos-
phate or aluminum hydroxide, and ASO4, which is comprised of mono-
phosphoryl lipid A and alum) are in vaccines licensed for use in the United
States. Although the exact mechanism of action of many adjuvants is not
completely understood, it is hypothesized that alum delays systemic ab-
sorption of injected antigens, resulting in antigen retention in particulate
form and in high concentration at the site of local injection (Tritto et al.,
2009). This in turn results in prolonged exposure of the cells of the innate
immune system to antigen (Tritto et al., 2009). Furthermore, alum may
directly activate cells of the innate immune system through its effect on lo-
cal inflammasome complexes (Coffman et al., 2010) leading to the release
of inflammatory mediators and enhancement of the immune response as
described above. The review by Coffman et al. (2010) provides a detailed
description of the mechanism(s) of action of clinically approved adjuvants
including alum and ASO4.
IMMUNE-MEDIATED MECHANISMS
Several immune-mediated mechanisms have been hypothesized to be
involved in the pathogenesis of tissue damage or clinical disease related to
natural infection or immunizations. A brief description of some of these
mechanisms follows.
Effector Functions of T Cells
T cells are the subset of lymphocytes that develop in the thymus. They
are further delineated by the expression of cell surface markers and the
production of inflammatory and immunoregulatory mediators. Two T cell
subsets, CD8+ and CD4+ T cells, are activated via recognition of peptides
derived from antigen. For activation of T cells to occur, the peptides are
bound to major histocompatibility complexes (MHCs) expressed on the
surface of specialized white blood cells called antigen-presenting cells. T
cells have various functions in the immune response.
CD8+ T cells are activated in response to antigens that gain access to
the cytosol of cells. These antigens are broken down into peptides. The
peptides are presented to CD8+ T cells after being bound to class I MHC
molecules. Class I MHC molecules are expressed on nearly all nucleated
cells (Harty et al., 2000). CD8+ T cells express a T cell receptor (TCR) that
binds peptide-class I MHC complexes. CD8+ T cells that express different
TCRs allow for recognition of many different antigens. The binding of
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60 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
the CD8+ T cell TCR to the peptide-class I MHC complex on professional
antigen-presenting cells (e.g., dendritic cells) activates the CD8+ T cells
which then respond against cytosolic infections such as viruses, intracyto-
plasmic bacteria, and protozoa (Harty et al., 2000). Activated CD8+ T cells
induce death of infected cells through mechanisms that include (1) release
of granules containing the pore-forming molecular perforin or (2) engage-
ment of Fas receptors on target cells (Harty et al., 2000). Both mechanisms
induce apoptosis, or programmed cell death, in the target cell. In addition,
activated CD8+ T cells secrete cytokines, molecules critical to intercellular
communication, that recruit and activate macrophages and neutrophils
(Harty et al., 2000).
In contrast to CD8+ T cells, CD4+ T cells are predominantly activated
in response to extracellular antigens that are endocytosed or phagocytosed,
broken down into peptides, and bound to class II MHC molecules on the
surface of professional antigen-presenting cells (Guermonprez et al., 2002).
Class II MHC molecules are expressed on dendritic cells, macrophages,
B cells, and activated T cells. The CD4+ T cells express TCRs that bind
peptide-class II MHC complexes. Recognition of peptide antigen-MHC
complexes activates CD4+ T cells against a variety of antigens including,
but not limited to, bacteria, parasites, and proteins. Activated CD4+ T cells
direct aspects of the immune response via the secretion of immunoregula-
tory cytokines and other soluble mediators. These inflammatory mediators
can induce B cells to undergo immunoglobulin (Ig) class switching (e.g.,
IgM to IgE); to support the activity of CD8+ T cells; to recruit and activate
eosinophils, basophils, neutrophils, mast cells, and macrophages; and to
down-regulate immune responses (Koretzky, 2008; Wan and Flavell, 2009).
Several lineages of CD4+ T cells, with overlapping and competing effects
based on those described above, have been identified (Wan and Flavell,
2009). One CD4+ T cell lineage, referred to as regulatory T cells, func-
tions to maintain self tolerance and immune homeostasis (Wan and Flavell,
2009). In addition, some CD4+ T cells can induce cytolysis via the mecha-
nisms described for CD8+ T cells (Soghoian and Streeck, 2010).
In summary, T cells contribute to the establishment and maintenance
of immune responses, the clearance of pathogens, and the maintenance of
self-tolerance. T cells play roles in many disease processes including, but
not limited to, rheumatoid arthritis, type 1 diabetes, and asthma (Wan and
Flavell, 2009).
Effector Functions of Antibodies and Autoantibodies
Antibodies are antigen-binding proteins produced by terminally differ-
entiated effector B cells called plasma cells. Antibodies that bind antigens
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EVALUATING BIOLOGICAL MECHANISMS OF ADVERSE EVENTS
derived from the host organism (i.e., self-antigens) are referred to as auto-
antibodies. Autoantibodies are considered one of the hallmarks of certain
autoimmune diseases; however, the presence of autoantibodies does not cor-
relate perfectly with disease. Autoantibodies have been detected in healthy
individuals as well as those with autoimmune diseases (Elkon and Casali,
2008; Zelenay et al., 2007). The mechanisms whereby autoantibodies exert
their effects in the disease process are the same used by antibodies against
foreign antigens (i.e., non-self-antigens). These include, but are not limited
to, opsonization, neutralization, complement activation, augmentation, and
engagement of constant region (Fc) receptors.
Neutralization of an antigen or pathogen expressing the target antigen
is one effector mechanism attributed to antibodies. For example, antibod-
ies against influenza virus hemagglutinin neutralize the virus by blocking
the interaction of the virus with the receptor on the target cell, thereby
preventing infection (Han and Marasco, 2011). In addition, while not
preventing influenza infection, antibodies against influenza neuraminidase
restrict replication of the virus by preventing release of virus from infected
cells (Han and Marasco, 2011). This is one of the ways vaccines, which in-
duce pathogen-specific antibodies, elicit protection from diseases. However,
neutralization of self-antigens by autoantibodies can also contribute to the
pathogenesis of some autoimmune diseases. For example, neutralizing auto-
antibodies against the cytokine granulocyte/macrophage colony-stimulating
factor (GM-CSF) are found in autoimmune pulmonary alveolar proteinosis,
which is characterized by dysfunctional alveolar macrophages and function-
ally impaired neutrophils (Watanabe et al., 2010). Autoantibodies against
GM-CSF block interaction of the cytokine with receptors on macrophages,
inhibiting their maturation, and on neutrophils, leading to impairment of
phagocytosis, adhesion, bacterial killing, and oxidative burst (Watanabe
et al., 2010).
Antibodies against surface-bound antigens can lead to the opsonization
(coating) of the pathogen or a cell expressing the antigen. For example, an-
tibodies against the capsular polysaccharide of Streptococcus pneumoniae
result in the opsonization of the bacteria and clearance of the bacteria by
phagocytic cells (Bruyn et al., 1992). In a proinflammatory setting, such as
antineutrophil cytoplasmic autoantibody–associated vasculitides, opsoniza-
tion can lead to the perpetuation of inflammation (van Rossum et al.,
2005). For example, opsonization of neutrophils by autoantibodies against
proteinase 3 (PR3) and myeloperoxidase (MPO) contributes to the activa-
tion of neutrophils resulting in their degranulation, which in turn leads to
vessel injury (van Rossum et al., 2005).
Antibody-antigen interactions can lead to complement activation (com-
plement activation is discussed in a subsequent section). Antibodies against
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62 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
bacteria lead to complement activation resulting in elimination of the bacte-
ria (Bruyn et al., 1992). Similarly, engagement of aquaporin-4, expressed on
the surface of astrocytes, by autoantibodies results in complement activation
leading to disruption of the integrity of the plasma membrane and astrocyte
injury (Cayrol et al., 2009).
Engagement of Fc receptors by antibodies bound to antigen can lead to
clearance of the antigen or antigen-expressing pathogen or cell, or to activa-
tion of the receptor-expressing cell. The Fc receptors on macrophages, by
binding to antibody-coated bacteria, allow the macrophages to engulf and
then kill the bacteria. One example, discussed above, is the opsonization
of Streptococcus pneumoniae by antibodies against the capsular polysac-
charide that leads to the clearance of the bacteria by macrophages (Bruyn
et al., 1992). Likewise, the clearance of apoptotic neutrophils opsonized by
autoantibodies against PR3 and MPO, as discussed above, is facilitated by
engagement of the Fc receptors expressed on the surface of the macrophages
(van Rossum et al., 2005). In addition, as described above, opsonization of
neutrophils by autoantibodies against PR3 and MPO contributes to the ac-
tivation of neutrophils. Autoantibodies against PR3 and MPO contribute to
neutrophil activation through engagement of Fc receptors by the constant
region of the autoantibodies whose variable regions (Fab) are binding either
PR3 or MPO on the same cell (van Rossum et al., 2005).
Autoantibodies also have the ability to augment the effects of the target
antigen. For example, the autoantibody complex interleukin-8 (IL-8) has
been shown to augment IL-8-induced neutrophil migration in acute respi-
ratory distress syndrome (Watanabe et al., 2010). IL-8-induced neutrophil
migration is more strongly induced by engagement of Fc receptors by
IL-8-autoantibody complexes than by engagement of the IL-8 receptor
alone (Watanabe et al., 2010).
As suggested above, autoantibodies use multiple mechanisms during
a disease process. Antigen-bound autoantibodies can both (1) engage Fc
receptors and (2) induce activation of the complement system. These pro-
cesses lead to the activation of inflammatory cells such as neutrophils and
macrophages, and to generation of proinflammatory mediators that play
pathogenic roles in autoimmune diseases.
Complement Activation
The complement system is comprised of more than 30 soluble or
membrane-bound proteins. Complement activation, an outcome of a
cascade of enzymatic reactions, leads to the generation of inflammatory
mediators that play a role in host defense via three physiological processes
(Dunkelberger and Song, 2010). First, complement activation leads to
the targeted lysis of infectious agents through the generation of the mem-
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EVALUATING BIOLOGICAL MECHANISMS OF ADVERSE EVENTS
brane attack complex (MAC), which forms membrane-penetrating pores in
pathogens (Dunkelberger and Song, 2010). Second, complement activation
leads to the opsonization of infectious agents by complement opsonins
and the engagement of complement receptors on phagocytic cells resulting
in the clearance of the infectious agent (Dunkelberger and Song, 2010).
Lastly, complement activation leads to the generation of proinflammatory
anaphylatoxins that act as vasodilators, cytokines, and inducers of smooth
muscle contraction; oxidative bursts from neutrophils; and histamine re-
lease from mast cells (Sarma and Ward, 2011). In addition to the physi-
ological processes described above, the complement system plays a role in
the selection, maintenance, and differentiation of B cells into plasma and
memory cells, and in the priming of CD4+ and CD8+ T cells (Dunkelberger
and Song, 2010).
Three pathways—classical, lectin, and alternative—lead to complement
activation and the generation of inflammatory mediators responsible for the
physiological processes discussed above. These pathways converge where
C3 convertases cleave the complement component C3 into the anaphyla-
toxin C3a and the opsonin C3b; from this point, further enzymatic reac-
tions generate additional anaphylatoxins, opsonins, and the MAC (Gros
et al., 2008). The pathways are discussed below.
The initiation of the classical pathway occurs when the complement
component C1q, in complex with the complement components C1r and
C1s, bind immune complexes (comprised of antigen bound by IgG or IgM
antibodies) (Rus et al., 2005). C1q can also initiate the classical pathway
by binding to C-reactive protein, serum amyloid P, gram-negative bacterial
walls, and central nervous system myelin (Rus et al., 2005). Autocatalytic
activation of C1r and C1s leads to an enzymatic reaction involving the
complement components C4 and C2 and the generation of fragments that
combine to form C3 convertase (Dunkelberger and Song, 2010).
The lectin pathway is initiated when pattern recognition receptors
(PRRs), such as mannose-binding lectin, bind to highly conserved structures
in microorganisms termed pathogen-associated molecular patterns (PAMPs)
(Dunkelberger and Song, 2010). PAMPs can be found on the surfaces of
yeast, bacteria, parasites, and viruses (Sarma and Ward, 2011). Similar to
the classical pathway, recognition of PAMPs by PRRs leads to an enzymatic
reaction involving the complement components C4 and C2 and the genera-
tion of fragments that combine to form C3 convertase (Dunkelberger and
Song, 2010).
Initiation of the alternative pathway occurs when C3 undergoes spon-
taneous hydrolysis on the surface of pathogens or other targets that have
neutral or positive charge characteristics and/or that support the binding
of activated C3 (Holers, 2008). The altered form of C3, called C3i or
C3(H2O), can bind factor B, which in turn is cleaved by factor D, leading
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64 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
to the generation of C3 convertase (Holers, 2008). In addition to promot-
ing the generation of the inflammatory mediators discussed above, the
alternative pathway increases complement activation through an amplifi-
cation loop (Holers, 2008). The amplification loop is engaged when C3b,
generated by C3 convertase from any of the three complement activation
pathways, binds factor B, which in turn is cleaved by factor D, leading to
further C3 activation (Holers, 2008). Sites of local injury and decreased
expression of complement regulatory proteins can promote engagement of
the amplification loop (Holers, 2008).
Hypersensitivity Reactions
Hypersensitivity reactions are immune-mediated reactions to sub-
stances, termed allergens, which do not generate adverse immune responses
in the majority of the population. Individuals who are “atopic” develop
immune responses to the allergens that lead to symptoms such as hay fever
or wheezing in response to pollens, or vomiting and lip swelling in response
to certain foods. These reactions develop after sensitizing exposure(s) and
reexposure to an allergen, and are broadly classified as immediate or de-
layed hypersensitivity reactions. Described below are two mechanisms clas-
sified as immediate hypersensitivity reactions involved in allergic reactions,
including the severe, potentially fatal, systemic allergic reactions that are
rapid in onset and known as anaphylaxis.
Immunoglobulin E–Mediated Hypersensitivity
Definition of immunoglobulin E–mediated hypersensitivity By far the
most common mechanism responsible for immediate hypersensitivity reac-
tions involves immunoglobulin E (IgE) and is termed immunoglobulin E–
mediated hypersensitivity, in which allergen-specific IgE antibodies undergo
synthesis and binding to high-affinity IgE receptors on the surface of mast
cells and basophils. Subsequent exposure of allergen to receptor-bound IgE
leads to cross-linking of IgE, activation of mast cells and basophils, and
release of inflammatory mediators (Simons, 2009).
Evidence needed to conclude that IgE-mediated hypersensitivity is operative
in anaphylaxis Positive skin test results and/or the presence of allergen-
specific IgE in serum indicate that a patient is sensitized to an allergen but
alone are not conclusive of IgE-mediated reactions or anaphylaxis (Simons,
2009); similarly, negative tests do not conclusively exclude clinical reactivity
to an allergen. Testing for mediators of allergic reactivity, such as hista-
mine and tryptase, may be useful in confirming an episode of anaphylaxis
(Simons, 2009). However, testing for these mediators is frequently not
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EVALUATING BIOLOGICAL MECHANISMS OF ADVERSE EVENTS
available, so physicians must rely on the clinical history, and signs and
symptoms of a reaction, to make the diagnosis (Sampson et al., 2006).
Examples of allergen exposures thought to cause IgE-mediated anaphy-
laxis Many allergens have been associated with the development of IgE-
mediated anaphylaxis. These include food (e.g., milk, egg, peanuts, tree
nuts, shellfish, gelatin), food additives (e.g., some colorants, spices, yeast),
venoms (e.g., insect stings), latex, and inhalants (e.g., animal danders and
grass pollen) (Simons, 2010).
Adverse events on our list thought to be due to IgE-mediated hypersensitiv-
ity reactions Antigens in the vaccines that the committee is charged with
reviewing do not typically elicit an immediate hypersensitivity reaction (e.g.,
hepatitis B surface antigen, toxoids, gelatin, ovalbumin, casamino acids).
However, as will be discussed in subsequent chapters, the above-mentioned
antigens do occasionally induce IgE-mediated sensitization in some indi-
viduals and subsequent hypersensitivity reactions, including anaphylaxis.
Complement-Mediated Hypersensitivity
Definition of complement-mediated hypersensitivity A much less frequent
cause of immediate hypersensitivity is due to complement-mediated hy-
persensitivity, which involves the activation of the complement pathway
by dialysis membranes, for example. Complement activation generates
the anaphylatoxins C3a and C5a which bind to complement receptors on
the surface of mast cells, leading to the release of inflammatory mediators
(Noone and Osguthorpe, 2003).
Evidence needed to conclude that complement-mediated hypersensitiv -
ity is operative in anaphylaxis Although the clinical history and signs
and symptoms of anaphylaxis are typically used to make the diagnosis of
anaphylaxis, measurement of inflammatory mediators such as histamine,
tryptase, kallikrein, and bradykinin, in addition to others, may be helpful
in confirming an episode of anaphylaxis (Sampson et al., 2006; Simons,
2010). During or shortly after an episode of anaphylaxis, the demonstration
of an acute elevation of C3a and C5a (both of which can increase vascu-
lar permeability and smooth muscle contraction) is useful in implicating
complement-mediated hypersensitivity as the operative mechanism in the
anaphylactic episode.
Examples of exposures thought to cause complement-mediated anaphy-
laxis A small number of substances have been associated with the de-
velopment of complement-mediated anaphylaxis. These include dialysis
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66 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
membranes, human proteins (e.g., transfusion or other blood product),
immune complexes, and oversulfated chondroitin sulfate-contaminated
heparin (Noone and Osguthorpe, 2003; Simons, 2010).
Adverse events on our list thought to be due to complement-mediated
hypersensitivity reactions The antigens and potential antigens contained
in the vaccines that the committee is charged with reviewing are not com-
monly associated with complement-mediated anaphylaxis.
Immune Complexes
When present in adequate concentrations, antigen and antibody gen-
erate large complexes, termed immune complexes, which can lead to ini-
tiation of the inflammatory cascade through complement activation and
engagement of Fc receptors, and to increased vascular permeability through
the release of vasoactive factors upon activation of mast cells and neutro-
phils (Gao et al., 2006; Malbec and Daeron, 2007; Mayadas et al., 2009;
Roubin and Benveniste, 1985; Volanakis, 1990). In addition, at cold tem-
peratures, in vitro, some antibodies can precipitate from serum; they are
called cryobglobulins (Tedeschi et al., 2007). The immune complexes may
include IgM rheumatoid factor and antibodies against pathogens (Tedeschi
et al., 2007). Immune complexes can cause pathologic damage and disease.
Evidence Needed to Conclude That Immune Complexes
Are Operative in a Clinical Case or an Animal Model
The first requirement before attributing a symptom complex to the
action of immune complexes is to demonstrate their presence. This can
be done in plasma, using assays such as the Raji cell assay or the enzyme-
linked immunosorbent assay to detect binding to plate-bound C1q, or to
look for immune complexes on red cells that transport the complexes to
the liver where they are ingested by Kuppfer cells (Bellamy et al., 1997;
Crockard et al., 1991; Kohro-Kawata et al., 2002; Zhong et al., 1997).
It is also useful to demonstrate immune complexes in the affected tissue
when tissue biopsy is available or needed for diagnostic purposes. Im-
munohistology showing co-localization of IgG and early components of
the complement cascade serves to demonstrate the presence of immune
complexes. To conclude that a particular antigen is responsible for immune
complex formation, it is necessary to show that the antigen is present at the
site of antibody deposition in tissue, or is within the circulating immune
complexes in plasma. It is not necessary to show that the entire antigen is
present, because serum and tissue proteases may digest much of the antigen
that is not protected within the antibody-binding site (Durkin et al., 2009).
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EVALUATING BIOLOGICAL MECHANISMS OF ADVERSE EVENTS
Therefore, negative studies for antigen may be considered inconclusive as
only a small moiety of antigen may remain and may not be easily detect-
able (i.e., antibody to the antigen may be targeted to previously digested
portions of the antigen).
Examples of Natural Infection, Vaccine, or Drug Exposure Thought to
Cause a Clinical Condition or Disease That Is Due to Immune Complexes
There are several conditions in which immune complex–mediated tissue
damage occurs.
• Hepatitis B infection is characterized by a number of accompany
ing comorbidities. Polyarteritis nodosum occurs in individuals with
chronic hepatitis, and is thought to be mediated by immune com-
plexes that include viral antigen and specific antibody (Cacoub and
Terrier, 2009).
• Some drug allergies can cause serum sickness which is an immune
complex disease with deposition of complexes in joints, pleura
or pericardium, and glomeruli causing local, generally reversible,
inflammation (Naguwa and Nelson, 1985).
• Systemic lupus is characterized by immune complexes in the circu-
lation, skin, pleura, and pericardium. When the immune complexes
are present in glomeruli, they cause glomerulonephritis, a serious
manifestation of the disease. The target antigens in lupus appear
to be apoptotic debris in circulating immune complexes, and both
trapped and tissue antigen in the kidney (Munoz et al., 2010). In
lupus, antibodies to the complement component C1q can bind to
tissue-bound immune complexes, making it difficult to clear the
complexes and increasing the consequent inflammation.
• Rheumatoid arthritis is a disease characterized by antibodies to IgG
(rheumatoid factor) and cyclic citrullinated peptide. Both antibod-
ies are thought to enhance inflammation in affected tissue, primar-
ily joints (Conrad et al., 2010; Wegner et al., 2010). In mouse
models, antibody-mediated enhancement of rheumatoid arthritis
has been demonstrated; in the human disease, the model remains
speculative.
• Streptococcal infections exhibit many antibodymediated sequelae.
In particular, arthritis and glomerulonephritis are considered to
be the consequence of circulating immune complexes that de-
posit in joints and glomeruli, initiating an inflammatory cascade
(Rodriguez-Iturbe and Batsford, 2007). These conditions are self-
limited because the immune complexes cease to form once strepto-
coccal antigen is eliminated.
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Albarran, B., L. Goncalves, S. Salmen, L. Borges, H. Fields, A. Soyano, H. Montes, and L.
Berrueta. 2005. Profiles of NK, NKT cell activation and cytokine production following
vaccination against hepatitis B. APMIS 113(7-8):526-535.
Albert, L. J., and R. D. Inman. 1999. Molecular mimicry and autoimmunity. New England
Journal of Medicine 341(27):2068-2074.
Anagnostou, E., and M. J. Taylor. 2011. Review of neuroimaging in autism spectrum dis-
orders: What have we learned and where we go from here. Molecular Autism 2(1):4.
Anderson, J. A., and J. I. Weitz. 2010. Hypercoagulable states. Clinics in Chest Medicine
31(4):659-673.
Anton, H. A. 1993. Frozen shoulder. Canadian Family Physician 39:1773-1778.
Arthur, W., and G. C. Kaye. 2000. The pathophysiology of common causes of syncope. Post-
graduate Medical Journal 76(902):750-753.
Aspinall, G. O., S. Fujimoto, A. G. McDonald, H. Pang, L. A. Kurjanczyk, and J. L. Penner.
1994a. Lipopolysaccharides from Campylobacter jejuni associated with Guillain-Barré
syndrome patients mimic human gangliosides in structure. Infection and Immunity
62(5):2122-2125.
Aspinall, G. O., A. G. McDonald, H. Pang, L. A. Kurjanczyk, and J. L. Penner. 1994b.
Lipopolysaccharides of Campylobacter jejuni serotype O:19: Structures of core oligo-
saccharide regions from the serostrain and two bacterial isolates from patients with the
Guillain-Barré syndrome. Biochemistry 33(1):241-249.
Audenaert, D., C. Van Broeckhoven, and P. De Jonghe. 2006. Genes and loci involved in
febrile seizures and related epilepsy syndromes. Human Mutation 27(5):391-401.
Avner, J. R. 2009. Acute fever. Pediatrics in Review 30(1):5-13.
Balosso, S., M. Maroso, M. Sanchez-Alavez, T. Ravizza, A. Frasca, T. Bartfai, and A. Vezzani.
2008. A novel non-transcriptional pathway mediates the proconvulsive effects of
interleukin-1beta. Brain 131(Pt 12):3256-3265.
Barnett, L. A., J. L. Whitton, L. Y. Wang, and R. S. Fujinami. 1996. Virus encoding an
encephalitogenic peptide protects mice from experimental allergic encephalomyelitis.
Journal of Neuroimmunology 64(2):163-173.
Bellamy, J. D., D. J. Booker, N. T. James, R. Stamps, and R. J. Sokol. 1997. Measurement
of red blood cell-bound C3b and C3d using an enzyme-linked direct antiglobulin test.
Immunohematology 13(4):123-131.
Berger, B. E., A. M. Navar-Boggan, and S. B. Omer. 2011. Congenital rubella syndrome and
autism spectrum disorder prevented by rubella vaccination—United States, 2001-2010.
BMC Public Health 11:340.
Berkovic, S. F., L. Harkin, J. M. McMahon, J. T. Pelekanos, S. M. Zuberi, E. C. Wirrell, D. S.
Gill, X. Iona, J. C. Mulley, and I. E. Scheffer. 2006. De-novo mutations of the sodium
channel gene SCN1A in alleged vaccine encephalopathy: A retrospective study. Lancet
Neurology 5(6):488-492.
Brue, S., A. Valentin, M. Forssblad, S. Werner, C. Mikkelsen, and G. Cerulli. 2007. Idio-
pathic adhesive capsulitis of the shoulder: A review. Knee Surgery, Sports Traumatology,
Arthroscopy 15(8):1048-1054.
Bruehl, S. 2010. An update on the pathophysiology of complex regional pain syndrome.
Anesthesiology 113(3):713-725.
Bruyn, G. A., B. J. Zegers, and R. van Furth. 1992. Mechanisms of host defense against infec-
tion with streptococcus pneumoniae. Clinical Infectious Diseases 14(1):251-262.
Cacoub, P., and B. Terrier. 2009. Hepatitis B-related autoimmune manifestations. Rheumatic
Diseases Clinics of North America 35(1):125-137.
Casanova, M., and J. Trippe. 2009. Radial cytoarchitecture and patterns of cortical connec-
tivity in autism. Philosophical Transactions of the Royal Society of London. Series B:
Biological Sciences 364(1522):1433-1436.
OCR for page 93
93
EVALUATING BIOLOGICAL MECHANISMS OF ADVERSE EVENTS
Casanova, M. F. 2007. The neuropathology of autism. Brain Pathology 17(4):422-433.
Cayrol, R., P. Saikali, and T. Vincent. 2009. Effector functions of antiaquaporin-4 autoantibodies
in neuromyelitis optica. Annals of the New York Academy of Sciences 1173:478-486.
Chan, Y., D. Smith, T. Sadlon, J. X. Scott, and P. N. Goldwater. 2007. Herpes zoster due to
Oka vaccine strain of varicella zoster virus in an immunosuppressed child post cord
blood transplant. Journal of Paediatrics & Child Health 43(10):713-715.
Chaplin, D. D. 2010. Overview of the immune response. Journal of Allergy and Clinical Im-
munology 125(2 Suppl. 2):S3-S23.
Chess, S. 1971. Autism in children with congenital rubella. Journal of Autism and Childhood
Schizophrenia 1(1):33-47.
Chouliaras, G., V. Spoulou, M. Quinlivan, J. Breuer, and M. Theodoridou. 2010. Vaccine-
associated herpes zoster ophthalmicus [correction of opthalmicus] and encephalitis in an
immunocompetent child. Pediatrics 125(4):e969-e972.
Coffman, R. L., A. Sher, and R. A. Seder. 2010. Vaccine adjuvants: Putting innate immunity
to work. Immunity 33(4):492-503.
Conrad, K., D. Roggenbuck, D. Reinhold, and T. Dorner. 2010. Profiling of rheumatoid ar-
thritis associated autoantibodies. Autoimmunity Reviews 9(6):431-435.
Corey, L. A., K. Berg, J. M. Pellock, M. H. Solaas, W. E. Nance, and R. J. DeLorenzo. 1991.
The occurrence of epilepsy and febrile seizures in Virginian and Norwegian twins. Neu-
rology 41(9):1433-1436.
Creten, C., S. van der Zwaan, R. J. Blankespoor, A. Maatkamp, J. Nicolai, J. van Os, and J. N.
Schieveld. 2011. Late onset autism and anti-NMDA-receptor encephalitis. 378(9785):98.
Crockard, A. D., J. M. Thompson, M. B. Finch, T. A. McNeill, A. L. Bell, and S. D. Roberts.
1991. Immunoglobulin isotype composition of circulating and intra-articular immune
complexes in patients with inflammatory joint disease. Rheumatology International
11(4-5):169-174.
Davies, J. M. 2000. Introduction: Epitope mimicry as a component cause of autoimmune
disease. Cellular and Molecular Life Sciences 57(4):523-526.
DeLong, G. R., S. C. Bean, and F. R. Brown, 3rd. 1981. Acquired reversible autistic syndrome
in acute encephalopathic illness in children. Archives of Neurology 38(3):191-194.
Dias, R., S. Cutts, and S. Massoud. 2005. Frozen shoulder. British Medical Journal 331(7530):
1453-1456.
Dover, C. J., and A. Le Couteur. 2007. How to diagnose autism. Archives of Disease in Child-
hood 92(6):540-545.
Dube, C. M., T. Ravizza, M. Hamamura, Q. Zha, A. Keebaugh, K. Fok, A. L. Andres, O.
Nalcioglu, A. Obenaus, A. Vezzani, and T. Z. Baram. 2010. Epileptogenesis provoked
by prolonged experimental febrile seizures: Mechanisms and biomarkers. Journal of
Neuroscience 30(22):7484-7494.
Dufour-Rainfray, D., P. Vourc’h, S. Tourlet, D. Guilloteau, S. Chalon, and C. R. Andres. 2011.
Fetal exposure to teratogens: Evidence of genes involved in autism. Neuroscience and
Biobehavioral Reviews 35(5):1254-1265.
Dunkelberger, J. R., and W. C. Song. 2010. Complement and its role in innate and adaptive
immune responses. Cell Research 20(1):34-50.
Durkin, M., L. Estok, D. Hospenthal, N. Crum-Cianflone, S. Swartzentruber, E. Hackett, and
L. J. Wheat. 2009. Detection of coccidioides antigenemia following dissociation of im-
mune complexes. Clinical and Vaccine Immunology 16(10):1453-1456.
Eapen, V. 2011. Genetic basis of autism: Is there a way forward? Current Opinion in Psy-
chiatry 24(3):226-236.
Elkon, K., and P. Casali. 2008. Nature and functions of autoantibodies. Nature Clinical Prac-
tice Rheumatology 4(9):491-498.
OCR for page 94
94 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
Ey, E., C. S. Leblond, and T. Bourgeron. 2011. Behavioral profiles of mouse models for autism
spectrum disorders. Autism Research 4(1):5-16.
Fenton, A. M., S. C. Hammill, R. F. Rea, P. A. Low, and W. K. Shen. 2000. Vasovagal syncope.
Annals of Internal Medicine 133(9):714-725.
Frye, R. E., and D. A. Rossignol. 2011. Mitochondrial dysfunction can connect the diverse
medical symptoms associated with autism spectrum disorders. Pediatric Research
69(5 Pt 2):41R-47R.
Fujinami, R. S., and M. B. Oldstone. 1985. Amino acid homology between the encephali-
togenic site of myelin basic protein and virus: Mechanism for autoimmunity. Science
230(4729):1043-1045.
Fujinami, R. S., M. G. von Herrath, U. Christen, and J. L. Whitton. 2006. Molecular mimicry,
bystander activation, or viral persistence: Infections and autoimmune disease. Clinical
Microbiology Reviews 19(1):80-94.
Fukuda, S., K. Ishikawa, and Y. Inuyama. 1994. Acute measles infection in the hamster
cochlea. Acta Oto-Laryngologica 514:111-116.
Galea, S. A., A. Sweet, P. Beninger, S. P. Steinberg, P. S. LaRussa, A. A. Gershon, and R. G.
Sharrar. 2008. The safety profile of varicella vaccine: A 10-year review. Journal of Infec-
tious Diseases 197(Suppl. 2):S165-S169.
Gangarosa, E. J., A. M. Galazka, C. R. Wolfe, L. M. Phillips, R. E. Gangarosa, E. Miller, and
R. T. Chen. 1998. Impact of anti-vaccine movements on pertussis control: The untold
story. Lancet 351(9099):356-361.
Gao, H., T. Neff, and P. A. Ward. 2006. Regulation of lung inflammation in the model of IgG
immune-complex injury. Annual Review of Pathology 1:215-242.
Garcia-Pineres, A., A. Hildesheim, L. Dodd, T. J. Kemp, M. Williams, C. Harro, D. R. Lowy,
J. T. Schiller, and L. A. Pinto. 2007. Cytokine and chemokine profiles following vaccina-
tion with human papillomavirus type 16 L1 virus-like particles. Clinical and Vaccine
Immunology 14(8):984-989.
Gershon, A. A. 2010. Measles virus (rubeola). In Mandell, Douglas, and Bennett’s principles
and practice of infectious diseases. 7th ed. 2 vols. Vol. 2, edited by G. L. Mandell, J. E.
Bennett, and R. Dolin. Philadelphia, PA: Churchill Livingstone Elsevier. Pp. 2229-2236.
Gershon, A. A., J. Chen, and M. D. Gershon. 2008. A model of lytic, latent, and reactivating
varicella-zoster virus infections in isolated enteric neurons. Journal of Infectious Diseases
197(Suppl. 2):S61-S65.
Ghaffar, F., K. Carrick, B. B. Rogers, L. R. Margraf, K. Krisher, and O. Ramilo. 2000. Dissemi-
nated infection with varicella-zoster virus vaccine strain presenting as hepatitis in a child
with adenosine deaminase deficiency. Pediatric Infectious Disease Journal 19(8):764-766.
Ghaziuddin, M., I. Al-Khouri, and N. Ghaziuddin. 2002. Autistic symptoms following herpes
encephalitis. European Child and Adolescent Psychiatry 11(3):142-146.
Ghaziuddin, M., L. Y. Tsai, L. Eilers, and N. Ghaziuddin. 1992. Brief report: Autism and her-
pes simplex encephalitis. Journal of Autism and Developmental Disorders 22(1):107-113.
Gillberg, C. 1986. Onset at age 14 of a typical autistic syndrome. A case report of a girl with
herpes simplex encephalitis. Journal of Autism and Developmental Disorders 16(3):
369-375.
Goines, P., and J. Van de Water. 2010. The immune system’s role in the biology of autism.
Current Opinion in Neurology 23(2):111-117.
Green, D. 2006. Coagulation cascade. Hemodialysis International 10(Suppl. 2):S2-S4.
Griffin, J. W., C. Y. Li, T. W. Ho, M. Tian, C. Y. Gao, P. Xue, B. Mishu, D. R. Cornblath,
C. Macko, G. M. McKhann, and A. K. Asbury. 1996. Pathology of the motor-sensory
axonal Guillain-Barré syndrome. Annals of Neurology 39(1):17-28.
Gros, P., F. J. Milder, and B. J. Janssen. 2008. Complement driven by conformational changes.
Nature Reviews Immunology 8(1):48-58.
OCR for page 95
95
EVALUATING BIOLOGICAL MECHANISMS OF ADVERSE EVENTS
Grubb, B. P. 2005. Neurocardiogenic syncope. In Syncope: Mechanisms and management.
2nd ed., edited by B. P. Grubb and B. Olshansky. Malden, MA: Blackwell Publishing.
Pp. 47-71.
Guermonprez, P., J. Valladeau, L. Zitvogel, C. Thery, and S. Amigorena. 2002. Antigen
presentation and T cell stimulation by dendritic cells. Annual Review of Immunology
20:621-667.
The Guillain-Barré Syndrome Study Group. 1985. Plasmapheresis and acute Guillain-Barré
syndrome. Neurology 35(8):1096-1104.
Hafer-Macko, C., S. T. Hsieh, C. Y. Li, T. W. Ho, K. Sheikh, D. R. Cornblath, G. M.
McKhann, A. K. Asbury, and J. W. Griffin. 1996. Acute motor axonal neuropathy: An
antibody-mediated attack on axolemma. Annals of Neurology 40(4):635-644.
Han, T., and W. A. Marasco. 2011. Structural basis of influenza virus neutralization. Annals
of the New York Academy of Sciences 1217:178-190.
Harty, J. T., A. R. Tvinnereim, and D. W. White. 2000. CD8+ T cell effector mechanisms in
resistance to infection. Annual Review of Immunology 18:275-308.
Hedera, P., S. Ma, M. A. Blair, K. A. Taylor, A. Hamati, Y. Bradford, B. Abou-Khalil, and
J. L. Haines. 2006. Identification of a novel locus for febrile seizures and epilepsy on
chromosome 21q22. Epilepsia 47(10):1622-1628.
Heida, J. G., S. L. Moshe, and Q. J. Pittman. 2009. The role of interleukin-1 beta in febrile
seizures. Brain and Development 31(5):388-393.
Herbert, M. R. 2005. Large brains in autism: The challenge of pervasive abnormality. The
Neuroscientist 11(5):417-440.
Holers, V. M. 2008. The spectrum of complement alternative pathway-mediated diseases.
Immunological Reviews 223:300-316.
Hornig, M., M. Solbrig, N. Horscroft, H. Weissenbock, and W. I. Lipkin. 2001. Borna disease
virus infection of adult and neonatal rats: Models for neuropsychiatric disease. Current
Topics in Microbiology and Immunology 253:157-177.
Illa, I., N. Ortiz, E. Gallard, C. Juarez, J. M. Grau, and M. C. Dalakas. 1995. Acute axonal
Guillain-Barré syndrome with IgG antibodies against motor axons following parenteral
gangliosides. Annals of Neurology 38(2):218-224.
IOM (Institute of Medicine). 2006. Genes, behavior, and the social environment: Moving
beyond the nature/nurture debate. Washington, DC: The National Academies Press.
Iyer, S., M. K. Mittal, and R. L. Hodinka. 2009. Herpes zoster and meningitis resulting from
reactivation of varicella vaccine virus in an immunocompetent child. Annals of Emer-
gency Medicine 53(6):792-795.
Johnson, E. W., J. Dubovsky, S. S. Rich, C. A. O’Donovan, H. T. Orr, V. E. Anderson, A.
Gil-Nagel, P. Ahmann, C. G. Dokken, D. T. Schneider, and J. L. Weber. 1998. Evidence
for a novel gene for familial febrile convulsions, FEB2, linked to chromosome 19p in an
extended family from the midwest. Human Molecular Genetics 7(1):63-67.
Kohro-Kawata, J., M. H. Wener, and M. Mannik. 2002. The effect of high salt concentration
on detection of serum immune complexes and autoantibodies to C1q in patients with
systemic lupus erythematosus. Journal of Rheumatology 29(1):84-89.
Koretzky, G. A. 2008. T lymphocyte signaling mechanisms and activation. In Fundamental
immunology. 6th ed., edited by W. E. Paul. Philadelphia, PA: Lippincott Williams &
Wilkins. Pp. 347-375.
Koziel, M. J., and C. L. Thio. 2010. Hepatitis B virus and hepatitis delta virus. In Mandell,
Douglas, and Bennett’s principles and practice of infectious diseases. 7th ed. 2 vols. Vol.
2, edited by G. L. Mandell, J. E. Bennett, and R. Dolin. Philadelphia, PA: Churchill
Livingstone Elsevier. Pp. 2059-2086.
OCR for page 96
96 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
Kramer, J. M., P. LaRussa, W. C. Tsai, P. Carney, S. M. Leber, S. Gahagan, S. Steinberg,
and R. A. Blackwood. 2001. Disseminated vaccine strain varicella as the acquired
immunodeficiency syndrome-defining illness in a previously undiagnosed child. Pediatrics
108(2):e39.
Kugler, S. L., E. S. Stenroos, D. E. Mandelbaum, T. Lehner, V. V. McKoy, T. Prossick, J.
Sasvari, K. Swannick, J. Katz, and W. G. Johnson. 1998. Hereditary febrile seizures:
Phenotype and evidence for a chromosome 19p locus. American Journal of Medical
Genetics 79(5):354-361.
Kuwabara, S., K. Ogawara, S. Misawa, M. Koga, M. Mori, A. Hiraga, T. Kanesaka, T.
Hattori, and N. Yuki. 2004. Does Campylobacter jejuni infection elicit “demyelinating”
Guillain-Barré syndrome? Neurology 63(3):529-533.
Landrigan, P. J. 2010. What causes autism? Exploring the environmental contribution. Current
Opinion in Pediatrics 22(2):219-225.
Lee, G., Y. Jeong, I. Wirguin, A. P. Hays, H. J. Willison, and N. Latov. 2004. Induction of human
IgM and IgG anti-GM1 antibodies in transgenic mice in response to lipopolysaccharides
from Campylobacter jejuni. Journal of Neuroimmunology 146(1-2):63-75.
Levin, M. J., K. M. Dahl, A. Weinberg, R. Giller, A. Patel, and P. R. Krause. 2003. Develop-
ment of resistance to acyclovir during chronic infection with the Oka vaccine strain of
varicella-zoster virus, in an immunosuppressed child. Journal of Infectious Diseases
188(7):954-959.
Levin, M. J., R. L. DeBiasi, V. Bostik, and D. S. Schmid. 2008. Herpes zoster with skin lesions
and meningitis caused by 2 different genotypes of the Oka varicella-zoster virus vaccine.
Journal of Infectious Diseases 198(10):1444-1447.
Levy, O., J. S. Orange, P. Hibberd, S. Steinberg, P. LaRussa, A. Weinberg, S. B. Wilson, A.
Shaulov, G. Fleisher, R. S. Geha, F. A. Bonilla, and M. Exley. 2003. Disseminated vari-
cella infection due to the vaccine strain of varicella-zoster virus, in a patient with a novel
deficiency in natural killer T cells. Journal of Infectious Diseases 188(7):948-953.
Li, H., A. Llera, E. L. Malchiodi, and R. A. Mariuzza. 1999. The structural basis of T cell
activation by superantigens. Annual Review of Immunology 17:435-466.
Lord, C., M. Rutter, S. Goode, J. Heemsbergen, H. Jordan, L. Mawhood, and E. Schopler.
1989. Autism diagnostic observation schedule: A standardized observation of commu-
nicative and social behavior. Journal of Autism and Developmental Disorders 19(2):
185-212.
Malbec, O., and M. Daeron. 2007. The mast cell IgG receptors and their roles in tissue inflam-
mation. Immunological Reviews 217:206-221.
Mankoski, R. E., M. Collins, N. K. Ndosi, E. H. Mgalla, V. V. Sarwatt, and S. E. Folstein.
2006. Etiologies of autism in a case-series from Tanzania. Journal of Autism and Devel-
opmental Disorders 36(8):1039-1051.
Mayadas, T. N., G. C. Tsokos, and N. Tsuboi. 2009. Mechanisms of immune complex-
mediated neutrophil recruitment and tissue injury. Circulation 120(20):2012-2024.
McIntosh, A. M., J. McMahon, L. M. Dibbens, X. Iona, J. C. Mulley, I. E. Scheffer, and S. F.
Berkovic. 2010. Effects of vaccination on onset and outcome of Dravet syndrome: A
retrospective study. Lancet Neurology 9(6):592-598.
Miles, J. H. 2011. Autism spectrum disorders—a genetics review. Genetics in Medicine
13(4):278-294.
Moran, A. P., H. Annuk, and M. M. Prendergast. 2005. Antibodies induced by ganglioside-
mimicking Campylobacter jejuni lipooligosaccharides recognise epitopes at the nodes of
Ranvier. Journal of Neuroimmunology 165(1-2):179-185.
Munoz, L. E., C. Janko, C. Schulze, C. Schorn, K. Sarter, G. Schett, and M. Herrmann. 2010.
Autoimmunity and chronic inflammation—two clearance-related steps in the etiopatho-
genesis of SLE. Autoimmunity Reviews 10(1):38-42.
OCR for page 97
97
EVALUATING BIOLOGICAL MECHANISMS OF ADVERSE EVENTS
Nabbout, R., J. F. Prud’homme, A. Herman, J. Feingold, A. Brice, O. Dulac, and E. LeGuern.
2002. A locus for simple pure febrile seizures maps to chromosome 6q22-q24. Brain
125(Pt 12):2668-2680.
Naguwa, S. M., and B. L. Nelson. 1985. Human serum sickness. Clinical Reviews in Allergy
3(1):117-126.
Nakayama, J. 2009. Progress in searching for the febrile seizure susceptibility genes. Brain
and Development 31(5):359-365.
Nakayama, J., Y. H. Fu, A. M. Clark, S. Nakahara, K. Hamano, N. Iwasaki, A. Matsui, T.
Arinami, and L. J. Ptacek. 2002. A nonsense mutation of the mass1 gene in a family with
febrile and afebrile seizures. Annals of Neurology 52(5):654-657.
Nakayama, J., K. Hamano, N. Iwasaki, S. Nakahara, Y. Horigome, H. Saitoh, T. Aoki,
T. Maki, M. Kikuchi, T. Migita, T. Ohto, Y. Yokouchi, R. Tanaka, M. Hasegawa, A.
Matsui, H. Hamaguchi, and T. Arinami. 2000. Significant evidence for linkage of febrile
seizures to chromosome 5q14-q15. Human Molecular Genetics 9(1):87-91.
Nakayama, J., N. Yamamoto, K. Hamano, N. Iwasaki, M. Ohta, S. Nakahara, A. Matsui, E.
Noguchi, and T. Arinami. 2004. Linkage and association of febrile seizures to the IMPA2
gene on human chromosome 18. Neurology 63(10):1803-1807.
Noone, M. C., and J. D. Osguthorpe. 2003. Anaphylaxis. Otolaryngologic Clinics of North
America 36(5):1009-1020.
Offringa, M., P. M. Bossuyt, J. Lubsen, J. H. Ellenberg, K. B. Nelson, F. U. Knudsen, J. F.
Annegers, A. S. el-Radhi, J. D. Habbema, G. Derksen-Lubsen, et al. 1994. Risk factors
for seizure recurrence in children with febrile seizures: A pooled analysis of individual
patient data from five studies. Journal of Pediatrics 124(4):574-584.
Ogawara, K., S. Kuwabara, M. Mori, T. Hattori, M. Koga, and N. Yuki. 2000. Axonal
Guillain-Barré syndrome: Relation to anti-ganglioside antibodies and Campylobacter
jejuni infection in Japan. Annals of Neurology 48(4):624-631.
Oldstone, M. B. 2005. Molecular mimicry, microbial infection, and autoimmune disease:
Evolution of the concept. Current Topics in Microbiology and Immunology 296:1-17.
Pardo, C. A., D. L. Vargas, and A. W. Zimmerman. 2005. Immunity, neuroglia and neuroin-
flammation in autism. International Reviews of Psychiatry 17(6):485-495.
Peiffer, A., J. Thompson, C. Charlier, B. Otterud, T. Varvil, C. Pappas, C. Barnitz, K. Gruenthal,
R. Kuhn, and M. Leppert. 1999. A locus for febrile seizures (FEB3) maps to chromosome
2q23-24. Annals of Neurology 46(4):671-678.
Petrovski, S., I. E. Scheffer, S. M. Sisodiya, T. J. O’Brien, and S. F. Berkovic. 2009. Lack of
replication of association between SCN1A SNP and febrile seizures. Neurology 73(22):
1928-1930.
Pittman, P. R. 2002. Aluminum-containing vaccine associated adverse events: Role of route of
administration and gender. Vaccine 20:S48-S50.
Poduri, A., Y. Wang, D. Gordon, S. Barral-Rodriguez, C. Barker-Cummings, A. Ulgen, V.
Chitsazzadeh, R. S. Hill, N. Risch, W. A. Hauser, T. A. Pedley, C. A. Walsh, and R.
Ottman. 2009. Novel susceptibility locus at chromosome 6q16.3-22.31 in a family with
GEFS+. Neurology 73(16):1264-1272.
Poirriez, J. 2004. A preliminary experiment of absorption of antinuclear antibodies by the
hepatitis B vaccine components, in a case of neurolupus. Vaccine 22(23-24):3166-3168.
Prendergast, M. M., A. J. Lastovica, and A. P. Moran. 1998. Lipopolysaccharides from Cam-
pylobacter jejuni O:41 strains associated with Guillain-Barré syndrome exhibit mimicry
of GM1 ganglioside. Infection and Immunity 66(8):3649-3655.
Pukhalsky, A. L., G. V. Shmarina, M. S. Bliacher, I. M. Fedorova, A. P. Toptygina, J. J. Fisenko,
and V. A. Alioshkin. 2003. Cytokine profile after rubella vaccine inoculation: Evidence of
the immunosuppressive effect of vaccination. Mediators of Inflammation 12(4):203-207.
OCR for page 98
98 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
Rees, J. H., N. A. Gregson, and R. A. Hughes. 1995a. Anti-ganglioside GM1 antibodies in
Guillain-Barré syndrome and their relationship to Campylobacter jejuni infection. Annals
of Neurology 38(5):809-816.
Rees, J. H., S. E. Soudain, N. A. Gregson, and R. A. Hughes. 1995b. Campylobacter jejuni
infection and Guillain-Barré syndrome. New England Journal of Medicine 333(21):
1374-1379.
Reif, D. M., A. A. Motsinger-Reif, B. A. McKinney, M. T. Rock, J. E. Crowe, Jr., and J. H.
Moore. 2009. Integrated analysis of genetic and proteomic data identifies biomarkers
associated with adverse events following smallpox vaccination. Genes and Immunity
10(2):112-119.
Rezaie, A. R. 2010. Regulation of the protein C anticoagulant and antiinflammatory path-
ways. Current Medicinal Chemistry 17(19):2059-2069.
Rodgers, G. M. 2009. Role of antithrombin concentrate in treatment of hereditary antithrom-
bin deficiency. An update. Thrombosis and Haemostasis 101(5):806-812.
Rodriguez-Iturbe, B., and S. Batsford. 2007. Pathogenesis of poststreptococcal glomerulone-
phritis a century after Clemens von Pirquet. Kidney International 71(11):1094-1104.
Ronald, A., and R. A. Hoekstra. 2011. Autism spectrum disorders and autistic traits: A decade
of new twin studies. American Journal of Medical Genetics. Part B, Neuropsychiatric
Genetics 156B(3):255-274.
Rose, N. R., and I. R. Mackay. 2000. Molecular mimicry: A critical look at exemplary in-
stances in human diseases. Cellular and Molecular Life Sciences 57(4):542-551.
Roubin, R., and J. Benveniste. 1985. Formation of prostaglandins, leukotrienes and paf-
acether by macrophages. Comparative Immunology, Microbiology and Infectious Dis-
eases 8(2):109-118.
Rus, H., C. Cudrici, and F. Niculescu. 2005. The role of the complement system in innate
immunity. Immunologic Research 33(2):103-112.
Sadleir, L. G., and I. E. Scheffer. 2007. Febrile seizures. British Medical Journal 334(7588):
307-311.
Sampson, H. A., A. Munoz-Furlong, R. L. Campbell, N. F. Adkinson, Jr., S. A. Bock, A.
Branum, S. G. Brown, C. A. Camargo, Jr., R. Cydulka, S. J. Galli, J. Gidudu, R. S.
Gruchalla, A. D. Harlor, Jr., D. L. Hepner, L. M. Lewis, P. L. Lieberman, D. D. Metcalfe,
R. O’Connor, A. Muraro, A. Rudman, C. Schmitt, D. Scherrer, F. E. Simons, S. Thomas,
J. P. Wood, and W. W. Decker. 2006. Second symposium on the definition and manage-
ment of anaphylaxis: Summary report—Second National Institute of Allergy and Infec-
tious Disease/Food Allergy and Anaphylaxis Network symposium. Journal of Allergy and
Clinical Immunology 117(2):391-397.
Sansonno, D., A. Carbone, V. De Re, and F. Dammacco. 2007. Hepatitis C virus infection,
cryoglobulinaemia, and beyond. Rheumatology 46(4):572-578.
Sarma, J. V., and P. A. Ward. 2011. The complement system. Cell and Tissue Research
343(1):227-235.
Schipul, S. E., T. A. Keller, and M. A. Just. 2011. Inter-regional brain communication and its
disturbance in autism. Frontiers in Systems Neuroscience 5:10.
Schlachter, K., U. Gruber-Sedlmayr, E. Stogmann, M. Lausecker, C. Hotzy, J. Balzar, E. Schuh,
C. Baumgartner, J. C. Mueller, T. Illig, H. E. Wichmann, P. Lichtner, T. Meitinger, T. M.
Strom, A. Zimprich, and F. Zimprich. 2009. A splice site variant in the sodium channel
gene SCN1A confers risk of febrile seizures. Neurology 72(11):974-978.
Schuchmann, S., D. Schmitz, C. Rivera, S. Vanhatalo, B. Salmen, K. Mackie, S. T. Sipila,
J. Voipio, and K. Kaila. 2006. Experimental febrile seizures are precipitated by a
hyperthermia-induced respiratory alkalosis. Nature Medicine 12(7):817-823.
OCR for page 99
99
EVALUATING BIOLOGICAL MECHANISMS OF ADVERSE EVENTS
Shantsila, E., and G. Y. Lip. 2009. The role of monocytes in thrombotic disorders. Insights
from tissue factor, monocyte-platelet aggregates and novel mechanisms. Thrombosis and
Haemostasis 102(5):916-924.
Sharrar, R. G., P. LaRussa, S. A. Galea, S. P. Steinberg, A. R. Sweet, R. M. Keatley, M. E.
Wells, W. P. Stephenson, and A. A. Gershon. 2001. The postmarketing safety profile of
varicella vaccine. Vaccine 19(7-8):916-923.
Shibasaki, K., M. Suzuki, A. Mizuno, and M. Tominaga. 2007. Effects of body temperature
on neural activity in the hippocampus: Regulation of resting membrane potentials by
transient receptor potential vanilloid 4. Journal of Neuroscience 27(7):1566-1575.
Sidhu, G., and G. A. Soff. 2009. The coagulation system and angiogenesis. Cancer Treatment
and Research 148:67-80.
Simons, F. E. 2009. Anaphylaxis: Recent advances in assessment and treatment. Journal of
Allergy and Clinical Immunology 124(4):625-636; quiz 637-628.
Simons, F. E. 2010. Anaphylaxis. Journal of Allergy and Clinical Immunology 125(2 Suppl.
2):S161-S181.
Soghoian, D. Z., and H. Streeck. 2010. Cytolytic CD4(+) T cells in viral immunity. Expert
Reviews of Vaccines 9(12):1453-1463.
Solomon, T., and H. Willison. 2003. Infectious causes of acute flaccid paralysis. Current
Opinion in Infectious Diseases 16(5):375-381.
Sriskandan, S., and D. M. Altmann. 2008. The immunology of sepsis. Journal of Pathology
214(2):211-223.
Sudhof, T. C. 2008. Neuroligins and neurexins link synaptic function to cognitive disease.
Nature 455(7215):903-911.
Susuki, K., Y. Nishimoto, M. Koga, T. Nagashima, I. Mori, K. Hirata, and N. Yuki. 2004.
Various immunization protocols for an acute motor axonal neuropathy rabbit model
compared. Neuroscience Letters 368(1):63-67.
Susuki, K., Y. Nishimoto, M. Yamada, M. Baba, S. Ueda, K. Hirata, and N. Yuki. 2003. Acute
motor axonal neuropathy rabbit model: Immune attack on nerve root axons. Annals of
Neurology 54(3):383-388.
Szyper-Kravitz, M. 2009. The hemophagocytic syndrome/macrophage activation syndrome: A
final common pathway of a cytokine storm. Israel Medical Association Journal 11(10):
633-634.
Talbot, T. R., J. T. Stapleton, R. C. Brady, P. L. Winokur, D. I. Bernstein, T. Germanson, S. M.
Yoder, M. T. Rock, J. E. Crowe, Jr., and K. M. Edwards. 2004. Vaccination success rate
and reaction profile with diluted and undiluted smallpox vaccine a randomized controlled
trial. Journal of the American Medical Association 292(10):1205-1212.
Tedeschi, A., C. Barate, E. Minola, and E. Morra. 2007. Cryoglobulinemia. Blood Reviews
21(4):183-200.
Theoharides, T. C., D. Kempuraj, and L. Redwood. 2009. Autism: An emerging “neuroimmune
disorder” in search of therapy. Expert Opinion on Pharmacotherapy 10(13):2127-2143.
Thomas, E. A., R. J. Hawkins, K. L. Richards, R. Xu, E. V. Gazina, and S. Petrou. 2009.
Heat opens axon initial segment sodium channels: A febrile seizure mechanism? Annals
of Neurology 66(2):219-226.
Tritto, E., F. Mosca, and E. De Gregorio. 2009. Mechanism of action of licensed vaccine
adjuvants. Vaccine 27(25-26):3331-3334.
Tsuboi, T. 1987. Genetic analysis of febrile convulsions: Twin and family studies. Human
Genetics 75(1):7-14.
van Dijk, J. G., R. D. Thijs, D. G. Benditt, and W. Wieling. 2009. A guide to disorders caus-
ing transient loss of consciousness: Focus on syncope. Nature Reviews. Neurology.
5(8):438-448.
OCR for page 100
100 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
van Rossum, A. P., P. C. Limburg, and C. G. Kallenberg. 2005. Activation, apoptosis, and
clearance of neutrophils in Wegener’s granulomatosis. Annals of the New York Academy
of Sciences 1051:1-11.
Vanderlugt, C. L., W. S. Begolka, K. L. Neville, Y. Katz-Levy, L. M. Howard, T. N. Eagar, J. A.
Bluestone, and S. D. Miller. 1998. The functional significance of epitope spreading and
its regulation by co-stimulatory molecules. Immunological Reviews 164:63-72.
Vargas, D. L., C. Nascimbene, C. Krishnan, A. W. Zimmerman, and C. A. Pardo. 2005.
Neuroglial activation and neuroinflammation in the brain of patients with autism. Annals
of Neurology 57(1):67-81.
Visser, L. H., F. G. Van der Meche, P. A. Van Doorn, J. Meulstee, B. C. Jacobs, P. G. Oomes,
and R. P. Kleyweg. 1995. Guillain-Barré syndrome without sensory loss (acute motor
neuropathy). A subgroup with specific clinical, electrodiagnostic and laboratory features.
Dutch Guillain-Barré study group. Brain 118 (Pt 4):841-847.
Volanakis, J. E. 1990. Participation of C3 and its ligands in complement activation. Current
Topics in Microbiology and Immunology 153:1-21.
Wallace, R. H., S. F. Berkovic, R. A. Howell, G. R. Sutherland, and J. C. Mulley. 1996. Sug-
gestion of a major gene for familial febrile convulsions mapping to 8q13-21. Journal of
Medical Genetics 33(4):308-312.
Wan, Y. Y., and R. A. Flavell. 2009. How diverse—CD4 effector T cells and their functions.
Journal of Molecular Cell Biology 1(1):20-36.
Waruiru, C., and R. Appleton. 2004. Febrile seizures: An update. Archives of Disease in
Childhood 89(8):751-756.
Wass, S. 2011. Distortions and disconnections: Disrupted brain connectivity in autism. Brain
and Cognition 75(1):18-28.
Watanabe, M., K. Uchida, K. Nakagaki, B. C. Trapnell, and K. Nakata. 2010. High avidity
cytokine autoantibodies in health and disease: Pathogenesis and mechanisms. Cytokine
and Growth Factor Reviews 21(4):263-273.
Waters, V., K. S. Peterson, and P. LaRussa. 2007. Live viral vaccines in a DiGeorge syndrome
patient. Archives of Disease in Childhood 92(6):519-520.
Wegner, N., K. Lundberg, A. Kinloch, B. Fisher, V. Malmstrom, M. Feldmann, and P. J.
Venables. 2010. Autoimmunity to specific citrullinated proteins gives the first clues to the
etiology of rheumatoid arthritis. Immunological Reviews 233(1):34-54.
Whitley, R. J. 2010. Varicella-zoster virus. In Mandell, Douglas, and Bennett’s principles
and practice of infectious diseases. 7th ed. 2 vols. Vol. 2, edited by G. L. Mandell, J. E.
Bennett, and R. Dolin. Philadelphia, PA: Churchill Livingstone Elsevier. Pp. 1963-1969.
Wieling, W., R. D. Thijs, N. van Dijk, A. A. Wilde, D. G. Benditt, and J. G. van Dijk. 2009.
Symptoms and signs of syncope: A review of the link between physiology and clinical
clues. Brain 132(Pt 10):2630-2642.
Willison, H. J., and N. Yuki. 2002. Peripheral neuropathies and anti-glycolipid antibodies.
Brain 125(Pt 12):2591-2625.
Wiznitzer, M. 2010. Dravet syndrome and vaccination: When science prevails over specula-
tion. Lancet Neurology 9(6):559-561.
Wong, S. S., and K. Y. Yuen. 2006. Avian influenza virus infections in humans. Chest 129(1):
156-168.
Yang, Y., S. Sujan, F. Sun, Y. Zhang, Y. Jiang, J. Song, J. Qin, and X. Wu. 2006. Acute
metabolic crisis induced by vaccination in seven Chinese patients. Pediatric Neurology
35(2):114-118.
Yokoyama, T., K. Tateishi, K. Tsushima, T. Agatsuma, H. Yamamoto, T. Koizumi, and K. Kubo.
2010. A case of severe ARDS caused by novel swine-origin influenza (A/H1N1pdm) virus:
A successful treatment with direct hemoperfusion with polymyxin B-immobilized fiber.
Journal of Clinical Apheresis 25(6):350-353.
OCR for page 101
101
EVALUATING BIOLOGICAL MECHANISMS OF ADVERSE EVENTS
Yuki, N. 2005. Carbohydrate mimicry: A new paradigm of autoimmune diseases. Current
Opinion in Immunology 17(6):577-582.
Yuki, N., K. Susuki, M. Koga, Y. Nishimoto, M. Odaka, K. Hirata, K. Taguchi, T. Miyatake,
K. Furukawa, T. Kobata, and M. Yamada. 2004. Carbohydrate mimicry between human
ganglioside GM1 and Campylobacter jejuni lipooligosaccharide causes Guillain-Barré
syndrome. Proceedings of the National Academy of Sciences of the United States of
America 101(31):11404-11409.
Yuki, N., T. Taki, F. Inagaki, T. Kasama, M. Takahashi, K. Saito, S. Handa, and T. Miyatake.
1993. A bacterium lipopolysaccharide that elicits Guillain-Barré syndrome has a GM1
ganglioside-like structure. Journal of Experimental Medicine 178(5):1771-1775.
Zelenay, S., M. F. Moraes Fontes, C. Fesel, J. Demengeot, and A. Coutinho. 2007. Physiopa-
thology of natural auto-antibodies: The case for regulation. Journal of Autoimmunity
29(4):229-235.
Zhong, W., P. Oschmann, and H. J. Wellensiek. 1997. Detection and preliminary characteriza-
tion of circulating immune complexes in patients with Lyme disease. Medical Microbiol-
ogy and Immunology 186(2-3):153-158.
Zimmerman, A. W., H. Jyonouchi, A. M. Comi, S. L. Connors, S. Milstien, A. Varsou, and
M. P. Heyes. 2005. Cerebrospinal fluid and serum markers of inflammation in autism.
Pediatric Neurology 33(3):195-201.
OCR for page 102
