3

Evaluating Biological Mechanisms
of Adverse Events

Charged with reporting on biological mechanisms, the committee reviewed 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 immunodeficiency. 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



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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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59 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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61 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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63 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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65 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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67 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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92 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY 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 57
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 57
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 57
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 57
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 57
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 57
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 57
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 57
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 57
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 57