4.1     Timing

     The central nervous system (CNS) is known to be susceptible to environmental insult (e.g., toxins and allergens) especially during prenatal/neonatal development. [ 37]  The CNS is particularly vulnerable at this stage in that there is a proliferation of nerve cell reproduction, growth, and migration.  A study indicates that allergen exposure and sensitization during pregnancy favor the development of atopy in the neonate [ 38 ]  In humans, repeated exposure to the antigenic proteins during pregnancy may effect the genetic code of immune cells making the fetus more susceptible to ASD. [ 39 ] 

    A study has indicated that 75% of people with a natural-latex allergy are female [ 40 ] and this is possibly due to a higher proportion of women in the exposed population.  For example, additional exposure risks may arise from: a) obstetric procedures; b) gynecological examinations; c) contact with contraceptives; and d) certain female professions (e.g., doctors, nurses, scientists) which carry an increased risk of occupational exposure to the Hev-b proteins.  Thus, prenatal exposure to the Hev-b allergens may affect the incidence of allergy induced autism. 

     In contradiction, a study that evaluated house dust mite (HDM)-specific IgE and IgG4 concluded that the priming of TH2 responses associated with persistent HDM-IgE production occurs entirely postnatally, as HDM reactivity in cord blood seems nonspecific and is unrelated to subsequent development of allergen-specific TH2 memory or IgE.  The researcher's suggested that these findings question the scientific basis for existing recommendations for allergen avoidance by high-risk women during pregnancy [ 41 ] 

     4.2     Frequency

     The frequency of exposure to the Hev-b proteins from NRL continues to rise.  For example, approximately 25% of the rubber used today comes from rubber trees while 75% are petroleum based (i.e., synthetic rubbers).  Global conflicts, politics, and petroleum supplies continue to affect the price and availability of synthetic rubbers making the use of natural rubber more desirable.

     Over the past 43 years, the world NRL consumption has grown at an average of 4.2% per year, increasing to an estimated 925,000 tonnes in 2003.  However, the growth was not smooth; NRL consumption had a slower growth period from 1960 to 1983, with an average growth rate of 2.1% per year and a faster growing period from 1984 to 2003, averaging 5.6% per year.  In terms of actual tonnage the increase was 159,000 tonnes and 597,000 tonnes for the respective periods.

     The main driving force of the faster growth rate of the latter period was and still is the AIDS-HIV threat and the consequent growing awareness of the need for protection, reflected in the rapid rise of demand for medical gloves, in particular, since the mid-1980s.  Gloves were the main reason for the rising NRL uptake over the past 20 years; it was and still is playing the leading role in the natural-latex world. The product range of NRL is wide and varied, ranging from industrial, household, and medical applications.

     Currently, it is estimated that more than 40,000 products contain NRL.  Another example of a pervasive source of exposure to NRL for children and adults is automobile tires.  Disposal of spent tires continues to be an environmental concern in that such materials are not easily recycled and disposal through incineration is often not cost effective due to the proper handling of pyrolytic byproducts including airborne particulate and toxic gases.  Efforts have been made to find new uses for spent automobile tires wherein they are ground into crumb rubber and used as filler in gardens or as playground surfaces.  Although such efforts are well intended, these practices continue to increase Hev-b protein exposure to the general population.

    Unfortunately, the U.S. Environmental Protection Agency (EPA) is also involved in the promotion of recycled natural rubber latex.  [ 41.5 ]  The use of crumb rubber from recycled tires has been touted by the EPA and a number of state environmental agencies as having beneficial impact on the environment.  [ 41.6 ] 

    A specific example wherein the United States Government is involved in the recycling of natural rubber latex, without regard for the antigenic proteins therein, is in U.S. Pat. 6,407,144.  In the Government Interests section of the patent it states, "The United States Government has rights to this invention pursuant to contract number DE-AC09-96-SR18500 between the U.S. Department of Energy and Westinghouse Savannah".  

    We should question if the recycling of Hevea-Brasiliensis natural rubber latex, without regard to the antigenic proteins therein, is good government policy when considering the health and safety of all Americans. 

    In other studies, tire dust from tread wear has been shown to be another route of exposure to NRL allergens. [ 42 ]   

     Futhermore, a study indicates that allergies are increasing [ 43 ] and one may reasonably suggest that NRL exposure has contributed.  In industrial societies, the Hev-b proteins may indeed be the most pervasive non-infectious antigens of the late twentieth century.

    In the book Silent Spring wildlife biologist Rachel Carson taught that man-made chemicals (e.g., pesticides, insecticides) that become universally common or repetitive can assume "the harmless aspect of the familiar".  In parallel the Hev-b proteins, some of which are suspected to be natural insecticides, have attained the harmless aspect of the familiar.  Even though many of the health and safety hazards of natural rubber latex (Hev-b) are well understood, industrial societies magnificent exploitation and comfortable dependence on such a material continues to stress human health based on an inertia sustained by the harmless aspect of the familiar.
  
     4.3     Intensity

     The intensity of immune responses during prenatal/neonatal development may be related to the severity of ASD. Inadvertently subjecting children to antigenic proteins can stimulate the immune system to form increased levels of IgE primed mast-cells and basophils that may bind to proteins essential for proper growth and development.  For example, the first time a child is exposed to an antigenic protein large amounts of IgE antibody are made.  These IgE molecules attach themselves to mast cells and basophils to form IgE primed cells. Thereafter, exposure to the antigenic proteins (Ag) cause the IgE primed cells to release granules and powerful chemical mediators including histamine, proteases, chemotactic factors, cytokines, and metabolites of arachidonic acid.

Click on Mast Cell to Animate.                 
                                                                                                                   
 


       

   A = Human Mast Cell                             B = Human Basophil

  Unfortunately, the IgE primed cells can also bind to other proteins having similar or homologous characteristic to the antigenic protein (i.e., cross-reaction).  Examples of homologous proteins that have been shown to cross-react with the IgE primed cells include foodstuff proteins and lipocalins.   

     The antigenic proteins in NRL that have been shown to significantly affect the level of IgE primed cells are the water soluble Hev-b proteins (e.g., Hev-b 1-3).  An example of prenatal/neonatal exposure to such proteins includes medical gloves used in health care facilities.  A study has shown that the antigenic protein content of such gloves can vary greatly and is due in part to processing techniques (i.e., protein leaching step). [  44 , 45 ] 

     4.4     Type of Exposure

     NRL is used in many products including medical gloves, nipples for baby bottles, pacifiers, clothing, and toys.  Additionally, medicinal vials are often sealed with NRL-based septum's.  Routes of exposure may play a role in determining the NRL sensitization.  For example, differences in natural-latex specific IgE profiles and pulmonary function following sensitization of mice by four different routes suggest that exposure routes leading to NRL sensitization may play a role in determining the primary allergens and the clinical manifestation of the immune response. [ 46 ] 

     Additionally, NRL is used in many adult products including condoms.  The prevalence of sexually transmitted diseases and birth control measures have dramatically increased the use of natural-latex based condoms.  Such  products are another route of exposure to the Hev-b proteins which may be increasing atopy globally.  Efforts are being made to deproteinize natural-latex based condoms to help reduce acquired immune responses therefrom. [ 47 ]  

5.     Gender

     The ratio of ASD by gender is about 4:1 (male/female).  Immunological differences based on gender may affect the frequency and intensity of an adverse immune response.  For example, it is generally known that the ratio of food allergies is 2:1 (male/female).  In addition, childhood asthma has shown a 3:1 (male/female) ratio, especially amongst young children. [ 48 ]  A study on the effects of gender on allergen-induced histamine release in ongoing allergic cutaneous reactions concluded gender influences the degree of in vivo antigen-induced histamine release from mast cells. [ 49]

    In animal studies, research on the differences in concentration of endogenous proteins in sex organs of BALB/c mice has shown that levels of NGF and IgE were consistently higher in organs of male mice in comparison to their female siblings. [ 49.1 ]

     Another theory on the incidence of ASD and gender has been directed at testosterone which is the principle male sex hormone.  For example, recent research suggests that there may be a link between ASD and testosterone levels in the womb as the fetus develops.  For example, according to researchers from Cambridge University, babies who produce high levels of testosterone while they are still in the womb have a higher chance of showing traits of ASD later on. [ 50 ]

     In other studies, testosterone deprivation has been shown to proliferate T-cell populations.  In general, testosterone blunts immunity when present and enhances immunity when absent. [ 51, 52 ]

    In animal studies, researchers have shown that testosterone reduces macrophage expression in the mouse of toll-like receptors 4, a trigger for inflammation and inate immunity. [ 53 ]

    Finally, the testosterone induced suppression of inate immunity may shift the bodies defense mechanism towards adaptive immunity (e.g., IgE), affecting the incidence of allergy-induced-autism. 

6.     Endorphins

    Endorphins are endogenous opioid neuropeptides that are considered "natural pain killers". [ 55 ]  Increased levels of endorphins may affect some of the symptoms associated with ASD. [ 56 ]  In parallel, a study has shown that circulating leukocytes can synthesize, store, and release neuropeptides including endorphins. [ 57 ] 

     Additionally, the recent finding of nerve growth factor in mast cells widens the spectrum of potential responses that back-fed peripheral neurons can produce during neuroimmune interactions. [ 58 ]  

    In animal studies, nerve growth factor has been shown to govern the enhanced ability of opioids to suppress inflammatory pain.
[ 58.1 ]

    Therefore, the frequency and intensity of an acquired immune response can effect opioid and NGF levels which may influence some of the symptoms associated with ASD.

7.     Neurotransmitters/Neuromodulators

     A cross-react immune response, induced by NRL, may affect the bodies protein-cycle resulting in a temporary neurotransmitter imbalance.  Within cells, exogenous proteins (e.g., foodstuff proteins) are often broken down into amino acids.  These amino acids can then be assimilated into other compounds (e.g., neurotransmitters/neuromodulators).  There are certain amino acids that are classified as "essential" meaning they must be attained from foodstuff proteins.  For example, tryptophan is an essential amino acid that serves as a precursor for the neurotransmitter serotonin. 

     A cross-react immune response induced by NRL-allergy may induce IgE antibodies to bind certain foodstuff proteins potentially limiting the bodies source of essential amino acids such as methionine and tryptophan [ 59 ].  At the same time, an atypical immune response induce mast cells to release histamine resulting in a temporary excess of this neurotransmitter/neuromodulator.  Throughout this immune response, the protein cycle is further stressed to accommodate antibody and mast cell proliferation and/or replacement.  Such an imbalance may adversely effect neuro-cognitive development during critical stages of brain development.

8.  Vaccines

     Much attention has been given to the theory that vaccinations may have increased the incidence of ASD. For example, it has been proposed that the mercurial-based preservative (i.e., Thimerosal) in vaccines cause adverse neurological development, and other biochemical disruptions, that may increase the incidence of ASD. [ 60 ]  Although mercury-based organics are well known to be harmful to the central nervous system in all individuals, its role in the development of ASD continues to be debated.  Furthermore, MMR vaccines have also been suspected of affecting ASD.  Several studies have shown that thimerosal and MMR exclusion failed to decrease the incidence of ASD. [ 61 , 62 , 63]

     Vaccines are a preparation of killed microorganisms, or living attenuated organisms, or living fully virulent organisms that are administered to produce or artificially increase immunity to a particular disease.  The microorganisms in the vaccines are composed of exogenous proteins that inherently trigger an immune response. [ 64 ]  Furthermore, other protein additives in the vaccines have been shown to cause allergic reactions.  For example, the presence of gelatin [ 65 ] in MMR vaccines may intensify the immune response in atopic individuals. [ 66 ] 

     Finally, it is speculated that a combination of vaccine and non-infectious antigenic protein insult may be comorbid factors in the etiology of allergy induced autism.  For example, temporary vaccine-induced hyper immunity may affect immune sensitivity to non-infectious antigenic protein insult. [ 67 ]  Therefore, research efforts should explore if a combination of infectious-based protein insult (e.g., MMR) and non-infectious antigenic protein insult  (e.g., Hev-b proteins, food allergens) affects the incidence and prevalence of allergies.    

9.     Hev-b Protein Elucidation

     NRL contains hundreds of proteins and the International Union of Immunological Societies currently recognize 16 to be allergens (i.e., Hev b-1 to Hev b-16).  For example, recently the Rubber Research Institute of Malaysia has discovered the Hev b-13 (43kDA in size) to be most allergenic.  Protein analysis on Hev b-13 at Yale University has revealed a similarity to the Early Nodule Specific Protein of leguminous plants (e.g., peanuts, soybeans). [ 68 ]

     The prevalence of cystine in Hev-b proteins, or proteins homologous to Hev-b proteins, reinforces its tertiary structure through intramolecular disulfide crosslinks. [ 69, 70 ]  A Study has shown that cross-link density often decreases the exogenous protein's digestive characteristic (i.e., denaturation), possibly increasing the probability of an immune response. [ 71 ] 

     Amino acid analysis of Hev-b 5 has shown a complete absence of cysteine (i.e., cystine). [ 72 ]  Hev-b 5 has been shown to have an unusually high glutamic acid content (i.e., 39% based on total amino acid residues).  Many of the proteins associated with food allergy are also rich in glutamic acid (e.g., fruits, meat, poultry, fish, eggs, dairy products).  Furthermore, Hev-b 5 has a high proline content (14%) [ 73 ] to provide a tertiary structure having random coil arrangement .  Such an arrangement may inhibit enzymatic degradation, due to steric factors, inducing antibody recognition.   

     In speculation, an acquired immune response to the Hev-b 5 protein may affect the development of ASD through glutamic acid disruption.  For example, glutamic acid is the most abundant excitatory neurotransmitter and is involved in cognitive functions like learning and memory in the brain. [ 74 ]  Organisms synthesize GABA [ 75 ] from glutamic acid, GABA disruption may affect prenatal purkinje cell activity and formation. [ 76, 77 ]

    If immune responses to Hev-b and proteins homologous to Hev-b proteins affect the protein cycle and compromise the levels of cysteine and glutamic acid, endogenous polypeptides formed from these amino acids may also be affected.  An example may be glutathione which is a tripeptide of cysteine, glutamic acid, and glycine. [ 78 ]  A study has shown that children with autism often have reduced levels of glutathione compared to non-autistic children. [ 79 ]  Glutathione functions to denature cytoplasmic proteins wherein disulfide bonds (i.e., cystine) are reduced to cysteine.  A deficiency of glutathione may be affecting protein denaturation increasing the probability of an immune response to exogenous cystine-based proteins.  

10.     Isoprenoids and Cholesterol

     Plants and animals have protein kinase that affect the expression of isoprenoids which are essential to growth and development. [ 80 ]  Protein kinase (e.g., small rubber particle protein, rubber transferase) in  NRL play a major role in isoprenoid synthesis to provide polyisoprene having high molecular weight. [ 81 ]   In humans, protein kinase play a major role in isoprenoid synthesis (e.g., farnesyl pyrophosphate and geranylgeranyl pyrophosphate) which are synthetic precursors for numerous molecules essential for cellular function as well as substrates in isoprenylation reactions. [ 82 ]  

     An acquired immune response to NRL-based protein kinase may affect allergy-induced-autism through disregulated kinase activity. For example, the isoprenoid pathway and its metabolites -- digoxin, dolichol, and ubiquinon -- has been assessed in autism.  There was reported an upregulation of the isoprenoid pathway as evidenced by elevated HMG-CoA reductase activity [ 83 ] in autism.  It has been proposed that autism may be considered a syndrome of hypothalamic digoxin hyper secretion consequent to an up regulated isoprenoid pathway. [ 84 ]  

     Additionally, a study has indicated that children with autism can have unusually low levels of cholesterol. [ 85 ]  It is known that mutations at chromosome 11q12-13 can affect the expression of cholesterol and ASD. [ 86 ]  For example, autism has been documented in a number of individuals with Smith-Lemli-Opitz syndrome (SLOS). A recent study of 26 individuals with SLOS found that 17 of them (53%) met criteria for autism (Tierney et al 2001). Clinical features of SLOS include microcephaly, 2-3 syndactyly of the toes, mental retardation, cleft palate, hypospadias in males and growth retardation. SLOS is an autosomal recessive condition, with carriers being unaffected. SLOS is caused by mutations in the DHCR7 gene on chromosome 11 (11q12-q13). DHCR7 produces 7-dehydrocholesterol reductase, which typically converts 7-dehydrocholesterol to cholesterol. Diagnosis is established by detection of elevated serum concentration of 7-dehydrocholesterol. [ 87 ]  In parallel, IgE responsiveness (i.e., atopy) has been associated with mutations at chromosome 11q12-13. [ 88 ]

11.     Cysteine & Proteins

     The cysteine residues in Hev-b proteins have been shown to play a major role in allergenicity.  For example, research has shown that recombinant NRL allergens wherein the cysteine residues are replaced with alanine form peptide variants that have markedly decreased IgE binding.  Furthermore, basophil activation testing has shown decreased activation with successive cysteine exclusion. [ 89 ] 

     In parallel, studies have indicated that children with ASD have significantly lower baseline plasma concentrations of cysteine. An acquired immune response to Hev-b proteins may affect the methionine pathway [ 90 ] and P450 detoxification [ 91 ] system through an NRL cross-react immune response to proteins having similar epitopes based on primary and/or tertiary structure. [ 92 ]

     The expression of other cysteine-rich endogenous proteins have been implicated in ASD including metallothionein proteins [ 93 ], IgA antibodies [ 94, 95 ], dipeptidyl peptidase [ 96, 97 ], and lipocalins (e.g., human retinol-binding protein).

    An example of an immune response to exogenous proteins includes proteases.  Specifically, it is well known that botanically-based proteases (e.g., papain [ 98 ], bromelain [ 99 ], etc.), which are homologous proteins to the Hev-b proteins, may cause allergic responses in atopic individuals.  Such proteases are often used as food additives and function as digestive enzymes. 

    Finally, it is speculated herein that the activity of some endogenous cysteine proteases (e.g., caspase [ 99.1 ] ) may be affected through non-competitive inhibition (i.e., allosteric inhibitor) wherein Hev-b protein sensitive primed-mast-cells hydrogen-bond to epitopes on said protease.    

12.     Spina Bifida

     Studies have shown that about 73% of individuals with spina bifida/hydrocephalus have NRL allergy.  It’s theorized that the increased sensitization in this population is related to early, frequent exposure to rubber products such as catheters used in bladder programs. These children also tend to have frequent surgeries and diagnostic tests, which increases their exposure to natural-latex gloves. Unfortunately, frequent surgical intervention is a risk factor even in children who do not have spina bifida; sensitivity to natural latex has been found in 34.1% of children with a history of three or more surgical procedures.

     There is a broad range of scores on intelligence tests among children with spina bifida/hydrocephalus ranging from the gifted to the retarded.  It is generally recognized that learning problems are routinely a part of children with spina bifida/hydrocephalus including attention, perceptual motor processes, reasoning and problem solving, organization and sequencing skills, and memory. [ 100 ]  It is speculated that immune responses to the Hev-b proteins, and cross-reactivity therefrom, may be affecting neuro-cognitive development in individuals with spina bifida/hydrocephalus.

13.     Hev-b Toxicity

     LD50 is a measure of how much constitutes a lethal dose.  In animal testing studies, the dose administered that kills half the test population is referred to as the LD50.  The LD50 of several chemicals that have been implicated in the etiology of ASD are described below:

     Thimerosal (ORL-RAT)                         =  75 mg./Kg. [ 101 ]

     Aspartame (ORL-RAT)                          =  >10,000 mg./Kg. [ 102 ]

     Natural Rubber Latex (Hev-b proteins)     =   unknown*

    * The Hev-b proteins are considered chronic non-infectious agents (i.e., allergens)  Their toxicity may be influenced by the intensity of an induced immune response based on genetic susceptibility and exposure (i.e., incidence, prevalence, and intensity of Hev-b protein insult).  Therefore, LD50 data on such proteins are extremely difficult to quantify even though individual's have died from anaphylactic shock. [ 103 ]

    In a study that evaluated NRL allergy in sudden infant death syndrome (SIDS), NRL-specific IgE concentrations were detected in 1 of 112 unselected cases.  The researchers concluded that NRL allergy is not a cause of SIDS. [ 103.1 ]  As a suggestion, based on the brief half-life of IgE, the inactivation of IgE-primed mast cells after an immune response, and IgE cross-reactivity it may be prudent to evaluate the expression of by-products (e.g., histamine and NGF) of the adaptive immune response to determine if anaphylactic shock is involved in the etiology of SIDS.  Researcher's continue to study the effects that mast cells and histamine release has on heart failure [ 103.2 ]

     It is generally accepted that allergies are increasing worldwide.  As previously discussed, Malaysia is one of the worlds largest producers of Hevea Brasiliensis and it has been reported that allergies are increasing at an alarming rate. [ 104 ]  If  repeated Hev-b protein exposure is increasing the prevalence of allergies it's reasonable to ask the questions:

     Q.     Are the Hev-b proteins, or the unclassified proteins within Hevea Brasiliensis and its hybrids, becoming more antigenic based

              on structure change (i.e. molecular evolution); [ 105 ]

     Q.     Are future generations becoming more sensitive to the Hev-b proteins, or the unclassified proteins within Hevea Brasiliensis

              and its hybrids, based on inherited immunity (i.e., adaptive immune response); and

     Q.     Does the prevalence of diseases within Hevea affect the dynamics of the antigenic proteins therein.  [ 106 ]    

14.     Sleep

     It is generally accepted that individuals with ASD often have sleep difficulties. [ 107 ]  In the Ontogenetic Hypothesis of rapid eye movement (REM) [ 108 ] sleep, active sleep in neonates is particularly important to the developing brain, possibly because it provides the neural stimulation that newborns need to form mature neural connections and for proper nervous system development (Marks et al. 1995).

     Studies investigating the effects of Active Sleep deprivation have shown that deprivation early in life can result in behavioral problems, permanent sleep disruption, decreased brain mass (Mirmiran et al. 1983), and result in an abnormal amount of neuronal cell death (Morrissey, Duntley & Anch, 2004). REM sleep is necessary for proper central nervous system development (Marks et al. 1995). Furthermore, the release of certain neurotransmitters, the monoamines (norepinephrine, serotonin and histamine), are completely shut down during REM.   

     In other sleep studies, histamine has been implicated as a significant endogenous compound involved with wakefulness. [ 109, 110 ]  In contradiction, a study has indicated that the use of an antihistamine doesn't help babies sleep. [ 111 ] 

     The frequency and intensity of IgE immune responses may induce irregular patterns of active sleep during neonatal development, affecting allergy induced autism .  For example atopic individuals, especially those having hevea brasiliensis sensitivity, may be continuously exposed to the Hev-b protein allergens (e.g., baby bottle nipples, pacifiers) increasing the frequency and intensity of mast cell degranulation and histamine release.  Additionally, cross-react immune responses (e.g., food allergies) induced by the Hev-b proteins may further intensify the immune response. 

     Therefore, irregular patterns of active sleep during neonatal development may be directly related to the frequency and intensity of IgE immune responses to the Hev-b proteins and cross-react immune responses therefrom.

15.     Hearing

     Hearing sensitivity has been observed in ASD.  Autoimmune inner ear disease(AIED) is a syndrome of progressive hearing loss and/or dizziness. [ 112 ]  AIED can cause reduction of hearing accompanied by tinnitus (ringing, hissing, roaring). [ 113 ]  The favored theory of AIED is cross reactions wherein antibodies or rogue T-cells cause accidental inner ear damage because the ear shares common antigens with a potentially harmful substance that the body is fighting off.

16.     Touch Allodynia

     Tactile sensitivity has also been observed to be an intermittent symptom of ASD.  Touch allodynia is an exaggerated response to a non-noxious stimuli and can be either static or mechanical.  For example, a person with touch allodynia may perceive light pressure or the movement of clothes over the skin as painful, whereas a "normal" individual will not feel pain.  An animal study has indicated that the balance of prostaglandin D2 (PGD2) and prostaglandin E2 (PGE2) may play a role in innocuous tactile stimuli evoked pain. [ 114 ] 

     Immune responses to allergens which can cause mast cells and basophils to release neurotrophins and inflammatory agents [ 115 , 115.5] may affect the neurochemical mechanism of touch allodynia.

     During prenatal development, maternal immune responses to allergens are known to increase the expression of (PGE2) [ 116 ] effecting the levels of cytokine IL-6.  IL-6 overexpression has been implicated in recurrent misscarriages. [ 117]    

17.     Regressive Autism

     Regressive autism refers to a segment of children that initially develop normally for a period of time then lose skills and acquire the symptoms of autism, commonly at 18-24 months of age. [ 118 ]   A study indicates that the "normal" development phase prior to the onset of regressive autism may be misleading in that early delays are evident. [ 119 ]

     With respect to the allergy-induced autism theory, children with autism have been shown to have distinctly different immune system reactions compared to typical children. [ 120 ]  For example, cytokine levels, monocyte count, and neopterin levels in some Autistic children have shown significant variability. [ 121 , 122 ]   The differential onset (e.g., early infantile vs. regressive) of ASD indicates an etiology influenced by immunology and environmental insult.

     If the etiology of regressive autism is influenced by IgE immune responses during prenatal/neonatal development, then later onset of such an acquired immune response may affect neuro-cognitive development in older children.  Attention-deficit hyperactivity disorder (ADHD) [ 123 ] often occurs in children between the ages of 3-7.  An acquired Hev-b immune response, and cross-react immune responses therefrom, at this period of brain development may influence the development of ADHD.

     In other neuro-cognitive research, a study indicates that the prevalence of allergy in adults may affect the incidence of Parkinson's disease. [ 124 ]

18.     Other NRL Induced Cross-Reactivity

    Wheat              [ 124.1 ]     

    Pine Wood/      [ 125 ] [ 125.1 ]
    Pine Chemicals

     Poinsettia         [ 126 ]

     Mold               [ 127 ]

     Vegetables       [ 128 ]

      Insect Venoms [ 129 ]

      Grass & Weed Pollen [ 130 ]

     Sugar Beets      [ 131]

      Fruits               [ 132 ]

     Tobacco           [ 133 ]

19.     Infection & Allergy

     A study published in Pediatrics investigated the association between infections in the first 2 years and subsequent diagnosis of autism spectrum disorders.  The researchers concluded that children with subsequent diagnosis of autism do not have more overall infections in the first 2 years of life than children without autism. [ 134 ]

     It is well known that allergies are often prevalent in children with autism spectrum disorders. [ 135 ]  A combination of infection and environmental insult may affect the development of allergies.  For example, Johns Hopkins scientists have found the first hard evidence that viral infections can help cause asthma and allergies, a connection long suspected but never directly confirmed in the lab. They showed that weak viral infections can cause immune system B cells to produce immunoglobulin E or IgE, a protein that orchestrates the reactions that cause allergies. [ 136 ] 

     Infection and environmental insult during prenatal/neonatal development may also affect the development of allergies.  For example, it has been shown that prenatal and early postnatal environments are significant predictors of total immunoglobulin concentration in adolescents.  The researchers concluded that infectious disease in infancy, as well as interactions between prenatal and postnatal environments, appear to have long-term effects on adolescent total IgE production. [ 137 ]

     An example wherein a stealth chronic-infection may be a comorbid factor in the etiology of allergy induced autism is Lyme disease.  An epidemiologic study is evaluating if there is a connection to the prevalence of Lyme disease and autism in children. [ 138 ]  

    If comorbid factors such as infectious insult affects adaptive-immunity sensitivity, then everyone is potentially a "natural-latex sensitive individual".  As previously discussed, the timing, frequency, intensity, and type of exposure to the Hev-b proteins must be considered, not just genetic succeptibility. 

     Furthermore, infection may also induce autoimmunity when atopy is present.  Specifically, infectious agents may cause mammalian cells to release endogenous protein-fragments that can induce an immune response.  Briefly, in the formation of endogenous-proteins deoxyribonucleic acid (DNA) is transcribed in the cells nucleus into messenger ribonucleic acid (mRNA).  The mRNA is then exported to the cytoplasm for translation into protein.  Translation occurs in ribosomes wherein transfer RNA (tRNA) deliver amino acids which are then bonded together to form a protein chain.  During an infection (e.g., viral), propagation within the cell can rupture the cell wall. Once cell containment is breached, tRNA-based protein-fragments within the cytoplasm can then leach into circulation through diffusion.  When atopy is present, the increased prevalence of b-cells (i.e., plasma & memory) and the fragments incomplete structure (e.g., nucleoprotein fragments) may induce an immune response.  An immune response to the protein fragment may increase the probability of a cross-react immune response to endogenous proteins having a homologous protein-fragment therein.  Because different cells produce different proteins, the type of cell infected may induce autoimmunity based on the cells genetic information. 

     Finally, as previously discussed chronic infection and/or dampened immunity may affect the gender incidence of allergy induced autism.  Studies have shown that increased testosterone levels tends to blunt immunity affecting the prevalence of infection. If enabling, the interaction of infection/allergy/testosterone-levels may explain the 4:1 (male/female) gender incidence of allergy induced autism .

20.     Fever

     Collision theory of reaction rates associated with an IgE immune response are important in guiding our understanding of allergy induced autism.  Several factors that may affect the frequency and intensity of the immune response include:

     i)     the number of antigens (e.g., Hev-b or proteins homologous to Hev-b proteins) in a unit volume of blood;

     ii)    prevalence of somatic hypermutation [ 139 ] or affinity maturation [ 140 ] of lymphocytes (e.g.,memory B
            cells) specific to the antigen in a unit volume of blood; and

     iii)   increased body temperature and blood flow.

     Increased body temperature and blood flow has been been shown to affect the binding rates of antibodies and antigens.  For example, leukocytes are known to display a "shear threshold effect"; this effect is due to an increase in collisions between receptor and ligand with increasing shear. [ 141 ]  Infection induced fever may be a co-morbid factor which increases the intensity of an Hev-b induced immune response.

     As an example, reducing Hev-b protein exposure (e.g., latex-based gloves and bottle nipples), especially during postoperative fever after birth, may help reduce the incidence of allergy induced autism in atopic individuals. [ 142 ]

     In contrast, the hygiene hypothesis states that an excessively hygienic environment early in childhood may predispose some people towards asthma, allergies, and other autoimmune diseases. [ 143]  Furthermore, the use of fever suppressants (e.g., acetaminophen) has been speculated in the etiology of autism.  [ 144 ]   

21.     Hev-b Proteins and ASD

     NRL from Hevea Brasiliensis contains about 2-5% protein by weight.  Analysis indicates about 200 dissimilar proteins [ 145] therein and about 50-60 are suspected allergens.  The World Health Organization - International Union of Immunological Societies (WHO - IUIS) has assigned names to about 13 of these allergens.  Several Hev-b proteins and their potential relationship to ASD are described below:  

     21.1     Hev-b 1 (rubber elongation factor)

    The Hev-b 1 protein has been shown to have HLA-DR4Dw4 (DRB1*040)-binding motif. [ 146 ]  An Hev-b 1 immune response may induce HLA antibodies [ 147 ] based on epitope homology.  A study indicates that abnormal HLA-DR expression may affect the developing CNS during the second and third trimester. [ 148 ]

     21.2     Hev-b 2 (beta-1,3-glucanases), Hev-b 7 (Patatin-like protein), and Hev-b 13 (Lipolytic esterase)

     The Hev-b 2,7, and 13 proteins have been shown to have carbohydrate epitopes that may induce an IgE response.  [ 149 , 150 ]   An Hev-b induced immune response to homologous glycoproteins may affect some of the symptoms of ASD. [ 151 ]  For example, the glycoprotein maltase [ 152 ] is an endogenous digestive enzyme that breaks down disaccharides (i.e.,.maltose to glucose) in the small intestine.  Lower maltase activity has been associated with gastrointestinal dysfunction in some autistic children. [ 153 ]  Other glycoproteins that may have homology to Hev-b 2,7, and 13 include antibodies, major histocompatability complexes, and hormones;

     21.3     Hev-b 5 (acidic latex protein)

      A study has indicated that about 75% of the ASD population are classified as mentally retarded. [ 154 ]  An endogenous protein that is known to greatly affect neuro-cognition is Fragile X Mental Retardation (FMRP). [ 155 ]  FMRP inhibition through an Hev-b cross-react immune response may play a direct role in the neural maturation process during prenatal/neonatal development.  For example, as previously discussed an immune response to Hev-b 5 may cause glutamate disruption.  In parallel, FMRP inhibition by glutamate disruption has been shown to affect the body's ability to translate mRNA. [ 156] 

     In continuation, it is suspected that glutamate receptors and Shank3 proteins play a synergistic role in the density and maturation of elongated spines.  [ 157 ]  For example, a secondary cooperative effect may exist between glutamate receptor activity and Shank3 during maturation of a nascent spine in a feedforward mechanism.  Therefore, disruption of the glutamate/Shank3 mechanism may induce the formation of low-density and immature elongated spines often associated with mental retardation. 

     21.4     Hev-6 (Hevein)

     CD23 (or Fc epsilon RII) is a C-type lectin that functions as a receptor for IgE and are found on mature B cells.  In parallel, Hev-6 protein is a lectin-like protein that is a dominant allergen in NRL. [ 158 ]  An Hev-b 6 induced immune response may affect the expression of CD23 on mature B cells and regulation of IgE.   

     21.5     Hev-b 8 (Latex profilin)

     An immune-response to proteins homologous to Hev-b 8 proteins may affect dendritic spine morphology during prenatal/neonatal allergy syndrome.  For example, profilin from mammalian cells are known homologous proteins to Hev-b 8 [ 159 , 160 ]  An Hev-b 8 induced cross-react IgE immune response to human profilin I, and to a lesser extent profilin II, may affect actin [ 161 ] dynamics in synaptic plasticity. [ 162 ]  Atypical dendrite spine morphology associated with profilin disruption may be associated with some of the symptoms of ASD;  

     21.6     Hev-b 9 (Latex enolase)

     Enolases are enzymes that participate in glycolysis by assisting in the conversion of glucose to pyruvate. [ 163 ]  Hev-b 9 displays an overall identity of 72% to human beta enolase. [ 164 ]  An Hev-b 9 induced cross-react immune response to human enolase may affect pyruvate levels through enzyme inhibition.  Pyruvate deficiency has been associated with seizure and epilepsy.  A study indicates that epilepsy in ASD is a comorbid complication at rates of up to 33%.  [ 165]  

     Furthermore, homologous enolases from yeasts, molds, and fungi are known to cross-react with Hev-b 9.  [  166, 167 ]  A study indicates that elevated levels of Candida Albicans in some autistic individuals may exacerbate many behavior and health problems, especially those with late-onset autism. [ 168 ]  An Hev-b 9 induced cross-react immune response to exogenous enolases (e.g., yeast infection) may further affect allergy induced autism;

     21.7     Hev-b 10 (Mn-superoxide dismutase)

    Superoxide dismutase is a potential cross-react protein associated with an Hev-b 10 immune response. [ 169 ]  Superoxide dismutase enzymes such as magnesium superoxide dismutase (MnSOD) are important antioxidant-defense proteins in nearly all cells exposed to oxygen. [ 170 ]  Furthermore, a study has indicated that superoxide dismutase imbalance may play a role in the pathophysiological mechanisms involved in autism; [ 171 ] and

     21.8     Hev-b 11 (Class I endochitinase)

     The latex from Hevea Brasiliensis contains high levels of both chitinases and chitinases/lysozymes. [ 172 ]  Human chitotriosidase is a potential cross-react protein associated with an Hev-b 11 immune response based on its homology to the chitinase family of proteins. [ 173 , 174 ]  An Hev-b 11 induced cross-react immune response to human chitotriosidase and plant-based chitinase may affect fungal immunity and food allergies in ASD.  For example, chitotriosidase deficiency may play a role in digestion of chitin-containing food as well as defense against chitin-coated microorganisms and parasites (e.g., fungal and bacterial pathogens).  [ 175 ] 

     The known and suspected Hev-b proteins may play a significant role in the development of atopy and allergy induced ASD.  An immune-response to one or more Hev-b proteins during prenatal/neonatal development may influence the frequency and intensity of autoimmune responses [ 176 ] affecting the degree of atypicality within the autism spectrum.  

22.     Food-Stuff Proteins & NRL

     Allergic responses to food-stuff proteins have been associated with allergy induced autism. [ 177]  Hev-b proteins may induce immune responses to food-stuff proteins based on antigenic protein/food-stuff protein complexes.  For example, casein is a hydrophobic phosphoprotein that has been used as a stabilizing additive in the manufacture of NRL-based gloves. [ 178]  A protein-protein interaction of Hev-b/casein may induce antigen-presenting cells such as dendritic cells [ 179 ] to inadvertently present fragments from both proteins onto the surface of other immune system cells, subsequently triggering an allergic response to the dissimilar proteins.

    In continuation, we must ask the question why do some neonates get milk-protein allergies. It can be speculated that sucking milk from natural rubber latex nipples may cause dendritic cells to induce an allergic response to the comingled milk food-proteins and latex nipple antigenic-proteins.     

    Corn starch is an example of a non-homologous polymer that has been associated with Hev-b proteins.  For example, corn-starch powder has been used as a slip aid in the manufacture of NRL-based gloves.  It is known that Hev-b proteins migrate from the glove and onto the corn-starch.  The contaminated powder readily becomes air-borne and often increases Hev-b exposure through inhilation. [ 180 , 181 ]  The corn-starch/Hev-b protein commingling may induce memory-b cell recognition of carbohydrate epitopes and affect cross-react immune responses.  For example, amylose [ 182 ] in corn-starch has similar ring-size gluocose units and glycosidic linkage configuration to maltose [ 183 ]. 

     Another example where casein is deliberately commingled with the Hev-b proteins is in water-based adhesives.  Specifically, casein thickeners (i.e. rheology modifier) are often added to natural rubber latex adhesives to enhance machining characteristics.  Furthermore, gluten is also commonly used in adhesives.  Thus, the deliberate commingling of food-stuff proteins with NRL should be prohibited in an effort to reduce the global incidence and prevale