The critically important job of fighting off infections falls to our immune system. As you might expect, this is a complex system because the invasions faced by the human body include diverse infectious agents as well as attacks from newly formed cancer cells. A large part of the immune system is located in or near the intestinal tract and helps prevent microorganisms in the intestine from entering into the rest of the body. Therefore, defects in the immune system can lead to an overgrowth of harmful organisms in the intestinal tract.
ANTIBODIES (OR IMMUNOGLOBINS)
The B-lymphocyte cells of the immune system produce antibodies called immunoglobulins. These antibodies are designed to react against specific antigens (or foreign molecules) introduced into the system by various types of microorganisms. Antibodies react against microorganisms (viruses, yeast, parasites, and bacteria) and allow them to be killed by the white blood cells. Composed mostly of amino acids, antibodies are proteins that are divided into five major antibody classes (IgM, IgG, IgE, IgA, IgD). Each antibody class has a unique chemical structure and a specific function. IgG stands for immunoglobulin G or antibody G and so forth. Each class contains thousands of different antibodies to different microorganisms, foods, and chemicals.
IgM
IgM is usually the first antibody produced by the immune system when a new microorganism is encountered and is the body’s early defense system. The presence of high amounts of specific IgM antibodies indicates a recent infection. Thus, high levels of IgM antibodies against Candida would indicate a recent Candida infection. IgM antibodies diminish a few months after infection.
IgG
IgG antibodies are produced by the B-lymphocytes when the body is attacked by the same microorganism in a subsequent invasion. It may also be involved in causing food allergies. IgG antibodies are the antibodies that provide long term resistance to infections after immunizations.
IgG Subclasses
Sometimes the total IgG in the blood may be normal but the concentration of one or more subtypes of IgG may be low. As a result, a normal IgG level can be misleading if it is not accompanied by normal levels of each subclass. There are four subtypes of IgG: IgG1, IgG2, IgG3, and IgG4.
IgE
IgE is the antibody most widely known for its involvement in allergies of all kinds. It may also be involved in protection of the body from parasites. Elevated IgE in blood is associated with a history of excessive allergies.
IgA
IgA is the antibody involved in protecting the nasal and intestinal lining from microorganisms. Secretory IgA (sIgA) is a special form of the IgA antibody that is secreted to protect the mucosa, which is the lining of the intestinal tract. Secretory IgA is apparently secreted by the gall bladder and then trickles down the bile ducts into the small intestine.
AUTISM SPECTRUM DISORDERS & PDD
Defects in all parts of the immune system are documented in people with Autism Spectrum Disorders. Studies done by Reed Warren Ph.D. at Utah State University and Sudhir Gupta MD Ph.D., a clinical immunologist at the University of California at Irvine Medical School, indicate most children with autism have a substantial immune abnormality of some type. Reported defects include myeloperoxidase deficiency, severe combined immunodeficiency, IgA deficiencies (partial and complete), IgG subclass deficiencies in 20 percent, and deficiencies in complement C4b. Poor digestive function has a number of causes. The reduced function may be the result of an immature gut in infancy and of heavy metals causing the chemical messages weaving through the body to trip the allergy system.
In Gupta’s study, 20 percent of the children with autism had a deficiency of IgA and eight percent lacked it completely. Warren and his colleagues also found that 20 percent of individuals with Autism had low serum IgA compared with none of the normal individuals used as controls.
Concentrations of IL-12 and interferon gamma are much higher in the blood of children with Autism than in normal children, indicating an immune activation, possibly due to adverse vaccine reactions. Optimal immune response to Candida infections necessitates a finely tuned balance of interferon gamma production; the dysregulation of the immune system, caused by IL-12-induced increases in gamma interferon, leads to increased Candida susceptibility in animals.
DOWN SYNDROME
The overexpression of genes resulting from trisomy 21 in Down Syndrome may be responsible for many of the abnormalities of the immune system reported in Down Syndrome.The level of superoxide disimutase-1, which is coded by a gene on chromosome 21, is on average, 150% of the values found in normal individuals’ blood as well as other cells. The high enzyme activity results in a high rate of conversion of superoxides to peroxides, resulting in high levels of peroxides that may damage DNA and lipids, and in low levels of the superoxides that are essential for killing microorganisms such as Staphylococcus aureus and Candida albicans.
Over-expression of lymphocyte function associated antigen-1(LFA-1), which is also coded on chromosome 21, can lead to an abnormal interaction between cells from the thymus, resulting in aberrant T-cell maturation and selection. Over-expression of the interferon receptor gene also located on chromosome 21 is common in Down Syndrome and can also contribute to immune deficiency. Low serum zinc common in Down Syndrome, could also cause weak immunity.
The most significant abnormality of the immune system in Down Syndrome is a 30-fold increase in the incidence of acute leukemia and a 200-fold increase in acute megakaryocytic leukemia. Thirty percent of adults with Down Syndrome are deficient in IgG-2 and/or IgG-4 and these deficiencies are also common in children with Down Syndrome. Elevations of IgG-1 and IgG-3 are common in persons with Down Syndrome. In children with the abnormal immunoglobulin pattern, selenium supplementation at a dose of 10 mcg/kg (4.54 mcg/lb.) body weight for six months significantly increased IgG-2 and IgG-4 levels and reduced the number of infections.
SEIZURE DISORDERS & EPILEPSY
Intractable childhood epilepsy is associated with low blood values of IgG-2 and IgG-4; replacement therapy may lead to remission of symptoms. IgG-4 may also be low in some children with febrile convulsions. The antiseizure drug carbamazepine (Tegretol) may cause a reduction in IgG-2 while phenytoin (Dilantin) may be associated with decreases in IgA, IgG-3, and IgG-4. Anti-IgA antibodies have been detected in epileptic patients with low serum IgA concentrations.
ATAXIA TELANGIECTASIA (AT)
Ataxia telangiectasia is a genetic disorder characterized by ataxia or impaired balance between the age of two and five years and worsens as the child gets older. There is usually a cortical cerebellar degeneration of the brain, involving mainly the Purkinje and granule cells; degeneration of these same cells in the cerebellum has also been detected in autopsy studies of individuals with autism. Affected children also have telangiectases, “spider” veins appearing in the corners of the eyes or on the surface of the ears and cheeks that are exposed to sunlight.
Telangiectases often do not appear until the age of six, and sometimes much older. Similarly, a history of recurrent sinopulmonary infections would heighten suspicion of AT. Many affected children with this disorder also have low serum IgA, IgG, IgG-2, IgG-4 and/or IgE. In 16 patients with ataxia-telangiectasia, eight had IgA deficiency, two had IgG and IgA deficiency and six patients showed no immunoglobulin class abnormality. IgG-4 and IgG-2 levels were undetectable or low in almost every patient in this group. An IgG-3 deficiency was associated with the IgG-2 and IgG-4 defect in three patients with undetectable IgA. IgG-1 was very low in one patient with a total IgG deficiency.
Children with AT are 1000 times as likely to develop cancer than other children. Gamma globulin treatment may be helpful for treatment of the impaired immunity in this disorder. The most consistent laboratory marker of AT is an elevated serum alpha-fetoprotein after the age of two years. At least one percent of the general population are “AT carriers”. This would mean that at least two million people in the United States alone carry one copy of the defective AT gene and one copy of a good one. It appears that carriers of this gene are much more susceptible to radiation effects and are more likely to develop cancer.
GASTROINTESTINAL DISORDERS, INCLUDING CELIAC DISEASE
Because the gastrointestinal tract is the largest lymphoid organ in the body, patients with immunodeficiency present with pathological conditions in the intestine. Several studies have documented a high prevalence of inflammatory, malignant, and infectious GI disorders in patients with common variable immunodeficiency or immunoglobulin A (IgA) deficiency. For example, celiac disease, an inflammation of the bowel, is commonly associated with IgA deficiency. The incidence of selective IgA deficiency is 10 times higher in patients with celiac disease compared to the general population. The diagnosis of celiac disease cannot be excluded if a person is IgA deficient, because the endomysial antibody test uses an IgA antibody specificity and could yield false negative results in such cases. Thus, it would seem wise to always test for IgA deficiency whenever the IgA endomysial antibody test for celiac disease is done.
HYPER IGE SYNDROME
The hyper-IgE (HIE) syndrome is characterized by high IgE serum levels, chronic dermatitis, and recurrent infections. Hyper IgE syndrome is due to an overproduction of IgE probably due to a terminally differentiated B cell population, no longer sensitive to regulatory signals. Common clinical findings are recurrent sinopulmonary tract infections, cold staphylococcal abscesses and chronic dermatitis. Many patients have serum IgE levels of 3,000 U/ml and blood eosinophilia (0.6 x 109 cells/l). Some patients have impaired antibody forming capacity to tetanus and pneumococcal antigens and low serum IgG-2 levels.
After initiation of the intravenous gamma globulin therapy, an improvement of infectious problems was observed in some studies. Serum IgE levels were highly correlative with serum IgG-4 levels (r = 0.75) in one study but do not correlate significantly with other IgG subclasses. The cytokine recombinant IL-4 enhanced not only spontaneous IgE synthesis but also IgG-4 synthesis in cultures of lymphocytes from patients with HIE syndrome as well as in healthy donors (P less than 0.01).
The effect of recombinant IL-4 on both IgE and IgG-4 synthesis was inhibited by low concentrations of recombinant IFN-gamma (p less than 0.01). The disturbed regulation of IgE and IgG-4 seen in patients with hyper IgE syndrome may be caused mainly by the disturbed regulation of both cytokines.
A child with joint deformities involving both hands, frequent fractures, chronic eczema and recurrent skin and soft tissue infections since infancy, was found to have a pneumatocele during admission. Immunologic abnormalities included extremely elevated serum IgE levels (18989 U/ml) and lack of immune response (anergy) to Candida, purified protein derivative, and tetanus toxoid. A high index of suspicion for HIE syndrome should be generated in patients with recurrent skin infections and orthopedic complaints.
ABNORMAL IGE IN ALLERGIES & OTHER CONDITIONS
Elevated values for IgE are found in allergic disorders including asthma, hayfever, parasitic infestations, deficiencies of the thymus gland, Wiskitt Aldrich syndrome, IgE myeloma, pemphigoid, periarteritis nodosa, and hypereosinophilic syndrome. Low values for IgE are found in ataxia telangiectasis and in various hypogammaglobulinemias.
If the total IgE exceeds 75-100 U/ml, a patient is likely to have significant IgE-mediated allergies that should be tested by specific IgE and other allergy tests. If the IgE is less than 10 U/ml, the patient is unlikely to have significant IgE-mediated allergies. Patients with intermediate values for total IgE will generally have intermediate numbers of IgE-mediated allergies.
IMPORTANCE OF ZINC TO THE IMMUNE SYSTEM
Zinc is an essential element that is commonly deficient in individuals who eat a diet high in cereal content but low in animal protein. Cereals contain phytic acid which binds zinc and inhibits its absorption from the intestinal tract.
Clinical signs of zinc deficiency may occur when plasma zinc concentrations drop below 65 mcg/dL. Zinc deficiency is associated with dermatitis, poor wound healing, negatively impacted growth and sexual development, and reduced taste acuity. Values less than 33 mcg/dL are particularly associated with loss of the senses of taste and smell, abdominal pain, diarrhea, skin rash, and loss of appetite.
Zinc deficiency may be common in children with autism who have had diarrhea for extended time periods and could contribute to their poor appetites. Zinc affects multiple aspects of the immune system, from the barrier of the skin to gene regulation within lymphocytes.
Zinc is also crucial for the normal function of cells which mediate nonspecific immunity, such as neutrophils and natural killer cell. B lymphocyte development and antibody production, particularly immunoglobulin G, is compromised by zinc deficiency. The macrophage, a pivotal cell in many immunologic functions, is adversely affected by zinc deficiency. This can dysregulate intracellular killing, cytokine production, and phagocytosis.
The effects of zinc on these key immunologic mediators is rooted in the myriad roles for zinc in basic cellular functions such as DNA replication, RNA transcription, cell division, and cell activation. Apoptosis or programmed cell death is potentiated by zinc deficiency. Zinc also functions as an antioxidant and can stabilize membranes.
ZINC DEFICIENCY & CROHN’S DISEASE
Low serum zinc in Crohn’s disease may cause clinical manifestations, such as acrodermatitis enteropathica and retinal dysfunction, which may be correctable with zinc supplementation.
ZINC TREATMENT OF CANDIDIASIS
Polizzi and coworkers evaluated the clinical efficacy of a treatment with cimetidine and zinc sulfate in an adult patient with chronic mucocutaneous candidiasis. Cimetidine was given at a dose of 400 mg three times daily; zinc sulfate at a dose of 200 mg daily, then adjusted to maintain blood zinc levels at the upper normal range. This treatment lasted 16 months. An impressive and significant reduction of the infectious events and an increased CD4 (helper/inducer) cell counts were observed. The authors conclude that this combined immunopotentiating treatment is safe and inexpensive to treat immunodeficiency disorders.
ZINC REDUCTION OF INFECTIOUS DISEASES
The August 1998 issue of the American Journal of Clinical Nutrition is devoted to studies on zinc and health. Anuraj Shankar, an immunologist at the Johns Hopkins School of Public Health, working with other experts in a child health study, found the trace mineral can have remarkable effects.
They found that adding small amounts of zinc to the diet could reduce the duration of a diarrhea attack by 20 to 30 percent and could stop up to 38 percent of cases from ever happening.
“The incredible thing about zinc is that if you look at the three major killers of children everywhere — diarrhea, malaria and pneumonia — we are seeing that zinc has a very significant impact on reducing the severity and incidence of those,” said Shankar.
Zinc supplementation reduced acute respiratory infections such as pneumonia by up to 45 percent and malaria by 35 percent, Shankar said in a telephone interview. One study in India found that children with low blood levels of zinc had more bouts of diarrhea, and were more likely to have fever along with diarrhea. A study in Vietnam found a 2.5-fold decrease in all respiratory infections when children received zinc supplements.
HYPERACTIVITY, ZINC DEFICIENCY, & FOOD DYES
Children with hyperactivity had significantly lower hair, blood, fingernail, and urine zinc compared to age and sex-matched controls. The yellow food dye tartrazine may bind to zinc in the blood as a chelating agent and thereby reduce blood zinc. Hyperactive children exposed to this food dye all developed significant negative symptoms within 45 minutes of ingesting this food dye in a colored drink.
ZINC DEFICIENCY & ANOREXIA NERVOSA
A number of studies have indicated that a high percentage of females with anorexia nervosa may have low serum zinc values, may choose diets with inadequate zinc content, and may respond favorably to zinc supplementation by increased weight gain and reduced depression and anxiety.
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