Specific Diseases In Which Immunodeficiency Is Common

by Dr. Shaw

Autism and PDD

Defects in all parts of the immune system are documented in children with autism.  Studies done by Reed Warren Ph.D. at Utah State University, Sudhir Gupta M.D. PhD., a clinical immunologist at the University of California at Irvine Medical School, and others indicate most children with autism have substantial immune abnormality of some type.  Reported defects include myeloperoixase deficiency, severe combined immunodeficiency, IgA deficiencies (partial and complete), IgG subclass deficiencies in 20%, and deficiencies in complement C4b.

In Gupta's study, 20% of the children with autism had a deficiency of IgA and 8% lacked it completely.  Reed Warren and his colleagues also found that 20% 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 activations, possibly due to adverse vaccine reactions.  An 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's Syndrome

The over expression of genes resulting from trisomy 21 in Down's syndrome may be responsible for many of the abnormalities of the immune system reported in Down's syndrome.  The level of superoixde 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 that are essential for killing microorganisms such as Staphylococcus aureus and Candida albicans.

Over expression of lymphocyte function associated with antigen-1 (LFA-1), which is also coded on chromosome 21, may lead to an abnormal interaction between cells form the thymus, resulting in aberrant T-cell maturation and selection. Over expression of the interferon receptor gene also located on chromosome 21 zinc is common in Down's syndrome and may also contribute to immune deficiency.

The most significant abnormality of the immune system in Down's syndrome is a 30-fold increase in the incidence of acute leukemia and a 200-fold increase in acute megakaryocytic leukemia.  30% of adults with Down's syndrome are deficient in IgG-2, and/or IgG-4 and these deficiencies are also common in children with Down's syndrome.  Elevations of IgG-1 and IgG-3 are common persons with Down's syndrome.  In children with abnormal immunoglobulin pattern, selenium supplementations 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.

Seizures and 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 be low in some children with febrile convulsions.  The antiseizure drug carbamzepine (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.  IgG1 was very low in one patient with a total IgG deficiency.

Gastrointestinal disorders including celiac disease

Because the gastrointestinal tract is the largest lymphoid organ in the body, it is not surprising that patients with 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 specifity and may 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/1).  Some patients have impaired forming capacity to tetanus and pneumoccoccal 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 on both IgE and IgG4 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 pneumatocele during admission. Immunologic abnormalities included extremely elevated serum IgE levels (1989 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 and other conditions

Elevated values of IgE are found in allergic disorders including asthma, hayfever, parasitic infestations, deficiencies of the thymus gland, Wiskitt Aldrick syndrome, IgE myeloma, pemphigoid, periarteritis nodosa, and hypereosinophilic sydnrome.  Low values of 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 number of IgE-mediated allergies.

Importance of Zinc to the Immune System

Information reproduced with permission of Dr. Shaw at Great Plains Laboratory.