J. Dennis Odell

Strong association of the third hypervariable region of HLA-DRβ1 with autism

We reported that the major histocompatibility complex (MHC) including the null allele of the C4B gene and the extended haplotype B44-C30-DR4 is associated with autism. We report now that the third hypervariable region (HVR-3) of certain DR β l alleles have very strong association with autism. The HVR-3 of DRβ1∗ 0401 or the shared HVR-3 alleles DR01∗ 0404 and DRβ1∗ 0101, was expressed on extended haplotypes in 23 of 50 (46%) autistic subjects as compared to only 6 of 79 (7.5%) normal subjects. Another HVR-3 sequence, the DRβ1∗ 0701 allele, was carried on extended haplotypes in 16 (32.0%) of the autistic subjects as compared to 8 (10.1 %) of the normal subjects.

Possible association of the exetended MHC haplotype B44-SC30-DR4 with autism

We previously reported that the complement C4B null allele appears to be associated with infantile autism. Since the C4B null allele is known to be part of the extended or ancestral haplotype [B44-SC30-Dr4], we investigated the incidence of [B44-Sc30-DR4] in 21 autistic children and their parents. This extended haplotype was increased by almost six-fold in the autistic subjects as compared with healthy controls. Moreover, the total number of extended haplotypes expressed on chromosomes of autistic subjects was significantly increased as compared with those expressed on chromosomes of healthy subjects. We conclude that a gene related to, or included in, the extended major histocompatibility complex may be associated with autism.

CD4+ helper T cell depression in autism.

CD4+ (helper) T cells are a heterogenous population of lymphocytes including at least two distinct subpopulations. To investigate the possibility that immune abnormalities in some subjects with autism may involve abnormal distributions of CD4+ and/or CD8+ cells, (suppressor) T cells, peripheral blood lymphocytes of 25 autistic subjects were characterized with monoclonal antibodies and flow cytometry. The autistic subjects had a significantly lower percentage and number of CD4+ cells, a lower number of T cells (CD2+ cells) and B cells (CD20+ cells), and a lower percentage and number of total lymphocytes than siblings and normal subjects. The level of blood values for female subjects appeared lower than those for males as compared to normal subjects of the same sex. These results suggest that a decrease in CD4+ cells is associated with autism.

Detection of Maternal Antibodies in Infantile Autism

Maternal antibodies reactive with antigenic proteins expressed on the cell surface of paternal lymphocytes can be detected in couples with histories of more than one miscarriage or stillbirth. It is possible, but not proven, that these antibodies also react with tissues of the fetus and result in fetal death. Since many mothers of autistic children have a history of pregnancy disorder, antibodies were studied in 11 mothers of autistic children who were 6 years of age or younger. Six of the mothers had antibodies that reacted with lymphocytes of the autistic child. Five of these six mothers had a history of pregnancy disorder. Since antigens expressed on lymphocytes are found on cells of the central nervous system and, perhaps, other tissues of the developing embryo, it is suggested that aberrant maternal immunity may be associated with the development of some cases of infantile autism.

Changes of soluble interleukin-2, interleukin-2 receptor, T8 antigen, and interleukin-1 in the serum of autistic children

Immune abnormalities in autistic children led us to study for indirect evidence of immune activation as measured by the serum analysis of soluble interleukin-2 (sIL-2), interleukin-2 receptor (sIL-2R), T8 antigen (sT8), and interleukin-1 (sIL-1). The serum concentration of these soluble antigens was quantitated by enzyme-linked immunosorbent assays. The concentration of sIL-2 and sT8, but not of sIL-2R and sIL-1, antigens was significantly (P less than 0.05) increased in the sera of autistic children over that in the control healthy children or children with mental retardation (non-Downs syndrome). This finding indirectly indicates that the activation of a subpopulation of T cells occurs in some children with autism.

Effects of Stimulant Medication on Cognitive Performance of Children with ADHD

The effect that treatment with stimulant medication has on the intellectual performance of children with attention deficit hyperactivity disorder (ADHD) was examined. Thirty-one children diagnosed with ADHD were given a WISC-III before any treatment was implemented. At least 1 year later, children were retested. At this time, 24 of the children were taking stimulant medications. Children receiving medications had significant increases in IQ scores, but no changes were found for those not taking medications. Changes in IQ scores were moderately related to parents’ perceived efficacy of the medication and parent-reported compliance with medication but were not strongly related to changes in parent-reported ADHD symptoms.

Decreased Expression of CD95 (FAS/APO-1) on CD4+ T-lymphocytes from Participants with Autism

Although autism remains an enigmatic disease, there is mounting evidence that the immune system plays an important role in the pathogenesis. Immune system involvement is apparently widespread as numerous humoral and cellular abnormalities have been reported in both the innate and adaptive responses. Fas (CD95/APO-1) is a type I cell-surface protein from the TNF/NGF-R superfamily present on the surface of many immune related cells. Fas activation is instrumental in starting a complicated chain of events that results in programmed cell death (apoptosis) by DNA fragmentation. Preliminary data is presented, which indicate that subjects with austism have lower levels of Fas on their CD4+ helper T cells (p = .048) than have normal subjects. Data also indicates subjects with autism have significantly higher levels of soluble Fas (p = .01) than have normal subjects. A maturing individual must eliminate cells for proper morphogenesis to occur. Preliminary data suggest that faulty apoptosis may be involved in the pathogenesis of autism.

Is Decreased Blood Plasma Concentration of the Complement C4B Protein Associated with Attention-Deficit Hyperactivity Disorder?

OBJECTIVE The complement system is a group of blood proteins that play an important role in defending against viral and bacterial infections. The objective of this investigation was to study the plasma levels of the C4B protein in attention-deficit hyperactivity disorder (ADHD) in an attempt to associate infections with the development of some cases of this disorder. METHOD C4B plasma protein levels were studied using an enzyme-linked immunosorbent assay in a group of 23 subjects meeting DSM-III-R criteria for ADHD and a similar number of age- and sex-matched controls. Also studied were parents of the ADHD subjects. RESULTS C4B plasma levels (157.0 micrograms/mL) in the ADHD subjects were significantly (p < .01) lower than those (239.3 micrograms/mL) in the normal age-matched subjects. Mothers of the ADHD subjects also had significantly lower C4B values compared with mothers of normal children. On the other hand, C4B values in the fathers were not significantly altered. CONCLUSIONS Decreased C4B levels in ADHD, if replicated, may represent an important marker for ADHD (or a subgroup of ADHD). It also seems plausible that C4B levels are an important etiological factor for ADHD.

C4B null alleles are not associated with genetic polymorphisms in the adjacent gene CYP21A2 in autism

BackgroundResearch indicates that the etiology of autism has a strong genetic component, yet so far the search for genes that contribute to the disorder, including several whole genome scans, has led to few consistent findings. However, three studies indicate that the complement C4B gene null allele (i.e. the missing or nonfunctional C4B gene) is significantly more frequent in individuals with autism. Due to the close proximity of the CYP21A2 gene to the C4B locus (3 kb) it was decided to examine samples from autistic subjects, including many with known C4B null alleles for common CYP21A2 mutations.MethodsSamples from subjects diagnosed with autism and non-autistic controls (controls) previously typed for C4B null alleles were studied. Allele specific polymerase chain reaction (PCR) methods were used to determine 8 of the most common CYP21A2 genetic mutations, known to completely or partially inhibit 21-hydroxylase, the enzyme encoded by the CYP21A2 gene.ResultsAlthough the combined autism and control study subjects had 50 C4B null alleles only 15 CYP21A2 mutations were detected in over 2250 genotypes. Eight mutations were detected in the autistic samples and 7 in the controls. The frequency of CYP21A2 mutations was similar between the autism and control samples. Only one individual (autistic) carried a chromosome containing both C4B null allele and CYP21A2 mutations.

Brief Report: Low Rates of Herpesvirus Detection in Blood of Individuals with Autism Spectrum Disorder and Controls

Previous research indicates that infection, especially from viruses in the family Herpesviridae, may play a role in the etiology of some cases of autism spectrum disorder (ASD). Using a case-control design and the polymerase chain reaction with site-specific primers, we screened newborn and childhood blood samples for the presence of eight human herpesviruses. Herpesvirus DNA was detected in 4 of 225 ASD individuals and 2 of 235 controls, with the most frequently detected virus being HHV-6B. Although this study does not detect a significant ASD-Herpesviridae association, it is limited by the use of site-specific primers. We suggest that new techniques using bioinformatics to search next-generation sequencing databases will be more revealing of possible ASD-virus associations.