MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES
RESEARCH REVIEWS 4: 137–141 (1998)
POSSIBLE IMMUNOGENETIC BASIS FOR AUTISM
Roger A. Burger* and Reed P. Warren
Utah State University, Logan, Utah
Autism results from several different etiologies or combina-
tion of pathological mechanisms. Mounting evidence indicates that
immune dysfunction along with an environmental pathogen may be
factors contributing to the development of some cases of autism.
One of the immune deficiencies observed in autism is abnormal
T-cell mediated immunity. Another is altered levels of certain
classes of antibodies (immunoglobulins), including decreased levels of
immunoglobulin A and deficient complement activity, based
on the inheritance of a null allele of the C4B gene. In addition
to the C4B gene, other genes on chromosome 6 also appear to be
associated with autism. In the developing child, genetically deter-
mined immune deficiencies might increase the risk for autism in two
ways: 1) A pathogen or its toxins might damage the brain, 2) the
pathogen might trigger an autoimmune mechanism that would
interfere with brain functioning. In the mother, immune deficiency
might allow a pathogen to persist in utero, damaging the fetal brain
directly or triggering a maternal immune response that creates
pathogenesis in the fetal brain. r 1998 Wiley-Liss, Inc.
MRDD Research Reviews 1998;4:137–141.
Key Words: autism; immune system
I
mmunologic disorders often have a genetic basis. The best
evidence for this in man comes from family studies, especially
studies of twins. The incidence of a particular disease in
monozygotic and dizygotic twins is compared. If a disease shows
a high concordance in all twins (both monozygotic or dizygotic
pairs), this would point to shared genetic or environmental
factors. This is because both monozygotic and dizygotic twins
tend to be brought up in similarly shared environmental
conditions. If high concordance is restricted to monozygotic
rather than dizygotic twins, however, then genetic factors are
likely to be more important than environmental factors. Studies
with twins have been undertaken for several human disorders in
which autoimmunity plays an important role. These include
insulin-dependent diabetes mellitus, rheumatoid arthritis, mul-
tiple sclerosis, and systemic lupus erythematosus. In each case,
around 20% of pairs of monozygotic twins show disease
concordance, compared with less than 5% of dizygotic twins.
Thus, both inherited and environmental factors may play a role
in inducing autoimmune disease.
Folstein and Rutter [1977] found a higher concordance
rate of autism in monozygotic twins than that seen in same-sex
dizygotic twins. Also, other family studies reveal that about 3–7%
of probands with autism have affected siblings [Bailey et al.,
1996], a rate exceeding by 50 to 100 times that expected by
chance. Thus, genetic factors are strongly implicated in this
disorder. Notably, certain genes located on chromosome 6 are
associated with autoimmune disorders, and, as discussed below,
appear to be associated with autism.
r 1998 Wiley-Liss, Inc.
Most immunologic disorders, especially autoimmune
disorders, are associated with infections. More than 20 reports
have been published on prenatal and postnatal viral infections in
autism [Gillberg and Coleman, 1992]. Other studies [Deykin and
MacMahon, 1979; Stubbs, 1978] have implicated infection by
other viruses with onset of autistic symptoms. Four studies found
an excess of births of children with autism in the month of March
[Gillberg, 1990], thus providing circumstantial evidence for viral
infection in autism. It is conceivable that a pathogen involved in
autism would be more operative or epidemic during the early
winter (the second trimester for March babies).
THE IMMUNE SYSTEM AND IMMUNE
ABNORMALITIES IN AUTISM
The Immune System
Blood cells (red cells, platelets, and white cells) arise in the
bone marrow and are derived from a common precursor cell, the
hematopoietic stem cell. Upon stimulation by unknown factors,
stem cells divide repeatedly. Some daughter cells develop into
red blood cells, others into platelets, and still others into the two
major types of white blood cells, the myeloid cells and the
lymphocytes. The myeloid cells include the monocytes and
granulocytes. Monocytes mature into macrophages, which are
one of two types of phagocytic immune cells. Macrophages,
widely distributed in body tissues, play a critical role in natural
(nonimmune) resistance to infections by engulfing and destroy-
ing many pathogens. The macrophages also play a major role in
immune activation by presenting antigens (typically foreign
substances not produced by one’s own system, but see below) to
lymphocytes.
B cells and T cells are the two major types of lymphocytes.
B cells become activated through exposure to an antigen by a
macrophage. They are further stimulated by peptide messengers
called lymphokines, which are produced by activated T cells.
The B cells differentiate into plasma cells that secrete antibodies,
including immunoglobulin A (IgA) (see Fig. 1). The molecules
of IgA are found in mucus-coated body surfaces such as the
respiratory, digestive, and reproductive tracts, where they
neutralize infectious agents. Mother’s milk delivers them to the
mucus lining of her newborn’s gut. Quantitatively, IgA is the
most important of immunoglobulins when both secretory and
serum IgA are taken into account. Its rate of synthesis exceeds
that of all other immunoglobulins combined. Selective IgA
*Correspondence to: Roger A. Burger, Immunology, Utah State University,
Logan, UT 84322–6895. E-mail: Roger@cpd2.usu.edu
 reported are significantly reduced num-
bers of CD41 T cells [Warren et al.,
1986, 1990; Yonk et al., 1990], a finding
confirmed by two other laboratories
[Wright et al., 1990; Denny et al., 1996].
4) Children with autism have shown
positive reactions to skin tests with several
allergens and abnormally high antibody
responses to tetanus and diphtheria anti-
gens after booster injections [Tsaltas,
1986]. 5) Warren and colleagues [1987]
reported decreased activity of natural
killer cells—a first line of defense against
viral infections and malignant cells. 6)
Plioplys and colleagues [1994a] observed
that a majority of their participants with
autism had increased numbers of DR1
(activated) T cells, thus suggesting im-
mune system activation. This finding was
confirmed subsequently by Warren and
colleagues [1995]. 7) Individuals with
autism have also shown aberrant cell-
mediated and antibody responses to
myelin basic protein [Weizman et al.,
1982; Singh et al., 1993] and neurofila-
ment proteins [Plioplys et al., 1994b].

GENETIC FACTORS: THE

MAJOR HISTOCOMPATIBILITY
COMPLEX OF GENES

Fig. 1. The production of IgA antibodies begins with the presentation of antigen by an Background
APC such as a monocyte. Both the B cell and T cell contact the APC and are activated by HLA molecules bind peptide frag-
the same specific antigen. The T cell produces lymphokines which induce a conversion of ments derived from pathogens and dis-
the activated B cell to a plasma cell. The plasma cell then secretes large numbers of IgA play them on the cell surface of APCs for
molecules that can bind and neutralize the specific antigen.
recognition by the appropriate T cells.
The consequences of such presentation
leads to destruction of virus-infected
cells, activation of macrophages to kill the
deficiency is the most common immuno- locus antigen) molecule that is com- bacteria that have been engulfed, and
deficiency disorder in man [reviewed by plexed (bound) to that antigen. This antibody production by B cells. Two
Ammann, 1991], having a prevalence HLA-antigen complex is expressed on different characteristics of HLA mol-
estimated at 1:800. Although its cause is the surface of an antigen-presenting cell
ecules make it difficult for pathogens to
not yet known, it may be related to an (APC) such as a macrophage or B cell (see
evade immune responses: 1) several
arrest in the development of B cells. An Fig. 2).
different HLA class I and HLA class II
IgA deficiency predisposes one to a
genes encode proteins with different
variety of diseases, including allergies and Immune System Abnormalities in
autoimmune disorders. Autism ranges of abilities to bind pathogenic
There are two main types of T Studies have documented numer- peptides; and 2) the HLA is highly
cells. One is the cytotoxic T cell (also ous abnormalities [see Gillberg and Cole- polymorphic, that is, there are multiple
called CD8 cell or ‘‘killer T cell’’), which man, 1992, for a recent review]: 1) Our forms (alleles) of an HLA gene. This is
destroys virally infected cells and tumor laboratory has reported decreased serum analogous to the polymorphisms seen
cells. The second type of T cell, the CD4 IgA levels in 8 of 40 individuals with with the gene for eye color, in which
cell, functions mainly as an activator of autism [Warren et al., 1997], a number different alleles lead to blue eyes, brown
other cells, including B cells and macro- that is far greater than might be expected eyes, and so on. In fact, the HLA genes
phages. Both T and B cells have on their by chance. 2) Stubbs [1976] observed that are the most polymorphic genes known
cell surface protein receptors that bind to some children failed to produce antibod- in the human genome.
antigens, and a mature lymphocyte has a ies following rubella vaccination, suggest- HLA covers a distance of more
receptor specific for only one particular ing that they lacked specific reactivity than 2 centimorgans of DNA, or about
antigen. The T cell antigen receptor with rubella. 3) Warren and colleagues 4 3 10 basepairs, and contain more than
(TCR) is very important. In order for T [1986] found that individuals with autism 100 genes. For simplicity, only those
cells to become activated, the receptor had decreased immune responses to genes that have been studied in individu-
must not only bind to a foreign antigen, T-cell mitogens [confirming an earlier als with autism will be included in this
but also to an HLA (histocompatibility finding by Stubbs et al., 1977]. Also review. These include genes for the class I
138 MRDD RESEARCH REVIEWS • POSSIBLE IMMUNOGENETIC BASIS FOR AUTISM • BURGER & WARREN
molecules, called HLA-B, genes for two
HLA class II molecules, called HLA-DR
and -DQ, and genes for three of the
complement components. The particular
combination of HLA alleles found of the
various HLA genes on an individual
chromosome is known as an HLA
haplotype (Fig. 3).
The number of different HLA
alleles affects antigen recognition indi-
rectly by controlling peptide binding.
The products of individual HLA genes
can differ from one another by up to 20
amino acids, making each allele quite
distinct. Most of these differences are on
the surface of the HLA molecule con-
fined to the site that binds peptides
(peptide-binding groove). Thus, the
amino acids lining the peptide-binding
groove determine the peptide-binding
properties of the different HLA mol-
ecules. The T cells responding to a given
protein antigen presented by several
different HLA molecules will usually
have to recognize different peptides. In Fig. 2. Foreign substances (antigens) are engulfed and processed by APC and presented
rare cases, a protein will have no peptides to T cells by the major histocompatibility complex (MHC). The MHC-antigen complex
interacts with the T-cell receptor (TCR) initiating activation through a complex series of
capable of binding to any of the HLA reactions within the T cell. The hypervariability of the TCR allows for the recognition of
molecules expressed on the APCs of an thousands of different antigens, giving the immune system the adaptability required to
individual. When this happens, the indi- protect the individual from infection.
vidual fails to respond to the antigen.

The Role of HLA in Autoimmunity

An adaptive immune response di-
rected at self-antigens (those produced by
one’s own body) is called an autoimmune
response or autoimmunity. The resulting
autoimmune diseases are characterized by
tissue damage. Well-known examples
include rheumatoid arthritis, which causes
destruction of synovial or joint-associated
tissue, and multiple sclerosis, which
involves damage to myelin tissue in the
brain. It is clear that autoimmunity is
initiated by responses involving T cells.
Cytotoxic T-cell responses and inappro-
priate activation of macrophages can
cause extensive tissue damage, and inap-
propriate T-cell help can initiate a
harmful antibody response to self-
antigens. Autoimmune responses are a
natural consequence of both B-cell and
T-cell receptors being able to recognize
any peptide, since such receptors will also
include those reactive to self-antigens. It
is not known what triggers autoimmunity
but both environmental and genetic
factors, especially HLA genotype, are
clearly important.
It was realized early in the study of
immunity that the powerful effector
mechanisms used to defend the individual
from disease could, if turned against the
individual, lead to severe tissue damage.
Typically, individuals do not mount
sustained T-cell responses to their own
MRDD RESEARCH REVIEWS • POSSIBLE IMMUNOGENETIC BASIS FOR AUTISM • BURGER & WARREN
Fig. 3. The human extended MHC on the short arm of chromosome 6 consisting of: the
HLA-DQ region and the DR regions (including the DRb1 gene); C4B, C4A, Bf, C2; the genes
for TNF a and b, and the HLA-B region. Spacing of genes in the illustration approximately
corresponds to the spacing of the genes on chromosome 6, except that the distance
between DR and C4B and between the TNF genes and HLA-B are greater than shown.
antigens and, although transient responses strated an association between disease
to damaged tissues do occur, these rarely susceptibility and the HLA class II alleles
cause further tissue damage. However, HLA-DR3 and HLA-DR4. Another
while a lack of immune response to one’s way of determining whether HLA genes
own tissue is the general rule, sustained are important in autoimmune disease is to
immune responses to self-tissues do study the families of affected individuals.
occur. In family studies, it has been shown that
The association of HLA alleles with two siblings affected with the same
autoimmune disease is not surprising, autoimmune disease are far more likely
since all autoimmune responses involve T than expected to share the same HLA
cells, and the ability of T cells to respond haplotypes. However, HLA genotype
to a particular antigen depends on HLA alone does not determine whether a
genotype. However, the way that HLA person develops disease. Identical twins,
alleles determine susceptibility to autoim- sharing all of their genes, are far more
mune disease is not known. likely to develop the same autoimmune
disease than HLA-identical siblings, dem-
Methods for Establishing the onstrating that other genetic factors also
Association Between the HLA affect disease susceptibility. Recent stud-
Genotype and Disease ies of the genetics of autoimmune diabe-
One determines such an association tes in humans and mice have shown that
by comparing the frequency of different there are several independently segregat-
HLA alleles in clinical populations with ing disease susceptibility loci in addition
the frequency in the normal population. to the HLA.
In insulin-dependent diabetes mellitus, There is evidence that several other
for example, this approach has demon- families of genes may play an important
139
 self-HLA molecules on APCs. Another
Table 1. List of HLA Extended Haplotypes and Their Reported very interesting finding was that some of
Disease Associations [Alper et al., 1989; Degli-Esposti et al., 1992] the mothers of children with autism had
B44-S30-DR4 on one of their chromo-
Class I Class III Class II Known Disease somes that did not pass to the child. On
its face, this finding would seem to argue
B BF C4A C4B DR DR_1 Abbreviation Associationsa
against an association between B44-S30-
44 S 3 0 4 0401 B44-S30-DR4 RA (child onset), FS DR4 and autism. However, if this
44 F 3 1 7 0701 B44-F31-DR7 CD, IgA Def extended haplotype is associated with an
57 S 6 1 7 0701 B57-S61-DR7 IgA Def, Psoriasis immune abnormality/deficiency, its pres-
13 S 3 1 7 0701 B13-S31-DR7 None reported ence in the mother may be sufficient to
7 S 3 1 15 0501 B7-S31-DR15 MS, CD
8 S 0 1 3 0301 B8-S01-DR3 GMG, IgA Def, SLE affect the child. As noted earlier, maternal
18 F 3 0 3 0301 B18-F130-DR3 IDDM immune deficiency itself may have al-
35 F 3,2b 0 1 0101 B35-F(3,2)0-DR1 HIV (rapid progression) lowed damage to the developing fetal
35 S 3 0 1 0101 B35-S30-DR1 HIV (rapid progression) brain. Interestingly, in mothers with
35 S 3 1 4 0404 B35-S31-DR4 None reported
62 S 3 3 4 0401 B62-S33-DR4 IDDM, RA
B44-S30-DR4 indications of autism were
65 S 2 112 1 0101 B65-S2(1,2)-DR1 IgA Def noted very early, at birth or within the
first year of life.
aRA, rheumatoid arthritis, and childhood onset; FS, Feltys syndrome; CD, Celiac disease; IgA Def, immunoglobulin A deficiency; MS,
Multiple sclerosis; SLE, systemic lupus erythematosus; GMG, myasthenia gravis; IDDM, insulin-dependent diabetes mellitus; HIV, human
immunodeficiency virus.
bThis designation denotes a fairly rare duplication of the C4A gene; one allele is C4A3 and the other allele is C4A2.
SUMMARY
Autism likely results from several
different etiologies or a combination of
role in increasing susceptibility to autoim- Studying HLA extended haplo- pathological mechanisms. As this brief
mune disease. In humans, normal plasma types is another way of determining review suggests, evidence suggests that
contains nine (C1–C9) heat-labile pro- whether a given disorder is associated some cases of autism are associated with
teins of the complement system. These with HLA. Extended haplotypes are immune abnormalities, pathogen-autoim-
proteins augment the antibacterial activ- observed when certain HLA haplotypes mune processes, and/or the HLA. Re-
ity of antibodies through a cascade of segregate together far more often than searchers in several centers in the United
interdependent reactions called the classi- expected from the relative distances States and Europe continue to investigate
cal complement pathway. Inherited total between their respective genes. Some the link between the immune system and
or partial deficiency of the early proteins unknown mechanism prevents crossovers autism. Extensive pedigree analysis of
(C4 or C2) of the classical pathway of (gene exchanges between chromosomes) individuals with autism and their rela-
complement is very strongly associated from occurring within this portion of the tives, further exploration of immune
with the development of systemic lupus HLA, resulting in a similarity of DNA abnormalities, and attempts to identify
erythematosus (SLE). These genes are sequences [Alper et al., 1989; Degli- linkages with autoimmunity may offer a
located between the genes for HLA-B Esposti et al., 1992]. As Table 1 shows, way of identifying families at increased
and HLA-DR (see Fig. 3). The mecha- about a dozen or so extended haplotypes risk for autism. j
nism of this association is unknown but with a gene frequency of 0.0043 or
may involve the inability to clear certain greater have been identified. One or
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