Genetics of Childhood Disorders: Streptococcal Infections and Autoimmunity

[Guest guest]

J Am Acad Child Adolesc Psychiatry,40:11,1346-1348 November 2001

Genetics of Childhood Disorders:

Autoimmune Disorders

Streptococcal Infections and Autoimmunity

Debra E. Bessen, Ph.D.

There is increasing recognition that microbial infections are important

contributors to a wide range of chronic conditions. Peptic ulcer disease may

be due to the bacterium Helicobacter pylori rather than to emotional stress

and diet. For years the conventional wisdom had been that no microbe could

survive the acidic conditions of the stomach. Until recently the blood-brain

barrier was considered impenetrable to plasma proteins, such as antibody and

complement. Now it is purported that several neuropsychiatric disorders of

childhood are rooted in a microbe-triggered autoimmune response. Clearly, a

contributing role for microbial infections in chronic diseases of the CNS

needs to be reassessed.

Inflammation, sometimes accompanied by a specific immune response, is often

a critical component of chronic diseases associated with infection. A role

for microorganisms in autoimmunity has been suggested for decades, although

for many diseases, such as multiple sclerosis and type I diabetes, the

unequivocal identification of the etiological agent(s) has been met with

difficulty. Perhaps the best-recognized link between autoimmunity and

infection lies with acute rheumatic fever (ARF) and the bacterium

Streptococcus pyogenes, also known as group A b-hemolytic streptococci

(GABHS). Diagnosis of ARF can be tricky, and it generally includes one or

more of the following major manifestations: (1) carditis, typically

involving the mitral valve; (2) a polymigratory arthritis, which resolves

without permanent damage to the joints; and (3) Sydenham chorea, a disorder

of gross motor function.

Essential to the diagnosis of ARF is evidence of a recent GABHS infection.

Documentation can take the form of a positive throat culture or an elevated

antibody titer to GABHS antigens. However, exceptions are made for some

cases of “pure chorea.” Unlike carditis or polymigratory arthritis, there is

the possibility of a delay of several months between the primary GABHS

infection and the onset of Sydenham chorea symptoms. By this time, the

organism is long gone from the host and anti-streptococcal antibody titers,

as well as plasma markers for acute inflammation (e.g., C-reactive protein),

have declined to normal levels. Inasmuch as chorea often appears during the

acute stage rheumatic fever and is a clearly defined syndrome, its

association with GABHS infection remains unchallenged.

Epidemiological studies were crucial in establishing the relationship

between GABHS and rheumatic fever. At the close of the 19th century in the

United States and Europe, diseases caused by GABHS, which notably include

scarlet fever, had a public health impact that rivaled tuberculosis. Prior

to the widespread use of antibiotics in the late 1940s, streptococcal

infections were difficult to control. Outbreaks of ARF within the military,

around the time of World War II, provided a rich source of information on

the epidemiology of this disease and its association with primary GABHS

infection.

ARF can follow an untreated GABHS infection of the upper respiratory tract

(URT). In most instances, a host immune response that is directed

specifically toward the invading organism will be mounted, resulting in

clearance of the primary infection within 2 weeks. In some cases, an

asymptomatic carrier state will develop, whereby the bacterium is believed

to be in a quiescent state, perhaps residing within the epithelial cells

lining the oropharynx and hidden from immune attack. There is a delay of 3

to 6 weeks following the primary bacterial infection and symptoms of ARF.

Not all individuals experiencing an untreated GABHS infection will develop

ARF. It is estimated that only 3% of the human population has a genetic

predisposition for developing rheumatic fever. Moreover, not all strains of

GABHS will trigger an acute rheumatic attack, even in a highly susceptible

host. This became strikingly apparent in the 1940s at Irvington House, a

group home for children with rheumatic heart disease. It is here that an

M-type 4 strain caused acute pharyngitis in many residents, yet failed to

induce a single episode of recurrent ARF.

It is widely accepted that only a GABHS infection of the throat can induce

ARF. In addition to pharyngitis, GABHS can cause impetigo, a purulent

infection involving the epidermal layer of the skin. Perhaps the unique

association between ARF and URT infection, but not skin infection, arises

from differences in the drainage of streptococcal antigens into the ducts of

the lymphatic system. There is also speculation that the apparent failure of

skin infection to induce ARF is due to the fact that GABHS strains which

cause impetigo are often distinct from the strains giving rise to

pharyngitis. Numerous epidemiological studies on ARF outbreaks in the United

States and Europe have led to the classification of several M-types of GABHS

as highly “rheumatogenic.”

The relative incidence of GABHS infection of the URT and skin varies in

accordance with both season and geographic location. In many temperate

climates, pharyngitis is common during the winter, whereas impetigo has a

lower overall prevalence and peaks during the summer months. In contrast, in

many tropical regions impetigo is highly endemic (Fig. 1). The highest

reported rate of rheumatic fever is found among the Aboriginal people of

tropical Australia. Curiously, acute pharyngitis is uncommon in Australian

Aborigines, and the so-called “rheumatogenic” M-types are rarely recovered.

Whether or not a throat infection by a rheumatogenic strain is a strict

requirement for ARF remains a hotly contested issue.

A true GABHS infection, as opposed to carriage, can be defined in

serological terms as a rise in antibody titer to GABHS antigens, such as

streptolysin O or deoxyribonuclease B. However, true infection of the URT

need not necessarily lead to overt clinical symptoms. It is important to

note that a clinically inapparent GABHS infection can trigger ARF. Beginning

in the mid-1980s, the Salt Lake City (Utah) region experienced a marked

increase in the incidence of ARF. Yet in about half of the cases, the

patient had no recollection of a sore throat in the weeks preceding the

acute attack. Were it not for outbreaks of ARF occurring in institutional

settings, such as military bases, at a time prior to the availability of

effective antibiotics, such as penicillin, the link between GABHS infection

and ARF would probably remain elusive, or at least less certain than it is

today.

There is a connection between GABHS and neuropsychiatric disorders, such as

Tourette syndrome (TS), obsessive-compulsive disorder (OCD), and possibly

attention-deficit/hyperactivity disorder (ADHD). Patients with these

neuropsychiatric disorders have elevated levels of expression of a

B-lymphocyte cell surface marker, known as D8/17, which is also elevated in

rheumatic fever patients and their first-degree relatives. The specificity

of D8/17 for rheumatic fever is very high when compared with several other

autoimmune diseases, such as rheumatoid arthritis. Whether the D8/17 marker

has a direct role in ARF is not yet known. Sydenham chorea is one of the

major manifestations of rheumatic fever, and many patients with Sydenham

chorea also exhibit obsessions and compulsions. Furthermore, considerable

comorbidity is observed among patients with TS, OCD, ADHD, and Sydenham

chorea. The basal ganglia is a primary target organ of Sydenham chorea, a

feature it shares with TS, OCD, and ADHD.

A practical approach for evaluating the association between GABHS infection

and neuropsychiatric disorders is to model new studies based on our current

knowledge of ARF. However, the epidemiological studies that uncovered the

link between GABHS and ARF may not be wholly applicable to TS, OCD, and

ADHD. Most cases of TS, OCD, and ADHD are sporadic and appear in community

settings. Outbreaks of acute TS, OCD, or ADHD have not been documented. Even

qualifying an episode of TS, OCD, or ADHD symptoms as an acute exacerbation

can be fraught with difficulties. GABHS infections are frequent within the

same group afflicted with TS, OCD, and ADHD. At its peak incidence, between

the ages of 5 and 7 years, it is estimated that half of all children

experience an average of one GABHS infection per year. If the time delay

between GABHS infection and acute episodes of TS, OCD, or ADHD were of the

magnitude observed for pure chorea, then a temporal relationship between

GABHS infection and the neuropsychiatric disorders would be difficult to

establish. The “background” level of GABHS infections may be too high.

Any attempt to establish a temporal relationship between GABHS infection and

an acute exacerbation of neuropsychiatric symptoms would be further

complicated if only a subset of patients were susceptible to the effects of

GABHS infection. Yet this is exactly what has been proposed.

Patients with PANDAS—an acronym for pediatric autoimmune neuropsychiatric

disorders associated with streptococcal infections—are thought to represent

only about 10% of all neuropsychiatric patients. If only some of the acute

episodes experienced by a PANDAS patient were rooted in a GABHS infection,

it may be impractical to design an epidemiological study that could capture

the effect—a very large sample size of human subjects would be required.

However, longitudinal studies of PANDAS patients are required to help

clarify the etiology and to determine whether exacerbations of symptoms are

secondary to repeated GABHS infections.

The molecular mechanisms underlying the development of ARF remain

ill-defined. Antibodies which react with both streptococcal antigens and

human host tissues, such as the brain and heart, have been identified. For

some antibodies, a pathological role is well-supported by studies using

experimental animal models for carditis. Because there is a strong familial

pattern of rheumatic fever, as there is for TS, OCD, and ADHD, is should be

possible to identify the genetic determinants of susceptibility for each of

these diseases and determine whether they overlap. Significant associations

between rheumatic fever and HLA markers have been observed for several human

populations that share the same ethnic background; however, the HLA markers

are unique to each ethnic group. Aside from the D8/17 antigen present on the

surface of B-lymphocytes, there are no stable biomarkers known for rheumatic

fever.

Defining the relationship between TS, OCD, ADHD, and GABHS infection is a

challenging problem. But the rewards of success could be enormous. ARF is a

readily preventable disease that can be managed through antibiotic

prophylaxis. Identifying those individuals who stand to benefit from

antibiotic therapy remains a central goal. Perhaps the answer will lie not

in the classical epidemiological approach that proved so successful in

decades past, but rather in the precise identification of molecular markers

that allow for stratification of patients into biologically relevant

subgroups.

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