Page 764 - Clinical Immunology_ Principles and Practice ( PDFDrive )

736 ParT Six Systemic Immune Diseases

are targeted against ribonucleoprotein antigens. Anti-Ro/SSA
recognizes two RNA binding proteins (the 52-kilodalton [kDa]
or the 60-kDa protein), whereas anti-La/SSB antibodies recognize
RNA polymerase III. Anti-Ro/SSA antibodies are found in over
70% of patients with SS but are also frequently encountered
in systemic lupus erythematosus (SLE) and other autoimmune
diseases, even in the absence of oral or ocular dryness. Anti-La/
SSB is more specific; it is present in 50% of patients with primary
SS or SS/SLE but is rarely seen in other diseases. The patho-
genic role of these antibodies has not yet been defined, except
in infants born to women with anti-Ro/SSA and/or anti-La/
SSB antibodies. These antibodies can cross the placenta and
bind to Ro and La antigens located on the cell surface of fetal
myocardial tissue, leading to fetal heart block. Other autoanti-
bodies, such as antinuclear antibodies (ANAs) and rheumatoid
factor, are frequently present in patients with both primary and
FiG 54.1 Minor salivary gland biopsy with characteristic periductal secondary SS. Although these antibodies lack specificity, they are
inflammation. markers of a systemic autoimmune response and thus can help
distinguish SS from other causes of salivary or lachrymal gland
dysfunction.
clinical spectrum similar to that of SS. The fact that some viruses,
such as Epstein-Barr virus (EBV), replicate in oropharyngeal and AUTONOMIC NERVOUS SYSTEM ABNORMALITIES
lachrymal glands has led to the hypothesis that these viruses
might contribute to the pathogenesis of SS. Other viruses, such Autonomic nervous system (ANS) abnormalities are common
as coxsackievirus or endogenous retroviruses, have also been in SS and may play a critical role in its pathogenesis. Xerostomia
proposed as agents of interest. However, to date, there is no and xerophthalmia, the cardinal manifestations of SS, are fea-
proof that any of these viruses plays a pathogenic role in SS. tures of cholinergic parasympathetic ANS dysfunction, whereas
sympathetic cholinergic failure results in xerosis and decreased
Epithelial Cell Activation and Chronic Inflammation sweating, which are frequently reported by patients with SS.
The histological hallmark of SS is a periductal mononuclear The complexity of the ANS, along with differences in meth-
infiltrate in salivary and lachrymal glands (Fig. 54.1). The majority odology and studied populations, has resulted in variable results,
of the infiltrating cells are CD4 T lymphocytes, whereas CD8 but abnormalities in SS have been reported in both sympathetic
cytotoxic T cells are found in smaller numbers. Activated B and parasympathetic ANS domains.
lymphocytes are also present, including autoantibody-secreting
plasma cells. CLINICAL MANIFESTATIONS
Epithelial cell activation, signified by the expression of HLA
class II molecules, is key to initiating recruitment of the inflam- Clinical manifestations resulting from dysfunction of salivary
matory infiltrate. The expression of these molecules, along with and lachrymal glands are the dominant features of SS. Symptoms
upregulation of adhesion molecules and chemokines, contributes secondary to other exocrine gland dysfunction, such as skin and
to the recruitment of inflammatory cells, such as T and B lympho- vaginal dryness, and chronic cough caused by tracheal dryness
cytes, macrophages, and dendritic cells (DCs), and suggests that are frequently reported. Multiple extraglandular manifestations
epithelial cells may act as antigen-presenting cells (APCs), actively can also be present, reflecting the systemic nature of the auto-
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participating in lymphocyte activation. The ensuing chronic immune process. 4
inflammatory process is characterized by a complex interaction
between activated epithelial cells and the innate and adaptive Constitutional Symptoms
immune systems. In the most severe forms of inflammation, the One of the most common extraglandular manifestations of
characteristic periductal infiltrates can progress to the formation SS is excessive fatigue. Approximately 70% of patients with SS
of germinal centers, which is associated with a higher risk of complain about disabling fatigue leading to reduced quality of
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lymphoma development. Extraglandular manifestations occur as life. Attempts to identify a biological basis for fatigue have
a result of similar lymphocytic infiltrations in other organs. This failed to reveal any correlations with levels of inflammatory
is described by some as autoimmune epithelitis to better reflect markers, cytokines, or autoantibodies. This fatigue is commonly
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the systemic nature of the disease. In most patients, only partial associated with arthralgia, malaise, and mental cloudiness (brain
destruction of the glands is noted. Local production of cytokines, fog), resulting in a diagnosis of fibromyalgia or chronic fatigue
autoantibodies, metalloproteinases, and other inflammatory syndrome. Less commonly, patients also experience low-grade
mediators may contribute to the dysfunction of the remaining fever and weight loss.
epithelial cells. It is increasingly recognized that the innate immune
system plays a crucial rule in the immunopathogenesis of SS. Ocular Involvement
Lachrymal gland dysfunction leads to dry, sandy eyes and sensa-
Autoantibodies tion of foreign body in the eyes. Frequently, there is a history of
Autoantibodies are the hallmark of systemic autoimmune dis- intolerance to contact lenses. Patients often complain of sticky
eases, including SS. The best-defined autoantibodies in SS are eyes and accumulation of thickened mucus as a result of loss of
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anti-Ro/SSA and anti-La/SSB antibodies. Both autoantibodies aqueous tear components.