Primary Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of salivary and lachrymal glands, clinically manifesting as oral and ocular dryness, respectively. B cell activation has long been considered a disease hallmark associated with hypergammaglobulinemia, cryoglobulinemia, and autoantibody production (1). Furthermore, it has been proposed that type I interferon (IFN)/BAFF axis activation (2–5) and, recently, interleukin-21 (IL-21) (6) are significant pathogenetic contributors. The autoantibodies most commonly found in sera from patients are against non–organ-specific antigens, such as Ro/SSA–La/SSB ribonucleoprotein complexes. In addition, it has been previously reported that other, organ-specific autoantibodies, such as antibodies against thyroid and mitochondrial antigens, frequently occur in SS overlapping with autoimmune thyroid disease (AITD) and primary biliary cirrhosis, respectively (1).
Abnormalities of the hypothalamic–pituitary–adrenal (HPA) axis in patients with primary SS, which manifest as blunted cortisol responses to corticotropin-releasing hormone stimulation, have been previously reported and were attributed to either blunted adrenocorticotropic hormone (ACTH) release from the pituitary gland or a primary adrenal defect (7). Antibodies to 21-hydroxylase (anti-21[OH]), a major adrenal autoantigen, are currently used to identify patients at increased risk of developing autoimmune adrenalitis. Autoimmune adrenalitis is the most common cause of adrenal insufficiency in developed countries and is characterized by lymphocytic infiltration and destruction of the adrenal glands. In cross-sectional studies, the prevalence of autoantibodies against 21(OH) in patients with Addison's disease has been estimated to range from 65% to 95%. This frequency tends to be higher in patients with shorter disease duration, declining over the years to a frequency of 60% after 35 years of followup. In individuals with evidence of diseases other than adrenal organ–specific autoimmune diseases, the presence of antibodies to 21(OH) has been shown to predict progression to overt autoimmune failure over 6 years in ∼15% of patients (8). However, there is currently no information regarding the presence of antibodies against adrenal antigens and the effect that their presence may exert on adrenal function in patients with primary SS.
In the present study, we aimed to evaluate the prevalence of antibodies to 21(OH) in a cohort of patients with primary SS and to investigate whether their presence could be related to evidence of primary adrenal insufficiency. Additionally, we sought to explore potential associations between anti-21(OH) titers and clinical, serologic, and histopathologic disease parameters, including B cell–activating cytokine gene expression in salivary gland tissue.
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The present study is the first to demonstrate a higher prevalence of adrenal autoimmunity on the basis of elevated anti-21(OH) titers in patients with primary SS. Patients with primary SS and positive anti-21(OH) titers exhibited a decreased prevalence of subjective ocular dryness and increased rates of leukopenia compared to those who were negative for anti-21(OH). Furthermore, serum anti-21(OH) titers strongly correlated with the expression of IFNα, BAFF, and IL-21 mRNA in MSG tissue. This finding suggests that these B cell–activating cytokines could be responsible for or contribute to the generation of an autoimmune response against organ-specific autoantigens (in this instance, the adrenal gland). While the presence of B cell hyperactivity in the setting of SS has been previously associated with leukopenia (11), the presence of sicca symptoms, either ocular or oral, does not often correlate with the degree of inflammation, implying that additional neurohormonal contributors might account for the observed dryness (7).
Although not associated with overt adrenal insufficiency, the presence of antibodies to 21(OH) in our group of patients with primary SS was associated with adrenal hyporesponsiveness following ACTH stimulation, implying that the previously observed hypofunctional HPA axis in patients with primary SS could be explained by a primary adrenal defect (7). However, as adrenal damage may be an evolving process, further followup and subsequent testing of these patients are required to delineate the prognostic value of anti-21(OH) positivity. It is tempting to suggest that this alteration in adrenal glucocorticoid secretory pattern in patients with 21(OH) antibodies could identify a group of patients in whom more severe forms of primary SS could evolve due to a relative adrenal hyporesponsiveness. However, this needs to be further clarified by long-term studies and continuous evaluation of adrenal glucocorticoid reserve.
While studies of the prevalence of antibodies to 21(OH) in systemic autoimmune diseases are rather limited, there is growing evidence of an increased prevalence of concomitant autoimmune diseases in patients with autoimmune adrenalitis. A recent study revealed that concomitant autoimmunity was increased in more than half of patients with autoimmune adrenal disease, as evidenced by the presence of various autoantibodies against thyroid antigens, glutamic acid decarboxylase, insulin, and parietal cell H+/K+-ATPase, respectively (12). In autoimmune thyroiditis, clustering of β cell and adrenal autoimmunity has also previously been reported (13), while in primary SS, autoreactivities against thyroid and mitochondrial antigens, and to a lesser extent, aquaporin 4 and celiac-specific antigens, are known to occur (14). These findings support the notion that autoimmune clustering is possibly related to the presence of shared genetic, immunologic, and/or environmental contributors.
The association of antibodies to 21(OH) with IFNα, BAFF, and IL-21 expression in MSGs in the setting of primary SS might provide some clues regarding the etiology of distinct autoimmune responses against organ-specific and non–organ-specific autoantigens in the setting of systemic autoimmunity, possibly through induction of B cell hyperactivity. In a case of hairy cell leukemia, IFNα treatment has been shown to result in generation of polyglandular autoimmune disease type 2 expressed as AITD, Addison's disease, and premature ovarian failure, all of which were reversed upon discontinuation of IFN treatment (15).
The contributory role of type I IFN in antibody production both in vitro and in vivo has been previously shown through class-switch recombination, polarization of antibody responses toward IgG2a/IgG2c production, and induction of BAFF, a B cell survival factor implicated in SS pathogenesis through induction of transitional type 2 and marginal zone–like B cells in the salivary glands and of autoantibody production (5). IL-21, a pleiotropic cytokine produced by CD4 and natural killer T cells, has also been shown to promote B cell differentiation into plasma cells, while it has been recently identified as a cytokine that potentially contributes to SS pathogenesis. The latter result is also supported by the IL-21 heightened serum levels in SS patients in association with serum IgG1 levels and increased expression of IL-21 in the lymphocytic infiltrations of MSGs in SS (6).
In conclusion, autoimmune adrenal disease occurs in ∼20% of patients with primary SS in association with adrenal hyporesponsiveness and markers of B cell activation, extending the list of currently known SS-associated organ-specific disorders. However, whether the presence of antibodies against 21(OH) defines a subset of primary SS characterized by more severe disease due to endogenous failure of suppression of a hyperactive immune system needs to be addressed in followup studies.
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All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Mavragani had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Mavragani, Schini, Gravani, Kaltsas, Moutsopoulos.
Acquisition of data. Mavragani, Schini, Gravani, Kaltsas, Moutsopoulos.
Analysis and interpretation of data. Mavragani, Schini, Gravani, Kaltsas, Moutsopoulos.