The Many Faces of Cardiac Sarcoidosis

Virian D. Serei, MD, PhD; Billie Fyfe, MD

Disclosures

Am J Clin Pathol. 2020;153(3):294-302. 

In This Article

Pathogenesis

The etiology of sarcoidosis is unknown. An exaggerated T helper 1 (Th1) cell response to unknown antigen is thought to drive nonnecrotizing granulomatous inflammation.[3,12] Macrophages and other innate antigen presenting cells from sarcoid patients are thought to be hyperresponsive to antigen. Pattern recognition receptors such as toll-like receptors are triggered by antigen to produce an enhanced Th1 response, characterized by increased tumor necrosis factor-α (TNF-α), interferon-γ, and interleukin 2, and presentation of antigen to effector T cells on MHC class I and class II molecules.[3,12] These events lead to aggregation of macrophages and influx of CD4+ Th1 cells.[12] The exaggerated Th1 responses can be attributed to variations in the class I and class II HLA molecules.[2,12] In particular, genetic studies have shown that variations in the HLA-DRB1 gene can confer risk or protection against sarcoidosis.[2]

Infectious and noninfectious antigens may trigger granuloma formation.[2,3,12] Despite failure to culture or histologically identify microorganisms from sarcoid specimens, molecular and immunologic studies have implicated Mycobacteria, Cutibacterium (formerly Proprionibacterium), and fungi in its pathogenesis.[2,3,12]

Postulated environmental agents include metals such as aluminum, zirconium, titanium, and beryllium; organic dusts such as pine tree pollen and wood dusts; and inorganic dusts such as clay, talc, glass fibers, and silicone.[2]

In cardiac sarcoid patients presenting as ARVC, a disease characterized by loss of desmosomal proteins with subsequent fibrofatty replacement of the ventricular wall and ventricular dilation, studies have shown a decrease in plakoglobin (γ-catenin), a desmosomal protein, at cardiac intercalated disks.[6,7]

The specific risk factors for cardiac sarcoidosis are also not well characterized. There are several genetic studies in the Japanese population, given their noted higher rate of cardiac sarcoidosis. Increased frequency of toll-like receptor 3 rs3775291 T allele, which is thought to skew towards a Th1 inflammatory milieu, was found in Japanese patients with cardiac sarcoidosis.[13] Polymorphisms in TNFA, which encodes TNF-α, have also been associated with cardiac sarcoidosis.[14]

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