Background:

Castleman Disease (CD) is a rare, atypical lymphoproliferative disorder with significant morbidity and mortality and a poorly understood pathophysiology. Defined by a shared lymph node (LN) histology, CD encompasses a wide range of clinical presentations from unifocal adenopathy with mild symptoms (unicentric CD, UCD) to multifocal adenopathy with a systemic inflammatory cytokine storm driving multi-organ dysfunction (multicentric CD, MCD). MCD can be further divided into human herpesvirus (HHV)-8-associated MCD and HHV-8-negative/idiopathic MCD (iMCD). Disease etiology, pathophysiology, including the identity of the pathogenic cells and transcriptional programs, remains largely unknown. Thus, a fundamental question in CD is whether an etiological mechanism of iMCD is an infectious disease, an inflammatory disease, or an autoimmune disease. In this study, we hypothesized that autoantibodies may be driving iMCD pathology in at least a subset of iMCD patients.

Research Methods:

We constructed two custom bead-based protein arrays to screen iMCD (n = 101) and health control (HC, n = 30) serum samples for IgG autoantibodies. The Connective Tissue Disease (CTD) array consisted of 52 antigens associated with traditional CTDs involved in Scleroderma, Myositis/Overlap Syndromes, Systemic lupus erythematosus (SLE)/Sjögren’s, GI/Endocrine, DNA-Associated, and Inflammation/Stress. The anti-cytokine autoantibody (ACA) array was comprised of 38 cytokines, chemokines, and cell surface proteins. Patient serum samples were sourced from the University of Pennsylvania (n = 38), the University of Arkansas for Medical Sciences (n = 45), and Osaka University (n = 18). A “positive” autoantibody result in any serum sample was defined as greater than 5 standard deviations (SD) above the average mean fluorescent intensity (MFI) of the HC and at least 3,000 MFI. Fisher’s Exact tests were used to determine associations between autoantibody positivity and disease status. Anti-IL-6 positivity was excluded in analyses as anti-IL-6 therapy was common in the iMCD patient cohort. We also evaluated prevalence of autoantibodies in iMCD patients compared to HC for the six subcategories of CTDs described above.