Background/Purpose: Hypocomplementemia, defined as low serum C3 and/or C4 concentrations, is common in patients with IgG4-related disease (IgG4-RD). While this has historically been linked with renal involvement, recent data have shown that hypocomplementemia is more accurately associated with extent of IgG4-RD across multiple sites rather than individual organ manifestations, suggesting that complement-driven inflammation is central to the disease process. We aimed to assess whether complement is deposited locally in IgG4-RD submandibular gland lesions.

Methods: We obtained submandibular gland tissue from 8 patients who fulfilled the 2019 ACR/EULAR IgG4-RD Classification Criteria and had undergone submandibular gland biopsy for diagnostic purposes. Other disease features, including sites of involvement beyond the submandibular glands and the presence or absence of hypocomplementemia, were not considered when identifying samples to be analyzed. We extracted disease features, laboratory results, demographic data, and treatment status at the time of biopsy from the medical records. All tissues were formalin-fixed and paraffin-embedded prior to sectioning. Immunohistochemistry was performed to stain for C3d, an end product of complement activation that persists in tissue longer than most other complement activation fragments. We similarly stained for C3d in a negative control (uninvolved submandibular gland) and positive control (human liver with primary sclerosing cholangitis).

Results: Demographic and disease characteristics of the 8 IgG4-RD patients studied are shown in Table 1. Six of the 8 patients (75%) were treatment-naïve at the time the biopsies were obtained. Five (62.5%) of the patients were female. The median disease duration at the time of biopsy was 301.5 days (IQR: 221, 1082.5). Only 3 patients (37.5%) had hypocomplementemia at any point in the disease course. Histopathologic features of the submandibular glands are shown in Table 2 and reflect the findings that are typical of submandibular glands involved by IgG4-RD. All samples demonstrated a dense lymphoplasmacytic infiltrate and most (5, 62.5%) demonstrated an IgG4+/IgG+ plasma cell ratio ≥40% (Figure 1A-D). All 8 submandibular gland biopsies showed deposition of C3d at sites of immune infiltration (Figure 1E-F), suggesting immune cells may be triggering complement activation. Additionally, C3d was also observed in several sites of fibrosis, suggesting complement may be contributing to fibrosis in IgG4-RD (Figure 1F-H). Staining patterns of positive and negative controls were as expected (Figure 1I-J).

Conclusion: Evidence of complement deposition was found in 8 of 8 submandibular glands included in this study. Complement activation was evident at this site of disease even in patients who demonstrated no sign of complement consumption in the peripheral blood (i.e., no C3 or C4 hypocomplementemia). These findings raise the possibility that tissue-targeted complement inhibition may be a useful treatment strategy in IgG4-RD and support the notion of complement-mediated inflammation being central to the disease mechanism of IgG4-RD.

Table 1. Demographics and disease characteristics of eight patients in whom submandibular gland biopsies were stained for complement deposition. Results reported as n (%) unless noted otherwise. §At any point in disease course. *1 patient was treated with methotrexate for comorbid rheumatoid arthritis.

Figure 1. Representative histopathology and immunostaining findings. (A) Low- and (B) high-powered hematoxylin and eosin stain of diseased submandibular glands (SMG) showing dense lymphoplasmacytic infiltrate. (C) IgG and (D) IgG4 stains of diseased SMG showing a large proportion of IgG4+ plasma cells. (E-H) C3d staining of diseased SMG showing C3d staining at sites of inflammation and fibrosis. (I) C3d stain of an uninvolved SMG (negative control) showing absent C3d staining. (J) C3d stain of human liver with primary sclerosing cholangitis (positive control) showing expected pattern of staining.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/complement-fragments-are-deposited-in-the-submandibular-glands-in-igg4-related-disease/