Immunohistological analysis reveals IgG1-dominant immunophenotype of tubulointerstitial nephritis unassociated with IgG4-related diseases

Abstract

Purpose: Tubulointerstitial nephritis (TIN) has various etiologies, including IgG4-related disease (IgG4-RD), autoimmune diseases, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and others. IgG4-positive plasma cell infiltration can occasionally be found in TIN unrelated to IgG4-RD. Therefore, there may be problems with usage of IgG4 immunostaining to differentiate between TIN with and TIN without IgG4-RD. This study aimed to compare the proportion of plasma cells that are positive for each IgG subclass and to clarify the predominant IgG subclass trends and clinical characteristics associated with IgG4-RD and non-IgG4-related interstitial nephritis.

Methods: The study enrolled 44 cases of TIN: 6 of IgG4-RD, 8 of autoimmune disease, 9 of AAV, and 21 of unknown disease group. In addition to clinical characteristics, IgG subclass composition of interstitial plasma cells was evaluated among 4 groups by immunohistochemistry.

Results: IgG1 was the predominant IgG subclass in TIN unrelated to IgG4-RD. In the IgG4-RD group, the IgG subclass rate was high in both IgG1 and IgG4. The rate of average IgG4-positive cells was significantly lower in the autoimmune disease group and unknown disease group compared with the IgG4-RD group.

Conclusion: The present study revealed IgG1-dominant immune profiles of TIN unrelated to IgG4-RD. Further investigation is required to elucidate the clinicopathological differences between IgG1-dominant and IgG4-dominant groups in IgG4-RD.

Keywords: IgG subclass; IgG1; IgG4; Plasma cells; Tubulointerstitial nephritis.

Fig. 1

IgG subclass profiles of four TIN groups. The average IgG subclasses percentage of four TIN groups classified by etiologies (IgG4-RD, autoimmune disease, AAV, and others) is shown in Box-and-Whisker plot. Significant p values of IgG subclass between IgG4RD and other 3 groups are indicated by * (IgG1, p = 0.036) and ** (IgG4, p < 0.01), respectively. There were no significant differences in the percentages of IgG2 (p = 0.344) or IgG3 (p = 0.115) positive plasma cells between IgG4-RD and the other groups. Blue, orange, gray, and yellow boxes indicate IgG1, IgG2, IgG3, and IgG4, respectively.

Fig. 2

Images of IgG subclass immunohistochemistry. Representative images of non-IgG4-related interstitial nephritis (a–e, case 44; etiology unknown), IgG1-dominant IgG4-RD (f–j, case 4), and IgG4-dominant IgG4-RD (k–o, case 2). b–e, g–j, and l–o are the images of IgG1 (b, g, l), IgG2 (c, h, m), IgG3 (d, i, n), and IgG4 (e, j, o), respectively. In a non-IgG4-related interstitial nephritis (case 44; etiology unknown), IgG1-positive plasma cells were most abundant. IgG4-RD cases were represented by IgG1-dominant (case 4) and IgG4-dominant (case 2) subgroups.

Fig. 3

IgG subclass profiles of IgG4-related kidney disease. Average IgG subclass percentage of IgG1-dominant (left) and IgG4-dominant (right) IgG4-RD are shown in Box-and-Whisker plot. Blue, orange, gray, and yellow boxes indicate IgG1, IgG2, IgG3, and IgG4, respectively.