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Review
. 2017 Sep;69(9):1722-1732.
doi: 10.1002/art.40168. Epub 2017 Aug 8.

Emerging Treatment Models in Rheumatology: IgG4-Related Disease: Insights Into Human Immunology and Targeted Therapies

Cory A Perugino  1 , Hamid Mattoo  2 , Vinay S Mahajan  2 , Takashi Maehara  2 , Zachary S Wallace  3 , Shiv Pillai  2 , John H Stone  3
Affiliations
Review

Emerging Treatment Models in Rheumatology: IgG4-Related Disease: Insights Into Human Immunology and Targeted Therapies

Cory A Perugino et al. Arthritis Rheumatol. 2017 Sep.
No abstract available

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Conflict of interest statement

The authors report no potential conflicts of interest.

Figures

Figure 1
Figure 1
(A) Head and neck illustration highlighting involvement of the lacrimal and major salivary glands. Lacrimal and salivary gland enlargement is most often bilateral in distribution. (B) Abdomen illustration highlighting typical organ involvement including the pancreas, bile ducts, kidneys, and retroperitoneal tissue. Radiographically, the retroperitoneal fibrosis often extends inferiorly to encase the iliac vessels. Not depicted here, the aorta and lung are other common sites of disease involvement.
Figure 1
Figure 1
(A) Head and neck illustration highlighting involvement of the lacrimal and major salivary glands. Lacrimal and salivary gland enlargement is most often bilateral in distribution. (B) Abdomen illustration highlighting typical organ involvement including the pancreas, bile ducts, kidneys, and retroperitoneal tissue. Radiographically, the retroperitoneal fibrosis often extends inferiorly to encase the iliac vessels. Not depicted here, the aorta and lung are other common sites of disease involvement.
Figure 2
Figure 2
Immunohistochemical staining for IgG4 (A and B) and CD3 (C and D) from the same cutaneous site pre- (A and C) and post- (B and D) rituximab treatment demonstrating a marked decline in tissue infiltrating B and T cells.
Figure 3
Figure 3
T-B collaboration, mediated by IL-4 and IL-21, is at the center of driving the differentiation of activated B cells into antibody-secreting cells. During this interaction, multiple processes occur including class-switch recombination (CSR) and somatic hypermutation (SHM), resulting in affinity maturation. T-dependent plasmablasts circulate for a short period of time before a small fraction of them home to the bone marrow where they differentiate into long-lived plasma cells. The initial decline in serum IgG4 levels following treatment is attributed to the loss of T-independent plasmablasts in the tissue and T-dependent plasmablasts in the blood. In the case of CD20-targeted therapy, the loss of plasmablasts occurs secondary to destroying their parent activated B cells. The slow and gradual decline in serum IgG4 levels is hypothetically due to a reduction in the bone marrow resident, long-lived plasma cells. Key: TFH = follicular helper T cell; IgG1 = immunoglobulin G1, IgG4 = immunoglobulin G4, , CD = cluster of differentiation.
Figure 4
Figure 4
At the site of disease, activated B cells are thought to possess a potent antigen-presenting capacity driving the expansion of effector T cells. The T cells implicated in the disease pathogenesis are cytotoxic CD4+ T cells (CD4+ CTL) rather than any traditional helper T cell subset seen in other rheumatologic diseases (i.e. Th1, Th17). CD4+ CTLs carry both cytotoxic and pro-fibrotic functions, the latter thought to occur by the secretion of transforming growth factor-beta (TGF-β), interferon-gamma (IFN-γ) and interleukin-1 beta (IL-1β). The resultant fibrosis takes a “storiform” pattern for unclear reasons and this conglomeration of activated B cells, CD4+ CTLs, and fibrosis forms the fibro-inflammatory lesions observed microscopically and tumefactive lesions observed clinically. Key: CD = cluster of differentiation; CD4+ CTL = CD4+ cytotoxic T lymphocyte; SLAMF7 = signaling lymphocyte activating marker family 7; TGF-β = transforming growth factor-beta; IFN-γ = interferon-gamma, IL-1β = interleukin-1 beta.
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References

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