IgG 4 related disease include Mikulicz’s disease and all above.
Case265
【Discussion】
It is known that IgG 4 related diseases include various diseases: hypophysitis, Mikulicz’s disease, inflammatory pseudotumor, retroperitoneal fibrosis, auto-immune pancreatitis, chronic sclerosing sialadenitis, sclerosing cholangitis and so on (1-3).
IgG 4 related disease is a tumefactive inflammatory disease histologically composed of accumulation of immune cells, proliferative (storiform) fibrosis and obstructive phlebitis (4, 5). Immune cells include plasma cells producing IgG4, helper T cell, regulatory T cell, cytotoxic T cell, natural killer cell, macrophages and eosinophils. In blood, IgG contains around 1200mg/dL and of these, IgG 4 contains 40mg/dL, less than 5% (5). When IgG 4 elevates 135mg/dL or greater, it satisfies one of the criteria of IgG4 related disease (3-5). IgG is produced by plasma cells differentiated from B cell and specialized for antibody production for counter to pathogen.
However, IgG 4 function is yet to be specified.
Histologic findings of IgG4 related disease mainly reflect the reparative responses; plasma cells producing IgG4 via Interleukin 10 released by regulatory T cell: storiform fibrosis created by fibroblasts via transforming growth factor (TGF)-β released by regulatory T cell (4). It is not clarified what attack or what antigen induce these reparative responses. The active form of this disease is immune response: plasma cells producing IgE and cytotoxic T cells via Interleukin 4 releasing helper T cell and eosinophils and basophils via Interleukin 5 releasing from helper T cell. These responses belong to allergy inducing bronchial asthma.
Recently, as another active form, it is reported that expression of chemokine ligand 1 (CCL1) and chemokine receptor 8 (CCR8) of immune cells induce not only chemotactic action of immune cells but also product interferon gamma causing phlebitis and granuloma (6-8). It is not clear what causes expression of axis between CCL1 and CCR8. This axis might cause inflammatory bowel disease such as Chron disease and ulcerative colitis.
Interleukin and chemokine belong to cytokine, communicating substance (small protein) between cells. They can be ligands to cell surface and attach to cell surface receptor. One ligand meet one receptor. Ligands and receptor express by antigen stimulation.
In our case, he had bilateral tumefactive lacrimal glands and laboratory test revealed high values of IgG4, meeting Miklicz’s criteria, namely IgG4 related disease. He was given steroid therapy, improving symptoms and maintaining its size.
【Summary】
We presented a seventy-two-year-old male for blurring vision. Six years before, he was diagnosed Mikulicz’s disease based on elevation of IgG4 vales and swollen lacrimal glands on MRI findings. Mikulicz’s disease is one of the IgG4 related diseases. IgG4 related diseases include inflammatory pseudotumor, retroperitoneal fibrosis, auto-immune pancreatitis. The histology of IgG4 related disease show accumulation of plasma cells producing IgG4 and lymphocytes of helper T cell, regulatory T cell cytotoxic cells, and eosinophils. Further, fibrosis and obstructive phlebitis are found. The reparative process works; IgG4 releasing from plasma cells via Int 10 from regulatory T cell, fibrosis via TGF-β from regulatory T cell. There considered to be two active form; one releasing IgE via Interleukin 4 and infiltration of eosinophils and basophils via Interleukin 5 inducing allergy: another expressing chemokine ligand (CCL1) and chemokine receptor (CCR8) inducing not only chemotactic action of immune cells but also obstructive phlebitis and granuloma formation via interferon gamma.
【References】
1.Kamisawa, T, et al. "IgG4-related disease". The Lancet. 2015; 385 (9976): 1460–1471
2.Wallace, Z S, et al. "IgG4-Related Disease: Clinical and Laboratory Features in One Hundred Twenty-Five Patients". Arthritis & Rheumatology. 2015. 67 (9): 2466–2475.
3.Stone J et al. 2012). "Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations". Arthritis & Rheumatism.2012; 64 (10): 3061–3067.
4.Deshpande V, et al. "Consensus statement on the pathology of IgG4-related disease". Modern Pathology. 2012; 25 (9): 1181–1192.
5.Khosroshahi, A, et al. 2015). "International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease". Arthritis & Rheumatology. 67 (7): 1688–1699.
6.Kang L, et al. CCR8 Signaling via CCL1 Regulates Responses of Intestinal IFN-γ Producing Innate Lymphoid CelIs and Protects From Experimental Colitis. Front. Immunol., 05 February 2021 | https://doi.org/10.3389/fimmu.2020.609400
7.Liu SS, et al. The chemokine CCL1 triggers an AMFR-SPRY1 pathway that promotes differentiation of lung fibroblasts into myofibroblasts and drives pulmonary fibrosis. Immunity 2021; 54: 2042-2056
8.Zen Y, et al. Possible involvement of CCL1-CCR8 interaction in lymphocytic recruitment in IgG4-related sclerosing cholangitis. J Hepatol. 2013 Nov;59(5):1059-64.
2022.5.2