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OP0204 Clonal Expansion of CD4+ Cytotoxic T Lymphocytes in IGG4-Related Disease
  1. H. Mattoo1,
  2. V. Mahajan1,
  3. T. Maehara2,
  4. E. Della Torre3,
  5. V. Deshpande4,
  6. W. Zachary5,
  7. M. Kulikova6,
  8. J.H. Stone5,
  9. S. Pillai1
  1. 1Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Boston, United States
  2. 2Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Fukuoka, Japan, Fukuoka, Japan
  3. 3Unit of Medicine and Clinical Immunology, IRCCS, Ospedale San Raffaele, Milan, Italy
  4. 4Department of Pathology
  5. 5Rheumatology Unit
  6. 6Massachusetts General Hospital, Boston, United States


Background IgG4-related disease (IgG4-RD) is a systemic condition of unknown etiology, characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates rich in IgG4+ plasma cells and CD4+ T cells (1). Given the longstanding history of atopy that characterizes a proportion of patients with IgG4-RD, it has been suggested that TH2 cytokines contribute to the pathogenesis of this condition (2). However, we recently demonstrated that allergic manifestations are not increased in patients with IgG4-RD compared to the general population (3). Similarly, CD4+TH2 cells are expanded only in the peripheral blood of IgG4-RD patients with concomitant atopy, questioning the hypothesis of IgG4-RD as a TH2 driven condition (4).

Objectives We aimed to characterize CD4+ T cell subsets in IgG4-RD subjects.

Methods We used flow cytometry to identify CD4+ effector/memory T cells as well as Th1, Th2, and T regulatory cells in a cohort of 101 IgG4-RD patients. Gene expression analysis was used to further characterize expanded cells. Results were validated by flow cytometry. Next-generation sequencing of the T cell receptor β chain gene was performed on CD4+ T cells in a subset of patients to identify their clonality. Tissue infiltration by specific T cells was examined using quantitative multi-color imaging.

Results CD4+ effector/memory T cells with a cytolytic phenotype (cytotoxic T lymphocytes (CTLs)) were expanded in IgG4-RD patients compared to healthy controls. Next-generation sequencing revealed prominent clonal expansions of these CD4+CTLs but not of CD4+GATA3+ memory TH2 cells in subjects with IgG4-RD. The dominant T cells infiltrating a range of inflamed IgG4-RD tissue sites were clonally expanded CD4+CTLs that expressed granzyme A and perforin. Clinical remission induced by rituximab-mediated B cell depletion was associated with a reduction in disease-associated CD4+ CTLs.

Conclusions IgG4-RD is prominently linked to clonally-expanded CD4+ CTLs in peripheral blood as well as in inflammatory tissue lesions. A TH2 signature might be primarily linked to a concomitant atopic diathesis. CD4+ CTLs might be of pathogenic importance in other fibrotic conditions including IgG4-RD.

  1. Della-Torre E, Lanzillotta M, Doglioni C. Immunology of IgG4-related disease. Clin Exp Immunol. 2015 Aug;181(2):191–206.

  2. Kamisawa T, Anjiki H, Egawa N, Kubota N. Allergic manifestations in autoimmune pancreatitis. Eur J Gastroenterol Hepatol. 2009 Oct;21(10):1136–39.

  3. Della Torre E, Mattoo H, Mahajan VS, Carruthers M, Pillai S, Stone JH. Prevalence of atopy, eosinophilia, and IgE elevation in IgG4-related disease. Allergy. 2014 Feb;69(2):269–72.

  4. Mattoo H, Della-Torre E, Mahajan VS, Stone JH, Pillai S. Circulating Th2 memory cells in IgG4-related disease are restricted to a defined subset of subjects with atopy. Allergy. 2014 Mar;69(3):399–402.

Disclosure of Interest None declared

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