BackgroundIgG4-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).ObjectivesWe aimed to characterize CD4+ T cell subsets in IgG4-RD subjects.MethodsWe 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.ResultsCD4+ 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.ConclusionsIgG4-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.ReferencesDella-Torre E, Lanzillotta M, Doglioni C. Immunology of IgG4-related disease. Clin Exp Immunol. 2015 Aug;181(2):191–206.Kamisawa T, Anjiki H, Egawa N, Kubota N. Allergic manifestations in autoimmune pancreatitis. Eur J Gastroenterol Hepatol. 2009 Oct;21(10):1136–39.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.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 InterestNone declared

In order to compare the antibody response in serum and secretions from healthy young subjects and the elderly (greater than 60 years), volunteers were immunized with the commercial inactivated influenza virus vaccine, by the usual (parenteral) route or orally. Also, young and old mice (mean age, 20 months) were orally immunized with live influenza virus. The older mice responded with a very slight rise in their serum and respiratory tract antibody levels compared with the young mice but showed no diminution in protection against lethal viral challenge. Elderly volunteers showed only slight serum antibody responses after parenteral immunization compared with the young. Neither group demonstrated a rise in serum antibody following oral immunization. With respect to the secretory IgA (SIgA) antibody response, certain differences were noted between the young and the elderly: the preimmunization levels of antibody to influenza virus were significantly greater in nasal secretions and saliva in the elderly as compared to the young volunteers, and the salivary antibody response was diminished in the elderly. This lack of a salivary antibody response in the elderly was explicable by the inverse relationship between the preimmunization SIgA antibody titers and the response to immunization. Oral immunization led to no more side effects than observed in the placebo control group.

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In the past three decades significant strides have been made in attempts at nonparenteral immunization. Appreciation of the importance of secretory immunity led to attempts to stimulate antibody production locally. The vaccines developed against respiratory pathogens as a result of this new knowledge have many practical limitations, such as the need for highly trained personnel, expensive equipment, very cooperative recipients for intranasal or aerosol administration, and a vaccine that is both adequately attenuated, immunogenic, and stable during storage. With recognition of the presence of a common mucosal defense system, new approaches to vaccine development have become possible. Oral immunization, by stimulating GALT, presents a promising approach for protecting many secretory surfaces against a variety of infectious agents. Recently, emphasis has been placed on developing an oral vaccine against S. mutans. McGhee et al. have demonstrated antibody to S. mutans in saliva and tears following oral ingestion of that antigen, without a rise in serum antibody, in both humans and rats. The rats were afforded protection from caries after rechallenge with both the original and cross-reacting serotypes of S. mutans. Similar results have recently been seen with viral antigens. Mice have been shown to have significant protection against influenza infection following oral immunization. And in a pilot study with human volunteers, the secretory antibody response in nasal washes was similar following either oral or parenteral vaccination. Oral immunization may prove to be far superior to parenteral vaccination against a variety of pathogens, because of fewer side effects and greater ease in vaccine preparation and administration.