Impaired intestinal tolerance in the absence of a functional complement system Pirkka T. Pekkarinen, MD, Kirsi Vaali, PhD, Hanna Jarva, MD, PhD, Eliisa.

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Transcription factors in allergic diseases

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Impaired intestinal tolerance in the absence of a functional complement system Pirkka T. Pekkarinen, MD, Kirsi Vaali, PhD, Hanna Jarva, MD, PhD, Eliisa Kekäläinen, MD, PhD, Iivo Hetemäki, MB, Sami Junnikkala, PhD, Merja Helminen, MD, PhD, Outi Vaarala, MD, PhD, Seppo Meri, MD, PhD, T. Petteri Arstila, MD, PhD Journal of Allergy and Clinical Immunology Volume 131, Issue 4, Pages 1167-1175 (April 2013) DOI: 10.1016/j.jaci.2012.09.004 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Lymphocyte populations in WTctrl, WTOVA, C3ctrl, and C3OVA mice. A, Flow cytometric analysis of splenocyte populations at the end of the experiment (n = 6). B, Proliferative response of splenocytes to OVA stimulation in vitro. Data are shown as the stimulation index (n = 18). C, Immunohistologic quantitation of CD3+ cells in the jejunum wall (n = 6, each symbol represents an individual mouse). Experimental groups are indicated in the figure. *P < .05. Journal of Allergy and Clinical Immunology 2013 131, 1167-1175DOI: (10.1016/j.jaci.2012.09.004) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 OVA-specific serum immunoglobulin response after oral tolerization and OVA immunization in mice. A, IgG1. B, IgG2a. C, IgG3. D, IgE. ELISA data are presented as OD values (n = 18). Background levels of OVA-binding antibodies in the sera of nonmanipulated mice of each strain (n = 3) are indicated with a horizontal line in each panel. Experimental groups are indicated in the figure. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2013 131, 1167-1175DOI: (10.1016/j.jaci.2012.09.004) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Activation markers in gut-homing T cells in C3-deficient patients. A, Western blot of serum C3 in the patients and a healthy control subject. B and C, Flow cytometric analysis of activation and memory markers in gut-homing integrin α4+β7+ double-positive T cells and nonmucosal α4−β7− double-negative T cells. The cells were gated to CD4+ or CD8+ lymphocytes, as indicated. Representative patient and control (child) data are shown in Fig 3, B. Control children, n = 5; control adults, n = 3. Journal of Allergy and Clinical Immunology 2013 131, 1167-1175DOI: (10.1016/j.jaci.2012.09.004) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Serum IgG and IgA levels against selected microbes in C3-deficient patients compared with those seen in age-matched healthy control subjects. The normal distribution of immunoglobulin levels in control subjects (n = 14) was determined, and the data from the C3-deficient patients are presented as SDs from the mean of control samples. Solid symbols, IgG; open symbols, IgA; squares, patient 1; circles, patient 2. Journal of Allergy and Clinical Immunology 2013 131, 1167-1175DOI: (10.1016/j.jaci.2012.09.004) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Cytokine balance in C3 deficiency in mice. A, Western blot analysis of C3 in cell-culture media, with a dilution series of normal mouse serum as a control. B and C, Relative expression of IL-10 and IFN-γ mRNA normalized against TCR Cα mRNA expression (Fig 5, B) and relative expression of IL-10 mRNA compared with IFN-γ mRNA (Fig 5, C) in WT splenocytes stimulated with anti-Crry mAb for 3 days. In Fig 5, C, each pair of connected circles represents an individual mouse (n = 8). D and E, Relative expression of IL-10 mRNA compared with IFN-γ mRNA (Fig 5, D) and IL-17A mRNA (Fig 5, E) in the mRNA in the jejunum wall (n = 6). The samples were analyzed by using quantitative PCR. The data are shown as relative expression (Δ cycle) by subtracting the IL-10 cycles from IFN-γ or IL-17A cycles. Experimental groups are indicated in the figure. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2013 131, 1167-1175DOI: (10.1016/j.jaci.2012.09.004) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions